Companion to psychiatric studies Book 1

Companion to Psychiatric Studies

Metabolic syndrome (or syndrome X) was delineated by also evident in children exposed to olazapine (Fraguas et al
Gerald Reaven and, although widely acknowledged, remains 2008), a fact that should urge particular caution.
controversial in its detail. For psychiatrists, it is descriptively
useful in maintaining awareness of the range of disturbances Weight gain and its metabolic associations in patients
that can be associated with medications utilised routinely. receiving antipsychotics can no longer be ignored with risk
The major features comprising metabolic syndrome are: in this area entering into prescribing choices (see below).
However, awareness alone does not translate to effective man-
1. increased abdominal (visceral) adiposity – seen in increased agement. A number of guidelines (Consensus Statement 2004;
waist circumference; NICE 2009a) recommend routine monitoring for features of
metabolic disorder in those in whom antipsychotics are indi-
2. atherogenic dyslipidaemia (low levels of high-density cated, though what should be monitored remains open to
lipoproteins (HDL) and elevated fasting triglycerides); debate. For those starting medication for the first time, weight
(and height), waist circumference, blood pressure and glucose
3. hypertension; and (random more pragmatic than fasting in acutely psychotic
patients) would all be part of good medical care and should
4. impaired fasting blood glucose or overt diabetes mellitus. not be seen as exceptional. Opinion diverges about whether
one should go beyond these basics. The author would only
Several operational diagnostic criteria have emerged see this as justified (i.e. useful and/or cost-effective) where
(Box 11.5), including the National Cholesterol Education there is clear indication, e.g. the patient is middle-aged, has
Programme (NCEP) and the National Heart, Lung and Blood relevant medical pointers and/or an established family history
Institute & American Heart Association (AHA) criteria (which of diabetes, dyslipidaemia, etc. For those on long-term anti-
differ mainly in that the latter requires a slightly lower fasting psychotics, monitoring should be annual and undertaken in
glucose). The most pragmatic, if least rigorous, are those of the primary care, as specialist settings are nowadays less geared
International Diabetic Association, based solely on waist cir- to this. What long-term monitoring should comprise remains
cumference. Applying these criteria, the CATIE study found for consensus agreement though in addition to the above, tests
baseline prevalences with NCEP and AHA criteria of 40.9% requiring fasting bloods should be incorporated (glucose,
and 42.7%, respectively, with significantly higher levels in cholesterol, HDL, LDL and triglycerides).
females compared to males (36% vs. 51–54%, respectively;
McEvoy et al 2005). Using waist circumference alone, the Following on from awareness is the issue of treatment.
prevalence in females was double that in males (73.4% vs. Where antipsychotic medication is necessary and consideration
36.6%). Even accounting for BMI, males were 85% more likely of the best individual choice has been made (see below), the
to have metabolic syndrome while the comparable figure in appropriate intervention would be prevention via life-style
females was 137%. Such levels of disorder are of great concern change. Experience does not bode well. In a unique RCT,
and fire a red flare across prescribing choices made without McCreadie et al (2005) implemented dietary changes (free
consideration of the issue. fruit and vegetables with instructions on preparation and super-
vision) in schizophrenic patients in both rural and urban areas of
CATIE also found that while there were marginal non- Scotland. Consumption of fruit and vegetables increased signif-
significant benefits in favour of olanzapine in terms of a longer icantly during the study period but 12 months after the inter-
time to discontinuation, significantly more of those on this vention stopped, had fallen to pre-intervention levels. No
drug discontinued because of intolerable non-target actions between-group differences emerged at any time in blood
(18% vs. risperidone group: 10%), the most sinister being micro-constituents, BMI, activity levels or cardiac risk. The
weight gain and metabolic changes (olanzapine 9% vs. others finding of early behavioural change becoming unsustainable over
1–4%). Table 11.3 demonstrates that these were not trivial time replicates those in other studies in schizophrenic patients,
over the relatively short timespan of 18 months but also that and while not supporting defeatism, should inform realism.
there was a ‘hierarchy’ of risk, at the top of which sits olanza-
pine with the ‘new’ ziprazidone and the ‘very old’ perphena- Hyperprolactinaemia All older and some new antipsy-
zine comparatively reassuring. Such metabolic changes are chotics produce hyperprolactinaemia from blockade of tubero-
infundibular dopamine pathways. Prolactin secretion is
Box 11.5 normally pulsatile with a circadian variation and is influenced
by food intake, stress and other factors. Regulation is com-
National cholesterol education program (NCEP) criteria plex involving not only tonic inhibition, in which dopamine
for metabolic syndrome plays a key role, but stimulation by a number of hormones
such as oestrogen and TRH. Interpretation of cross-sectional
Males Females measurement is thus complicated. In general, older antipsy-
chotics are all associated with two- to ten-fold increases in
Abdominal circumference > 40" > 35" blood levels in both sexes (Meltzer & Fang 1976). However,
Fasting triglycerides these increases are orders of magnitude less than elevations
High-density lipoprotein !150 mg/dl found with pituitary adenomas so comparing symptomatology
Blood pressure in antipsychotic-treated patients ‘by analogy’ with prolactino-
<40 mg/dl <50 mg/dl mas is risky. Dose–response relationships are weak, reflecting
Fasting glucose* both the complexity of prolactin’s physiology and the
!130/85 mmHg or on

antihypertensives

!110 mg/dl or on insulin or oral

hypoglycaemics

National Heart, Lung and Blood Institute & American Heart Association (AHA)

Criteria are similar except for a fasting glucose !100 mg/dl.

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Table 11.3 Clinical antipsychotic trials of intervention effectiveness (CATIE)

Metabolic adverse effects

Weight gain >7% Weight change Glucose* Glycosol Cholesterol* Triglycerides*
(lbs/mo) (mg/dl) Hb* (%) (mg/dl) (mg/dl)

Olanzapine 30% 2.0 (0.3) 13.7 (2.5){ 0.4 (0.07) 9.4 (2.4) 40.5 (8.9)
0.5 (0.2) 7.5 (2.5) 0.04 (0.08) 6.6 (2.4) 21.2 (9.2)
Quetiapine 16% 0.4 (0.3) 6.6 (2.5) 0.07 (0.08) À1.3 (2.4) À2.4 (9.1)
À0.3 (0.3) 5.4 (2.8) 0.11 (0.09) À8.2 (3.2) À16.5 (12.2)
Risperidone 14% À0.2 (0.2) 2.9 (3.4) 0.09 (0.09) 1.5 (2.7) 9.2 (10.1)

Ziprasidone 7%

Perphenazine 12%

*Exposure adjusted mean change from baseline.
{No significant difference.
Data from Lieberman et al (2005).

pharmacology of individual drugs. In general, relatively selec- sophisticated application of medical expertise – flexible utili-
tive D2 antagonists such as sulpiride and amisulpride, and sation of what is a large family of drugs, maintaining at all
potent ones such as haloperidol, tend to be associated with times minimum effective doses.
more ready and higher elevations than broad-spectrum and
low-potency agents. Clozapine seems devoid of this action, a In contrast to some guidelines, the present author would
claim that can also be largely substantiated for quetiapine not recommend routine monitoring of prolactin and would
and sertindole. With olanzapine, early rises appear ill-sus- urge clinicians to utilise their clinical skills in appraising rele-
tained, with a tendency to revert to base-line. As high- vant symptomatology rather than resorting to laboratory inves-
potency drugs, risperidone and its metabolite, 9-hydroxyris- tigations. The risks of being unable to competently interpret
peridone (paliperidone), are on this test similar to older com- results of special investigations and, on the basis of uncer-
pounds with clear dose-related increases. tainty, ordering more (e.g. brain scans) seem currently greater
than a clinical skills-based approach.
Antipsychotic-induced hyperprolactinaemia has been asso-
ciated with decreased libido, impaired quality of orgasm and Not mediated via general pharmacology
galactorrhoea in both genders, though the gynaecomastia
occasionally found in males and often attributed to increased Toxic and allergic reactions
prolactin, more likely reflects a disturbance of oestrogen/andro-
gen ratios. Menstrual irregularities may take the form of both Minor, transient increases in hepatic enzymes are not uncommon
oligo- and amenorrhoea. Both genders may also suffer dimin- and may occur with early exposure to any antipsychotic. Approx-
ished fertility from, in males azoospermia, and in females ano- imately 5–7% of those starting olanzapine will show this phe-
vulation. Of particular recent concern is the suggestion that nomenon which is clinically insignificant. However, later rises
chronic low-grade increases in prolactin promote osteoporosis. (2nd to 3rd week onwards) are of potentially greater significance.
Bone mineral turnover is regulated by oestrogen and testoster-
one and reduced levels of these associated with hyperprolacti- About 1–2% of exposures to chlorpromazine will result in
naemia may result in increased rates of turnover (Byerly et al clinical jaundice, which represents a striking decline from the
2007). This is now of sufficient concern to force caution from drug’s early days (Regal et al 1987), probably the result of
the USA, though not yet the UK, regulator. It is, however, better manufacturing with removal of contaminants. Jaundice
not the only reason why those receiving antipsychotics may can present without symptoms or be associated with sub-
develop osteoporosis, other risks including poor diet and dimin- jective feelings of fatigue, nausea, pruritis and vomiting. Histo-
ished mobility. The possibility that long-term use of prolactin- logical examination shows not only allergically mediated
elevating medication might increase the risk of breast cancer cholestatic change but scattered hepatic necrosis, so direct
in females has been of theoretical concern for many years but toxicity is also part of the pathology. Phenothiazine-induced
so far has no supportive evidence. jaundice is usually benign and although symptoms may resolve
with continued exposure, this is not to be recommended.
While the hyperprolactinaemia of pituitary adenoma can Fulminant hepatic necrosis is an extremely remote but poten-
be reduced (sometimes dramatically) by potent dopamine tially fatal outcome and although the author has only encoun-
agonists such as bromocriptine, this cannot be recommended tered a single case, the experience is not one he would
in drug-induced states in view of the major complication it recommend. Cross-sensitivity among antipsychotics is rare,
introduces into therapy, including potentially negative effects so a switch to another drug is usually all that is required for
on mental state. However, amantadine, also effective as an resolution, though this may take 6–8 weeks. Primary biliary
antiparkinsonian agent, may in more symptomatic cases be an cirrhosis is very uncommon, the prognosis appearing better
option. The major treatment to be recommended comes from than the idiopathic condition (Regal et al 1987). About 5–
10% of patients on chlorpromazine develop a typical general-
ised, hot, erythematous skin rash within 10–14 days of first

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exposure. This can be treated with antihistamines but again it Agranulocytosis with clozapine is also reversible following early
is prudent to change drug as the rash may be a harbinger of detection and discontinuation of the drug but can be fatal if
more sinister allergic reactions to follow. allowed to persist. Data from long-term monitoring in the UK
suggest an incidence of 0.73% at 1 year and 0.8% at 2 years
While 2–3 weeks may be necessary for these allergic reac- (Atkin et al 1996). This probably represents an idiosyncratic
tions to develop on first exposure, once sensitised, re-exposure allergic response in affected individuals but no clear predictors
will produce an immediate and severe recurrence. Thus, have been identified. It occurs early in exposure, with over
evidence of allergic reaction should prompt a prominent warn- 80% of cases developing in the first 3 months, the peak being
ing on case notes and banning of the ‘culprit’ drug for all time! in the third month. No cases have emerged after 2 years. The
drug may also produce an eosinophilia which appears benign.
Chlorpromazine-induced photosensitivity is far from infre-
quent with dermatology-derived prevalences of 3% pertaining There is no specific treatment for clozapine-induced
to severe cases only. Clinical experience suggests that milder agranulocytosis, though granulocyte-colony stimulating factor
cases characterised by itching discomfort and slight erythema (G-CSF) has been used in experimental situations. Once a
are much more common. The pathology results from a mixture decline in white count is established, the only management is
of phototoxicity and photoallergy, with an action in the UVA withdrawal of clozapine, which carries a high probability
range. It is therefore less the heat that is important than the of resolution. Permission (from the manufacturer) for
sun’s ‘brightness’, so patients can receive considerable burning re-exposure is unlikely and such action would require to be
in conditions that feel cool. Similar problems may occur, less ‘off-license’ – in which case it would be worth checking one’s
often, with other antipsychotics. Treatment is avoidance of medical indemnity is up to date!
bright sunlight and use of high-factor barrier creams.
Although other antipsychotics, especially phenothiazines, can
Pigmentation is again a problem largely associated with phe- produce similar effects on the granulocyte cell line, accurate
nothiazines, and one rarely commented on nowadays. Earlier comparative data are surprisingly not available. In the only sys-
descriptions were of widespread deposition of a melanin-type tematic evaluation, patients receiving various phenothiazines
pigment on mainly exposed areas, including eyes, though this were monitored over 8 weeks. Transient leucopenia was noted
oculocutaneous melanosis extends to deposition in internal in 10%, while agranulocytosis was estimated to occur in
organs. Skin deposits impart a silvery or bluish/purple hue to 1:1200 exposures (Pisciotta 1978). This is a higher risk than
patients, most often females (‘purple people’). This phenome- the 1:1400 exposures attributed to clozapine but the data are
non probably results from chronic use of high-dose regimes, not comparable. It is generally agreed that agranulocytosis is an
hence its decline. Deposition of pigment in the lens of the established but rare complication of phenothiazine treatment,
eye is still common and although this infrequently impairs the risk being less than with clozapine. The mechanism in cases
vision, the risk of cataract is increased three to four-fold in progressing to frank agranulocytosis is likely to be allergic but
those on long-term antipsychotics (Isaac et al 1991). Early with stable neutropenia a low-grade toxicity more likely
concerns that this may be a particular risk with quetiapine accounts for the majority.
have not been substantiated. Pigmentary retinopathy appears
to have been a problem particular to high-dose thioridazine. Suppression of other marrow lines, such as erythrocytes and
platelets, has been associated with antipsychotic exposure, but
Hair loss is a not infrequent complaint of patients on along with haemolytic anaemia, comprises only sporadic
psychotropics, especially women, and is a genuine observation, reports and these events must be very uncommon.
though one more likely to be associated with tricyclics and
mood stabilisers than antipsychotics (Warnock 1991). Usually The message from the haematological data with drugs other
it represents merely a speeding up of normal shedding and than clozapine is that antipsychotics in general can be toxic to
although the hair may thin, it does not as a rule result in bone marrow. This is important to bear in mind when subject-
patches of complete loss, though full alopecia areata has been ing clozapine-treated patients to polypharmacy as adverse
described (Kubota et al 1994). effects of clozapine may be on a marrow already under pres-
sure. If amber alerts arise, rather than awaiting the next result,
On occasion depot formulations cause injection site reac- the task should be to relieve all such additional stress on
tions. These have been reported with fluphenazine decanoate marrow function from other medications (including anti-
and haloperidol decanoate and comprise a firm, tender and depressants as well as antipsychotics).
sometimes pruritic mass which can remain for up to 3 months
(Hamann et al 1990). This may not relate simply to flawed Antipsychotics can mediate change in a number of immuno-
injection technique but more probably to impaired vascularisa- logical parameters. IgM isotype antiphospholipid antibodies
tion with consequent delayed absorption. For this reason, can be detected in up to 50% of patients, again particularly
injection sites should be rotated. with chlorpromazine, though the significance of this is
unknown. A high prevalence of venous thrombosis has been
Specific issues reported in patients receiving standard antipsychotics, espe-
cially low-potency drugs (Zornberg & Jick 2000), and while
Haematological effects Antipsychotics can potently suppress this may be the consequence of incidental factors such as
marrow function. Although any type of drug can be implicated, weight gain and immobility, immunopathic changes promoting
the problems are individually greatest with clozapine, and col- anticardiolipin antibody production and an associated clotting
lectively with phenothiazines. Clozapine-induced neutropenia, diathesis may also be relevant. While ‘lupus anticoagulant’
reversible on discontinuation, has a cumulative incidence of can also commonly arise (Canoso et al 1990; Zucker et al
2.33% at 1 year, approximately 3% at 2 years, with a small 1990), phenothiazines only very rarely cause drug-induced
(0.5–0.75%) but continuing risk thereafter (Owens 1996).

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systemic lupus erythematosis. These immunological abnormal- probable reflection of, in equivalence terms, lower dose utilisa-
ities are poorly understood but speak of profound effects of tion and broad binding profiles. No typical cases have been
greater potential significance than their neglect would justify. reported with clozapine, though those started on clozapine will
inevitably have been on prior antipsychotic regimes, itself a
Myocarditis/cardiomyopathy (clozapine only) Both myocardi- factor in reducing liability. Acute dystonias are heralded by
tis and cardiomyopathy have been reported in patients receiving increasing agitation and restlessness, and awareness of discom-
clozapine (Kilian et al 1999). Although the exact prevalence is fort and impaired function in the affected part, followed by
unknown, it may be as high as 1:500 first exposures. The mech- the sudden onset of usually static postural distortions, which
anism is unclear but may not represent a single pathology. in adults tend to be localised to head and neck (‘craniocervical’
Myocarditis probably reflects direct binding of clozapine to dystonia), though in children may be generalised. Conjugate
myocardial tissue producing an allergically mediated functional upwards deviation of the eyes, usually with an emphasis to
impairment which may also result from direct myocardial tox- one side, is referred to as oculogyrus. The risk relates directly
icity. It is also not known whether these cardiological disorders to potency/dosage and rates of increment, and inversely to
represent two separate pathological processes or whether car- age. While in retrospective studies, young males are over-
diomyopathy is the end result of prior, undetected myocarditis. represented, this does not hold in prospective studies where
gender differences in dosages are accounted for. Acute
Heart rate usually rises slightly (<100 beats/min) in patients dystonias respond readily to anticholinergics.
first exposed to clozapine because of its anticholinergic (vagal)
actions and as a reflex response to anti-adrenergically mediated Parkinsonism is the conceptual and practical EPS issue for
hypotension. However, persistent increase in resting heart rate psychiatrists yet is one of the least studied. Its importance lies
(>120 beats/min) after initial dose titration and stabilization in its subtle, pervasive symptomatology, its unresolved position
(i.e. beyond the first 4–8 weeks), or the development of pain, in relation to the fundamental action of antipsychotics (see
exercise intolerance or palpitations, are indications for cardio- above) and the ease with which it can be confused with other
logical referral. Cardiologists are aware of this problem and disorders, especially negative schizophrenic symptomatology.
usually able to accommodate with a swift assessment.
Although drug-induced parkinsonism comprises the same
Those starting on clozapine should have a pretreatment ECG core triad as parkinsonism from all causes – bradykinesia,
against which subsequent change can be measured. Should rigidity and tremor – the emphasis is different from typical
myocarditis or cardiomyopathy be established, their association Parkinson’s disease (PD), with bradykinesia predominating.
with irreversible disability and a mortality of up to 25% means Bradykinesia (aka ‘hypokinesia’/‘akinesia’) comprises not only
clozapine must be stopped swiftly and permanently. the signs of motor slowing but a crucial galaxy of symptoms,
including fatigue, anergy, apathy, ‘dysphoria’, etc., easily con-
Extrapyramidal non-target actions fused with primary mental state abnormality. Typical drug-
induced disorder differs from typical idiopathic PD in terms
Extrapyramidal side-effects (EPS or EPSE) have long repre- of: (1) rigidity that is mild, often requiring reinforcement
sented the non-target action of antipsychotics not only in terms to elicit; (2) a low prevalence ( 10%) of low-frequency/
of providing a ‘window’ on mode of action but also as a source high-amplitude ‘resting’ tremor but high prevalence (>70%)
of concern. Although better recognised than at one time, their of high-frequency/low-amplitude ‘postural’ tremor; and (3) a
full impact is rarely acknowledged and with claims for new presentation that is more generalised than unilateral.
drugs so readily endorsed, a generation of psychiatrists has
emerged ill-versed in their subtleties and significance. Much Weakness or ready fatiguability, usually in axial trunk mus-
in what promotes these disorders resides beyond the ‘liability’ cles or proximal limbs, apathy and social disengagement may
inherent to individual drugs (mentioned above), and beyond precede the onset of objective signs. Motor poverty, evident
the ‘dopamine endowment’ that makes some patients more with the patient sitting, is seen in loss of interactive posture
susceptible than others. It also lies with how antipsychotics and gesture while slowing is evident in rising from a chair or
are used – even high-liability drugs such as haloperidol used in rapidly alternating movements such as finger/thumb opposi-
in low but therapeutically effective doses need not produce tion and supination/pronation. In hypomimia (facial masking –
EPS (Rosebush & Mazurek 1999; Oosthuizen et al 2001). not to be confused with retardation) facial contours are
Thus, one key to what follows is expertise in prescribing as softened, the eyes staring (‘reptilian stare’ from reduced blink
well as in recognition and management. Only a brief overview rate), the mouth partially open. Drooling (sialorrhoea from
is provided here (Box 11.6) in the hope that further essential impaired swallowing of normal amounts of saliva) should be
information will be sought from dedicated works (e.g. Owens uncommon. Cogwheeling may be present but is not a require-
1999). ment, rigidity of any sort being worthy of note. Truncal
posture is more likely to be slightly hyperextended (‘poker
There is no entirely satisfactory method for classifying spine’) than flexed as in PD. Postural instability is particularly
antipsychotic-induced motor disorders but the syndromal worth seeking as this is often a feature. The surest signs
perspective has the advantage of face validity and clinical are evident on walking, but again not within a PD frame of
relevance. reference, for gait itself (length/height of step, sequencing) is
usually unexceptional. Walking in an uninhibited environment
Acute dystonias come on within 5 days of first exposure or will reveal loss of pendular arm swing, with hyperpronation
dose increment in 90% of instances. They affect up to one- (‘knuckles-to-the-front’) and progressive upper limb flexion
third of patients on older high-potency drugs but fewer on and abduction.
low-potency compounds and, with the exception of risperi-
done, are infrequently encountered with newer drugs, a

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Box 11.6

A summary of the extrapyramidal side-effects of antipsychotic drugs

Acute dystonias Risk factors:
Prevalence: Potency/dose
Rate of increment
Low potency drugs: 8–11% Age (biphasic – higher rates in young people ? reflect dosing; in
High potency drugs 36% older people, ? insipient Parkinson’s disease)
? individual DA ‘endowment’
Gender:
Retrospective studies: M>F Onset:
Prospective studies: equal Gradual – predominantly bradykinesia (signs þ symptoms)

Risk factors: Course:
Age (inverse) Signs tend to resolve over first 3 months or longer
Potency/dose
Rate of increment Treatment:
Cocaine Change dose/potency
Anticholinergics
Distribution: (mild) dopamine agonists (e.g.amantadine)
Inverse with age (generalized in children)
Response:
Onset: Subjectively good; signs often persist
Rapid (minutes to hours)
90% in first 5 days Tardive dyskinesia
Prevalence:
Treatment:
Anticholinergics 20–25% overall
Up to 60% in selected samples
Response:
Complete Incidence:
4–5% per year
Akathisia
Prevalence/incidence: Gender:
Equal – (F > M reported probably an artefact of populations
30–40% studied)

Gender: Risk factors:
Equal Age
Age at first exposure
Risk factors: Potency/dose
Potency/dose Drug-free intervals
Rate of increment Akathisia
? Black race
Onset:
Days to weeks (can occur after single dose of high-potency drug, Onset:
especially by injection) Gradual, usually after years
Dystonia can occasionally come on rapidly after only weeks
Treatment:
Modified regime: lower dose/lower potency Course:
Anticholinergics, beta-blockers, benzodiazepines Variable – some tend to resolution

Response: Treatment:
Often disappointing Primary prevention
ALWAYS: minimum effective dose
Parkinsonism Presynaptic depleters (e.g. tetrabenazine)
Prevalence: GABA agonists
? free radical scavangers
Syndromal: 15–30% clozapine (esp. for tardive dystonia)
Symptoms: ? universal

Gender:
Cross-sectional studies: F>M
? artefact of population composition

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The prevalence of drug-induced parkinsonism is difficult to is an anticholinergic. Results are however variable and these
assess because no clear agreement exists on what comprises are perhaps most efficacious in the 50% of sufferers with coin-
the syndrome. Furthermore, disorder tends to diminish the cidental parkinsonism. Benzodiazepines are popular but their
longer patients are on stable regimes, so figures depend on use is largely empirical. Trial evidence has failed to support
when the examination is performed. Prevalence is usually initial enthusiasm for beta-blockers.
quoted at between 15% and 40% with older drugs but with
careful examination the true prevalence is likely to be higher. Tardive dyskinesia refers to a syndrome of involuntary
CATIE reported a figure of less than 10% with new drugs movements developing in the course of long-term exposure
(Lieberman et al 2005) though the assessment tool used was to antipsychotic (and other predominantly antidopaminergic)
relatively insensitive (the Simpson-Angus). Females are con- drugs. Any type of hyperkinetic movement disorder – tics,
ventionally reported as having higher rates but this probably chorea, dystonia, etc. – may comprise the syndrome but
reflects dosing and age differences in study samples rather tremor is specifically excluded. Muscles of the lower third of
than inherent gender predisposition. the face are involved in 80% of cases, giving rise to the
‘bucco-linguo-masticatory (BLM) triad’, comprising involun-
Onset can begin within a few days of exposure or dose tary activity of the tongue, which may sweep the inner buccal
increment, with the majority evident within 2–3 months. surface (‘bon-bon’ sign) or irregularly protrude (‘fly-catcher’
Onset depends on drug potency, the dose regime and the sign), combined with grinding/chewing lateral and/or antero-
rate of dose increments. No age group is exempt, though the posterior jaw movements, and puckering/pursing movements
risk increases with age, when antipsychotics may release a of the lips. Symptomatology may, however, involve any or all
tendency to idiopathic PD. body areas, including internal muscle groups (oropharynx,
larynx, diaphragm).
Management should start with re-appraising the treatment
plan, especially drug potency/dose and rate of dose increases. Prevalence depends on a series of variables, especially the
Anticholinergics are widely used and although patients may age of the sample. Overall, it has been estimated at 20–25%,
feel subjectively better, objective symptomatology often per- though most of this disorder is mild. Incidence is 4–5% per
sists. The traditional view that anticholinergics should not be year but much higher (25–30%) if first exposure is in middle
started automatically with antipsychotics has been followed age. Over time, however, some established cases resolve spon-
in previous editions of this text but like others (Rosenheck taneously. The risk appears greatest in the early years of expo-
2005) the author has modified this opinion and would sure but disorder can emerge without warning at any time.
now recommend that anticholinergics should be started coinci-
dentally with high-potency, older drugs such as haloperidol. Predisposing factors from retrospective studies include age,
With other drugs, the recommendation remains that action drug-free intervals (>1–3 months), alcohol abuse, metabolic
should be justified by emergence of symptomatology. Dis- disorders such as diabetes, plus cognitive impairment, affec-
continuation of anticholinergics should be attempted after tive symptomatology and ‘negative’ schizophrenia. Reported
3–6 months in view of the tendency to resolution. For theo- associations with female gender probably reflect interposing
retical reasons (exacerbating psychosis), dopamine agonists influences, such as age. Prospectively, associations have been
have never found favour, caution that may be unjustified. established with antipsychotic dosage, again emphasising the
Amantadine has been shown to have equal efficacy to anticho- need for cautious use. In addition, intermittent exposure pat-
linergics but with less impairment to memory and learning and terns (i.e. drug-free intervals) have again emerged, something
no worsening of psychosis. to be discussed with patients when recommending mainte-
nance regimes. Associations with race (higher risk in Afro-
Akathisia comprises: (1) an unpleasant (i.e. ‘dysphoric’) Caribbeans; lower risk in Asians, especially Chinese) may
inner restlessness; and (2) an urge to move either individual represent genetic or treatment differences.
body parts or the whole body (e.g. pacing). Incidence is up
to 40% over 2 weeks in patients on older drugs. Incidence rates Tardive dyskinesia was for many years one of the major
with new drugs are unclear though seem to be lower. Even topics of psychiatric research, reflecting a perception that it
clozapine can produce a state of subjective restlessness, represented the most important extrapyramidal adverse effect
phenomenologically similar to akathisia. Predisposing factors of antipsychotics. It is doubtful if this can be sustained in view
are again dependent on potency/dosage and rate of increment. of the realisation that course is less relentless and outcome less
Parenteral administration also increases the risk. Akathisia may negative than was thought, while parkinsonism is so common
have a very early onset – within hours of oral and 30 minutes and intrusive. The majority of cases of tardive dyskinesia
of parenteral usage – and can be readily confused with mental remain mild with the likelihood of it resolving or declining in
state disorder. prominence over time. In some cases, however (<10%), symp-
toms can be severe and irreversible, especially in patients over
Some patients show restless, non-goal directed behaviour 40. A further concern is cases in which dystonia dominates, for
without feeling particularly agitated subjectively. This situa- tardive dystonia is particularly incapacitating and resistant to
tion tends to emerge with chronic symptomatology and is best intervention and always distressing even if relatively rare
classified as tardive akathisia. The alternative term, pseudo- ( 1% of exposures). The clinical dilemma is that at point of
akathisia, is more appropriately reserved for patients who look onset the ultimate extent of involuntary movements or the
‘akathisic’ but are victims of tardive dyskinesia, usually of resultant incapacitation cannot be predicted.
dystonic type.
Management of tardive dyskinesia remains predicated on
Acute akathisia responds disappointingly to specific inter- primary prevention – strictly limiting indications for anti-
ventions. After a review of treatment, the usual first choice psychotic use, and utilising lowest effective and simplest dose

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regimes during all phases of management. Incidental mental Box 11.7
state disorder, such as depression or anxiety, should be ade-
quately treated. Benzodiazepines may be helpful by virtue of Indications for antipsychotic drug use
their non-specific anxiolytic actions and because they are
GABA-facilitatory. Further proposed interventions include • Treatment of acute schizophrenic episodes, including acute
the dopamine agonist bromocriptine and there is evidence to exacerbations of chronic schizophrenia, schizophreniform and
support a beneficial role for the presynaptic depleting agent schizoaffective disorders
tetrabenazine. The free radical scavenger, alpha-tocopherol
(vitamin E), seemed initially promising, and although sub- • Acute management of delusional (paranoid) disorders
sequent evidence is inconclusive, this is a relatively safe inter- • Maintenance of remission in patients with recurrent psychotic
vention. The position of new antipsychotics as potential
treatments remains to be established but clozapine should be disorders of schizophrenic and schizoaffective type
considered, especially in those with predominant dystonia, as • Treatment of manic and hypomanic episodes (bipolar 1 and 2)
this drug may have antidystonic actions though any benefits
will only become evident over a protracted time-scale (24–30 with or without psychotic symptoms
months). • Treatment of psychotic depression
• Prevention of relapse and maintenance of remission in patients
Neuroleptic malignant syndrome (NMS) comprises dramatic
temperature rise (sometimes amounting to hyperthermia), with recurrent major affective disorders (bipolar and recurrent
extrapyramidal symptomatology (especially rigidity), confusion (psychotic) depression)
and autonomic lability. Creatine phosphokinase is usually strik- • Management of psychotic symptomatology occurring in the
ingly elevated. The disorder is presumed to have a basis in context of acute or chronic organic brain syndromes (avoid in
extrapyramidal disruption and has been reported most com- withdrawal states because of tendency to lower seizure
monly in young males early in antipsychotic treatment. This is threshold)
a rare development but published prevalences, ranging from • Management of psychiatric emergencies
0.02% to 2.4%, help us little. A study of almost 10 000 Chinese
patients suggested a figure of 0.12% (Deng et al 1990), which antipsychotics of different type in adequate dose for an ade-
best fits with clinical experience. quate trial period (minimum 6 weeks)’, based on the US Mul-
ticenter study (Kane et al 1988).
There is however a problem with this concept, in that the
diagnosis is often made in the presence of other medical con- In recent years, several newer antipsychotics have achieved
ditions that could more readily explain the symptomatology licensed indications for treating different phases of bipolar
(Levinson & Simpson 1986). Suspicion of the diagnosis affective disorder (e.g. risperidone, olanzapine, aripirpazole,
should be a cue to rigorous physical investigation. NMS has quetiapine). It must be appreciated that ‘licensed indications’
a reported mortality of 20% (Shalev et al 1989) and can merely reflect a requirement placed on the manufacturer
result in residual neurological deficits in survivors. However, of a medicinal product to justify promotional claims with
it usually resolves on discontinuation of the implicated anti- evidence. It does not mean that compounds having such indica-
psychotic and the instigation of palliative measures, such as tions are the only ones of their class to possess the action.
rehydration, correction of electrolyte imbalance and, if neces- There is no reason to suppose that those benefits demon-
sary, use of benzodiazepines. Anticholinergics may be tried in strated for certain new antipsychotics in bipolar affective
those with profound rigidity but must be used with care, as disorder are restricted to licensed drugs.
they may add to confusion and further impede heat loss by
impairing sweating. Non-selective anticholinergics (see below) There has been great debate over the past 30 years –
should be avoided. The dopamine agonist, bromocriptine, may encompassing old and new compounds – about whether anti-
be helpful in a dose of up to 60 mg per day but its use, and that psychotics ‘treat’ the negative features of schizophrenia, i.e.
of the peripheral muscle relaxant Dantrolene (10 mg/kg) is whether they exert efficacy. The problem is beset with
empirical. Antipsychotics are not precluded in future by an conceptual problems as to what comprises ‘negative’ symp-
episode of unequivocal NMS but it is wise to change to an tomatology and whether, on cross-sectional examination,
alternative compound and, most importantly, to introduce it authentic illness features (‘primary’) can be distinguished clin-
ultra-slowly. ically from similar, but pathophysiologically distinct features
(‘secondary’ negative symptoms), including: (1) anxiety and
Therapeutics social withdrawal secondary to positive features; (2) retarda-
tion of depression; and (3) bradykinesia of parkinsonism, etc.
Indications (Carpenter et al 1985). The view expressed here is consistent
with previous editions – that there is no evidence antipsychotic
In adult psychiatry it is possible to specify indications for anti- drugs exert therapeutic efficacy on primary negative symp-
psychotics fairly clearly (Box 11.7), though in subspecialty tomatology, a conclusion applying as much to new compounds
practice these may be less defined. Clozapine is the only drug as to older ones (Moller 1993; Owens 1996). This is in line
with specific indications – treatment-resistant schizophrenia or with the conclusions of a recent expert panel (Kirkpatrick
extrapyramidal intolerance. In this context, ‘treatment resis- et al 2006). Improvements attributed to efficacy most likely
tance’ is defined as ‘failure to respond to at least two reflect better EPS tolerability – and that includes responses
to clozapine.

Great care should be exercised in recommending the long-
term use of antipsychotics solely as agents for non-specific
behavioural control.

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Clinical psychopharmacology CHAPTER 11

Strategies Box 11.8

There is no first-line antipsychotic for the treatment of acute Some considerations in an individualised risk:benefit
psychotic states. At time of writing, National Institute for appraisal for antipsychotic prescribing
Clinical Excellence (NICE) guidelines for schizophrenia are
under review but 2002 guidance strongly favoured ‘atypical’ • Age
drugs (e.g. NICE 2002). These are promoted as reflecting Young, first episode
‘good practice’ but were drawn up on the basis of partial and Middle-aged, first episode
largely industry-sponsored information and have remained in Middle-aged, recurrence
effect for some years after effectiveness data rendered them
clearly redundant. • Body habitus
Weight
Rather than approaching antipsychotics as ‘typical’/‘atypi- Fat distribution (centripetal)
cal’, ‘old’/‘new’, attempts at artificial subclassifications should
be set aside. This volume recommends a return to considering • Personal cardiovascular risks
‘antipsychotics’ as a single class of compounds comprising Blood pressure
members with varied pharmacological characteristics (see Smoking history
Box 11.1), any of which might find a place in treatment. Exercise patterns
A particular criticism of guidelines is that, by being Alcohol use
‘evidence-based’ (i.e. based largely on trial data) they draw Diet
conclusions from special populations with predefined entry/
withdrawal criteria who do not reflect ‘real life’. As a result, • Family history
guidelines cannot adequately reflect variability in patients Cardiovascular disease
and, most importantly, in the illnesses they present. Hypertension
Sudden (premature) death
Post-CATIE, many authors recommend ‘tailored’ or ‘perso- Diabetes
nalised’ prescribing but few give direction on how this might Obesity
be achieved. The present chapter recommends decision-
making based on the principles applied by regulatory bodies • Non-specific symptomatology
in relation to licensing – the risk:benefit ratio. This combines Agitation
the evidence with a judgement on ‘clinical need’ – e.g. cloza- Anxiety
pine has a highly unfavourable ‘risk’ loading but because of insomnia
great clinical need, the risk:benefit ratio is considered favour-
able, while the absolute risks from thioridazine were slight • Level of engagement
yet, because of the many alternatives, clinical need deter- Suspicion/hostility
mined an unfavourable risk:benefit ratio. As all antipsychotics Trust
(possible exception clozapine – see below) are of compar- Evaluation of acceptability of ‘non-target’ profiles
able efficacy and effectiveness, we need only concentrate on Estimated compliance (adherence þ monitoring)
‘risk’. This is as well, for with a diverse class of drugs and as
many permutations of psychotic illness as there are patients, • Past treatment history
‘risk’ presents a large array of variables for consideration Known EPS liability
(Box 11.8). Known metabolic liability
Known tolerability to general adverse effects
An important difference between a drug’s ‘therapeutic Known compliance (adherence þ monitoring)
index’ and its ‘risk:benefit appraisal’ is that the former is Patient preference
inherent to the compound and static, while the latter is flexi-
ble, changing in response to context. A ratio that is favourable No matter how many times and over how many years doc-
when the patient is acutely disturbed may be less so when they tors are shown that they tend to use antipsychotics in unneces-
are in remission and frankly unfavourable if they are seeking sarily high doses, they still use doses that are unnecessarily
competitive employment. What may be favourable when they high! This is especially so for the high-potency compounds –
are young with a negative family history may shift as they age in terms of dose equivalence, haloperidol regimes can be four
and a positive family history of diabetes emerges. times, and fluphenazine six times, those comprising chlor-
promazine (Baldessarini et al 1984). High doses early on
The principles of antipsychotic use (Box 11.9) are designed (remembering that the ‘highest’ dose for a drug-na¨ıve individ-
to ensure that throughout a patient’s illness the clinician ual is the first one) promote non-target actions that may be
flexibly applies medical expertise to optimise and individualise highly intrusive and hence impair compliance (i.e. they
the risk:benefit appraisal. As mentioned, clinical experience increase ‘risk’). A more important issue is that high doses
(and some evidence) still support the view that the primary may actually be countertherapeutic (i.e. also detract from
class action of antipsychotics (reduction in positive symptoms) ‘benefit’). There is an old but neglected literature on ‘neuro-
is delayed. While acknowledging the many pressures to leptic toxicity’ (‘behavioural toxicity’) illustrating that increas-
increase doses rapidly and early, these should be resisted as ing doses can become associated with increasingly poor
they will only add to the ‘risks’ while detracting from the response, an early observation supported by dose–response
‘benefits’. studies which show, in general, parabolic responses – i.e.
increasing doses eventually produce symptom exacerbation.

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Companion to Psychiatric Studies

Box 11.9 1994), though less than might be anticipated. There is, how-
ever, no evidence that they exert any preferential effects on
Principles of antipsychotic drug use outcome independent of compliance, and their pharmacokinet-
ics can make ‘fine tuning’ of regimes difficult. The same is true
• Structured management of long-acting injectables. Furthermore, by virtue of their
administration by another individual, some patients feel the
Prioritising problem areas element of treatment choice is compromised by these formu-
lations. There is evidence that for maintenance purposes pimo-
Identifying ‘phases’ of treatment with clear aims zide, a drug of exceptionally long half-life, may be effective in
alternate day or four times a week regimes (McCreadie et al
Acute : Aims - engagement 1980), something that may be applicable to other long half-life
drugs, such as aripiprazole.
management of non-specific symptoms
Antipsychotic dose equivalence is more craft than science.
instituting tolerable regime Equivalence tables (Table 11.4) are largely derived from clini-
cal studies with variable dose protocols and do not take
avoiding/managing emergencies account of many crucial variables including pharmacokinetic
differences. They are crude, poorly reliable (especially for
Post-acute : Aims - consolidation high-potency compounds) and should be considered as nothing
more than the median point of ranges within which compara-
‘fine-tuning’ tolerability ble efficacy can be reasonably expected. Conversions between
oral and depot formulations are even less reliable, as most do
rationalisation of medication(s) not take into account the pharmacokinetic factors particularly
relevant to depots nor the fact that these are invariably used in
resocialisation/ rehabilitation maintenance management when overall dose requirements
are lower.
Maintenance : Aims - stabilisation

reintegration

maximising well-being

tapering to lowest maintenance doses

long-term recommendations

monitoring

• Realistic time-scales

Dissociation between onset of ‘nontarget’ (early) and ‘target’
(delayed) actions
Avoidance of overzealous early dose increments
• ALWAYS: minimal effective doses

One explanation is that as extrapyramidal effects increase, Antidepressants
the associated ‘anxious dysphoria’ provides the dynamo that
drives re-emergence of the very symptoms one is trying to Introduction
eradicate. Such a mechanism might underlie ‘efficacy’ benefits
attributed to clozapine which actually better reflect EPS Observation of patients receiving antituberculous treatments
tolerability. led to the first antidepressants (monoamine oxidase inhibi-
tors) and the most enduring theory of affective disorder
A final important point in maintaining conservative dose (below) but enthusiasm was soon tempered. Although less
regimes is the time-scale over which one should be planning. hepatotoxic than antituberculous agents, MAOIs still pro-
With schizophrenia at least, a number of first-episode studies duced serious and occasionally fatal side effects. This, com-
agree that time to ‘improvement’ is in the region of 2–3 months. bined with the introduction of the tricyclics, plus an
influential 1965 MRC trial showing no benefits over placebo,
Trial data do not confirm the intuitive belief that sedative, pushed MAOIs into the therapeutic doldrums. On the other
low-potency drugs have advantages in the management of hand imipramine, initially investigated as a potential rival to
agitated, behaviourally disturbed patients, though this may be chlorpromazine, became the first of a group that was to exert
one example in which the unique circumstances of clinical unrivalled dominance as antidepressants for 30 years. The
trials do not translate well to routine treatment environments. breakthrough in their pharmacology came in 1962 when Julius
There are two advantages of sedative and low-potency drugs: Axelrod and colleagues discovered that they inhibited the
(1) they can impact immediately on non-specific symptom- reuptake of biogenic amine transmitters at presynaptic mem-
atology (agitation, insomnia, etc.) patients find distressing brane sites. It was the 1980s before relative selectivity of
and hence can produce early signs of therapeutic advantage; reuptake inhibition was brought to fruition with compounds
and (2) they have an inherently lower liability to produce whose use is now sufficiently extensive to raise political and
extrapyramidal adverse effects. Furthermore, their general social concerns.
non-target actions may inherently restrain overzealous pre-
scribing! In acute episodes, the majority of schizophrenic There are many weaknesses in the classification of anti-
patients will respond to doses in the range of 400–600 mg depressants. Clomipramine, chemically a tricyclic, is phar-
chlorpromazine per day or its equivalent (Kane 1987), though macologically akin to selective serotonin reuptake inhibitors
dosages should be tailored rather than adhering to fixed sche- (SSRIs) while moclobemide, considered an MAOI, is structur-
dules. The situation in other clinical indications is less clear ally a substituted benzamide. A pharmacologically based system
but the same principles apply. While most antipsychotics are of classification inevitably forces ‘blacks and whites’ from what
suitable for once-daily dosing, it can be useful to spread doses are shades of grey but does provide lines of separation that can
throughout the day to capitalise on sedative effects, at least have some clinical value (Table 11.5).
during the acute phase.

Depots are widely used in the UK in maintenance, where
they have been shown to enhance compliance (Davis et al

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Clinical psychopharmacology CHAPTER 11

Table 11.4 Some antipsychotic dose equivalences Table 11.5 ‘Functional classification of antidepressants on basis
of ‘lead’ pharmacological action
Antipsychotic Dose (mg/day)

Lead pharmacological action Drug

Relative to: chlorpromazine 100

Orals Monoamine oxidase inhibition Phenelzine
Noradrenaline transporter blockade Isocarboxizid
Pericyazine 24 Serotonin transporter blockade Tranylcypromine
Moclobemide
Trifluoperazine 5 Dopamine transporter blockade
5HT2A receptor blockade Desipramine
Fluphenazine 2 Doxepin
Nortriptyline
Perphenazine 8 Protriptyline
Reboxetine
Flupentixol 2
Amitriptyline
Haloperidol 3* Citalopram
Clomipramine
Pimozide 2 Duloxetine
Risperidone 2{ Fluoxetine
Fluvoxamine
Olanzapine 5 Imipramine
Paroxetine
Quetiapine 75 Sertraline
Trimipramine
Aripiprazole 7.5 Venlafaxine

Ziprasidone 60 Bupropion

Clozapine 50{ Mirtazapine
Trazodone
Depots

Fluphenazine decanoate 10–25/2 weeks

Flupentixol decanoate 16–40/2 weeks After Richelson (2001).

Zuclopentixol decanoate 80–200/2 weeks

Haloperidol decanoate 40–100/4 weeks Secondary amines

Pipothiazine palmitate 20–50/4 weeks NC
Relative to: haloperidol 2{
Risperidone 1–2{ CH3 CH3
H H
*More recent clinical studies concur with functional imaging that the minimal effective CH2 CH2 CH2 N CH CH2 CH2 N
dose for haloperidol is <5 mg/day, suggesting equivalence in the region of 1:100. Desipramine Nortriptyline
{From US Mulicenter Study (Kane et al 1988) which utilised very high doses. It is
perhaps more accurate to assume 1:1 equivalence. As their group name implies, tricyclics comprise two benzene
{APA (1997) – more accurate to consider 1:1 equivalence (Remington et al 1998). rings joined by a central ring which in the classical compounds
From Atkins et al (1997) and Woods (2003). is seven membered. Substitutions at position 5 can be either
nitrogen, as with imipramine-type compounds, or carbon, as
Tricyclics with amitriptyline. The former are therefore dibenzazepine
analogues of phenothiazines whereas the latter, technically a
Chemical structures dibenzocycloheptene, is closely related to the thioxanthenes.
On the basis of their side-chain attachments they may be sub-
9 10 11 1 Tertiary amines classified as tertiary (e.g. imipramine, amitriptyline) or second-
ary (e.g. desipramine, nortriptyline) amines.
82
In general, tricyclics vary only slightly in structure based
7 N5 3 C on modifications to their side-chains, despite some differ-
6 4 CH CH2 CH2 N ences (essentially of emphasis) in their pharmacology. A few
Amitriptyline deviate more in their central ring structure, e.g. amoxapine,
CH2 CH2 CH2 N CH3 CH3 a metabolite of the dibenzoxazepine antipsychotic loxapine
Imipramine CH3 CH3 (and alternatively might be referred to as norloxapine) and
maprotiline with a six-membered central ring stabilised by an
ethylene bridge. Both of these have been withdrawn in the UK.

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Companion to Psychiatric Studies

Pharmacokinetics alcohol-dependent patients with coincidental hepatic cirrhosis
and portocaval shunting. On the other hand, chronic alcohol
Tricyclic antidepressants are all well absorbed from the gas- ingestion without compromised hepatic blood flow increases
trointestinal tract, a process not prone to interference by, the magnitude of first-pass metabolism via enzyme induction.
for example, concomitant drug administration. The rate of A further reason why tricyclic effects can be so toxic in over-
absorption, and hence time to peak levels, is more rapid for dose relates to changes that occur in kinetic variables (see
tertiary amines (approximately 1–3 hours) than for secondary below).
amines (approximately 4–8 hours) (Preskorn 1993). The
speed of absorption (Tmax) and the size of the postabsorption Plasma protein binding for tricyclics is high (90–95%) as is
peak (Cmax) may be related to the likelihood of certain their lipophilicity, accounting for large distribution volumes.
adverse effects developing, such as sedation, agitation and Elimination half-lives are on average in the region of 20–24
membrane ‘stabilisation’ underlying some cardiac actions. hours, with those for imipramine and desipramine somewhat
Although this has been used as an argument in favour of the less and for amitriptyline and nortriptyline rather longer.
preferential use of secondary amines, this is probably only of Protriptyline (withdrawn in the UK), with t1/2 values in the
clinical significance in selected individuals, such as the elderly region of 75–80 hours, is exceptional and, with daily dosing
or those with a clear history of previous intolerance. Further- regimes, accumulation is possible. Overall, however, half-lives
more, divided dose regimes may be used to attenuate Cmax are compatible with once daily dosing and steady state within
without altering steady-state levels. 5–7 days. Amoxapine, with an average half-life in the region
of 8 hours, may be better suited to split-dosing. Lofepramine
All tricyclics are subjected to heavy first-pass effects, with also has a short half-life but since this compound functions as
only about 50–60% of an oral dose reaching the systemic circula- a ‘pro-drug’ with rapid conversion to desipramine, the half-life
tion. With 70% metabolism, first-pass effects are particularly figure is of less clinical importance.
large with dosulepin (dothiepin). As with antipsychotics, at ther-
apeutic levels clearance is flow-dependent and decreased The kidney is the major route for elimination of tricyclics
by hepatic disease or states that impede hepatic through- and the most important source of alteration in pharmacoki-
put. The major metabolic steps involve hydroxylation of the netic parameters by age, illness or other incidental factors
ring structures and demethylation of the terminal nitrogen (Rudorfer & Potter 1987).
(Baldessarini 1985). Hydroxylation appears to be the rate-
limiting step and makes the largest contribution to breakdown, Pharmacodynamics
resulting in the formation of metabolites that in unconjugated
form may be present in blood and brain in concentrations Mode of action
greater than the parent drug. Conjugated and unconjugated
hydroxy metabolites account for up to 85% of an oral dose of In its generic format, the (Biogenic) Amine Hypothesis states
imipramine and 55% for amitriptyline (Rudorfer & Potter that:
1987). The actions of hydroxylated tricyclic metabolites are
however complex and difficult to study, especially for the . . .depression is associated with functional deficit of neurotransmitter
tertiary amines. In vitro, and possibly in vivo, they do appear amines at critical CNS synapses and mania with functional excess.
to share reuptake inhibition actions similar in type and degree
to their parent drugs and they make a contribution to efficacy This was refined into ‘subhypotheses’ when Schildkraut
and probably tolerability (Young 1991). There is a suggestion (1965) postulated that the disturbance lay with catecholamine
from animal studies that they may be more cardiotoxic than (predominantly noradrenergic) mechanisms, while Coppen
parent drugs, though the human relevance of this is unclear. pointed to the indoleamine, serotonin.
Demethylation of the side-chain converts tertiary compounds
to secondary amines, and these to primary amines. Secondary The theory arose from observations of the effects on mood
amines are of course active and a number are commercially of various compounds, initially presynaptic depleting agents
marketed in their own right, whereas primary amines are inac- and monoamine oxidase inhibitors, and while there is much
tive. Tricyclic metabolism may however not be unidirectional. that supports it, it must be viewed as the ‘theory’ it is, i.e. a
There is evidence that with administration of secondary amine set of working proposals that provide for the testing of certain
compounds, some 15% of patients develop detectable levels essentially therapeutic models. There is evidence that it is at
of tertiary drug in plasma, e.g. desipramine to imipramine one level an oversimplification. Mouse gene knockout models
(Rudorfer & Potter 1987). suggest that the role of dopamine may have been underesti-
mated (Perona et al 2008) while the tricyclic tianeptine,
A number of drugs interfere with hepatic metabolism of licensed in some European countries, enhances serotonin
tricyclics (see below), but of particular note is alcohol, which reuptake!
has a triphasic effect. Acute ingestion to intoxication in non-
dependent individuals impairs metabolism by competition Despite the sway the Biogenic Amine Hypothesis has held,
resulting in a two- to three-fold increase in the amount of unal- the precise mode of action of tricyclics remains unknown.
tered drug reaching the systemic circulation. This is one reason They modify transmission by: (1) receptor actions; and (2)
why combination overdoses can have such adverse medical effects on reuptake. As a group they have a strong affinity
consequences. A similar effect may be evident in chronically for histaminic (H1) (pharmacologically, some might be better
considered antihistamines), muscarinic cholinergic and a1-
adrenergic receptors (Table 11.6). They have only weak affin-
ity for dopamine D2 receptors, with amoxapine, trimipramine

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Clinical psychopharmacology CHAPTER 11

Table 11.6 Binding affinities of various tricyclics for different (diminished sensitivity of the cell to neurotransmitter), which
receptor types (as percentage of reference compound) may be associated with downregulation (loss of receptor
protein) at presynaptic a2-adrenergic sites and postsynaptic
Tricyclic Receptor type b1-adrenergic and 5HT2a/2c sites as well as upregulation
(increased receptor protein) of postsynaptic a1-adrenergic
H1* M{ a1{ D2} receptors. These in turn have effects on intracellular chemis-
try and protein expression wherein the ‘therapeutics’ most
Imipramine 128 2.6 16.4 0.9 likely lie (cf. below).

Amitriptyline 1282 13.3 55.2 1.9 In recent years, novel theories relating to the mode of
action of antidepressants have emerged, e.g. their influence
Desipramine 12.8 1.2 11.5 0.6 on brain-derived neurotropic factor (BDNF) in local brain
areas such as the dentate gyrus of the hippocampus, or in
Nortriptyline 141 1.6 25.4 1.6 modifying membrane steroid transporters that regulate
access of glucocorticoids to the brain. Ultimately it is at the
Clomipramine 45 6.4 38.8 10 level of molecular biology that better understanding is likely
to come.
Trimipramine 5211 4 62.7 10.6
Adverse (non-target) actions
Doxepin 5915 2.9 62.7 0.8
A knowledge of the receptor-binding properties of tricyclics
*Histaminergic receptors: Reference diphenhydramine can be helpful in understanding adverse effect profiles though
{Muscarinic cholinergic receptors: Reference atropine as with antipsychotics, extrapolation of in vitro data to the
{Alpha-1 noradrenergic receptors: Reference phentolamine clinical context is inherently limited, something pharmacoki-
}Dopaminergic receptors: Reference chlorpromazine netic variations and the effects of active metabolites further
Data from Richelson (1996). complicate.

and clomipramine the most potent at these sites, though even Mediated directly via receptor antagonism
these have only about one-tenth or less the affinity of chlor-
promazine (Richelson 1996). These direct receptor actions Histaminic actions Tricyclics as a group are potent antago-
occur quickly and are responsible for ‘early synaptic events’ nists of histaminergic H1 receptors. Some, such as doxepin and
which mainly mediate non-target effects though may play trimipramine, bind with 50–60 times greater affinity than
some role in the therapeutic action. reference antihistamines. Amitriptyline has approximately
10 times greater affinity than imipramine, which in turn has
Presynaptic reuptake is an important mechanism in neuro- approximately 2–3 times the affinity of protriptyline and clo-
transmission in order to prevent receptor overstimulation. mipramine. Desipramine, on the other hand, has only very
Following transmitter–receptor decoupling, free transmitter weak affinity for these receptors (Richelson 1996). Antihista-
is taken back into the presynaptic cell via monoamine trans- minic activity is the major contributor to the sedative side-
porters (SERT, (serotonin); NET, (noradrenaline or norepi- effects of tricyclics. Nonetheless, in clinical situations where
nephrine); DAT, (dopamine)) for recycling, a process that is anxiety and agitation are intrusive, these ‘non-target’ actions
energy and sodium dependent. Details of the mechanism can be a valuable aid to management.
underlying reuptake inhibition have remained elusive though
there is now evidence that this involves allosteric modification Sedation diminishes reaction time, a basis for concern that
of the transporter protein, the drug binding to an extracellulary- those on sedative antidepressants may be disproportionately
facing vestibule thereby stabilising the extracellular gate represented in road traffic accidents. While there are data
closed, producing a physical barrier to ingress of transmitter supporting both increased relative risk (Leveille et al 1994)
molecules (Singh et al 2007). In vitro, the secondary amines and increased culpability (Currie et al 1995), the largest
(e.g. desipramine, nortriptyline, protriptyline) are more potent epidemiological study suggests only a minor increased risk
and selective inhibitors of noradrenaline reuptake than of sero- overall – and one no greater in those taking antidepressants
tonin. Although there is doubt that such selectivity operates than in those taking any other types of medication (Bramness
in vivo (Frazer 1997), considering antidepressants by their lead et al 2008).
‘functional’ characteristic can provide a basis for more rational
treatment choices, especially following first-line failures (see As a consequence of sedative properties, tricyclics can
Table 11.6). increase sleep time. They are not sleep-inducers but rather
act to maintain sleep in those with early wakening. They
While the augmentation of transmitter within the syn- may however be associated with prominent and distressing
apse is the necessary first step in a therapeutic effect, and dreams (perhaps a result of anticholinergic effects).
one that occurs rapidly, it is not per se the cause of mood
elevation. After initial augmentation of transmitter within Antihistaminic activity may also contribute to what is for
the synapse, longer-term modification of neurotransmission patients one of the most unwanted effects, namely, weight
occurs with chronic ingestion (‘delayed synaptic events’), gain, which can be considerable and a major reason for non-
details of which remain obscure but include desensitisation compliance. Potential associations with metabolic syndrome
have not been extensively investigated but current evidence
suggests that tricyclics do not interfere with glycaemic control

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Companion to Psychiatric Studies

in those with existing diabetes (Knol et al 2008). The like- 1997). The best predictor of orthostatic drop during treat-
lihood of weight gain seems greatest with amitriptyline and ment is simply a postural drop prior to exposure (Glassman
least with the secondary amines (Fernstrom & Kupfer 1988). et al 1979).
The mechanisms underlying it are complex and may involve
factors such as carbohydrate craving. As noted above, postural hypotension deserves to be taken
for the potentially serious adverse effect it is. In addition to
Anticholinergic actions Tricyclics have clinically relevant promoting both cerebral and myocardial ischaemia, it may lead
affinity for muscarinic cholinergic receptors, with amitrip- to falls, especially in the elderly. While specialist studies
tyline and protriptyline the most potent antagonists and nor- suggest that hip fractures occur 2–3 times more often in those
triptyline and desipramine the least. Indeed these latter on tricyclics (Ray et al 1987), especially amitriptyline and clo-
drugs have less affinity for cholinergic sites than paroxetine mipramine, the former showing an effect even at low dose
(Richelson 1996). (Vestergaard et al 2008), epidemiological studies of fracture
risk in general are less clear cut (see below). Noradrenergic
Anticholinergic actions, mostly peripheral, make a major antagonism at a1 sites mediates a reflex tachycardia and is
contribution to the adverse effects patients complain of most. probably the other major contributor to sexual dysfunction
Impaired salivary flow, especially in the resting state, results in including impotence, impaired or premature ejaculation and
uncomfortable dryness in the mouth which, as with antipsycho- anorgasmia.
tics, may promote low-grade but potentially significant oral
infection and dental caries. A similar reduction in lacrimation Dopaminergic actions Most tricyclics have little affinity
may predispose to corneal infection and damage, especially for dopamine (D2) receptors, the exceptions being trimipra-
with contact lens use. Relative paralysis of accommodation mine, clomipramine and amoxapine, the latter associated with
causes pupillary dilatation and blurring of vision, which is most the gamut of EPS. Caution should be exercised in use of this
marked with changes in focal length (e.g. in changing from dis- drug in the elderly. Clomipramine has been reported to
tance sight to reading), and rarely, in predisposed individuals, produce the same clinical manifestations of hyperprolactinae-
may promote angle closure glaucoma. Inhibition of the cardiac mia as antipsychotics, but in practice the prevalence is lower
sphincter may result in oesophageal reflux and heartburn. and this only infrequently presents management problems.
Constipation and bowel hypomotility may, as discussed above, A higher risk of movement disorders has not been specifically
have major and sometimes catastrophic consequences, as when attributed to either trimipramine or clomipramine.
paralytic ileus ensues. Impaired elimination and frank urinary
retention is usually, though not exclusively, a problem in males, Specific issue
especially those with underlying prostatic hypertrophy. Sexual
dysfunction can undoubtedly be associated with this group’s CARDIAC FUNCTION For many years, the pharmacology of
anticholinergic actions, especially poorly sustained erections,
but contrary to popular medical belief these effects are proba- tricyclics was seen through the prism of toxicity, contributing
bly relatively minor when placed in the context of frequent to a perception that these were uniquely cardiotoxic com-
sexual dysfunction in untreated affective disorders (Kennedy pounds. However, studies under therapeutic conditions reveal
et al 1999). Impaired cholinergic–noradrenergic balance may, a more favourable picture. Direct effects on the heart show
however, underlie infrequent cases of priapism. mainly in the two crucial areas of rhythm and conduction,
actions most likely mediated through blockade of myocardial
Vagal blockade results in mild sinus tachycardia (average ion channels, though as surprisingly little work has been under-
<10 beats per minute), rarely clinically significant, but when taken in this field, it is still not possible to be precise about the
combined with reflex tachycardia secondary to hypotension mechanism (Gillman 2007).
may increase oxygen demand in those with ischaemic heart
disease sufficiently to promote rate-related angina or so-called Tricyclics have properties of Class I antiarrhythmics,
‘silent’ ischaemia (Jefferson 1989). promoting membrane stabilisation through inhibition of fast
sodium channels. They share both Type IA (quinidine-like)
Central anticholinergic actions may produce memory effects resulting in decreased amplitude of Purkinje fibre
impairment which is likewise usually not significant though in action potentials and membrane responsiveness with slowed
the elderly this effect, exaggerated by pharmacokinetic changes, conduction, and Type IB (lidocaine-like) effects of decreased
may promote major cognitive problems and frank confusion. duration of action potentials and effective refractory period
(Jefferson 1989). At therapeutic blood levels they are clini-
Noradrenergic actions Doxepin, trimipramine and ami- cally effective in the treatment of supraventricular tachycar-
triptyline all have strong affinity for a1-receptors with imipra- dias and some dysrhythmias of ventricular origin. However,
mine, clomipramine and nortriptyline intermediate and any drug with antiarrhythmic properties may be proarrhy-
desipramine and protriptyline relatively weak (this compares thmic in some patients, especially when blood levels are
with trazodone, which also has moderate affinity, and sertra- high or when two Type I drugs are combined. Thus, tricylics
line, which has little; Richelson 1996). As a result, tricyclics should be avoided in patients already receiving a Type I
can cause lightheadedness or a ‘woozy’ feeling on walking, antiarrhythmic.
especially when changing position consequent upon postural,
or orthostatic, hypotension. This occurs in about 5–10% of On ECG, tricyclics can prolong QTc, both in therapeutic
even young healthy individuals on tricyclics and up to 20% of doses and in patients without pre-existing heart disease (Reilly
older populations, 4% of whom may sustain injuries (Frazer et al 2000), and can produce T-wave changes. As noted above,
this is a potential concern and the arguments about the extent
to which this should translate into practical concern are as

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with antipsychotics. No reliable data as yet exist on relative elderly patients taking tricyclics may experience a worsening
risk, though the effect is probably a group one. of white matter hyperintensities on magnetic resonance imag-
ing (Steffens et al 2008), suggesting subtle microvascular
Tricyclics have little effect on A-V nodal conduction but actions over time. Both these findings require replication but
delay intraventricular conduction in the His-Purkinje system, again urge care with the use of psychotropics in the elderly.
an action, in general, related to blood levels. The major poten-
tial consequence is precipitating or advancing the level of heart Like most antipsychotics, tricyclics alter the EEG and lower
block. In patients with normal cardiac conduction, this risk is seizure threshold. Hence they can precipitate seizures, the
small (<1%) and reversible (Roose et al 1987). The same likelihood relating to dose and the rate of dose increment.
applies to those with pre-existing first-degree block but Roose The risk is, however, low, with prevalence rates estimated to
and colleagues also found that 9% of those taking imipra- be in the region of 0.1–0.5% (Skowron & Stimmel 1992).
mine who had pretreatment bundle branch block developed The risk is substantially higher with maprotiline, even in the
second-degree block during treatment, also reversible on dis- absence of predisposing factors (Blackwell & Simon 1988).
continuation. While the authors acknowledged the increased This drug (withdrawn in the UK) is also associated with an
risk of tricyclics exacerbating conduction disorders in those increased risk of skin rashes ( 3% in the first 2 weeks of
with pre-existing abnormality, they also pointed out that, from exposure).
a cardiological perspective, tricyclics still represent relatively
safe antiarrhythmic agents. Controversy has existed about whether antidepressants in
general, and tricyclics in particular, precipitate hypomania/
There remains debate about the effects of tricyclics on mania in non-bipolar depressed patients. This seems unlikely,
cardiac contractility. Clinical evidence, only suggestive, does those developing morbid elevation of mood during treatment
not support the view that tricyclics (nortriptyline, amitripty- being predisposed to bipolar disorder or experiencing with-
line, imipramine and doxepin at least) adversely affect left drawal phenomena (Kupfer et al 1988). A disorder of speech,
ventricular performance (Glassman & Biggar 1981). sometimes referred to as dysarthria but better described as
speech ‘blocking’ or hesitancy, has been described with a rarity
Therefore, the evidence to date is that at therapeutic levels that probably does not reflect its frequency. This resembles
tricyclics have few detrimental actions in the absence of pre- stammer and is easily confused with agitation associated with
existing cardiac disease and in certain circumstances may have the depression itself.
beneficial actions. With care, these drugs appear to have a
relative margin of safety in most patients with signs of cardiac Other rarely reported adverse effects include skin rashes,
failure. Nonetheless, in those with and those at risk of devel- blood dyscrasias, cholestatic jaundice and hepatic necrosis
oping heart disease, ECG monitoring is recommended. (transient mild elevations in liver enzymes are not uncommon
and are usually of no clinical significance). Overall, the risk
Not mediated directly via receptor antagonism of allergic reaction to these drugs is very low. Oedema from
inappropriate secretion of antidiuretic hormone and non-
Other important adverse effects of tricyclics do not relate vibratory tinnitus have also been reported.
directly to receptor antagonism. Enhanced noradrenergic
transmission is probably behind the anxiety and agitation Recent reports suggest a link between long-term use of
sometimes seen, especially within a few days of exposure tricyclics and non-Hodgkin lymphoma, the adjusted incidence
(cf. SSRIs). This has been referred to as the ‘jitteriness’ rate ratio being 1.53 (95% CI ¼ 1.06–2.21) overall compared
or ‘early tricyclic syndrome’ but appears phenomenologi- to non-exposed controls and 2.50 (1.43–4.34) in those with
cally similar to akathisia. The same mechanism is the likely 10 or more prescriptions followed for 5 years or more (Dalton
explanation of low amplitude, high frequency tremor. As pre- et al 2008). These results are preliminary and refer to a con-
dicted by their pharmacology, comparative studies suggest dition itself relatively rare, so absolute numbers likely to
these symptoms are most frequent with desipramine and pro- be involved would be small. Nonetheless, they must raise
triptyline (Cole & Bodkin 1990). Reports of hypertension are concerns. The mechanism remains unknown.
few, possibly reflecting an absence of routine monitoring but
it has been suggested that transient rises early in exposure are Using the UK GP Research Database, Jick and Li (2008)
not uncommon, perhaps more with amoxapine and in those found a 70% increase in venous thromboembolism in those
with pre-existing hypertension (Jefferson 1989). Sweating, taking specifically amitriptyline but not other antidepressants,
sometimes amounting to hyperhidrosis, affects up to 10% of the risk increasing with dose. This small increased risk is sub-
patients, and probably also reflects a group action. Even when stantially less than that found for venous thrombosis in those
mild, this can be subjectively distressing and is always worth taking low-potency phenothiazines and may sway interpreta-
asking about. tion towards diminished activity as the crucial factor rather
than the more complex mechanisms suggested above.
Recent work has highlighted similar, if less substantial,
cerebrovascular concerns with long-term tricyclic use as with The prevalence of adverse reactions to tricyclics is difficult
antipsychotics (above). In a case-controlled epidemiological to estimate as published studies adopt differing methods and
study of over 1000 individuals experiencing a cerebrovascular thresholds for recording. Their propensities would, however,
event (haemorrhagic or ischaemic stroke or ‘other’) a 34% seem to be less than clinical folklore indicates. The most sys-
increased event risk was found in those taking a tricyclic (Chen tematic investigation reported a prevalence of 15.4% (Boston
et al 2008), the comparable figure for SSRIs being 24%. The Collaborative Drug Surveillance Program 1972), which is
mechanism is again unknown but of interest is the finding that comparable to the 18% found in comparative studies with
newer antidepressants (below).

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Monoamine oxidase inhibitors The traditional irreversible and non-selective MAOIs are
unique psychopharmacological agents, in that their clinical
Chemical structures effects bear little relationship to pharmacokinetics. The rea-
son is that these drugs mediate so-called mechanism-based
Irreversible/non-selective O reactions – that is, they are relatively inert compounds in
themselves, but are converted by MAO into highly reactive
CH2 CH2 NH NH2 CH3 NH NH C CH3 intermediates which then inactivate the enzyme via a process
Phenelzine of irreversible, covalent bonding (Amrein et al 1989). This
N results in what has been variously called a ‘suicide’ effect
O (the enzyme’s affinity for drug results in its irrevocable inacti-
vation) and a ‘hit-and-run’ effect (the action can be detected
Isocarboxazid long after the drug itself has been eliminated).

CH CH NH2 The newer MAOIs also have ‘breakneck’ kinetics. Moclobe-
CH2 mide is readily absorbed and reaches peak plasma concentra-
tions in approximately 1 hour. Metabolism is rapid and
Tranylcypromine complete with elimination half-life in the range of 1–3 hours.
Some metabolites may be pharmacologically active but to a
Reversible/selective (type A) clinically insignificant degree. Protein binding, at around
50%, is relatively low but bioavailability appears to increase
Cl CO NH CH2 CH2 N O with regular dosing (Amrein et al 1989). A mechanism-based
reaction has been postulated for moclobemide but, even if
Moclobemide true, the consequences are fundamentally different from those
with the traditional drugs, as enzyme binding is reversible.
While our concern is the antidepressant monoamine oxidase
inhibitors (MAOIs), compounds with this action have wide Selegiline is a selective, irreversible inhibitor of MAO-B in
medicinal applications as antimicrobial, antineoplastic and low oral dosage. Although valuable in treatment of Parkinson’s
antihypertensive agents. disease, in the higher oral doses necessary for antidepressant
action, MAO selectivity is lost. However, administering sele-
Of the three ‘traditional’ antidepressant MAOIs available giline by transdermal patch allows the brain to accumulate
in the UK, phenelzine and isocarboxazid are derivatives of antidepressant concentrations of drug with minimal disrup-
hydrazine (NH2NH2), while tranylcypromine is a cyclopropy- tion to gastrointestinal MAO-A (Wecker et al 2003). This
lamine, formed by substituting the isopropyl side-chain of formulation is approved for antidepressant use in the USA.
amphetamine with a cyclopropyl variant.
Pharmacodynamics
Exploration of the pharmacology of monoamine oxidase
inhibition resulted in compounds with selectivity and/or revers- Mode of action
ibility of action not seen with the traditional drugs. Moclobe-
mide, originally developed as a potential lipid-lowering agent, MAO is a flavin-adenosine-dinucleotide (FAD)-containing
is chemically a substituted benzamide and the only new MAOI enzyme situated mainly in the outer membranes of mitro-
currently available in the UK as an antidepressant. Selegiline chondria. It has a wide and dense distribution. It is the major
(or L-deprenyl), which is a metamphetamine derivative, is intracellular enzyme catalysing the oxidative deamination of
pharmacologically within this group. biogenic amines to their corresponding aldehydes and in the
CNS its function is intimately related to reuptake. By metabo-
Pharmacokinetics lising cytoplasmic amines and maintaining their concentration
at low levels, its action facilitates inward-directed transporter
The pharmacokinetics of isocarboxazid have not been studied, activity from the synapse. However, the precise relationship
but phenelzine and tranylcypromine appear to have fairly com- between these intracellular events and concentrations of
parable properties (Mallinger & Smith 1991). They are readily monoamines in the extracellular space is more complex than
absorbed and reach peak concentrations in 1–2 hours. Elimina- was originally thought and remains unclear.
tion is also swift, with half-lives in the range of 1½ to 4 hours
(especially short for tranylcypromine). This is due to rapid and In 1968, Johnston identified two subtypes of MAO – ‘A’
almost complete hepatic metabolism. Protein binding is high and ‘B’ – which differ in their preferential substrates and
and bioavailability low. Even now, the underlying metabolic inhibitors. The preferred substrates for type A include nor-
steps are poorly understood. Acetylation was thought to be adrenaline and serotonin, while phenethylamine, benzylamine
an important step in phenelzine metabolism, with ‘acetylator and N-methylhistamine are preferential substrates for type B.
status’ (slow or fast) a major determinant of efficacy and Dopamine, tyramine and tryptamine have no preference for
especially tolerability. However, it is now unclear whether either subtype.
acetylation is the predominant metabolic route. Plasma
steady-state levels of phenelzine appear to rise over the first Some qualifications are necessary to the conventional wis-
6–8 weeks of exposure, suggesting that either the drug itself dom about traditional MAOIs (Baldessarini 1985). The enzy-
or a metabolite may inhibit its metabolism. matic ‘hari-kari’ noted above has allowed their effects to be
viewed as irreversible, with inhibition only overcome by man-
ufacture of new enzyme. While this in general is true, a degree

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Clinical psychopharmacology CHAPTER 11

of reversibility is evident with tranylcypromine, recovery of individual sensitivity to the consequences and hence are not
enzyme function being somewhat more rapid (7–10 days) ‘non-target’ in the sense mentioned above (cf. lithium).
following its discontinuation than after cessation of hydrazine
derivatives (2þ weeks). Secondly, although these drugs are The major adverse effect associated with traditional MAOIs
considered non-selective, this is relative. Phenelzine has an is hypotension. Unlike tricyclics, where this is largely postural,
approximately 6:1 preference for type A, while tranylcypromine with traditional MAOIs, lowering of supine blood pressure is
has a slight (2:1) predilection for type B. Only isocarboxazid has also evident, with potentially more disabling consequences.
roughly equal affinity for both subtypes. It seems unlikely, how- The reported prevalence of postural hypotension varies consider-
ever, that these differences translate into anything clinically ably with an average of 14% for tranylcypromine and slightly
meaningful. Finally, while mechanism-based reactions form the less for phenelzine (Rabkin et al 1985). The supine component
essential characteristic of the processes mediating efficacy, tends to develop early (within the first week) but in a further
aspects of their adverse effect profile indicate that these drugs difference with tricyclics, postural hypotension most frequently
also partake in more conventional pharmacological interactions. builds up over the first 4 weeks or so of exposure. The mecha-
nism underlying these actions is unclear, though has been postu-
One of the problems with studies evaluating the place of lated to relate to accumulation of biogenic amines (because of
MAOIs in treatment is dosage. It has been suggested that in slowed metabolism) with a consequent increase in the activity
order to obtain therapeutic benefits, blockade of MAO must of precursors. This may result in the formation of amines with
be in the region of 80–85%, levels only achieved by doses of less direct sympathomimetic activity which, in effect, act as
phenelzine in the higher range (>45 mg per day) (Baldessarini ‘false transmitters’ (Baldessarini 1985). Hypotension may be
1985). However, these estimates may be flawed, as they one of the adverse effects that relates to pharmacokinetic para-
refer to blockade performed on platelets, which contain only meters and therefore altering dose regimes can be helpful as
MAO-B. Nonetheless, this does emphasise that even with the first step in management.
drugs acting in a unique way, adequacy of dosing is an essential
prerequisite of therapeutic efficacy. Traditional MAOIs do not have any direct actions on car-
diac rhythm, conduction or contractility and a reduction in
Identification of MAO subtypes led to the search for drugs basal heart rate usually accompanies treatment, so they may
with selective patterns of inhibition, particularly to type A be useful in treating depressed patients with cardiac disease
(Rudorfer 1992). The first of these was still irreversible, so who are either on compatible, or no, cardiac medication. They
clorgyline, a selective inhibitor of MAO-A, did not find com- have also long been reported to possess anti-anginal properties,
mercial sponsorship. However, a number of selective inhibi- probably mediated via a diminution in sympathetically regu-
tors of MAO-A that are also reversible have been developed, lated arteriolar tone. However, although acting to alleviate
including brofaromine, cimoxatone and toloxatone, though of pain, they do not modify ischaemic changes on ECG, so are
these RIMAs (Reversible Inhibitors of MAO type A), only in fact merely converting symptomatic to asymptomatic
moclobemide has thus far received a wide launch. Despite pro- ischaemia (Jefferson 1989).
ducing very similar plasma concentration time-course curves to
tranylcypromine, the consequences of this with moclobemide Dry mouth, constipation, and urinary difficulties, including
are dramatically different, with maximum inhibition evident retention, and sexual disturbance, such as impotence and
after the first dose (Mallinger & Smith 1991). Although moclo- orgasmic dysfunction – symptoms conventionally viewed as
bemide has a swift elimination half-life, it produces MAO-A ‘anticholinergic’ – can develop on these drugs which have
blockade for 8–10 hours, though a decline in inhibition is inherently little antimuscarinic activity. Such symptoms,
evident towards the end of even a t.i.d. dose schedule. established mainly with phenelzine but also found with tranyl-
cypromine, can be prominent, with urinary retention occasion-
Rises in intracellular amine levels may be sufficient to ally affecting females. Rather than reflecting single system (i.e.
modify transmitter flows resulting in downregulation of some cholinergic) disorder, these are probably manifestations of
receptor types, including b-adrenoreceptors, and dramatic an excess of adrenergic sympathetic tone resulting from
rises in ‘trace amines’ such as 2-phenylethylamine and trypt- peripheral cholinergic/noradrenergic imbalance.
amine, while blockade of GABA-transaminase (amongst other
enzymes), results in elevated levels of the major inhibitory Traditional MAOIs can produce elevation of mood in those
transmitter GABA. As with tricyclics, however, such changes not predisposed to bipolar disorders and hypomania/mania in
only set the scene for more important intracellular events, those who are (Rudorfer 1992). They should be avoided in
including alternations to signalling pathways and gene expression, schizophrenic patients, as they may precipitate or exacerbate
that remain to be elucidated. ‘positive’ psychotic symptomatology. Tranylcypromine is the
sole first-generation antidepressant to which abuse and depen-
Adverse effects dency can be attributed, a fact no doubt not unrelated to its
close structural relationship to amphetamine, analogues of
Studies of the pharmacology of traditional MAOIs have which are a product of its metabolism (Mallinger & Smith
focused on their enzyme-blocking action to the exclusion of 1991).
other actions that may be more pertinent to adverse effects –
e.g. features relating to peak plasma concentrations that As a result of their generally stimulant actions, traditional
are modifiable by alterations to methods of administration MAOIs may be associated with insomnia as well as agitation
(Mallinger & Smith 1991) and not compatible with exclusively and general psychomotor ‘arousal’. However, hydrazine com-
mechanism-based activity. However, most unwanted effects pounds can be sedative, especially on first exposure. Prolonged
of MAOIs seem to reflect the target pharmacology and phenelzine use has on occasion been associated with pyridox-
ine (vitamin B6) deficiency, resulting in peripheral neuropathy,

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Companion to Psychiatric Studies

reversible with B6 supplements. Rare cases of diuretic-resis- yeast extracts like ‘Marmite’, fish and meat extracts such as
tant oedema, probably associated with inappropriate ADH ‘Bovril’, and certain vegetable components such as broad bean
secretion, have been reported. The hepatotoxicity found pods and banana skins. Spoiled meats should be avoided, along
with iproniazid does not appear to be an issue with currently with soy sauce and soy-based condiments. It would also be
available drugs. However, tranylcypromine should be avoided prudent to go easy on the guacamole, and caviar should be kept
in those with pre-existing liver disease as there is a risk of for celebrating cessation of treatment. Most alcoholic drinks
precipitating an encephalopathic-type picture (Blackwell & have low pressor amines levels and the problems with coinges-
Simon 1988). tion relate more to potentiation. Chianti wines, prohibited
in the past, were somewhat unjustly singled out. Red wines
The adverse effect profile of moclobemide appears more in general have higher amounts of pressor amines than whites
favourable than tricyclics or traditional MAOIs. In particular, and a palate attuned to canned and bottled beers should be
autonomic side-effects seem less prevalent, especially dry cultivated in place of home brews and real ales.
mouth. Restlessness, disturbed sleep, daytime fatigue and
tremor can however occur, as can transient dizziness and head- The position surrounding cheeses is less clear. Some, such
ache (Baumhackl et al 1989). Confusion, reversible on discon- as cottage or cream cheeses, are without risk, as are sour cream
tinuation, has been reported rarely. and yoghurt. However, the problem with other cheeses relates
less to their absolute amine values which, in reference lists,
Pharmacodynamic interactions would indicate a limited source of concern, than to the fact
that levels vary widely (up to 100-fold) and unpredictably in
MAOIs are associated with two types of pharmacodynamic comparable samples. Manufacturing processes, especially of
interaction which raise unique safety issues. strong cheeses, lend themselves to wide variations in amine
content across batches and to a lack of uniform distribution
Hypertensive crises within samples produced from the same batch. Hence, caution
should be exercised with all cheeses, especially matured ones.
The major concern with traditional MAOIs is not an adverse or There is no particular proscription on ‘blue’ cheeses, as was
toxic effect but a drug–drug interaction, where food constitu- once recommended, but the German ‘Liederkranz’, with its
ents are pharmacoactive. Hypertensive crises were described unusually high tyramine content, is verboten!
soon after introduction of the group and were crucial to the
perception of hazard that led to them being side-stepped. The risk of hypertensive crises with RIMAs is theoretically
It was some years before the biochemistry of these potentially much reduced, though not eliminated. In practice, no specific
fatal reactions was understood (Blackwell 1963) and although dietary restrictions are necessary with therapeutic doses of
this offers reassurance, an element of unpredictability remains. moclobemide or with selegiline transdermal patches.
Because of their early association with ingestion of strong
cheeses ( 80%), the syndrome is still sometimes unjustifiably Serotonin syndrome (‘serotonin toxicity’)
referred to as the ‘cheese reaction’.
Although becoming prominent with the introduction of SSRIs,
Hypertensive crises result from the direct absorption of this will be mentioned here as it is with MAOI overdose and
pressor amines formed as part of the bacterial decarboxylation combinations that the syndrome is seen at its most severe.
of amino acid constituents of certain protein-containing foods.
Normally, these amines (e.g. tyramine, phenylethylamine and Serotonin ‘overload’ was first observed clinically in 1955 in a
histamine) are neutralised by MAO in the gut wall but the loss TB patient receiving iproniazid. It is one of what have been called
of this protective barrier by enzyme inhibition allows them ‘toxidromes’ (toxic syndromes), emphasising that it is not an idio-
free passage to the systemic circulation, stimulating inappro- syncratic reaction but a concentration phenomenon represent-
priate release of noradrenaline from peripheral sympathetic ing the extreme end of the spectrum of intrasynaptic serotonin
nerve terminals and/or adrenaline from the adrenal medulla. concentrations (Gillman 2006). Hence, the preference now is
The resulting symptoms are similar to phaeochromocytoma – for the term ‘serotonin toxicity’ (ST). It is one of those rare
pallor, anxiety, nausea, sweatiness, with pounding occipital examples of a potentially fatal iatrogenic disorder that can be pre-
headache and palpitations from both forceful and irregular cipitated by erroneous administration of a single medication dose.
heart beat. Associated with this is a dramatic paroxysmal
rise in blood pressure. In severe cases, death can ensue from The strongest pointer to the diagnosis (Fig. 11.4) is a history
cerebrovascular accident or cardiac failure or arrest. The risk of relevant drug ingestion. In the presence of this, clonus on its
appears greatest with tranylcypromine. own is sufficient to reliably diagnose toxicity (Gillman 2006).

When the mechanism of hypertensive crises was delineated, Three mechanisms are relevant – reuptake inhibition, pre-
attempts were made to diminish the risk by defining the synaptic release and MAO inhibition – any of which can be
pressor amine content of foods, with the aim of removing from accentuated by one of the others. Thus, ST may result from
the diet those with the highest contents. In the US, this led to single drug usage (e.g. overdose) or from a pharmacodynamic
listings of over 700 items (Frazer 1997) and a recommended interaction. Mild symptoms may occur with therapeutic doses
diet not much more palatable than bread and water! Problems of relevant medication but develop more frequently follow-
of estimation contaminated much of this work and it is now ing overdose. Approximately 15% of those taking an SSRI
clear that the dietary restrictions required of patients taking overdose will develop moderate symptoms, the figure with
traditional MAOIs are in fact modest (Baldessarini 1985), venlafaxine being 30%, one possible pointer to explaining the
with only gastronomes of a faddy disposition finding them excess mortality following venlafaxine overdose compared to
burdensome. Clear proscriptions apply to pickled herring, SSRIs. Amitriptyline is associated with only at most mild
toxicity symptoms in overdose and while clomipramine is

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Clinical psychopharmacology CHAPTER 11

Fig. 11.4 Symptoms of serotonin toxicity Neuromuscular hyperactivity Autonomic hyperactivity Mental state
(‘serotonin syndrome’) (After Gillman 2006). Tremor Diaphoresis Anxiety
Clonus Fever Agitation
Tachycardia
Myoclonus Tachypnoea Excitement
Hyperreflexia Mydriasis

± Hypertension

Pyramidal rigidity

Ataxia Hyperthermia Confusion
Seizures Rhabdomyolysis
Ventricular arrhythmias
Respiratory arrest

Death

pharmacologically ‘SSRI-like’, toxicity less frequently follows in over-the-counter cold remedies of so-called ‘indirectly
overdose than with conventional SSRIs. On the other hand, acting sympathomimetics’, which pharmacologically release
overdoses of non-selective/irreversible MAOIs, especially serotonin – including ephedrine, pseudoephedrine, phenylpro-
tranylcypromine, can be associated with serious illness. panolamine and zylometazoline. Information on blanket avoid-
ance of ‘cold cures’ is as important nowadays for those being
Prescribed combinations are what doctors must be aware prescribed non-selective/irreversible MAOIs as dietary advice.
of, the most widely documented being the premature switch
from an SSRI, especially fluoxetine to clomipramine. Because ST represents a spectrum of disorder which at its severest is
of the extremely long half-life of the active metabolite most frequently seen by clinical toxicologists. The presence of
desmethylfluoxetine, a washout of 4–5 weeks is recommended neurological signs – especially clonus – in someone known to
before starting clomipramine after a course of fluoxetine. be prescribed a relevant drug (above) represents a medical
At one time, MAOI/TCA combinations were widely recom- emergency, usually requiring intensive care treatment including
mended but are now shunned, though perhaps without regard intubation, induced paralysis, temperature control and 5HT2a
to the knowledge-base that could vindicate some such regimes. antagonists.
For example, amitriptyline plus MAOI is not associated with
increased risk of ST (Gillman 2006). New generation antidepressants

Severe fatal reactions are nowadays most commonly the con- Structures H
sequence of overdose combinations that produce particularly OC
violent pharmacodynamic responses, such as a non-selective/ NC
irreversible MAOIs plus SSRI (reuptake inhibition) or amphet- O CH3 F3 C CH3
amine (amfetamine) or fenfluramine (both presynaptic seroto- CH2 CH2 CH2 N CH2 CH2 N
nin releasers). It would further be highly risky to combine an CH3
MAOI with MDMA (‘ecstasy’). Methylphenidate, on the other H
hand, is insufficiently effective as a serotonin releaser to raise F Citalopram
concern. Data from the largest prospective study (Hunter Area F Fluoxetine
Toxicology Service: HATS) in Australia suggest that 25% of
overdoses involving combinations of moclobemide with an NHCH3
SSRI result in life-threatening toxicity (Gillman 2006).
O
It is worth remembering that the classification of several
drugs may hide their SSRI/MAOI actions. Non-antidepressants OO
with SSRI activity include sibutramine, tramadol, pethidine CH2
(meperidine), fentanyl, methadone, dextromethorphan, dex-
tropropoxyphene, pentazocine and even chlorpheniramine. N Cl
The potency of opiate analgesics in general in this regard
remains unclear but caution should be exercised with the H Cl
use of opiates in those receiving SSRIs and vice versa. Non- Paroxetine Sertraline
antidepressants with MAOI actions include procarbazine and
the antibacterial linezolid. An additional concern is the use

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There is no unifying chemical structure to drugs considered Table 11.7 Some pharmacokinetic parameters of SSRI
under this heading. Amongst the survivors of the first wave antidepressants
are mianserin, a distant tetracyclic cousin of cyproheptadine,
and trazodone, a triazolopyridine (or phenylpiperazine). Tmax (hours) Protein Half-life Active

The SSRIs can be seen as comprising the second wave. As a binding (%) (hours) metabolites
rule they are novel molecules whose divergent structures help
little towards understanding their pharmacology. A third wave Citalopram 4–6 75 (or 30–36 þ
of drugs has also emerged which selectively inhibit noradrena- Escitalopram
line reuptake (reboxetine), putatively inhibit the reuptake of Fluoxetine less)
both serotonin and noradrenaline (venlafaxine, duloxetine) or Fluvoxamine
enhance serotonergic and noradrenergic transmission via antag- 6–8 94 24–72 þþþ
onist actions at a2-noradrenergic sites pre- and postsynapti- Paroxetine 2–8 77 –
cally, such as mirtazapine, a close structural analogue of Sertraline 15 (single
mianserin (‘6-aza-mianserin’). Nefazodone, also a phenylpiper- 2–8 95 dosing) –
azine with complex receptor antagonist properties in addition 6–8 99 17–22 (multiple þ
to selective actions on serotonin reuptake, can be hepatotoxic dosing)
and was withdrawn in Europe in 2003. Escitalopram is a puri-
fied preparation of the active isomer of citalopram, advantage 20
supposedly resting on modifications to pharmacokinetics.
As with ‘paliperidone’, it must be doubtful whether these are 25
sufficient to consider this a ‘different’ compound.
disproportionately large increases in blood levels (Preskorn
While these ‘classifications’ have some basis in pharma- 1993). In the case of fluvoxamine and paroxetine, metabolism
cology, they often advance the cause of marketing more than does not appear to result in active metabolites. With the others
science. It may be commercially sensible to promote venlafax- it does, though the contribution these make to efficacy is not
ine as different from the SSRIs but at the lower doses most uniform. Fluoxetine’s major metabolite, desmethylfluoxetine
frequently recommended, it is probably just that! The same (‘norfluoxetine’), is roughly equipotent in relation to serotonin
is probably true of duloxetine. Current evidence supports reuptake inhibition as the parent but its real importance lies
only clomipramine as being both a significant serotonin and in its exceptionally long elimination half-life (7–15 days).
noradrenaline uptake inhibitor at therapeutic doses (Gillman Metabolic parameters may be extended in those with hepatic
2007). For marketing purposes, bupropion (licensed in the disease. Desmethylfluoxetine has a major impact on clinical
UK as an aid to smoking cessation but as an antidepressant in action and on treatment decisions, especially following dis-
the USA) stands out as a ‘dopamine reuptake inhibitor’, continuation. The mono- and di-methylated metabolites of
obscuring the fact that the actions of its major metabolite on citralopram are likewise serotonin reuptake inhibitors though
noradrenergic function may be more clinically relevant. are respectively 4 and 13 times less potent than the parent
(Boyer & Feighner 1991). Desmethylcitalopram is however
Pharmacokinetics considerably more potent than its parent in inhibiting
noradrenaline reuptake. The clinical impact of these in vitro
Mianserin is rapidly absorbed and subject to extensive first- findings is likely to be modified by the fact that both metabo-
pass effects. Its bioavailability is less than 30%. Time to lites penetrate the brain poorly and although opinions differ,
peak is in the region of 3 hours and its half-life is between it appears they make little contribution to the therapeutic pack-
10 and 20 hours, though is much extended in the elderly. age. Citralopram’s half-life is extended in the elderly. The
It is completely metabolised and some products, such as primary metabolite of sertraline, desmethylsertraline, is 5–
desmethylmianserin, are weakly active. 10 times weaker as a serotonin reuptake inhibitor than the par-
ent. Its elimination half-life however is, at over 60 hours, some
Trazodone is rapidly absorbed (Tmax ¼ 1–2 hours) and two and a half times that of sertraline, and while in the elderly
prone to first-pass effects, though 60–80% reaches the sys- this variable is unchanged for sertraline, the half-life of the
temic circulation. First-pass metabolism may be saturable metabolite is prolonged. For most clinical scenarios it seems
and plasma levels may follow non-linear pharmacokinetics. unlikely that desmethylsertraline contributes to the therapeutic
Half-life is, for an antidepressant, relatively short at 5–9 hours effect, though there may be some clinical effects in the elderly.
and excretion is mainly renal. A major metabolite of trazodone,
m-chlorophenylpiperazine (m-CPP), has anxiogenic properties It can be appreciated that for some members of this group
which counter the sedative ones of the parent and may pro- steady state can take some time to achieve – citalopram up
duce clinical effects in patients who attain high blood levels to a week, fluoxetine 10 days to 3 weeks and for norfluoxetine
(Preskorn 1993). anything from 4 to 8 weeks.

The main SSRIs are particularly distinguished by variable Venlafaxine is presented as a racemic mix of two active
pharmacokinetics (Table 11.7). All are well, if slowly, enantiomers. It is readily absorbed with Tmax values in the
absorbed and with fluoxetine may be delayed further by food range of 2–3 hours and first-pass effects are substantial.
(Goodnick 1991). Likewise all are extensively metabolised. Protein binding is low compared to other antidepressants
Both fluoxetine and paroxetine inhibit their own metabolism, (<30%). Its half-life is also short (approximately 5 hours)
so show non-linear kinetics, with increasing doses producing but that of its major metabolite, O-desmethylvenlafaxine,

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Clinical psychopharmacology CHAPTER 11

which is active, is about twice that of the parent. Excretion is and is postulated to work by enhancing noradrenergic transmis-
almost exclusively renal. sion which is associated with a parallel increase in serotonergic
function.
Duloxetine is well absorbed though this may be delayed
by food. Cmax is unaffected. Tmax is on average 6 hours SSRIs on the other hand are set apart by having little or no
(up to 10 hours after food). The drug is >90% bound to both affinity for neurotransmitter receptors. Paroxetine has moder-
albumen and a1-acid glycoprotein. Elimination half-life, at ate affinity for muscarinic receptors with which sertraline,
12 hours on average, is short for once daily dosing. It is exten- fluoxetine and citalopram also interact detectably, though
sively metabolised with excretion mainly ( 70%) urinary. weakly. Sertraline also interacts with a1-adrenoreceptors and
fluvoxamine with dopamine D2 receptors. This, however,
Reboxetine is structurally related to both fluoxetine and the represents a fairly inert binding profile and one that contri-
now withdrawn viloxazine. It too is presented as a racemic butes little to adverse tolerability. Venlafaxine appears to be
mixture of two enantiomers which appear to have similar a pure reuptake inhibitor with no affinity for the commonly
kinetics. It is rapidly absorbed (Tmax 2 hours) with an elim- studied receptor subtypes (Richelson 1996), while trazodone
ination half-life is in the region of 13 hours. It is highly protein is a fairly potent a1 antagonist.
bound, mainly to a1-glycoprotein. Metabolites are mostly
excreted in the urine though some may also be excreted in There are two problems trying to fit these largely in vitro
faeces. Unlike most antidepressants, it appears to have little data into a coherent theory of efficacy: (1) raising intrasynaptic
interaction with the cytochrome P450 system (Dostert et al transmitter levels is only the proximate event precipitating a
1997). This, together with its lack of action on serotonergic complex series of changes ‘down the line’ which extend
systems or against MAO, suggests in theory that combined beyond receptors to gene events modifying expression of
use may be particularly uncomplicated. receptor and other proteins; and (2) in vitro data, largely ani-
mal based, cannot account for receptor and other changes
Mirtazapine is again an enantiomeric ‘composite’ ((R)-(À) inherent to and underlying depressive illness per se.
and (S)-(þ)) with cytochrome P450 polymorphisms effecting
only the (S)-(þ) enantiomer. Absorption is only minimally Serotonergic neurones arising from the raphe nucleus are
dependent on gastric contents, with Tmax at around 2 hours. widely dispersed in the brain, their function modified in a
Half-life, which varies from 20 to 40 hours, is comfortably complex way by a series of surface receptors for serotonin
suitable for once daily dosing. It is 80–85% protein bound itself (autoreceptors) and noradrenaline (heteroreceptors),
with 50% bioavailability largely due to first-pass effects. most of whose actions are inhibitory (Fig. 11.5). Autorecep-
It does not modify its own metabolism, and interactions with tors on cell bodies (somatodendritic (5HT1a) autoreceptors)
other drugs are rare and clinically insignificant. inhibit action potential firing and presynaptic 5HT1b/d
(depending on species) autoreceptors inhibit synthesis and
Pharmacodynamics release of serotonin, while presynaptic a2-noradrenergic het-
eroreceptors, activated by noradrenaline, also inhibit serotonin
Mode of action release. Somatodendritic a1-noradrenergic heteroreceptors, on
the other hand, stimulate the neuron when activated by
Although developed on ideas emerging from the Biogenic noradrenaline. Even this may be a simplification as over a
Amine Hypothesis, the mechanism(s) whereby these newer dozen subtypes of serotonin receptor have been identified
antidepressants achieve therapeutic efficacy remain(s) unclear. using cloning techniques.

Reuptake inhibition is achieved by blockade of respective Animal studies suggest that initial blockade of reuptake
transporter proteins for serotonin, noradrenaline and dopa- mechanisms results in only modest increases in intrasynaptic
mine. SSRIs selectively block SERT thereby impeding the amine levels. This is because these changes trigger negative
flow of serotonin into the presynaptic bulb (Goodwin 1996 ; feedback loops designed to prevent accumulation of excessive
Frazer 1997). This selectivity is, however, relative and all serotonin. However, with long-term exposure, desensitisation
currently available drugs to some extent also block NET, and downregulation of the inhibitory somatodendritic and pre-
though for the majority this action is weak. Citalopram is by synaptic serotonin autoreceptors results in increased neuronal
far the most serotonergically selective of the current drugs firing (somatodendritic autoreceptors), and increased seroto-
but paroxetine is the most potent (Richelson 1996). Sertraline nin synthesis and release (presynaptic autoreceptor mechan-
is the only drug which significantly blocks DAT, being equiva- isms). Thus, desensitisation and downregulation act in a
lent to methylphenidate (Richelson 2001). Venlafaxine, sophisticated way to impair – though not abolish – the cell’s
marketed as a ‘serotonin and noradrenaline’ reuptake inhibitor natural ‘defence’ in the form of its negative feedback loops,
on the basis of animal data is, in humans, best considered an thereby increasing intrasynaptic serotonin levels that are sus-
SSRI at normal therapeutic doses as below 200 mg per day tained in the presence of on-going reuptake inhibition (Richelson
its potency for blocking NET is very low (Richelson 2001). 2001). Although persuasive, not all data support this model,
It is only at high doses ( 375 mg/day) that blockade of especially in vivo brain imaging studies in patients with major
NET becomes significant. Reboxetine is a selective reuptake depressive disorders.
inhibitor of noradrenaline, though is substantially less potent
in this regard than desipramine (Richelson 2001). Receptor changes mediate not only cell firing but the
actions of ‘second messengers’ which modify intracellular
Mirtazapine is unusual as it does not block amine trans- chemistry. An emerging stream of research seeks to explore
porters to any significant degree but has a complex receptor- mechanisms of antidepressant action in terms of these intra-
binding profile involving antagonism at especially presynaptic cellular reactions, especially gene-mediated events. Although
a2-adrenoceptors and 5HT (5HT2a, 5HT2c and 5HT3) sites

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a1 adrenergic was estimated at between 1:2000 and 1:4000 exposures
heteroreceptors (Blackwell & Simon 1988). These data remained controversial
and in a unique move, the manufacturer went to Court to pre-
+ vent withdrawal of the drug in the UK. Mianserin requires
close haematological monitoring for at least the first 3 months
Somatodendritic region 5HT1A of use, particularly in the elderly, something which limits
Raphe nucleus autoreceptors its value in the population in whom, because of its lack of
cardiotoxicity, it may otherwise be most useful.
–
Trazodone produces marked sedation and lethargy, and in
Presynaptic Presynaptic some pharmacological models, has significant antianxiety
5HT1B/1D effects. As a result, it has achieved wide popularity, despite
a2 adrenergic receptors being a relatively ineffective antidepressant. Again, it can be
heteroreceptors associated with dry mouth, blurred vision, etc. in the absence
(species specific) of cholinergic antagonist properties, probably relating to its
potent a1-antagonist actions. This may also be the mechanism
–– behind a relatively high prevalence of priapism (Warner et al
5HT 1987), though this does not correlate with antiadrenergic
actions in general. Priapism may require surgical intervention,
Terminal region Postsynaptic 5HT Postsynaptic with impotence a not infrequent outcome so male patients
Cortex, hippocampus etc. 5HT1A transporter 5HT2A should be advised to stop the drug at the first signs of any
increase in frequency/duration of erections and seek medical
receptors receptors advice. Trazodone appears to have minimal effects on cardiac
function at therapeutic doses.
Fig. 11.5 Raphe nucleus serotonergic neuron; schematic
representation of control systems (after Richelson 2001). Contrary to clinical lore, SSRIs are not free from adverse
effects but share a profile fairly characteristic of the group,
it is not yet possible to link these directly to clinical effects, though different from other antidepressants (Boyer &
targets of interest include effects on BDNF, metabotropic Feighner 1996). They all possess an increased liability to gas-
glutamate receptors and glucocorticoid receptors in certain trointestinal upset, with nausea the commonest adverse effect
brain areas, including hippocampus and frontal cortex. (2–35%) and sufficiently severe to force discontinuation in
5–8% of patients. Abdominal discomfort/pain, frank vomiting
Adverse (non-target) effects and diarrhoea also occur with greater frequency than other
antidepressants. These effects develop early in exposure,
Mianserin is strongly sedative and, despite having no anti- before the establishment of steady state, and tend to ease as
cholinergic actions, is associated with dry mouth and a non- this is reached and probably reflect ‘early synaptic events’
significant increase in pulse rate. It can also promote fits but (above). Dry mouth and constipation may be more frequent
the risk is if anything lower than with tricyclics. Its major with paroxetine, reflecting its weak receptor binding profile.
advantage is that it has very little direct effect on cardiac func- A further common group effect is headache, usually occipital
tion. Prolonged PR interval and decreased T-wave amplitude in situation and pounding in quality. This tends to increase in
are inconsistent ECG findings with chronic treatment and frequency with continued exposure (Frazer 1997).
there is even the suggestion of enhanced cardiac func-
tion (non-significant), as shown by an increase in the ejection While these drugs cannot be conveniently considered ‘stim-
fraction (Kopera 1980). ulant’ or ‘non-stimulant’, fluoxetine appears to be particularly
associated with nervousness, anxiety and agitation which is
In 1979, blood dyscrasias were reported with mianserin, likely to carry over into insomnia and reduced quality of sleep,
including neutropenia/leukopenia and agranulocytosis with even with the drug taken in the morning. The others, espe-
associated fatalities. An excess of cases – and deaths – cially fluvoxamine and paroxetine, seem less likely to produce
occurred in the over 65s. The overall rate of agranulocytosis these effects and may indeed be associated with sedation and
daytime fatigue.

It is not clear precisely where this ‘restless’ state lies in rela-
tion to akathisia but, as with tricyclics, it is phenomenologi-
cally very similar. SSRIs also possess the potential to cause
acute dystonic reactions and rarely parkinsonism, which are
identical to those movement disorders caused by standard
antipsychotics (Owens 1999). The prevalence is unknown
but likely to be very low. SSRIs have also been reported to
exacerbate tardive movement disorders.

The frequency of sexual dysfunction (Lane 1997) with
SSRIs is hard to specify with figures differing between studies
but abnormal ejaculation/orgasm, anorgasmia, impotence and
decreased libido are common with this group, more so than

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with tricyclics. One review suggested that 34% of patients on 2008). This is a replicated finding and, surprisingly, places
fluoxetine reported sexual difficulties – 10% with reduced SSRIs above other groups of psychotropics in terms of fracture
libido, 13% decreased responsiveness and 11% both (Jacobsen risk. The mechanism is unknown but risk correlates specifi-
1992). There may be differences in prevalence with different cally with SERT blockade potential and not inhibition of other
compounds, though this cannot be concluded with certainty. systems (Vestergaard et al 2008) so is unlikely to be secondary
Furthermore, the pattern may differ across drugs with some, to obesity, reduced mobility, etc. The relationship is strongest
such as sertraline, causing more sexual dysfunction in males in the elderly and dose-dependent. With evidence for higher
than females (Frazer 1997). doses producing enhanced efficacy being controversial, espe-
cially in the elderly, this is an important factor for clinicians
SSRIs have different effects on weight than traditional anti- to balance in considering dose escalations.
depressants (Boyer & Feighner 1996). Fluoxetine and sertra-
line have anorectic effects and are associated with a tendency The other new generation drugs appear to share the rela-
to weight loss, especially in higher doses. On the other hand, tively favourable adverse effect profile of the SSRIs. Little
patients on long-term paroxetine tend to gain somewhat. The in the way of drowsiness or sedation has been reported with
others appear more neutral in this regard, at least in standard venlafaxine, in line with its minimal receptor binding, and
doses. Absolute declines in weight during treatment depend early nausea appears for the most part to resolve rapidly. How-
on initial body weight, with greater loss in more obese ever, it may cause a dose-related increase in blood pressure in
patients, though there is also a suggestion (unconfirmed) that 5–10% of patients, though this appears to be transient in about
the elderly may be more liable. half (Frazer 1997). Fits were mentioned above. Effects on
weight are inconsistent, with early tendency to lose weight
This group also exerts virtually no effects on cardiac con- being followed at 6–8 months by a slight increase, which may
duction and they are not dysrhythmogenic (Coupland et al of course relate more to well-being than adverse actions. As
1997). However, they can produce bradycardia which may with sertraline, sexual dysfunction may be more evident in
be clinically significant and symptomatic, especially in the males. Mirtazapine’s receptor binding profile would allow
elderly and those with certain forms of pre-existing heart the assumption that it may be associated with less in the way
disease. of nausea (5HT3 antagonism) but more in the way of day-time
fatigue and impaired motor performance (H1 antagonism)
A further uncommon adverse effect concerns the develop- than the majority of the newer drugs. Weight gain can be
ment of a haemorrhagic diathesis resulting in bruising and considerable with this drug.
frank haematomata. This may be as a result of inhibition of
platelet serotonin uptake and is more likely to be associated ‘Suicidality’
with laboratory abnormalities in platelet aggregation tests than
in bleeding times. There is, however, an approximately three- The issue of concern in recent years has been the putative asso-
fold increased risk of upper GI bleeding in those on SSRIs that ciation between SSRI use and ‘suicidality’, especially in young
increases substantially if non-steroidal anti-inflammatory drugs people, an issue about which the media set a trenchant tone.
are also being taken (relative risk: 15.6, 6.6 to 36.6). A similar
if less dramatic increase is also seen with aspirin (7.2, 3.1 to The issue is complex. ‘Suicidality’ is a blanket term used
17.1) (de Abajo et al 1999). Risks are reduced with coinci- in standardised assessments of new drugs covering several
dental use of acid-suppressing agents (de Abajo & Garcia- phenomena from ideation (self-harming, passive and active
Rodriguez 2008). SSRIs (including venlafaxine) should be suicidal thoughts) to acts (both injurious and completed). It
used with caution in those with a history of upper GI bleeds is thus an imprecise pointer to specific issues. Furthermore,
and especially in those taking NSAIDs and aspirin, in whom it has been standard teaching since the introduction of antide-
an alternative should be sought. pressants that, especially early in exposure, the risk of suicidal
thinking and acts increases in some individuals. This was men-
Like all antidepressants, SSRIs have the potential to lower tioned in the 1960 edition of the standard UK text of the time
seizure threshold though the risk of seizures is very low. (Mayer-Gross, Slater & Roth). The suggestion was that since
Fluvoxamine and venlafaxine appear to impart a slightly retardation improved before mood and thought content,
greater risk of fits, though with an incidence of around 0.2% patients became more ‘motivated’ to act on ideas of self-harm.
or less it remains slight. Prolonged fit duration has been An alternative is simply that early synaptic events create a
reported in fluoxetine-treated patients receiving ECT and the degree of dysphoric restlessness that adds to, rather than
combination is best avoided. Bupropion, with a dose-related releases, core depressive symptomatology. Formal evidence
increase averaging 0.6–1.0%, imparts the greatest risk. was however lacking and no data existed for comparison with
newer antidepressants, especially paroxetine, the drug into
One factor in seizure risk can be hyponatraemia which may which the UK media sank its teeth! Both the UK Committee
develop with or without inappropriate ADH secretion in those on Safety of Medicines and the FDA addressed the issue, the
receiving SSRIs. This risk is greatest in the elderly when it is former in a re-analysis of all data from drug trials for new com-
associated with coincidental physical illness and drug usage pounds submitted for regulatory approval and the latter, in
(Kirchner et al 1998). It is an early development (usually addition, by reviewing 372 RCTs for antidepressants in general
within the first 3 weeks) and should be sought in anyone (Laughren 2007).
developing confusion and fits. Skin rashes have been reported
and although very rare should prompt a change of regime in The FDAs pooled analysis supports long-standing clinical
view of the possibility that this presages an evolving vasculitis. impression – with a twist. Antidepressant treatment of major
depression is associated with a significantly increased risk of
Recent evidence points to approximately a 50% increased
risk of osteoporotic fractures with SSRI use (Bolton et al

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treatment-emergent suicidal ideation or suicidal behaviour – Toxicity of antidepressants in overdose
but only in young adults under 25 years (OR ¼ 1.88, CI
1.25–2.84). The risk in older adults is non-significantly For many years much of what was known of the clinical
decreased (OR ¼ 0.85, CI 0.67–1.07) (Laughren 2007). This pharmacology of tricyclics was based on overdoses which are
general pattern has been replicated, the particular risk in young unrepresentative of their actions in therapeutic doses. Even
people residing with females though not with duration of today, the toxicity of antidepressants remains largely the
treatment (Olfson & Marcus 2008). Both the CSM and toxicity of the tricyclics.
FDA regulatory reviews of SSRIs indicated a similar risk of
‘suicidality’ restricted to ‘young people’ (defined up to age The pharmacokinetic parameters of tricyclics change fol-
18 by CSM). lowing overdose, the major factor underlying their toxicity
(Jarvis 1991). Firstly, absorption is substantially delayed and
Thus, with major depressive disorder antidepressant treat- it is common at postmortem to find drug residues in the sto-
ment in general is associated with an increased risk of seriously machs of patients dying from tricyclic overdose. This probably
detrimental thoughts and actions but that this effect is only results from anticholinergic effects. Furthermore, considerable
statistically significant in young people. In older adults, antide- enterohepatic recirculation takes place, contributing to the
pressants operate protectively, reducing the risk of ‘suicidality’. maintenance of high blood levels.
In formulating a risk:benefit appraisal, UK authorities con-
cluded that of the new drugs, only fluoxetine efficacy At high blood levels, tricyclics shift from first order to zero
data were sufficiently robust to balance this risk and justify a order kinetics – i.e. the amount metabolised is fixed rather than
positive opinion in those 18 or under. This is the only new proportionate. This results from saturation of hepatic enzymes,
antidepressant to receive regulatory approval for this age group. specifically rate-limiting hydroxylation pathways (Jarvis 1991).
Clinicians in adult practice should not, however, be compla- Thus, high blood levels sustain themselves by delayed absorp-
cent. There is evidence that in sponsored trials in adults, non- tion, enterohepatic circulation and saturated metabolism,
fatal end points are under-recorded (Gunnell et al 2005) and thereby prolonging the half-life by as much as two-fold.
it is prudent when treating any patient – regardless of age – to
recall the advice of those whose expertise lay not in statistics Furthermore, metabolism is dependent on cardiac output, so
but in clinical practice and view exposure to antidepressants any compromise in this will further impede metabolism. At high
as having the potential to precipitate negative events, something levels, tricyclics are profoundly cardiotoxic, mainly as a result of
about which patients should be informed. potent actions in delaying ventricular conduction time, resulting
in QT prolongation, QRS elongation and ventricular premature
‘Suicidality’ remains a relatively rare occurrence with anti- beats, which may progress to ventricular tachyarrhythmias that
depressant exposure. The mechanism (despite above sugges- can in turn be associated with strikingly inefficient pump action.
tions) is unknown. It is not clear whether the risk is greater In addition, a clinically unimportant positive inotropic action at
with new antidepressants than TCAs though from the broad therapeutic levels inverts to a negative action at high levels,
clinical profiles of both groups it is likely that patients will which further contributes to output failure.
be more aware of the phenomenon with SSRIs because, unlike
TCAs, most newer drugs lack clinically significant sedative Pulmonary gas exchange is seriously impaired because of the
properties, and as we have seen may promote ‘arousal’. This central depressant effect common to the group, but also from
may underlie resurgence of the issue. local alveolar damage (Roy et al 1989). The consequence is acid-
aemia. Falls in pH are associated with reduction in the amount of
One way of evaluating the impact of adverse experiences is drug that is protein bound and hence the amount of pharmacody-
from discontinuation rates in comparative clinical trials. In two namically active free drug increases. Because such a large propor-
large meta-analyses of published studies (Montgomery et al tion of tricyclic is protein bound, very slight reductions in binding
1994; Anderson and Tomenson 1995), fewer patients receiv- greatly increase the percentage of free drug. For example, a
ing SSRIs (14.9% and 14.4%, respectively) than tricyclics reduction in binding from 95% to 93% could theoretically
(19% and 18.8%, respectively) dropped out. In both instances increase the free fraction by 50% (Jarvis 1991).
these differences were statistically significant but far from
dramatic and are unlikely to represent differences that are The major clinical manifestations of tricyclic poisoning
clinically significant (Anderson & Tomenson 1995). A further are signs of anticholinergic toxicity and CNS and cardiovascu-
meta-analysis concluded that of every 100 patients treated lar depression. Patients appear flushed and hot, with widely
with a tricyclic, 31 would be likely to drop out of treatment, dilated pupils and peripheral tremulousness. Sedation and
while the comparable figure for those on an SSRI would be drowsiness, combined with motor signs of disco-ordination,
28 (Hotopf et al 1997). Other studies have found no differ- progress to frank confusion as a prelude to coma. Breathing
ences in drop-out rates (Trindade et al 1998). Thus, contrary becomes rapid and shallow and tachycardia of sinus or supra-
to established perception, in terms of overall intrusive non- ventricular type is usually evident. Cardiac irregularities may
target actions, there is not much to choose between TCAs also be apparent. Around 4–8% of patients may fit or go into
and newer antidepressants. The pattern is clearly different status. While both maprotiline and amoxepine have been
however (Trindade et al 1998) and it might be that one factor withdrawn in the UK, these are available in other markets
in the success of newer drugs is simply that, when present, and can cause serious complications following overdose – a
TCA non-target actions are commented on more readily. seizure risk of up to 36% and permanent neurological damage
The real advantage of new drugs lies less with tolerability in 2% with maprotiline as vehicle (Knudsen & Heath 1984)
than safety. and a 10% risk of renal failure with amoxapine (Jennings
et al 1983).

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For the reasons mentioned, it is important to attempt literature, and then only anecdotally. A similar phenomenon
gastric lavage in tricyclic overdose, even if there has been a was noted with MAOIs. The issue has however received
delay in discovering the individual. Otherwise, treatment is greater prominence in connection with SSRIs (Lejoyeux &
essentially supportive. In view of the risks of antiarrhythmic Ades 1997). In this context, the term ‘discontinuation’ has
drugs in the context of antiarrhythmic overdose, and the gained favour for reasons that, although elegantly argued, are
fact that respiratory depression may require intubation, such unconvincing. It is beyond our present focus to review the
supportive measures are for medical specialists. Even when meanings of ‘dependency’ and the implications of rebound
the clinical situation appears stable, it is important to be symptomatology on cessation of regular drug ingestion, on
wary of overzealous attempts by medical colleagues to return which there is little expert consensus. From our point of view
overdose patients to psychiatric units quickly. As knowledge – and in line with public understanding – the development of
of the pharmacokinetics would suggest, half-lives – and risk symptomatology on reduction or cessation of a drug is a reflec-
periods – will extend for some days after a serious overdose. tion of the key role that compound played in nervous system
functioning and, regardless of theoretical implications, repre-
Antidepressants account for 20% of fatal drug poisonings sents withdrawal of that function. Such symptomatology is
in England and Wales, with TCAs involved in up to 90% of therefore intuitively and, until proven otherwise, scientifically
cases (Morgan et al 2004). They therefore occupy a unique ‘withdrawal’ in nature. Attempts to term it something else are
place in the ‘hierarchy’ of risk for completed self-harm by at best ill-founded, at worst deceptive.
overdose. Dosulepin holds a particularly unenviable position,
being involved in 44% of fatalities between 1993 and 2002, Sudden cessation of protracted, and especially high-dose,
while amitriptyline was implicated in 30% (Morgan et al tricyclic regimes can be associated after a day or two with
2004). Comparatively, 48.5 deaths/million prescriptions were the development of symptomatology that can be considered
attributable to dosulepin and 28 to each of amitriptyline and in five categories (Dilsaver et al 1987): (1) somatic, including
imipramine. These represent only slight falls for amitriptyline/ nausea, vomiting, diarrhoea, sweating and malaise; (2) sleep,
imipramine over the previous decade while dosulepin has including poor quality, decreased duration and vivid anxiety-
not altered (cf. Montgomery et al 1989). Dosulepin may laden dreams; (3) movement disorders, especially akathisia
have unique inherent toxicity but the favour it once found in and parkinsonian-type symptoms; (4) ‘activation’ symptoms,
primary care, where diagnostic and monitoring issues came comprising mania/hypomania, anxiety, panic attacks and frank
into play, may be relevant. The inherent sedative properties clouding; and (5) cardiac arrhythmias. Despite reported pre-
of these compounds is also a major element behind these data, valence figures ranging from 16% to 100%, these are probably
for while cardiac effects ensue with overdose, the major con- uncommon in a degree that merits clinical attention. Preva-
sequence of the above pharmacokinetic changes is serious lence may be greater with tertiary amine compounds than
respiratory depression. secondary ones, or alternatively risk may relate more to the
potency of the drug’s cholinergic antagonist properties (as with
It is with safety that the advantage of newer antidepres- antipsychotics), though these remain proposals.
sants lies. It remains unclear just how great the risk of com-
pleted suicide is with SSRIs as they are mostly involved in In line with conventional pharmacological actions in drugs
‘polydrug toxicities’, where SSRIs are used in combination(s) of short half-life, withdrawal symptoms following MAOI
(Cheeta et al 2004). However, recent data for England and treatment can be severe, especially with tranylcypromine
Wales indicate they were implicated in only 71 fatalities over (Halle & Dilsaver 1993), and include ‘rebound’ depression or
a decade, the corresponding figure for all TCAs being 2787 manic/hypomanic symptomatology with agitation, irritability,
(Morgan et al 2004). Deaths per million prescriptions for SSRIs insomnia, myoclonic jerks and frank confusion/delirium.
are, for most compounds, <1 though for citalpram it is 1.9, a
figure still unexplained. Venlafaxine seems to occupy an inter- The re-named ‘discontinuation syndrome’ associated with
mediate position (deaths/million prescriptions 8.5) perhaps stopping SSRIs is slightly different (Haddad 1997). It usually
related to cardiac or seizure effects following overdose. emerges within 24 hours and comprises anxiety and irritabil-
ity, alteration in sleep and gastrointestinal symptoms with, in
Thus, the major medical advantage of new generation addition, flu-like symptoms of coryza, myalgia and shaking
antidepressants lies with their safety in overdose (Boyer & chills. Particular features include ‘dizziness’, consisting of both
Feighner 1996), resulting in a fundamental shift in the risk: true movement-sensitive vertigo and a ‘floating’, ‘spaced out’
benefit ratio for antidepressant treatment. The consequence sensation akin to mild inebriation, ataxia and burning shock-
is that more individuals than ever are receiving antidepressant like sensations (cf. benzodiazepines), tingling or hypoaesthe-
treatment which either illustrates a vast and hitherto unmet sias. It has also been suggested that aggressive and impulsive
need, or sloppy diagnostics and a rush to medicalise all life’s behaviour are further novel SSRI ‘discontinuation’ symptoms
woes, issues beyond the remit of the present chapter. but may represent coincidental phenomenology. These fea-
tures can develop with all members of the group, but seem
Antidepressant withdrawal most associated with compounds of shorter half-life. Thus,
(‘discontinuation’) syndromes they appear relatively uncommon following cessation of fluox-
etine, but may affect up to one-third of those coming off
It has been known since 1959 that sudden cessation of tri- paroxetine (Haddad 1997). A similar situation has been
cyclics could be associated with development of a withdrawal described after sudden stopping of venlafaxine.
syndrome, though this was rarely commented on in the
Withdrawal syndromes can sometimes be dramatic, espe-
cially when patients stop medication without advice. This is

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particularly the case with the traditional MAOIs. Although 1996) and in-patients (Anderson 2000) do better with TCAs.
they are overwhelmingly brief and self-limiting events, lasting The suggestion therefore is that on these parameters of ‘sever-
only 2 or 3 days, they may be more protracted with the older ity’, TCAs have the edge. From a clinical perspective, this is a
drugs. Most do not, however, require specific intervention. conclusion the present chapter would endorse. Venlafaxine on
They do nonetheless emphasise the importance of gradual the other hand, may veer more towards the TCAs in terms of
tapering of antidepressant regimes over days or preferably a somewhat enhanced efficacy (Stahl et al 2002). Mirtazapine,
weeks, something made more problematic with the fixed trazodone and moclobemide are weak and limited anti-
dosing schedules of some newer agents. depressants but have symptomatic value in other domains
(e.g. anxiety).
This is an issue much underestimated by doctors, both in its
potential frequency and impact. In view of increasing patient Strategies
awareness – and web-generated misunderstandings – it would
be prudent for doctors to inform patients of the possibility of The argument that favours newer antidepressants over tri-
withdrawal symptomatology. cyclics is presented in stark terms that over-simplify a com-
plex balance of choices. As with antipsychotics (above),
Therapeutics antidepressant choices, especially by the specialist, should be
based on an individualised risk:benefit appraisal. Because of
Indications (Box 11.10) the suggestion, clinical and evidential, that certain patients
may respond preferentially to TCAs, unlike with antipsycho-
Even after two decades, debate continues about the relative tics, a ‘benefit’ variable should be considered in treatment
place of different antidepressant types in clinical practice. planning – including illness factors such as severity, clinical
This not only reflects how trial data are interpreted but also classification, treatment setting, etc.
the diversity of clinical contexts in which antidepressants are
utilised – different age groups, treatment settings, etc., not just Tolerability, however, remains a major factor in treatment
‘types’ of depression. Overall, trial data suggest comparable planning. By the parameter of ‘trial drop-outs’, the position
efficacy for all antidepressants in major depression (Frazer in favour of SSRIs is less clear-cut than clinical ‘lore’ suggests.
1997; Anderson 2000). There is however evidence that com- Nonetheless, in routine practice it may be that certain types
pared to SSRIs, those with traditional ‘melancholia’ (Perry of tricyclic-related adverse effects (e.g. anticholinergic) are
simply more unpleasant and although not leading directly to
Box 11.10 refusal, may impair quality of life. Contrariwise, many patients
with major depressive disorders are deeply distressed by anxi-
Indications for antidepressants ety/agitation and insomnia, features to which non-target TCA
actions are well suited. It might be argued that poor tricyclic
• Treatment of episodes of major depression of moderate-severe compliance emanates as much from unsophisticated prescrib-
degree especially with maximal ‘biological’ loading and not ing as from problems inherent to the group. By skilful appli-
clearly secondary to other conditions (caution with bipolar cation of the data above, tricyclics can be effectively and
depressions in view of risk of precipitating hypomania/mania -– acceptably utilized.
risk : TCAs > SSRIs)
Compliance is a further consideration. New drugs, by
• Prevention of relapse in recurrent non-bipolar depressions offering convenient, usually single tablet/once daily regimes
• Anxiety states including obsessive-compulsive disorder are inherently easier for patients to maintain. However, ‘fine-
tuning’ of dosages and of increments/reductions is limited.
(especially SSRIs and clomipramine) Newer drugs require no life-style (e.g. dietary) restrictions.
• Eating disorders – especially bulimia nervosa (fluoxetine in high
A strong argument in favour of new drugs is that, although
dose) costing more in themselves, they are more cost-effective in
• ‘Atypical’ (or ‘Columbia’) depression – a heterogeneous the long run. Considerable effort has gone into justifying this
argument but it is clear that the outcome of such analyses
combination of biological symptomatology (hyperphagia, depends on the information fed into analytical models and
hypersomnia, profound fatigue (‘leaden paralysis’)) and analytical such analyses have produced contrary conclusions (Hotopf
concepts (narcissism, romantic preoccupation, disappointment et al 1996).
in relationships (‘hysteroid dysphoria’)) that reportedly respond
better to MAOIs (phenlezine) than TCAs (Quitkin et al 1993) The argument on which there is ‘no contest’ is safety.
• Post-traumatic stress disorder (in association with psychological Although the risk of pharmacodynamic interactions with
interventions) MAOIs is small – especially when physicians provide ade-
• Attention deficit disorder with hyperactivity in children (strongest quate, accurate information and comprehensive monitoring –
evidence to date relates to imipramine) these effects can be serious and since they are not applicable
• Pain syndromes: TCAs. Approximately 30% of patients with to other antidepressants, MAOIs must remain third-line
chronic pain from diverse causes such as diabetic neuropathy, treatments. The greatest safety issue, however, is following
post-herpetic neuralgia and atypical facial pain will experience overdose, a parameter which also holds MAOIs to a third-line
>50% symptom reduction – overall efficacy comparable to position. All newer antidepressants have a strikingly more
anticonvulsants (McQuay et al 1996) favourable toxicity profile than tricyclics, of which dosulepin,
• Enuresis in children (especially imipramine) amitriptyline and desipramine appear particularly associated
• Premature ejaculation (SSRIs)

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Clinical psychopharmacology CHAPTER 11

with fatal overdose outcomes (Cassidy & Henry 1987). The Box 11.11
question then is the magnitude of the problem, some arguing
the contribution is substantial (Henry 1996), others that the Principles of antidepressant use (depressive episodes)
data are open to interpretation (Hotopf et al 1996). Those
deaths per year attributable to TCAs (250–300 in England • Diagnostic precision:
and Wales) are potentially preventable but data cannot reveal sadness is not the same as depressive illness
the extent to which these represent the outcome of inade- medication is not a panacea for life’s ills
quate treatment – a problem with tricyclic prescribing, Application of operationalised criteria should follow a clinical,
especially in primary care (Beaumont et al 1996) – or other skills-based diagnosis.
factors such as inadequate risk assessment and supervision.
It is, furthermore, not clear how many victims of tricyclic • Assess appropriateness of drug use:
overdose might be saved by side-stepping these drugs, as ‘sub- avoid in mild/moderate depression and borderline personality
stitution’ might merely result in the determined resorting to disorders
other means. The biggest problem with tricyclics is simply that (cf. NICE guidelines 2009b)
a fatal overdose may comprise as little as 10–15 times the
therapeutic dose and 2–3 times the therapeutic blood level, • Risk assessment:
leaving the distressed little room for ‘error’. severity and self-harm assessed independently
evaluate ‘hopelessness’ as strongest pointer to self-harm risk
While antidepressant prescribing choices remain more finely evaluate risk of impulsive as opposed to planned self-harm
balanced than is sometimes made clear, there are situations in (e.g. with comorbidities such as personality disorder)
which new generation antidepressants justify a first-line position:
• ‘Not all non-target actions are adverse’!
• in patients in whom impulsive or planned misuse is an Consider prominence of anxiety/agitation, sleep disturbance and
active or predictable issue; other subjectively distressing symptoms in treatment choices

• in primary care situations where depressive disorders may • Specific antidepressant efficacy is inevitably delayed:
be more amenable and where, by virtue of time constraints, 10–14 days for improvements to start
high levels of support and close monitoring are not feasible; 4–6 weeks to consolidate
Advise patient to avoid premature discontinuation
• in cases of medical complexity such as severe heart disease,
recent CVA or coincidental complex drug regimes; • Patients can tolerate much if they know what to expect:
Discuss broad non-target profile of chosen compound
• in those in whom impaired motor performance may cause
occupational restrictions; • Treatment should be ‘adequate’:
the commonest cause of ‘treatment-resistant depression’ is
• previous tricyclic intolerance; and inadequate dosages, contributing to needless adverse
• the need to cultivate tenuous cooperation by avoiding effects in a context of inadequate therapy
Evidence that dose increases with new drugs increase
unacceptable adverse effects, e.g. a fear of weight gain, etc. likelihood of
improvement is poor but is accepted clinical practice
The elderly present special considerations because, although The therapeutic dose of most TCAs is in the range 150–225 mg/day
for pharmacokinetic and other reasons they are undoubtedly
more susceptible to the riskier adverse effects of tricyclics • Do not persevere indefinitely with failed regimes:
(including a small increased risk of cerebrovascular events), Absent/suboptimal response after 6–8 weeks on an adequate
they may also be more prone to depressions which respond dose — change antidepressant type, not just drug
less favourably to newer drugs.
• Long-term treatment should also be adequate:
Failure of first-line treatments is common in depression, the minimum 6 months before tapered reduction
usual clinical action being to increase doses or switch to an up to 1 year (or longer) in severe, disabling life-threatening or
alternative preparation. There is limited evidence to support recurrent illnesses
either of these options. In those who fail to respond to an
SSRI, switching to another type of antidepressant is associated who identified the sulphate from the mineral, petalite, with
with a statistically significant likelihood of improvement, elemental lithium isolated by electrolysis in 1855. As a highly
though 22 non-responders need to be switched to a non- reactive element, it has found wide commercial application –
SSRI to achieve a single remitter (Papkostas et al 2008). from rubber processing, long-life batteries, strengthening glass
and ceramics, to the construction of nuclear bombs. Only 1%
Principles of antidepressant drug use are outlined in Box 11.11. of annual supplies is devoted to medicinal use.

Mood stabilisers In 1841, Lipowitz recommended lithium salts for gout,
beginning their medical applications. This followed the obser-
Lithium salts vation that in vitro they increased the solubility of urates
but despite half a century of use, this was not an effective
Introduction treatment as very large and toxic doses would have been
required. From 1864, however, lithium was listed in the
Lithium is a silvery-white alkali metal and the lightest of British Pharmacopoeia and the chloride, and especially bro-
all solids, occupying position 3 in the periodic table. It was mide, salts were widely used as hypnotics throughout the lat-
discovered in 1817 by the Swedes, Arfwedson and Berzelius, ter part of the 19th and early 20th centuries. Lithium

265

Companion to Psychiatric Studies

bromide was in addition one of the first compounds regularly accuracy it is not the milligram dosage that is important but
employed as an antianxiety agent. the millimolar concentration. In general, 37 mg of the carbon-
ate salt is equal to 1 mmol of lithium. This has implications for
Reports of toxicity appeared at the end of the 19th century prescribing especially when changing to liquid formulations.
but despite this, in the 1940s unmonitored lithium chloride
was enthusiastically endorsed as a salt substitute in the low Pharmacokinetics
sodium diets then fashionable for the management of hyper-
tension. In early 1949, reports of fatalities in the United States In terms of pharmacokinetics, slight differences exist between
led the FDA to ban medicinal use of lithium, a perception of lithium formulations, knowledge of which is helpful in maxi-
hazard that delayed its reintroduction as a psychotropic agent mising tolerability while minimising the toxicity that can read-
(1970) by more than a decade after it entered widespread ily result from its narrow therapeutic index. There is however
use in Europe. a difficulty with terminology, in that different preparations are
marketed as having discrete absorption characteristics that
Lithium salts found early favour in treating severe forms may not in practice be quite so discrete.
of affective disorder. In the 1870s, the American physician,
William Hammond, recommended massive oral doses of Lithium is readily and almost completely absorbed. Some
lithium bromide for the acute treatment of mania and melan- 20% of an orally administered dose is absorbed from the stom-
cholia, while in the 1880s the Danish neurologist, Carl Lange, ach, a process not dependent on gastric acidity. Absorption is
favoured alkaline salts for the treatment of what he called however predominantly (>70%) from the small bowel and
‘periodic depression’, part of a belief at the time that some occurs by passive diffusion through the lateral intercellular
mood disorders were one manifestation of the ‘gouty diathesis’. spaces and the absorptive pores of the epithelial tight junctions
(Diamond et al 1983). Absorption is hence fastest when con-
The modern psychiatric use of lithium began when Dr. John centrations in the bowel lumen are highest. The rise in plasma
Cade of the Victoria Department of Mental Hygiene in levels is rapid with standard preparations, peak levels being
Australia hypothesised that mania might be the result of the reached in 1–2 hours. Lithium is not protein bound and its
build-up of some unidentified toxin, while depression might volume of distribution is approximately that of total body
represent ‘a correspondingly deprivative condition’. Returning water. Oral bioavailability is 90% or above, though varies with
to purine metabolism, he noted that in guinea pigs, urea pro- different formulations.
duced a state of hyperexcitability and he wished to see if uric
acid enhanced the toxicity of urea. He therefore administered Unlike sodium and potassium, lithium shows no strong
lithium urate, the most soluble of urate salts, and found that preferential distribution across cell membranes, but the rate
contrary to expectation, this protected the animals against the of passage is not uniform across all body tissues and at equilib-
excitant properties of urea. On this flimsiest of bases, he gave rium there are differences in a variety of tissue-plasma concen-
lithium to 10 ‘excited’ patients, most of whom were chronically tration gradients (Cooper 1987). Thus, in the liver the
manic, publishing his dramatic results in 1949. Mood stabilisa- concentration of lithium tends to be lower than in extracellular
tion occurred in a week or so while six chronic schizophrenic fluid while in muscle, bone and thyroid it is two to four times
patients did not improve, though the doses Cade chose, cour- higher. The concentration in brain is roughly the same as that
tesy of a 1927 text of materia medica, were very high and one of extracellular fluid, which is approximately 50% of plasma
of the original group eventually died of toxicity. The 1949 concentration. This indicates that in pharmacokinetic terms,
publication stimulated little interest but in Denmark, Erik lithium is best represented by a two-compartment model
Stromgren suggested further exploration and the work of the (Poust 1987).
Aarhus group, led by Mogens Schou, became highly influential
in developing lithium as a safe and effective treatment. Half-life values vary considerably even after single dosing,
depending on volume of distribution and renal clearance. The
Chemical structure shortest half-lives are thus generally found in young adults
(e.g. 18–20 hours). Overall the half-life is regarded as being
The lithium atom is represented by two electrons in a single in the region of 22–24 hours and does not vary with different
balanced orbit around the nucleus. The outer electron is pow- salts. Steady state is therefore achieved within 4–7 days. How-
erfully shielded from the attractive force of the nucleus, so the ever, the half-life increases with long-term treatment and with
energy required to displace it is very low, while the so-called increasing age by as much as 25–30% (Goodnick et al 1981).
‘second ionization’ energy is much higher. Thus, the chemistry This has obvious clinical relevance in that accumulation may
of lithium is essentially that of the Liþ ion. Furthermore, as occur over time, with consequent increase in toxicity risk.
the therapeutic benefits of different salts in psychiatric appli-
cations are identical, the same applies to the pharmacology. There are no metabolic steps in the body’s handling of
lithium, almost all of which is excreted via the kidneys (<5%
Bulk lithium mainly comes as sulphate and carbonate salts faecal and insensible losses). Lithium is secreted in most body
with some as lithium hydroxide, though of these only lithium fluids including sweat, saliva, tears, ejaculate and breast milk
carbonate is used in psychiatric practice. It is manufactured and possibly also intestinal secretions. Being unbound, it is
commercially from the reaction between lithium sulphate and freely filtered by the renal glomerulus along with other
sodium carbonate. Lithium citrate is also available, particularly cations, such as sodium and potassium. Also like sodium, some
in liquid formulations. 70–80% of filtered lithium is reabsorbed in the proximal
tubules by a mechanism which is competitive with sodium.
The lithium content of dosage formulations is standardised. However, while filtered sodium undergoes further reaborption
Lithium, however, acts as an electrolyte in the body and for

266

Clinical psychopharmacology CHAPTER 11

in the distal nephron (loop of Henle, distal tubule, collecting themselves alter pharmacokinetic data (Goodnick & Schorr-
ducts), lithium does not. The speed at which lithium is Cain 1991). While not altering the basic contention that
excreted – i.e. the lithium clearance – is therefore linked to understanding the drug’s pharmacokinetics is an important
proximal tubular fluid output, and as such is not constant, aid to rational practice, it does illustrate the need to utilise
though usually comes in at 20–30% of glomerular filtration such information as a guide only.
rate. Clearance is increased with extracellular volume expan-
sion, as for example during pregnancy but, more significantly, Pharmacodynamics
decreases with water or sodium depletion and coadministra-
tion of certain drugs – particularly thiazide diuretics, some Mode of action
antihypertensive agents and NSAIDs. Thus, in terms of
increasing the risk of toxicity, not only must disorders that The mode of action of lithium remains unknown. Unlike most
impair glomerular filtration (such as renal disease and increas- drugs, it does not target a specific protein (receptor or
ing age) need to be kept in mind, so too do states of decreased enzyme) but as a widely distributed, highly reactive cation,
sodium intake or increased extrarenal loss. The adverse effects influences chemical processes at a series of physiological levels,
of water deficiency may be mitigated somewhat if dehydration yet still seems to produce clinical effects that are fairly
is acquired via increased sweating, such as with inadequate focused. The changes it initiates occur rapidly yet therapeutic
fluid intake in hot climates or with fever, as increasing blood effects are delayed and benefits lost gradually, implying the
lithium levels will be associated with increased loss of lithium ultimate targets are downstream (e.g. gene-mediated events).
in sweat. However, this ‘homeostatic’ mechanism cannot be
counted on to provide adequate protection and patients must Lithium acts on membrane electrophysiology. Sharing as it
be given prudent advice. does many of the physical properties of other physiologically
active cations such as sodium, potassium and calcium, it can
The advantages of single dosing have long been evident. pass readily through ion channels associated with these. Thus,
Single daily dosing of standard lithium is not as a rule possible one of the earliest suggestions for explaining its mode of action
in healthy individuals as, in order to maintain adequate levels was that it may stabilise electrolyte balances across neuronal
over a 24-hour dosing interval, high average doses are required membranes, something possibly disturbed in affective dis-
with peak levels well into the toxic range. Assuming a half-life orders. It could do this by stimulating Na/K-ATPase, the
of 24 hours, a single dose regime of a standard preparation can energy-dependent enzyme responsible for controlling the bal-
be expected to produce 12-hour blood levels approximately ance of sodium and potassium across cell membranes via the
25% higher than those with the same daily dose given in a sodium pump mechanism. Lithium cannot however substitute
t.i.d. schedule. Furthermore, giving a single dose of 900 mg for sodium in the pump arrangement, so excessive replace-
standard lithium can result in peak levels almost four times ment of sodium by lithium, as might happen in toxicity, could
those of trough levels, whereas on a t.i.d. regime the result in a failure of membranes to maintain polarisation and to
same daily dose results in a less than a two-fold difference conduct an action potential (Baldessarini 1985). While this
(Baldessarini 1985). could underlie the catastrophic CNS collapse seen with severe
and escalating toxicity, its role in the therapeutic action is
In order to minimise the size of the postabsorptive peak likely to be remote. These more probably relate to other
a number of formulations have been introduced which go mechanisms that act to stabilise neuronal activity, support
by a number of names – ‘slow release’, ‘controlled release’, neural plasticity and provide neuroprotection (Jope 1999).
‘sustained release’, etc. Various ingenious methods have been
used to achieve the aim of a delayed rise to a lower peak level, The first set of mechanisms is neurotransmitter modulation.
including decreasing the solubility, embedding the drug in a Lithium has been shown to have many effects on many trans-
non-digestible porous carrier or gel, using ion exchange resins mitters, including biogenic amines and acetylcholine. Acutely,
or controlled disintegration coatings, etc. These have resulted it increases neuronal uptake of catecholamines but chronically,
in preparations that have at least some of the desired character- potentiates serotonergic and noradrenergic function (Manji
istics which, unlike the early attempts, are attained at little, or et al 1991). It may also prevent or modify the receptor super-
sometimes no, cost to bioavailability (Goodnick & Schorr-Cain sensitivity response to chronic catecholamine antagonists, such
1991). In general, peak levels with these formulations are as antipsychotics (Baldessarini 1985), either directly or via its
achieved after 3–6 hours, with ‘Liskonum’ delayed somewhat ability to reduce dopaminergic activity. It also enhances cholin-
more than others. ‘Camcolit-400’ and ‘Priadel’ appear to have ergic and inhibitory GABAergic transmission. In the short
similar characteristics, while lithium citrate achieves the lowest term, it stimulates release of serotonin in especially the hippo-
peak levels and also appears to have the lowest 12-hour plasma campus and longer term, may increase activity in presynaptic
levels (Shelley & Silverstone 1987). Although data are contra- hippocampal neurons, resulting in receptor downregulation.
dictory, there is a suggestion that the area under the curve However, lithium has also well-established neuroprotective
(AUC) is less with the citrate syrup than carbonate in tablet actions, something that may translate into a reduced risk of
form, suggesting lower bioavailability. Liquid citrate may, how- Alzheimer’s disease (Kessing et al 2008) and recent work on
ever, be an option in those who find tablets difficult to swallow. neurotransmitters has focused on its ability to attenuate cer-
tain types of excitatory neurodegeneration and apoptosis,
One complication in presenting the pharmacokinetic profile actions thought to be mediated via a decrease in glutamatergic
of lithium is that most studies have been done on normal activity (Jope 1999). Despite much work, data from neuro-
volunteers, whereas there is evidence that the disorders for transmitter studies have been insufficiently consistent to
which the drug is being taken (i.e. affective disorders) may contribute to a coherent hypothesis, though it may be that it

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Companion to Psychiatric Studies

is the multiplicity of these effects that, in some way, ‘resets’ via competition with magnesium for a binding site on the ade-
the excitatory/inhibitory balance in particular brain areas, nylyl cyclase molecule but with chronic exposure, mediation
providing a ‘final common pathway’ to symptom control. seems to be via G-proteins (Manji et al 1995).

Secondly, lithium affects second messengers and modifies The most studied signalling modifications relate to the
cell signalling and mechanisms that support the cell’s cytoskel- phosphoinositide/protein kinase C (PI/PKC) system (Fig. 11.6).
eton thereby contributing to neural plasticity. Inositol phospholipids are relatively minor components of cell
membranes but major participants in receptor-mediated signal
Neuronal membrane receptors mediate two sorts of events transduction pathways. The brain is dependent on recycling
– those involving the propagation of electrical potentials on inositol phosphates to maintain inositol levels so when it was
the membrane surface and those that result from the trans- found that lithium is a powerful inhibitor of inositol mono-
lation of receptor events into modifications in intracellular phosphatase (IMP), which converts inositol monophosphate
functioning. Agents mediating the first set of events – i.e. neu- to free inositol, the ‘inositol depletion hypothesis’ was pro-
rotransmitters themselves – might therefore be considered the posed as the core mechanism of action (Berridge et al 1982).
‘first’ messengers in neurophysiological processes, while those In its simplest form this is certainly incorrect but may be rele-
mediating the transduction of electrical information at the vant to specific actions in specific brain areas or cell types. Long-
receptor into changes at the level of intracellular effectors term IMP inhibition results, via a number of intermediary steps,
might then be thought of as ‘second’ messengers. These intra- in downregulation of certain isoforms of the enzyme protein
cellular messengers, which include adenylyl cyclases, inositol kinase C (PKC), with downstream changes in brain function,
1,4,5-triphosphate, arachidonate, protein kinase C isoenzymes, including synaptic events such as regulation of neurotransmitter
guanine nucleotide binding proteins (or G-proteins) and release in which PKC isoforms have been implicated (Lenox &
calcium, act on specific target proteins to initiate signaling Wang 2003). Interestingly, the widely used anticancer drug,
cascades. Lithium has long-established effects on a number tamoxifen, which amongst other things inhibits PKC and has
of second messengers, including cyclic AMP, possibly depression as a known side-effect, also has striking antimanic
mediated by its complex actions on G-proteins. These remain properties, a replicated finding (Bebchuk et al 2000; Yildiz et al
poorly understood but seem to result in a ‘stabilising’ action 2008). Recently, considerable interest has also focused
where the lowest cAMP levels are boosted while the maximal on lithium’s ability to inhibit GSK-3b (glycogen synthase
stimulated increases are reduced (Jope 1999). It also attenu- kinase-3), an enzyme that also plays a role in neurotransmitter
ates amine-induced (e.g. noradrenaline) coupling of cAMP to release and synapse formation as well as being crucial in the
adenylyl cyclase, something that may occur in peripheral cells maintenance of the cytoskeleton through phosphorylation of
and underlie some of the drug’s adverse effects, such as tau and other microtubule-associated proteins (MAPs). Other
thyroid impairment. These effects may be mediated acutely

Synapse Postsynaptic membrane Intracellular substance Nucleus
Agonist
G-protein-coupled Lithium-responsive
Phosphatidylinositol receptor gene network
pathway
Activation
Wnt-GSK pathway
Wnt PLC
Hydrolysis

PIP2 DAG PKC
IP3
Ca++

PI IP2

IP Lithium

IMPase Inhibition
Inositol
Inhibition
(’stabilisation’)

b-catenin P

LRP Dsh GSK-3b b-catenin

Frizzled

Fig. 11.6 The mode of action of lithium: some key pathways (after Lenox & Wang 2003 and Giles & Bannigan 2006). PLC

= phospholipase C; PIP2 = phosphotidylinositol 4,5 biphosphate; DAG = diacylglycerol; PKC = protein kinase C; IP3 = inositol-1,4,5-trisphosphate;
IP2 = inositol biphosphate; IP = inositol monophosphate; IMPase = inositol monophosphatase; PI = phosphatidylinositol. Wnt ligand; LRP (low density
lipoprotein receptor related) and frizzled = Wnt co-receptors; Dsh = disheveled; GSK-3 = glycogen synthase kinase 3.

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Clinical psychopharmacology CHAPTER 11

signaling pathways currently the focus of study involve BDNF double their reference plasma levels but still remain within a
and Bcl-2. defined ‘therapeutic’ level, so those running in the lower range
and side-effect free may start to develop unwanted effects as,
The third level at which lithium acts is currently the most for example, when age-related renal decline produces gradual
speculative but may ultimately provide the most profound rises in plasma levels – even though these levels remain tech-
insights. This is establishing the presence and components of nically ‘therapeutic’. For purposes of emphasis, the features of
a ‘lithium-responsive gene network’ (Lenox & Wang 2003). toxicity are highlighted separately below.
Interest has focused on MARCKS (myristoylated alanine-rich
C-kinase substrate), a protein with a key role in neuroplastic The most frequently reported adverse effects are gastrointes-
processes in both the developing and the mature brain, tinal. The majority of patients will experience a degree of nau-
which along with its mRNA is strikingly downregulated by sea, especially evident after starting lithium and prior to
chronic lithium treatment (Wang et al 2001). This establishes establishment of steady state. For the reasons noted, some
an important principle but as yet the search for lithium- may continue to experience this for an hour or two after each
responsive transcription factors and promoter elements dose. However, this usually abates with long-term treatment
remains in its infancy. However, one recent example of a (>1 year) (Schou et al 1970). Alternatively, patients may com-
potentially relevant modification to expression of a particular plain of bloated epigastric discomfort. Pain on the other hand is
gene is illustrative. By the nature of its symptomatology and uncommon. Nausea seems to relate to the biochemical changes
its inherent periodicity, there has long been speculation about effected by lithium in the cells of the gut wall and as such is
possible associations between mood disorders, especially bipo- unlikely to be helped by taking the tablets with or after food.
lar disorder, and disturbance of the body’s circadian rhythms.
Recently it has been shown that lithium modifies key compo- Occasionally nausea may be associated with frank vomiting
nents that maintain the circadian clock. GSKb stabilises the in the absence of toxicity, though this too usually settles rap-
nuclear receptor Rev-erb-a which is a negative component of idly. It appears that even small amounts of the ion are irritant
the circadian clock, an action that lithium blocks, thereby to the lower bowel and loose motions are a common experi-
allowing activation of the ‘clock gene’ Bmal1 (Yin et al 2006). ence. Watery diarrhoea can be found at therapeutic levels,
but in view of its potentially sinister implications, toxicity is
It may not be necessary to accept that all of lithium’s usually a safer assumption. Unlike most other adverse effects,
mental state actions are mediated via the same pathway(s) – lower intestinal symptomatology may be more frequently
recent research has linked the drug’s mild antidepressant found with ‘slow’ or ‘sustained’ release products, as their
actions to effects on nitrous oxide pathways (Ghasemi et al mode of action, by significantly delaying absorption, delivers
2008) – but understanding its complex pharmacology probably more ion to the lower bowel. It is important to take note of
takes us closer to understanding the fundamental patho- vomiting and diarrhoea that are sustained, if only for a few
physiology of major psychiatric disorder(s) than any other days, even in the presence of therapeutic blood levels, because
pharmacological probes currently can. of the consequences of fluid and sodium loss. Patients may
complain of constipation, especially with chronic exposure.
Adverse effects
Disturbed salivary flow, in the form of either increased
Lithium is a highly reactive, toxic ion with the lowest margin of salivation or dryness in the mouth, is also described. The for-
safety of any drug in clinical psychopharmacology. Although mer is frequent, something that with objective measurement
therapeutic monitoring has reduced the risk of toxicity dramat- is evident in over three-quarters of patients, and may be asso-
ically, treatment can still be associated with a wide range of ciated with salivary gland enlargement. The latter is however
unwanted effects (Table 11.8). Indeed, with close monitoring potentially more troublesome. For a number of years, concern
it has been suggested that very few of those on standard was expressed about the high prevalence of dental caries in
lithium (around 10%) will escape completely (Vacaflor 1975). patients on lithium, which was thought to reflect interference
The prevalence of most unwanted effects is lower with ‘slow’ or with enamel production. Lithium does not, however, appear
‘sustained’ release formulations, now the most commonly used. to interfere with aspects of tooth development or maintenance
(Curzon 1987) and it is now thought that decline in dental
Lithium’s pervasive actions illustrate the limitations of con- status is the consequence of a chronically dry mouth. Infre-
sidering drug effects dichotomously as ‘therapeutic’/‘adverse’ quently, patients may complain, sometimes bitterly, of a metal-
(or even ‘target’/‘non-target’!) for many of its unwanted lic taste, probably the result of salivary secretion of the ion.
effects and those of toxicity develop on a continuum.
Thus, while it is usually possible to distinguish between the The diuretic properties of lithium were noted by Garrod
major unwanted effects that occur therapeutically and those in the 19th century and polyuria with compensatory polydipsia
indicative of toxicity, an overlap exists and the distinction is, affects up to 50% of patients (Walker & Kincaid-Smith 1987).
in the early stages of transition at least, largely a matter of The problem relates to a failure of concentration and with
degree. In fact, even with patients considered on the basis of laboratory evaluation the majority of patients on lithium will
a standard 12-hour blood level, to be within the therapeutic show some increase in urine production on a normal fluid
range, unwanted symptomatology can still be striking. This intake. Lithium appears to interfere with the action of vaso-
reflects both the rate of rise to, and the maximum height of, pressin on the distal nephron, traditionally viewed as inhibition
the post-absorptive peak, as well as rates of clearance, the of adenylyl cyclase-mediated increase in the conversion of
latter particularly influenced by physical illness which predis- ATP to cyclic AMP, though this has recently been challenged
poses to both impaired tolerability and increased toxicity risk. in favour of direct downregulation of the concentrating protein
It is worth bearing in mind that over time patients can almost aquaporin-2 (Li et al 2006). The effect can be a mild increase

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Table 11.8 Adverse and toxic effects of lithium

Gastrointestinal Urinary CNS CVS Endocrine Miscellaneous
Neutrophilia
Adverse effects Epigastric Tremor Weight gain
St12hSLi discomfort ‘Dullness’
Dysphoria Teratogenicity
Altered salivation Slowed Skin disorders Uncommon Common
– exacerbations
Metallic taste Polyuria cognition – de novo
Nausea Polydipsia Impaired
Loose bowel
creativity
motions Lethargy

0.6–1.2 mmol/l Constipation Lethargy Impaired AV Hypothyroidism
Vomiting Apathy conduction Asymptomatic
Diarrhoea Tremor (coarse)
Myoclonic jerks goitre
Fasciculations Hyperthyroidism
Drowsiness
Toxic effects Anorexia "Polyuria (low Dysarthria
< 2.0 mmol/l Persistent nausea sp. gravity) Ataxia
Increasing Choreoathetosis
"Polydipsia Attentional
vomiting
Watery/bloody deficits
#Awareness
diarrhoea Confusion
Coma
2–4 mmol/l

>4 mmol/l Hypotension
Dysrhythmias

Circulatory
collapse

Death

St12hSLi, standardised 12-hour serum lithium.

in urinary volume which is largely asymptomatic or that which can be in the region of 20–25% and so require closer
shows mainly as nocturia, through to full and profoundly monitoring.
incapacitating vasopressin-resistant nephrogenic diabetes insi-
pidus. The natural assumption would be that this might be Impairment in urinary concentrating ability was for a long
helped by spreading the administration of, particularly, slow time thought to be reversible and of little consequence.
release preparations over the day to attain lower peaks. This complacency was shattered with the publication of the
There is, however, a suggestion that in the long term, the first in a series of reports suggesting a strong correlation
lower troughs associated with single daily administration between duration of exposure to lithium and impaired concen-
may be more protective to the kidney, and at a clinical level trating ability (Hestbech et al 1977). Of particular concern
the most effective way of dealing with polyuria may be to was the demonstration that the functional deficit correlated
utilise single dosing regimes (Perry & Alexander 1987: Lju- with histological changes of a chronic focal interstitial nephrop-
bicic et al 2008). An alternative strategy is the addition of athy. Long-term administration of lithium has been confirmed
the potassium-sparing diuretic, amiloride, which decreases to be associated with structural changes, though those origi-
urinary output without reducing lithium clearance. Thiazide nally causing concern may in part be non-specific, as similar
diuretics may also achieve a reduction in urine volume but findings have also been reported in psychiatric patients not
at greater risk of producing rises in lithium blood levels, treated with lithium (Kincaid-Smith et al 1979). A common
factor, therefore, may be long-term exposure to maintenance

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medications. However, it now seems clear that a potent predis- to 75% (average 25%) and increases can be striking (Torrent
posing factor to these ‘non-specific’ structural changes is acute et al 2008). There is some support for the view that the rate of
lithium toxicity. In this situation, permanent renal damage may increase is greatest in the first 1–2 years of chronic exposure,
ensue that is associated with progressive impairment of concen- with stabilisation thereafter. The mechanism is unknown
trating ability. Lithium treatment does appear to be associated but weight gain has been found to predict later hypothyroid-
with a specific histological change in the form of distal tubular ism and may thus reflect a genuine ‘metabolic’ dysfunction
dilatation, following both acute and chronic exposure, though (Henry 2002).
the long-term significance of this remains unclear.
Lithium interferes with a number of hormone functions,
Thus, with prolonged and stable exposure to lithium the like- the most prominent of which involve the thyroid. Within a
lihood of impairment of glomerular filtration rate and the risk of few months on treatment, slight falls in T4 with compensa-
permanent or progressive renal damage is slight, though this risk tory rises in TSH are common. These do not usually take
is increased by episodes of acute toxicity (Hetmar et al 1991). values beyond normal reference ranges and they usually stabi-
lise within 12 months, though TSH may remain on the high
A low-amplitude/high-frequency tremor of predominantly side. Early in treatment, patients may develop signs of hyper-
postural type is a common complaint and exceedingly inconve- thyroidism, though this is very uncommon. Of much greater
nient and embarrassing. This is one of the adverse experiences frequency is the gradual development of hypothyroidism.
that most clearly relates to the rate and height of the postab- Antithyroid antibodies are present in just under 10% of the
sorptive peak and which may be helped by a change in pre- general population and are more prevalent in females. Their
paration and/or schedule. It appears to be at least in part presence rises sharply after the middle of the fifth decade.
adrenergically mediated and may respond to a beta-blocker. In one 15-year follow-up of lithium-treated patients, 1.7%
Although tremor may be pronounced at therapeutic levels, became seropositive annually with 1.5% developing hypothy-
moderately severe degrees of disorder or greater should arouse roidism. Once patients developed antithyroid antibodies, the
suspicion of toxicity. A further sign is that the quality of the likelihood of them requiring replacement therapy increased
tremor may change to one with coarser characteristics, though eight-fold (Bocchetta et al 2007). Females are about three
coarsening with increase in amplitude may simply be features times more represented than males (Myers & West 1987).
of ageing. However, there remains some dispute about the interpreta-
tion of these findings for in controlled studies, long-term lith-
Lithium can affect cardiac conduction, and although this has ium treatment does not appear to increase the prevalence of
not traditionally been considered a matter of concern (Martin thyroid autoimmunity (Baethge et al 2005) suggesting that
et al 1987), there may be some cause for circumspection what is found in lithium-treated populations simply reflects
(Reilly et al 2000). The commonest ECG finding is a notched, population characteristics. It is likely there is no single path-
flattened and occasionally inverted T-wave, which is not signif- way to lithium-induced hypothyroidism but it is possible to
icant. However, conduction deficits at the sinoatrial and atrio- identify the group most at risk as comprising females over
ventricular nodes have been reported, the former resulting in 45, with circulating antithyroid antibodies and a slight but
sick sinus syndrome or sinus node arrhythmias, which may be sustained elevation of TSH. The risk of hypothyroidism
asymptomatic or present with faintness or paroxysmal tachy- necessitates regular (e.g. annual) monitoring of thyroid func-
cardia, while A-V block associated with the latter is usually tion, which should be extended to examination of the gland
asymptomatic. Sinus node arrest requiring a pacemaker has itself.
also been noted (Oudit et al 2007). Brugada syndrome has
been reported following toxicity but also with therapeutic Lithium-induced goitre is rarely commented on but using
levels (Laske et al 2007). This ECG diagnosis (ST segment ultrasonography appears common, affecting over 50% of those
elevation and right bundle branch block in leads V1–V3) is exposed long term (Bauer et al 2007). Most will not be evident
usually associated with structural right ventricular pathology by palpation and enlargement on its own does not necessarily
but 20% of cases result from one of many polymorphisms herald hypofunction. Again, the mechanism is unknown but
in the gene encoding for Na ion channels in myocytes appears to reflect impairment of iodine uptake and/or incor-
(SCN5A). The consequence is dispersion of the repolarisation poration into thyroid hormone. The development of asymp-
signal both transmurally and epicardially, precipitating ventric- tomatic goitre or biochemical or even clinical hypothyroidism
ular tachyarrhymias, including fibrillation and sudden death. are not contraindications to continued use of lithium. Current
Lithium-related cases represent rare events but as with pro- recommendations are that sustained elevation of TSH, even in
longed QTc, this is something psychiatrists should be alert to the presence of normal T4, is sufficient indication for thyroid
in those with pre-existing cardiac disease and in males with a supplementation. Rarely, multinodular goitres may require
family history of sudden death, where detailed pretreatment surgery. There is no evidence that long-term lithium treatment
ECG assessment is recommended. The Brugada phenome- increases the risk of thyroid carcinoma.
non is more prevalent in most Asian populations than in
Europeans. Such changes appear to be reversible on stopping Asymptomatic hypercalcaemia associated with hyper-
lithium though persistent abnormality (as may occur follow- parathyroidism has traditionally been seen as rare but may be
ing overdose) usually requires insertion of an implantable more common than is appreciated (Khandwala & van Uum
defibrillator. 2006), since measurement of calcium and parathyroid hor-
mone is not routinely undertaken. Although hypercalcaemia
Long-term ingestion of lithium can be associated with is usually mild, its long-term consequences are unknown and
weight gain. Reported prevalence rates vary widely from 20%

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it may not resolve following discontinuation of lithium so Although not strictly a side-effect, there has been concern
routine monitoring, before and during prolonged treatment, in recent years about the risk of rebound mania occurring with
would seem prudent. Despite possessing some insulin-like greater than expected frequency following abrupt discontinua-
properties, lithium probably does not alter glucose metabolism tion of lithium (Faedda et al 1993). While this may relate to a
to any clinically significant degree, even in those with diabetes possible ‘withdrawal’ type phenomenon, it may equally speak
mellitus. of the drug doing what is expected of it in holding off manic
episodes which would have developed earlier in its absence.
A series of skin disorders can develop in the course of Lithium, in line with all other psychotropics, should always
lithium treatment, though the reported total prevalence of be discontinued gradually.
around 1% (Lambert & Dalac 1987) seems an underestimate.
The commonest is acne vulgaris, which may present as a wors- Generations of psychiatrists have been taught to view
ening of pre-existing disorder in the usual distribution or lithium as uniquely teratogenic but evidence from both
as a recrudescence of symptomatology long in abeyance. animals and humans suggests this risk has been exaggerated,
It may, however, develop without prior abnormality when the potential overall being low (Giles & Bannigan 2006) (see
the distribution is often eccentric, involving thighs or upper below).
arms. It tends not to come in cycles like idiopathic acne and
can lead to patients discontinuing treatment. It may improve Toxicity
slightly with dose reduction but this in itself is unlikely to
be sufficient. Treatment should be conservative in view of a The upper limit of normal for the standard 12-hour lithium
possible interaction between lithium and tetracyclines. level in most laboratories is 1.2 mmol/l. With modern meth-
ods of estimation, the test is readily standardised and the
Of more serious import is psoriasis, which may also repre- margin of error slight. Accepting this as the upper limit does
sent an exacerbation of prior disorder or, less commonly, not of course mean that a value of 1.21 equals toxicity. There
its first manifestation. All types of psoriasis have been is no clear point of transition and some patients may get sub-
described and the condition may be associated with character- stantially above this level before developing clinical features.
istic nail changes. This does not respond well to conventional Nonetheless, patients showing an upward trend or a single
treatment though inositol supplements may produce signifi- reading above this level, which represents an uncharacteristi-
cant benefits (Allan et al 2004). Other skin disorders include cally high value, and who develop a change in their pattern of
seborrhoeic dermatitis, follicular keratosis and pruritic macu- tolerability should be suspected of moving to toxicity. Most
lopapular erythematous eruptions. As with other psychotropic patients will show an altered tolerance by the time blood levels
drugs, lithium treatment may be associated with hair loss, are in the range of 1.4 –1.5 mmol/l, and clear signs of toxicity
and frank alopecia may be more frequent – though still rare – will be evident with levels over 2 mmol/l.
than with previously discussed compounds. The mechanisms
are unknown. Most cases of lithium toxicity occur in the context of long-
term administration (i.e. ‘chronic’ toxicity) and hence repre-
Increases in white blood counts of up to 40%, reflecting sent a relatively insidious departure from a stable situation.
mainly a neutrophilia, are common in the first week of lithium While symptomatology can emerge swiftly, their antecedents
exposure. A similar stimulatory effect may apply to platelets. can usually be traced back over 24–48 hours or longer.
Lithium has been suggested as a treatment of various marrow
deficiency disorders but this action becomes less evident Gastrointestinal features – anorexia and persistent or obtru-
with prolonged use, so clinical utility is lost. It may be most sive nausea, culminating in vomiting – are usually the first signs
apparent with lower doses. (see Table 11.8). At the same time patients may experience
dry mouth and insatiable thirst associated with production of
Controlled studies in normal volunteers suggests that lith- voluminous amounts of dilute (i.e. low specific gravity) urine,
ium produces a slight but detectable impairment of cognition which may contain glucose. Diarrhoea may then develop,
and subjective affective symptoms of mental slowness, lethargy which may be bloody. With this combination of disturbances,
and dysphoria, sometimes with accompanying restlessness dehydration rapidly ensues or progresses. Tremor accentuates
(Judd et al 1977a; Judd et al 1977b). Some of this may be with a course, jerky quality emerging which may extend to
related to the increasingly appreciated tendency of lithium all body parts. Patients feel increasingly weak. In addition,
to promote or exacerbate mild pre-existing extrapyramidal as levels rise, muscle fasciculations and myoclonic-like jerks
dysfunction. Particular problems may be encountered by those or typical choreoathetoid movements develop, associated with
whose occupation requires creativity. generalised hypertonicity. A general breakdown in neuromus-
cular coordination shows in dysarthria and ataxia. Disruption
Lithium accumulates in bone, but earlier concerns about of higher mental functions is a sign of serious toxicity, with
prolonged treatment exacerbating osteoporosis are unfounded. victims becoming increasingly lethargic and drowsy, with
To the contrary, there is accumulating evidence suggesting lack of interest and awareness, attention deficits and frank
it exerts a protective effect against fractures (Bolton et al confusion/delirium. Rarely, confusion following overdose can
2008), for which there is a mechanism (lithium activates be caused by nonconvulsive status epilepticus, something also
a key signaling pathway (Wnt) in the stimulation of bone occasionally found with therapeutic levels (Bellesi et al
formation and density). Caution should still be exercised with 2006). Incipient circulatory failure is signalled by hypotension
its long-term use in children and adolescents, in whom long- and irregularities of cardiac rhythm. Fits are likely to emerge
term effects on developing bone are unknown. There are rare at this stage, leading on to stupor and preterminal coma.
reports of lithium worsening or unmasking the symptoms of
myasthenia gravis.

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Because of delayed brain penetration and egress of lithium, of major affective disorders. However, anticonvulsants have
clinical signs of CNS toxicity may not occur in unison with complex kinetics and potentially serious adverse effects,
escalating blood levels, and may persist when levels are making them different from lithium in their handling.
declining, and even after they are back to the therapeutic
range. Rarely, a long-lasting cerebellar syndrome is seen Carbamazepine is a tricyclic compound, closely related
(Niethammer & Ford 2007). structurally to imipramine. It was synthesised in 1953 in the
hope it could emulate the actions of chlorpromazine. It did
It is essential to educate patients on the often simple however possess unique features of its own and in the 1960s
measures that can be effective in avoiding lithium toxicity, was introduced as a highly effective anticonvulsant.
such as maintaining hydration and salt intake, and being
sensitive to any change in tolerability. In particular, the onset Carbamazepine is rather slowly and erratically absorbed,
of gastrointestinal symptoms should always be emphasised as with peak levels attained in 4–6 hours, though with Retard
an important ‘warning’ where patients themselves can effec- formulations Tmax may be up to 24 hours. Bioavailability is
tively intervene by simply stopping lithium for 1, or at most 2, in the range of 80–90%. There are substantial first-pass effects.
days. Based on half-life, blood levels can be expected to drop Its apparent volume of distribution is in the moderate
by about 50% in 24 hours, assuming maintenance of normal range. At around 75%, it is less protein bound than most psy-
renal function. Discontinuation is an effective, and necessary, chotropics. Its half-life is dependent not only on its complex
strategy in the management of toxicity of any degree. However, metabolism but also on the fact that for the first 2–3 months
in addition to ‘chronic’ intoxication, lithium can be used of chronic treatment it induces its own metabolism to a
(rarely) as a vehicle of self-harm, resulting in ‘acute’ or ‘acute- substantial degree, a process starting within the first week.
on-chronic’ intoxication where kinetics may be somewhat Thus, with single doses, half-life values are in the region
different. of 25–45 hours, whereas with chronic administration these
fall dramatically to 7–24 hours. After 1 month, the initial
The treatment of choice for toxicity has moved on from steady-state levels may have fallen by as much as 25% (Brodie
‘forced’ diuresis (1–2 l of isotonic saline i.v. over 6 hours) to 1987).
haemodialysis (Eyer et al 2006). Volume repletion sufficient
to maintain eunatraemia and enhanced elimination (furose- The major metabolic pathway in the liver is epoxidation
mide or amiloride) may be sufficient in milder cases. Haemo- by arene oxidase to form carbamazepine-10,11-epoxide, which
dialysis is highly efficient in reducing half-life and removing has a shorter half-life than the parent but is pharmacologi-
drug but does not appear to improve patient outcome after cally active and toxic. This is, in turn, metabolised by epoxide
intoxication (Bailey & McGuigan 2000), perhaps reflecting hydroxylase to the inactive trans-carbamazepine-diol (or carba-
the injurious consequences of delay. Furthermore, since move- mazepine-10,11dihydrodihydroxide), which is excreted in
ment of distributed ion back into the vascular space may result the urine. Fifteen to 20% of a carbamazepine dose is metabo-
in ‘rebound’ plasma elevations, it may need to be repeated. lised by direct conjugation with glucuronic acid. Epoxide
Peritoneal dialysis is usually insufficiently effective for the hydroxylase is inhibited by a number of drugs, notably val-
medical emergency lithium intoxication represents. proate, coadministration of which can result in a dramatic
decrease in the ratio of carbamazepine to its epoxide meta-
Anticonvulsants (‘antiepileptics’) bolite (from 10:1 to 2:1), triggering toxicity in patients whose
blood levels remain within the therapeutic range (Wilder
N 1992). Furthermore, carbamazepine increases hormone clear-
CONH 2 ance and can negate the actions of the contraceptive pill, espe-
Carbamazepine cially low oestrogen formulations. Its metabolism is unaltered
by lamotrigine.
CH3 CH2 CH2 O
CH C Sodium valproate is the soluble sodium salt of valproic acid,
a poorly soluble branched chain carboxylic acid.
CH3 CH2 CH2 OH
Absorption is rapid with unmodified formulations, peak
Valproic acid levels being attained in 30–60 minutes. The drug is, however,
a powerful gastric irritant and a number of slow-release formu-
The first favourable report of anticonvulsants in major affec- lations, such as enteric-coated tablets, are widely used which
tive disorders was by Takezaki and Hanoaka in 1971, though have Tmax values in the region of 4–6 hours. Protein binding
it was Ballenger and Post (1980) who stimulated widespread is up to 95% but is inversely dependent on dietary fat content.
interest. To date, most work has concerned carbamazepine Binding of valproate is saturable within the therapeutic range,
and sodium valproate, but with the introduction of new anti- thus rapid increases in dose can be associated with dispropor-
convulsants, especially lamotrigine, interest is widening and tionately large increases in free drug levels, which rapidly
this class now occupies an important place in the treatment undergo metabolism with consequently lower than expected
blood levels. Valproate displaces carbamazepine from protein
binding sites and its introduction can result in transient toxic-
ity of the latter. Half-life varies with preparation, the range
being 5–20 hours (Wilder 1992).

The metabolism of valproate is complex. One pathway is
via the microsomal cytochrome P-450 system, which produces
two potentially toxic metabolites, 4-en- and 2,4-en-valproate.

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The more significant pathway (with solo administration) is via unknown mode of action though in vitro it does exert an inhib-
mitochondrial b-oxidation, the pathway extensively utilised in itory effect on voltage-gated sodium channels, which may
the degradation of fatty acids in general. This produces 3- modulate presynaptic release of inhibitory neurotransmitters
hydroxy- and 3-oxo-derivatives and 2-en-valproate, which has such as glutamate. The drug is readily absorbed after oral
anticonvulsant properties and a long half-life. Therapeutic ingestion (Tmax 1.5–4.5 hours) and, unusually, undergoes
environments that stimulate P-450 metabolism such as coad- little first-pass metabolism. Also, unusually, it is only some
ministration of inducers (e.g. carbamazepine, phenobarbitone) 50–55% protein bound. Half-life varies widely (<12 hours to
lead to excessive build-up of toxic metabolites which may be >60 hours) with multiple dosing. Given alone, it induces its
the mechanism underlying the infrequently reported but own metabolism resulting in up to 25% reduction in half-life.
potentially fatal hepatic necrosis, to which children under 2 It is metabolised to inactive moieties, predominantly by con-
are especially prone. Another rare but potentially serious sce- jugation with glucuronic acid, with less than 10% excreted
nario is in those with inherited or acquired metabolic diseases unaltered in urine.
who are deficient in carnitine, an important constituent of fatty
acid metabolism (Coulter 1991). Valproate decreases carnitine In terms of general adverse effects, lamotrigine is well toler-
levels, and in such patients may precipitate encephalopathy. ated, with only a small minority developing nausea, headache,
dizziness, ataxia, diplopia and somnolence. However, its major
In the UK, sodium valproate is the most commonly utilised problem relates to hypersensitivity-type reactions, in particular
preparation but research establishing the place of valproate in skin rashes. Approximately 5–10% of patients develop rashes,
the treatment of affective disorders has mostly utilised the most of which will be benign but in a small minority ( 1
semi-sodium salt (Depakote). This is a 50:50 mix (strictly, per 1000) these progress to serious systemic illness, including
1:1 molar relationship) of sodium valproate and valproic acid. the potentially fatal Stevens–Johnson syndrome. Toxic epider-
This could be clinically significant if these formulations mal necrolysis has been reported rarely. While the majority of
differed significantly in their pharmacokinetics but any differ- rashes occur within the first 8 weeks, they can also develop
ences are slight, being restricted mainly to rate of absorption. later in treatment. The risk is increased by rapid dose escala-
Divalproex dissociates readily to the valproate ion in the gut tions and possibly by exceeding recommended doses and com-
and has similar bioavailability to the sodium salt. bining lamotrigine with valproate. As clinically it is not possible
to distinguish benign from serious reactions, development of
Carbamazepine and valproate can produce significant any rash in patients receiving lamotrigine should trigger imme-
adverse effects. Both can cause gastrointestinal upset, and are diate discontinuation. Active symptoms may persist for some
sedative. Carbamazepine can, like all tricyclic drugs, slow intra- time and permanent disfigurement can ensue.
cardiac conduction and produce arrhythmias. Hypocalcaemia
can occur and inappropriate ADH secretion may be asso- Other anticonvulsants utilised in the treatment of bipo-
ciated with hyponatraemia and oedema. Idiosyncratic reactions lar illnesses include gabapentin, topiramate and oxcarbazine.
include marrow suppression, hepatotoxicity, (morbiliform) There is currently no evidence for an antimanic action with
skin rashes, photosensitivity and rarely Stevens–Johnson these drugs and reported benefits in other phases of illness
syndrome and a lupus-type syndrome. remain controversial. Topiramate does appear to possess
beneficial effects on weight reduction (McElroy et al 2007).
Valproate can cause tremors, skin rashes and hair loss and
may also be associated with oedema. Rarely, acute pancreatitis, Calcium channel antagonists
hepatotoxicity and hyperammonaemia can ensue, the latter
potentially fatal in those with rare, genetically determined It is suggested that calcium channel antagonists may have clin-
disorders of the urea cycle. Concern has been expressed about ical utility in bipolar affective disorders, though most of the
changes to ovarian function with chronic use (Isojarvi et al evidence remains anecdotal or based on small or open studies
1993). ‘Polycystic ovarian syndrome’ (PCOS) can be found (Dubovsky 1993). Early interest remained with verapamil,
in association with epilepsy and it was argued this might not whose value may be limited to patients with relatively mild
be an issue in those with affective disorders. This is, how- disorder and/or patients who, for whatever reason, are unable
ever, not the case. Oligomenorrhoea and hyperandrogenism to take lithium. More recent evidence suggests that drugs of
(hirsutism, acne, male-pattern alopecia, elevated androgen the dihydropyridine type, such as nifedipine and nimodipine,
levels) has been found in 10.5% of valproate-treated women may be particularly useful in rapid cycling bipolar disorders.
compared to 1.4% of those on another mood stabiliser (rela-
tive risk, 7.5) (Joffe et al 2006). Although apparently revers- The calcium channel antagonists reduce calcium influx
ible, this is an important action with the drug’s increasing use through potential-dependent calcium channels during cell stim-
as a mood stabiliser in women of child-bearing age and one ulation. The actions of lithium on intracellular transduction
psychiatrists are insufficiently aware of. It is something that pathways include desensitisation of the receptor-stimulated
may require monitoring in terms of reproductive–endocrine phosphatidylinositol cycle that mobilises calcium, and inhibi-
function. tion of calmodulin, the calcium activation protein. Further-
more, both carbamazepine and at least some antipsychotics
Both carbamazepine and valproate have serious teratogenic also antagonise calcium cellular influx. There is therefore reason
potential and should be avoided in pregnancy (see below). to explore the therapeutic application of these compounds,
though the justification for their use at present remains largely
Of the other anticonvulsants marketed in recent years, only empirical.
lamotrigine has come to occupy an important place in manage-
ment of major affective disorders. Lamotrigine is a phenyltria-
zine, chemically unrelated to other psychotropics and of

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Therapeutics Box 11.13

Indications Principles of lithium use

Indications for lithium are tightly circumscribed (Box 11.12), • Establish base-line medical parameters
with treatment of manic episodes and long-term prophylaxis, Haematology
especially against manic relapse, having the strongest evidence Biochemistry (esp. electrolytes and creatinine)
base (Geddes et al 2004; Smith et al 2007). However, espe- Thyroid function (esp. ‘high-risk’ individuals – see text)
cially in the USA, anticonvulsants have come to assume ECG (esp. ‘high-risk’ groups – see text)
a prominent role, perhaps related to increasing evidence of
similar efficacy and effect sizes (Smith et al 2007; Ceron- • Note renal status
Litvoc et al 2009). This shift may also reflect a perception of Traditional creatinine clearance too inaccurate to be of value in
easier use and patient preference – as well as marketing pres- psychiatric patients; serum creatinine and/or estimated GFR
sures! The place of lithium in the adjunctive treatment of (see text) adequate
resistant depressions and of lithium, valproate and carbamaze-
pine in the prophylaxis of recurrent unipolar depressions is • Exclude pregnancy
more equivocal. In Europe, lamotrigine is licensed for • Standardised 12-hour serum lithium (Amdisen 1977):
prevention of relapse with any mood event in bipolar 1 disor-
ders, though belief in its benefits on acute-phase depressive Morning fasting blood 12 hours after last dose when patient has
symptomatology is gaining clinical support. These effects are achieved steady state (4–5 days): originally validated with
probably modest but may be greater with more severe depres- multiple dosing schedules but applicable to single ‘nocte’
sions (Geddes et al 2009). Calcium channel antagonists have dosing also.
been insufficiently investigated and should be reserved for
empirical use in refractory cases, especially rapid cycling or Dose tailored to achieve blood level of 0.6–1.2 mmol/l (for
‘ultradian’ (ultra-ultra rapid) types. maintenance, above 0.45–0.5 may suffice)

Strategies • Avoid generic prescribing
Bioavailability can vary between preparations, albeit slightly
Lithium’s role as a first-line agent in recurrent bipolar disorder (Priadel 400 versus Camcolit 400)
has long been challenged (Moncrieff 1997) but in Europe it ‘Slow’/‘sustained’ release preparations can only be superficially
continues to hold, if tenuously, to its traditional position. This distinguished on the basis of tablet strength (400 mg –
is however a slightly different position to the one held in the modified release; 250 mg – unmodified) Inexperienced
USA where it is utilised not only as a prophylactic instrument dispensers may not appreciate this and, for those taking for
but also as a treatment one, introduced at point of diagnosis. example 1 Gm, may dispense 4 Â 250 mg as ‘easier’ than
European practice has been, and remains, that acute episodes two and a half at 400 mg. This can result in a very high Cmax
of mood illness are treated appropriately first, after which and clinical toxicity
lithium (or other mood stabiliser) would be introduced.
• Prescribe flexibly:
Despite its undoubted value, the benefits of lithium – and Certain adverse effects may be obviated by manipulation of
indeed all treatments for bipolar disorders – are less effective dose and/or formulation to minimise Cmax
in real life situations than early trial evidence suggested.
Recent meta-analysis indicates about a 40% benefit for lithium • Education:
over placebo (Geddes et al 2004) so expectations in deal- On signs representing a shift from ‘tolerability’ to ‘toxicity’
ing with what is a major and, for most, disabling disorder On the on-going need to avoid dehydration
must be realistic. Having decided on lithium’s use, the major
therapeutic principles are summarized in Box 11.13. • Monitoring:
Of lithium levels: 3 monthly (in stable, compliant patients, 2 – 3
There is no hard and fast rule about how frequently serum times/year is probably sufficient)
lithium levels should be assessed but in patients who are stable Of tolerability: annually (routine bloods, renal function (eGFR),
and compliant, three or four times per year is adequate. thyroid function (Ca þ parathyroid with chronic use)

Box 11.12 Thyroid function should be evaluated annually as routine, or
6 monthly in those at higher risk, such as middle aged/elderly
Indications for lithium use females with circulating autoantibodies, to which calcium and
parathyroid hormone should be added. The advantages of
• Treatment of manic/hypomanic episodes routine monitoring of renal function are unclear, though this
• Prophylaxis of bipolar affective disorders remains a conventional recommendation. It would certainly
• Prophylaxis of recurrent unipolar depression be indicated in the wake of an episode of frank toxicity. Renal
• As adjunctive agent in treatment of major depressive disorders function was traditionally monitored by the usual means of
estimating creatinine clearance, a Herculean and ultimately
unresponsive to antidepressants alone pointless undertaking in psychiatric contexts. Routine creati-
nine levels have been seen as a simpler and more reliable alter-
native. Recently, in line with recommendations from renal
physicians, the estimated glomerular filtration rate (eGFR),
now widely undertaken routinely, has been suggested (Morriss
and Benjamin 2008), with values in the range 30–59 ml/min an

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indication for close (3 monthly) monitoring. A decrease of The 1,4-benzodiazepine structure was discovered by chem-
more than 4 ml/min per year should trigger specialist referral. ist Leo Sternbach who, in the mid-1950s, was searching for
Following the decision to discontinue, lithium doses should be behavioural properties in compounds studied previously as
tapered downwards gradually over several weeks/months potential dyes. In fact, the compounds were not benzheptox-
because of the risk of rebound mania (Suppes et al 1991). diazines as thought but a new analogue of quinazoline, known
since the 1890s. These investigations were getting nowhere
There are no such clear principles that apply to the other and Sternbach was in the throes of ‘house cleaning’ when,
mood stabilizers. Blood monitoring is often undertaken with in 1957, he submitted, without enthusiasm, one such com-
carbamazepine, and increasingly with valproate, but its value pound for screening (Sternbach 1983). Pharmacologist Lowell
is doubtful. There are as yet no clearly established therapeutic Randell noted that in animals this derivative possessed a simi-
ranges for affective disorders comparable to that for lithium. lar psychopharmacological profile to meprobamate. Confirma-
Blood levels may help identify poor or non-compliance and tion in humans led to the launch (1960) of chlordiazepoxide,
for carbamazepine, very high levels will increase the likelihood the vanguard of a pharmaceutical avalanche.
of toxicity. The most sensitive pointers to this are however
probably clinical, and regular symptomatic monitoring is a Benzodiazepines were the first drugs in which the influence
better practice principle than blood levels. of marketing can be seen. They have four group actions –
antianxiety, hypnotic, anticonvulsant and muscle relaxant.
Benzodiazepines and other There is, however, no evidence that different compounds have
differential clinical profiles in these areas (Baldessarini 1985).
sedatives/hypnotics Benzodiazepines differ in some key pharmacological para-
meters – notably potency and distribution – but not in their
Introduction differential effects (unlike some newer drugs – see below).
Even today, professional wisdom has it that different drugs
Like alchemy, the means for attaining effective relief of in the group should be prescribed for different clinical indica-
anxiety and insomnia are ancient, and continuing, ambitions. tions, a perception encouraged by the irrational licensing
In the 19th century, alcohol and marijuana served this purpose conditions imposed by regulatory authorities.
and, if you could afford it, opium and laudanum (tincture of
opium). Later, specific compounds structurally and pharmaco- Structures
logically similar to alcohol, such as chloral hydrate and paralde-
hyde, were introduced, while bromide salts found vogue well R1
into the 20th century. N R2

The first drugs termed ‘sedatives’ were the barbiturates, A B R3
synthesized by Fischer and von Mering in 1903 from the con-
densation of malonic acid with urea (and called after ‘a charm- R7 N
ing lady named Barbara’!). At their peak in the 1950s, this R4
large group comprised 20% of all prescriptions in the UK.
However, barbiturates are blighted by high dependency poten- C R2'
tial and a very narrow therapeutic index, problems also afflict-
ing their various analogues, such as glutethamide and 1,4-Benzodiazepines
methaqualone, popular in the 1960s and 1970s. Barbiturates
are medically obsolete, except in a few cases of difficult- NHCH3 CH3
to-manage epilepsy, yet availability is increasing with access N O
to ‘on-line’ pharmacies and it is possible the coming genera-
tion will encounter more problems with these drugs than the N
present one.
Cl N Cl N
The first so-called ‘tranquilliser’ was meprobamate, a pro- O
panediol derivative synthesised in 1951, whose ‘popularity’
was attested to above. Although safer than barbiturates, it still Chlordiazepoxide Diazepam
had a relatively narrow therapeutic index and could produce
dependency. HO CH3
N O
No class of psychotropic agent better illustrates the tri-
umphs and failures of psychopharmacology than the benzodia- OH N
zepines. By the end of their first decade, they were the most OH
prescribed drugs in the developed world; by the end of the Cl N Cl
second, the most vilified. Neither of these positions was, or Cl N
is, justified. Benzodiazepines were undoubtedly excessively
prescribed for problems better dealt with in other ways but Lorazepam Temazepam
for their target conditions, they are highly effective as part of
a specific and supervised management plan.

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7-Nitrobenzodiazepine 1,5-Benzodiazepine Triazolobenzodiazepine Absorption is unpredictable from injection sites, especially in
HO patients on continuous dosing regimes, the exception being
N CH3 N lorazepam which appears to be rapidly absorbed from intra-
O CH3 N muscular sites (Richens 1983). The rate of absorption, which
is the rate-limiting step in onset of action, varies but is overall
N N rapid. Diazepam and flurazepam are amongst the most rapidly
absorbed, while temazepam, despite its licensed indication, is
O2 N N Cl N O Cl N amongst the slowest (Greenblatt & Shader 1987). In general,
Cl absorption can be slowed but not decreased by food, which
delays gastric emptying and time to reach the proximal bowel.
Clonazepam Clobazam Alprazolam For some compounds, however, absorption may be impaired
by aluminium-based antacids. Peak levels are usually achieved
The basic components of the majority of benzodiazepines in 30–90 minutes with the rapidly absorbed compounds, and
comprise a benzene (or A) ring chlorinated at the R7 position, 2–4 hours for the slower ones. Rectal administration, in the
joined to a seven-membered diazepine (i.e. double nitrogen) UK mainly confined to children with epilepsy, is a highly effi-
ring (B ring), the two nitrogens of which are sited at the cient route for liquid formulations, with Tmax’s of 15 minutes
R1 and R4 positions (hence 1,4-benzodiazepines) and to which (Richens 1983).
is attached a phenyl (or C) ring at position 5. The major varia-
tions in chemical substituents that characterise different drugs The group is highly protein bound, mainly to albumen, with
largely involve the B ring. levels of up to 98% for diazepam and 94–97% for chlordiaz-
epoxide. Lorazepam and nitrazepam are less protein bound at
This basic structure has been subject to modifications. 85–90%, and alprazolam is the least, with a free fraction of
The simplest is the transposition of one of the nitrogens 30% (Moschitto & Greenblatt 1983).
from the R4 to the R5 position. The major representative
of the 1,5-benzodiazepines is clobazam. Clonazepam is a 7- Benzodiazepines are as a rule widely distributed, though
nitrobenzodiazepine. Other modifications produce compounds for each drug this is a function of its lipophilicity. Thus,
that, although originally described as ‘non-benzodiazepines’, highly lipophilic compounds such as diazepam have large
are more appropriately considered benzodiazepine variants. apparent volumes of distribution and are widely and rapidly
These include the triazolobenzodiazepines, as exemplified distributed, while drugs such as lorazepam have lower Vd
by alprazolam and triazolam (withdrawn in the UK) and the values and are more slowly and less extensively distributed.
thienodiazepines such as brotizolam (unlicensed in the UK), The kinetics therefore technically conform to a ‘two-compart-
in which the benzene ring is replaced by a thiophene ring. ment model’, with the plasma concentration curve reflecting
distribution as well as metabolism. Distribution characteristics
Pharmacokinetics have considerable clinical relevance, especially with single par-
enteral dosing (see below). Half-lives also vary greatly across
As with SSRIs, benzodiazepines differ most from one another compounds and individuals, and are susceptible to the range
in pharmacokinetic properties, which are complex, many relat- of variables that influence both delivery of drug to hepa-
ing to differing physicochemical properties imparted by struc- tocytes and the functional integrity of these, a point of partic-
tural differences. ular note in predicting susceptibility of neonates to these
drugs. Flurazepam has a half-life that, at approximately
All benzodiazepines are weak organic bases which, when 1–2 hours, is as short as any psychotropic agent, while that
subjected to physiological buffering, become lipid soluble to for clonazepam, at 50–70 hours, is as long as any. Figures for
varying degrees from moderate to high. This variability in lipid chlordiazepoxide in the range of 6–30 hours are shorter than
solubility is a major factor contributing to pharmacokinetic those for diazepam, which are in the region of 20 hours in
and clinical distinctions between compounds. Of the drugs most healthy adults, but may reach as high as 70 hours in some
encountered in psychiatric practice, flurazepam is 10% individuals.
more lipid soluble than diazepam, whereas temazepam and
lorazepam are only 50% as lipid soluble. Midazolam, used Metabolism is hepatic, virtually total and for most com-
in anaesthetics, is the most lipid soluble of all (50% more so pounds complex, though often incestuously inter-related
than diazepam) (Greenblatt & Shader 1987). (Fig. 11.7). For a few, such as lorazepam and temazepam,
which share in common shorter half-lives, metabolism com-
Absorption from the GI tract is complete and followed prises simply conjugation with glucuronic acid, which pro-
by extensive first-pass metabolism for most compounds. duces the water solubility necessary for renal excretion

Fig. 11.7 Interconnected biotransformation Desmethyl- Diazepam
pathways for some commonly utilised chlordiazepoxide Minor pathway
benzodiazepines. Glucuronidation

Chlordiazepoxide Demoxepam Temazepam

Diazepam Major pathway Desmethyl- Glucuronidation
diazepam Oxazepam

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(Richens 1983). These drugs therefore produce no active CI– Outer layer
metabolites. For compounds undergoing more extensive βα Inner layer
metabolism, the fastest and hence first step involves dealkyla- γβ
tion of alkyl substituents of the B ring, a process that strongly
determines the half-life: where the alkyl group is large or sited α
far from the ring itself, dealklyation is rapid and half-lives
short (e.g. flurazepam); with small alkyl substituents posi- Cell membrane
tioned close to the ring (e.g. chlordiazepoxide), dealkylation
is slow and half-lives longer (Kaplan & Jack 1983). For drugs Fig. 11.8 GABAA receptor (motif for benzodiazepine
with methyl substituents at the N1 position, demethylation binding) (adapted from Figure 5.6 p.112, Iversen et al, 2009, with permission;
takes place, which is a relatively slow process. Perhaps the
most important aspect of metabolism is hydroxylation at originally adapted from a figure by S M Paul in Bloom & Kupfer:
the R3 site which, for a number of drugs, produces desmethyl- Psychopharmacology: the 4th generation in progress. Raven Press, 1995).
diazepam, a fully active metabolite which undergoes slow
oxidation prior to excretion and thus has a very long half-life GABAA (or GABAA-R: ‘rapid’) receptors are members of a
(30–100 hours). superfamily of ligand-gated ion channels that includes nicotinic
cholinergic, inotropic glutamatergic and 5HT3 receptors. They
Knowledge of the pharmacokinetics of benzodiazepines comprise a ring-shaped cylinder of transmembrane protein
illustrates the powerful impact a drug’s physicochemical prop- subunits arranged in five groups traversing the membrane
erties and its intermediate metabolites can have on clinical (Fig. 11.8). Nineteen genes have been identified as coding
expectations, and explains some apparent paradoxes. For for subunits designated a (1–6), b (1–3), g (1–3), d, E, y and
example, knowledge of flurazepam’s ultra-short half-life but p (1 each), plus three rho (r) subunits (sometimes referred
the long half-life of its major and active metabolite, desalkyl- to as ‘GABAC’ receptors). Alpha and b subunits interact
flurazepam (50–100 hours), allows one to predict that potent promiscuously insofar as each stimulates binding to the other,
hangover and toxicity might be seen with this drug, espe- a relationship in which g subunits are crucial. Coassembly
cially in the elderly. Indeed, cumulative effects are to be anti- of a and b with a g subunit is the minimum requirement
cipated with those drugs, such as diazepam, which have for a high-affinity benzodiazepine binding site, a motif
desmethyldiazepam as a metabolite, and advice on driving sometimes referred to as the omega- (i.e. benzodiazepine-)
and contact with machinery is particularly important when 1 receptor.
recommending these.
These receptor components act as gate-keepers to the func-
The conflicting impact of distribution and half-life is evi- tional element of the complex – a gated ion channel for
dent with single intravenous use, common practice to which chloride. Despite the close functional relationship between
benzodiazepines lend themselves. Going by half-life values, it subunits, it is solely the GABA-related subunits which control
would be reasonable to expect that intravenous diazepam the channel. Benzodiazepines do not independently activate
would have a longer action than lorazepam, a drug of much this process (Roy-Byrne 2005). Stimulation opens the ion
shorter half-life. This is not the case because diazepam is rap- channel with influx of chloride into the cell, resulting in a state
idly distributed, resulting in swift declines in plasma levels to of hyperpolarisation which decreases the firing rate. Thus,
as low as one-fifth peak, and consequent loss of acute action. benzodiazepines facilitate normal GABA inhibitory effects,
The less widely distributed lorazepam maintains a longer achieved by increasing the number of channels opened or
action, despite its significantly shorter half-life (Greenblatt & the frequency of opening, not by prolonging the duration of
Shader 1987). opening of a few. The mechanism of channel opening involves
allosteric modulation (i.e. physical distortion) of the complex.
Pharmacodynamics
Not only do GABAA receptors differ in density in different
Mode of action CNS areas, so does their structure (i.e. assembly of subunits)
resulting in great heterogeneity. With up to 800 subtypes
In 1977, Braestrup and Squires in Denmark and Mohler and proposed, there is enormous room for variants underlying
Okada in Switzerland almost simultaneously discovered spe- different ‘types’ of symptomatology and different targets of
cific benzodiazepine receptor sites in the mammalian brain drug actions.
that bind labelled diazepam with high affinity. These are now
known to represent part of a GABA receptor-chloride ionophore This leaves unanswered two critical questions: (1) how does
complex, sites also known to bind alcohol and barbiturates. this relate to the pathophysiology and alleviation of anxiety?:
and (2) what is/are the elusive endogenous ligand/ligands
Receptors for the major inhibitory amino acid neurotrans- (‘endozepines’) that naturally couple with benzodiazepine
mitter, gamma amino butyric acid (GABA), come in two recognition sites?
forms delineated by Hill and Bowery in 1981 on the basis of
sensitivity (GABAA) or insensitivity (GABAB) to the plant
alkaloid, bicuculline. Baclofen is the major agonist at GABAB
sites which are coupled to their signal transduction mechan-
isms by G-proteins. Benzodiazepines do not interact with
GABAB receptors.

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Adverse effects benzodiazepine use but in most instances these probably repre-
sented incidental disorder unrelated to the drug. Certainly
Benzodiazepines have perhaps the highest therapeutic index of such problems, if genuine, are extremely rare.
all psychotropic drugs – and are extremely effective. As noted
with some other drugs, it becomes problematic as to whether Shortly after the introduction of chlordiazepoxide, a ‘syn-
complaints of ‘side effects’ represent ‘non-target’ actions or drome’ of paradoxical behavioural disinhibition, or ‘dyscon-
simply too much ‘target’ ones! They have little or no auto- trol’, was described (Ingram & Timbury 1960). The problem
nomic actions but may promote mild hypotension with over- appears more frequently in women, and although reported
zealous intravenous administration. Some patients complain most with chlordiazepoxide, is probably not unique to this.
of dry mouth and blurred vision, though whether these are The usual scenario is one of ‘confinement’, where the individ-
drug effects is unclear. ‘Dizziness’ or ‘wooziness’ which lacks ual perceives themself as trapped, and is then challenged.
the rotational, impelled qualities of vertigo may occur and is Confrontation in this situation can provoke a rage response,
probably lightheadedness related to mild blood pressure with intemperate and assaultive behaviour. This phenomenon
changes. Benzodiazepines do not alter the electrical or mechan- is perhaps better recognised with other CNS depressants,
ical functioning of the heart. At therapeutic doses, they do not especially alcohol, but it is important to bear in mind that in-
interfere with respiration but given rapidly i.v. can produce patient settings may be perceived as confining and forced pro-
significant respiratory depression and even arrest, especially fessional interventions as confrontational. Attempts to achieve
swiftly distributed compounds (e.g. diazepam). This is revers- behavioural containment with benzodiazepines might unwit-
ible with the benzodiazepine antagonist, flumazenil. tingly trigger the opposite.

Patients not infrequently experience decreased mental The final adverse effect is the most serious, and the one
acuity or frank daytime drowsiness and sedation. This can be that forced a radical reappraisal of the risk–benefit ratio of
evident early in exposure, when it usually fades. It may, benzodiazepines – physiological dependency. As early as the
however, emerge later during chronic exposure as a result of 1970s, it was clear that long-term use of benzodiazepines
accumulation of drugs/metabolites of long half-live. Despite could be associated with tolerance effects. Patients frequently,
this, however, there is remarkable tolerance to such clinical if not usually, lost the sedation associated with early exposure,
consequences of accumulation (Baldessarini 1985). REM rebound in patients who stopped long-term benzodiaze-
pine hypnotics was known from sleep EEGs (Oswald & Priest
Impaired psychomotor performance results from seda- 1965) and withdrawal-type features, including fits, were well
tion and from a primary deficit in information processing recognised after sudden cessation. However, full physiological
(Hindmarch 1980). As a group, benzodiazepines impair reac- dependency was thought to be a problem only in those who
tion times which can lead to significant functional deficits. abused medication. Furthermore, complaints from those stop-
Some performance deficits can be demonstrated soon after ping suddenly were similar to symptoms for which the drugs
exposure but, while these may ease with time, deviations from had been prescribed in the first place. Petursson and Lader
the norm can also become evident later from accumulation. (1981) showed conclusively that a withdrawal syndrome –
Most short half-life drugs, even those marketed as hypnotics, and hence physical dependence – could develop with benzodi-
will still be readily detectable in blood samples the following azepine regimes in the therapeutic range.
day. It is imperative that all patients taking a benzodiaze-
pine are advised of the impact this can have on daily tasks The symptoms of benzodiazepine withdrawal are, as a rule,
(e.g. driving, operating machinery), especially those requiring delayed compared to most withdrawal states. They are also
dexterity or high-level alertness. unusual in that they combine affective features with unique
perceptual disturbances. Some 5–7 days after stopping,
Benzodiazepines impair short-term memory. Traditionally patients start to feel increasingly unsettled, with anxious
viewed as a retrograde amnesia, controlled studies have shown dysphoria, diminished sleep (quality and duration) and day-
that the problem is almost exclusively an anterograde one, time fatigue. Flu-like symptoms supervene such as sweating,
with impairments of recall relating solely to events after drug listlessness, anorexia, muscle aches and headache. Perceptual
administration (King 1992). This also appears to be secondary changes take the form of heightened sensitivity to sound,
to sedation. Patients on routine treatment schedules are usu- light and touch, and may develop a ‘temporal lobe’ quality of
ally unaware of this effect but after intravenous administration distorted environmental relationships, e.g. doors or fireplaces
it can be striking. This can be used to therapeutic benefit in, sloping to one side. Surroundings can seem alien and frank
for example, cardioversion or endoscopy, where a benzodi- depersonalisation may occur. In addition, bizarre paraesthesiae
azepine beforehand will impair recollection of unpleasant may be experienced, such as numbness, tingling or a feeling of
interventions. It can, however, be exploited in incidents of movement, or a characteristic sensation of ‘walking on cotton-
so-called ‘date rape’. wool’. Fits are rare on withdrawal from therapeutic regimes.

Patients occasionally develop unsteadiness from mild There was a time when clinics were besieged by patients
discoordination but ataxia, dysarthria and general breakdown claiming persistence of such features months, or even years,
of coordination are signs of the CNS depression comprising after cessation of benzodiazepines, but this is untenable.
intoxication, and such features should be viewed in this light, Features of benzodiazepine withdrawal last for 1–2 weeks at
even if the history is of ‘therapeutic’ use only. most. Belief in the endurance of symptoms was – and is –
a reflection of their impact, the patient’s expectation and
Rare reports have appeared of skin rashes, blood dyscrasias, recurring anxiety.
headache, gastrointestinal upset, weight gain, impaired sexual
function and dyskinetic movement disorder associated with

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The risk of dependency with chronic benzodiazepine use Zolpidem is an imidazopyridine that binds selectively and
cannot be confidently quantified as it depends on individual with high affinity to the a-1-containing GABAA receptors
factors such as personality type, duration of exposure and but with much lower affinity ( 10-fold) to a-2 and a-3 and
pharmacokinetic parameters of the drug used. The best esti- not at all to a-5. Clinically, its anxiolytic, muscle relaxant
mate is that after 6 months continuous exposure, a risk in and anticonvulsant properties are weak. Despite these differ-
the region of 45% can be anticipated (Tyrer et al 1981). ences, it can be displaced from its binding sites by flumazenil.
However, features such as withdrawal anxiety/sleep distur- Zolpidem is well absorbed with bioavailability around 70%.
bance may be found in some patients after only 6 weeks of It is over 90% protein bound and has a half-live of 2–2.5 hours.
treatment (Power et al 1985). The risk must therefore be A relatively large proportion (>30%) of excretion is faecal.
judged as substantial. As would be predicted, withdrawal As it is metabolised solely by the CYP3A4 system, there is a
symptoms are more likely with drugs of relatively short relatively high risk of kinetic interactions. Confusional states
half-life, such as lorazepam. However, consistently the most and psychotic symptoms such as hallucinations have been
important determinant identified is duration of treatment – described as has somnambulence, though whether the risks
the longer the exposure the greater the likelihood (O’Brien are greater than with benzodiazepines is unclear. Zolpidem is
2005). certainly associated with dependency and is popular on the
illicit scene. Recently, remarkable reports have suggested an
Evidence to support specific treatments for benzodiazepine alerting action in patients with persistent vegetative and other
discontinuation is poor. Minimal interventions, such as advice minimally conscious coma states, though conformation of what
as to the presence of the problem and the need for reduction, is currently an inexplicable phenomenon is awaited.
is significantly better than nothing (OR 2.8, 1.6–5.1) (Oude
Voshaar et al 2006). The next step, systematic discontinua- Zaleplon, a pyrazolopyrimidine, is a full agonist for the ben-
tion under professional supervision, is also effective (OR 6.1, zodiazepine a-1 receptor, to which it binds with high affinity.
2.0–18.6) though few studies have been undertaken. Of aug- Affinity for a-2 and a-3 subtypes is lower. It has been pro-
mentation strategies (substituting an alternative compound), moted on the basis of its particularly short half-life ( 1 hour).
addition of imipramine may be helpful and group CBT has With Tmax also at around 1 hour the drug has a very sharp
been reported as beneficial, though analysis of data from such concentration curve compared to most psychotropics. It is
studies is usually inappropriate. If the problem has resulted rapidly metabolised to largely inactive metabolites. These
from use of a short half-life compound, switching to diazepam, favourable kinetics probably underlie the fact that zaleplon is
with its relatively long half-life, makes the task of tapered associated with few residual effects on waking. Despite this,
reduction easier (Higgitt et al 1985). it appears otherwise comparable to benzodiazepines in sleep
parameters such as onset latency, total duration, etc. (Dundar
Benzodiazepines are very safe. Even in overdose, fatality is et al 2004) though there are reports of better retention of per-
usually only associated with combined ingestion with other formance skills than with other hypnotic agents (Patat et al
drugs, especially alcohol. 2001). There is however no evidence that the dependency
issue is resolved with long-term use.
Other sedative/hypnotic agents
An alternative approach to anxiety management is buspir-
In recent years compounds have been identified that, although one, an azapirone (or azaspirodecanedione). This does not act
chemically not benzodiazepines, appear to act within the on the GABAA–benzodiazepine–chloride ionophore, though
GABAA–chloride ionophore complex. its complex actions are incompletely understood. It is a partial
5HT1a agonist and relatively weak antagonist of dopamine,
While chemically a cyclopyrrolone, pharmacologically zopi- apparently at predominantly presynaptic sites. It is rapidly
clone is similar to benzodiazepines in binding indiscriminately absorbed, undergoes extensive presystemic effects and has a
and with high affinity across the benzodiazepine site (a-1, half-life of only 2–4 hours. Buspirone’s spectrum of action is
a-2, a-3 and a-5 GABAA containing receptors). Whether restricted to anxiety, with little/no hypnotic, anticonvulsant
claims that it mediates its sedative/hypnotic response by pro- or muscle relaxant components. Its action is also not instanta-
ducing a different pattern of allosteric modulation of chloride neous, requiring some 10 days to become apparent and up to
channels is unclear. Clinically, its similarity to benzodiazepines 3 weeks to develop fully. It should not be used to substitute
is borne out on a range of sleep parameters (Dundar et al for benzodiazepines or alcohol in withdrawal regimes and
2004). It is presented commercially as a racemic mix, though should be avoided in those at risk of fits (mild proconvulsant
a refined product (eszopiclone) is available in some markets. action) and in combinations with MAOIs. It may produce mild
The drug is rapidly absorbed and widely distributed. Half-life gastrointestinal upset and dizziness and, notwithstanding its
is around 6 hours, though considerably longer in the elderly putative pharmacology, elevated prolactin and precipitation
( 9 hours). Protein binding is low (50–60%) and metabolism or exacerbation of extrapyramidal disturbances. Its metabo-
extensive, including up to 50% that is decarboxylated and lism is inhibited by naringenin in grapefruit juice producing
excreted via the lungs. Like benzodiazepines, zopiclone impairs substantial increases in blood levels. Because of its relative lack
performance motor skills, tolerance to which is only partial, of interactions with alcohol and apparent safety in overdose,
hence with prolonged use impairment continues to be evident buspirone has sustained a presence but on-going questions
in driving assessments (Staner et al 2005). A particular side- regarding efficacy have limited its use.
effect is dysgeusia (bitter metallic alteration in taste). Its abuse
potential is clear (Bannan et al 2007). Pregabalin, an anticonvulsant also used in the management
of pain syndromes, is licensed in Europe for treatment of

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generalised anxiety disorder. It binds to a subunit of voltage- Box 11.14
gated calcium channels in the CNS, though how this relates
to its mode of action is unknown. Unusually, it is not protein Indications for sedatives/hypnotics
bound and undergoes virtually no metabolism so interactions
are few. Its place in the treatment of anxiety states remains Primary
to be deterimined. • Short-term management of anxiety states, especially

A disparate variety of other drugs are sometimes useful generalised anxiety disorder without depressive,
in the range of disorders covered by sedative/hypnotics. hypochondriacal or other features
The ‘old stand-bys’, chloral hydrate and triclofos, are still • Short-term management of panic disorder, especially without
sometimes used in those rare situations in which hypnotics agoraphobia, the presence of which may necessitate inadvisably
are indicated in children and can, in desperation, be tried in prolonged exposure before efficacy accrues. Nowadays,
adults. Chloral, which added to alcohol comprised the origi- however, imipramine is often considered a preferential strategy
nal ‘Mickey Finn’, can be quite irritant to the stomach and tri- for the drug treatment of panic states
clofos is better tolerated. Highly sedative antihistamines, such • Short-term management of insomnia, especially when
as promethazine, can be useful sleep inducers but the thia- characterised by nocturnal anxiety and delayed initiation of sleep
mine analogue chlormethiazole (clomethiazole) is a potentially For these indications, ‘short-term’ is usually defined as 2-4
addictive and unpleasant compound that should be avoided. weeks
• The emergency and prophylactic treatment of seizure disorders.
Therapeutics The major value of benzodiazepines as a group is in the
emergency treatment of status epilepticus, in which they are
Indications highly effective. They are also of great value in preventing seizure
activity in states, such as withdrawal, where the seizure
NICE Guidelines (NICE 2004, amended 2007), in line threshold is lowered. In the long-term prophylaxis of epilepsy,
with others, recommend SSRIs for the treatment of anxiety their ability to obstruct generalisation of a fit and to maintain an
states, a position recent review of the evidence supports elevation of the seizure threshold tends to undergo tolerance,
(Hoffman & Matthew 2008). Furthermore, in generalised and they are of less value in this situation, although some, such
anxiety disorder, effect sizes have been shown to be compara- as clonazepam which has an extremely long half-life, appear to
ble (SSRIs, 0.36: BDZ, 0.38) (Hidalgo et al 2007). Yet be more effective in this regard
benzodiazepines remain widely used in clinical practice, not • Containment of psychiatric emergencies. In such situations their
just for the short-term role recommended by guidelines. case of administration, rapidity of onset and safety make them
Moderate increases in SSRI use represent largely combina- ideal for the management of severe behavioural disturbance
tion (with benzodiazepines), not solo treatment (Stevens & associated with usually psychotic disorders, where they are
Pollack 2005). Thus, while psychiatrists may consider pre- safer than parenterally administered antipsychotics
scribing guidelines too restrictive for the complex problems
they confront clinically, it is important that use of benzodia- Secondary
zepines and other sedatives/hypnotics remains constrained • It has been proposed that in high dose (e.g. diazepam up to
within clear clinical indications (see Box 11.14) rather than
once again being allowed to return to the unmonitored, 100 mg per day) benzodiazepines have a primary antipsychotic
repeat-prescribing practices of the 1970s. action (Lingjaerde 1991). The evidence for this remains
unconvincing, but where these drugs may be helpful is as
Strategies adjunctive treatments of acute psychotic states, particularly
schizophrenia, In this situation their value may be in lessening
The use of sedatives/hypnotics is difficult because at one the subjective anxious/dysphoria of ‘akathisic-type’ adverse
level it is so easy – ‘The problem is they work’! And they effects, which have themselves been implicated in exacerbating
work quickly. Because they are effective with a highly advan- the positive features of the illness (Owens 1999)
tageous therapeutic index, they appear to offer easy solutions • In the treatment of non-extrapyramidally mediated rigidity/
for target disorders which are in fact illusory. CBT techni- spasticity
ques are effective in treating anxiety states and may be supe- • As pre-operative or inducing agents in relation to minor surgery.
rior to hypnotics in treating sleep disorders (Morgan et al
2004) – but that requires participation and effort! More Miscellaneous drugs
than any other type of psychotropic agent, these drugs must
be seen as part of a comprehensive package of care, with Anticholinergics
the drugs the junior partner. Principles of their use are
summarized in Box 11.15. Anticholinergics are synthetic analogues of belladonna alka-
loids with wide applications in medical practice. They have
While newer hypnotic agents may offer some advan- been used in the treatment of Parkinson’s disease since the
tages, no compound used for sedative/hypnotic purposes can 1920s, but have been largely superseded by dopamine agonists.
at present be freed from the major risks of misuse and Nowadays, over 80% of anticholinergic prescriptions are to
dependency. counter non-target actions of antipsychotics.

Despite being among the most prescribed drugs in psychiat-
ric practice, anticholinergics are amongst the least studied.

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Box 11.15 compound could offer clinical advantage. Furthermore, heat
stroke has been described with its use (Adams et al 1977)
Principles of sedative/hypnotic drug use and it should be avoided in those living in hot climates or
who have a prior history, or current suspicion, of
• Continuous treatment should be time-limited, as far as neuroleptic malignant syndrome.
possible to 2–4 weeks
Trihexyphenidyl-related compounds. These include
• An intermittent pattern of recommended use is preferable, trihexyphenidyl itself (benzhexol), as well as biperiden and
where possible, particularly in relation to insomnia procyclidine. Biperiden (withdrawn in the UK for
commercial reasons) is the most M1 selective
• The risks of dependency should be explained to the patient prior anticholinergic and trihexyphenidyl the least, with
to implementing treatment—but should be done in relation to procyclidine only somewhat less selective than biperiden.
the facts. One dose of temazepam on a long-haul flight is not the The advantage of choosing a more selective drug is the
makings of a junky! lower likelihood of producing unwanted peripheral
anticholinergic effects. A disadvantage of trihexyphenidyl is
• Intramuscular use, as a rule, offers little advantage over the oral that it may be more prone to causing excitement (Dutz
route in emergency situations, while application of some of the 1992). Procyclidine is well absorbed, with Tmax varying
pharmacokinetic data can contribute to maximising their effects from 1 to 8 hours. It has a relatively short half-life
with emergency, ‘stat’ intravenous use (t1/2 8–16 hours) suggesting that twice daily dosing is
possible. Biperiden, still popular outside the UK, is rapidly
Pharmacodynamically, they act as antagonists at muscarinic absorbed with a Tmax of 1–2 hours. Its elimination
cholinergic receptors with little action at nicotinic sites. half-life, in the region of 18 hours, might be compatible
Muscarinic receptors are metabotropic G-coupled receptors with once daily dosing.
pharmacologically characterised into isotypes M1 to M5. The
main therapeutic target of anticholinergics is the M1 subtype, In general, anticholinergics should not be used in rigid
widely distributed throughout the CNS (M2 and M3 subtypes prescribing schedules but should be started in low doses (e.g.
are predominantly active peripherally, e.g heart rate and bron- procyclidine 2.5 mg b.d.) and increased flexibly until resolu-
chiolar patency). However, the antiparkinsonian effects of tion of target symptomatology (Owens 1999). Although they
anticholinergics correlate poorly with their actions at musca- can sometimes produce sedation, the more usual response in
rinic sites and an alternative pharmacodynamic explanation is low doses is excitement, and they should not be given after
via dopamine reuptake inhibition. tea-time as they can significantly interfere with sleep (Johnstone
et al 1983) though this action may undergo tolerance. They
What is known pharmacokinetically has mainly been should furthermore be used sparingly – even relatively selec-
derived from patients with Parkinson’s disease, which may tive drugs can produce their own pattern of side-effects;
be flawed in psychiatric populations. Coincidental administra- they can exacerbate positive psychotic features; and while
tion of antipsychotics has been reported to produce a kinetic unpopular among drug misusers, in patient populations they
interaction resulting in elevations of antipsychotic blood levels have a widespread reputation of being euphorogenic and have
though this remains unconfirmed, and if valid may not be a a well-established potential for misuse.
class effect.
L-Tryptophan
Anticholinergics commonly used in psychiatry are of three
types: The essential amino acid L-tryptophan is derived from dietary
sources. As the precursor of serotonin, it has antidepressant
Tertiary amines related to diphenhydramine. Orphenadrine properties though these are inadequate for use as primary
combines antimuscarinic with antihistaminic properties. treatment. It has however an established adjunctive role,
It has a variable therapeutic margin but can be fatal with usually in combination with a tricyclic, in the management of
overdoses as low as 10 times the therapeutic dose (Dutz treatment-resistant depression. It is best avoided in combina-
1992). Little is known about its pharmacokinetics, although tion with an SSRI in view of the possibility of precipitating
with a reported half-life in the range of 14–18 hours, it is serotonin toxicity.
suitable for twice daily dosing. It is doubtful if the
combination of actions found in this drug offer any A rare, potentially fatal, multisystem allergic disorder,
advantages for its indicated psychiatric use, and reports of eosinophilia myalgia syndrome, appeared in the early 1990s
its relative toxicity should raise concern. in patients taking tryptophan from mainly herbal sources
Compounds combining atropine-like and diphenhydramine- which likely resulted from a manufacturing issue in a single
like actions. The only widely used member of this group is Japanese plant. Registering patients and prescribers with the
benzatropine (benztropine), which is also the least selective, license-holder has now been suspended but any allergic-type
combining both atropinic and antihistaminic actions. symptoms (fever, myalgia, arthralgia, eosinophilia) should
Because of its wide spectrum of actions it is particularly prompt immediate cessation and further investigation.
likely to interact with other drugs sharing a similar broad
spectrum, the most obvious being low potency
antipsychotics. It is hard to see how such an unfocused

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Beta-noradrenergic antagonists Rivastigmine is predominantly metabolized by sulphate conju-
gation, while donepezil and galantamine utilize CYP3A4 and
Beta-blockers, and particularly propranolol, have been widely 2D6 hepatic isoenzymes. AChEIs demonstrate a non-linear
used in psychiatry for the treatment of the somatic manifesta- relationship between dose and cholinesterase inhibition, with
tions of anxiety though, in general, results are disappointing. different drugs achieving their plateaux at different doses.
Their major benefit may be in the management of symptom- Clinical improvement in cognition, functional abilities and
atology that is specifically environmentally triggered, such as behaviour are dose-related and are suggested to result from
performance anxiety in musicians or actors. Propranolol was 30–70% enzymatic inhibition (Jann et al 2002).
at one time advocated as an adjunctive treatment in severe or
resistant schizophrenia, a risky undertaking with the high-dose Although intuitively sound, acetylcholinesterase inhibition
regimes advocated. It was subsequently shown that benefits may be inherently limited, as the often profound decreases
might well have resulted from a pharmacokinetic interaction in synthesis of M1 receptor-linked phosphinositides found in
of propranolol in increasing antipsychotic blood levels, and this the neurons of demented patients may not only reflect a
approach has faded. reduction of receptor numbers but also a loss of functional
competency in those which remain (Shvaloff et al 1996).
There has also been interest in propranolol as a treatment of Cholinergic facilitation is certainly not improved by coinciden-
akathisia but the greater the trial literature the more sober the tal administration of anticholinergics, something more com-
appraisal. In the low doses suggested (20–60 mg per day) mon in those on acetylcholinesterase inhibitors (Johnell &
propranolol is, in the absence of a history of asthma, safe and Fastbom 2008), a replicated embarrassment readers of the
if it is going to work, it is likely to do so within a few days. This present chapter will be spared!
might, however, be seen as the first-line approach primarily in
patients who develop akathisia in the absence of coincidental An alternative strategy is inhibition of excitotoxic amino acid
parkinsonism. neurotransmitters which, it has been postulated, play an impor-
tant role in the pathophysiology of traumatically and degen-
The non-selective beta-blocker, pindolol, has been advo- eratively mediated brain pathologies, including dementias.
cated as an antidepressant augmentation strategy, largely on Of those endogenous amino acids known to act in an excitatory
the basis of its putative 5HT1a antagonist action, which results transmitter role (e.g. glutamate, aspartate, homocysteine), gluta-
in increased intrasynaptic serotonin. Reviews highlight matergic receptors are the best characterized. These comprise
conflicting results (Olver et al 2000) perhaps related to the two groups: metabotropic, activating the second messengers
possibility that in vivo it acts predominantly as a 5HT1a agonist phospholipase C and adenylate cyclase; and ionotropic, opening
(Clifford et al 1998)! cation permeable channels mediating calcium and potassium
influx. Of the latter type, N-methyl-D-aspartate (NMDA)
Drugs used in the treatment of dementia receptors are the most studied. NMDA antagonism has been
shown to promote a neuroprotective effect in a number of path-
Developments in the field of cognitive enhancement only ological states. Memantine, a voltage-dependent, uncompetitive
recently seemed the most exciting in psychopharmacology. NMDA receptor antagonist, licensed for moderate to severe
Reality has, however, set in as the limitations of current dementia, is the only drug so far to exploit this hypothesis.
strategies become apparent.
The place of AChEIs in the management of Alzheimer’s-
Deficits in cholinergic transmission underlie the ‘cholinergic type dementia has become contentious. This is not because
hypothesis’ of dementia (Bartus et al 1982), which formed the benefits cannot be demonstrated – recent Cochrane reviews
major starting point for drug development. Inhibition of for rivastigmine (Birks et al 2000), galantamine (Loy &
the enzyme acetylcholinesterase with the aim of extending Schneider 2006) and donepezil (Birks & Harvey 2006) all
the action of acetylcholine, has been the approach most pur- show modest improvements in cognition and other domains
sued. The first widely studied acetylcholinesterase inhibitor in those with mild to moderate dementia up to 26 weeks,
(AChEI) was tacrine (tetrahydroaminoacridine). Results were the latter review finding benefits across the severity range for
disappointing, especially in view of its hepatotoxicity ( 28%) up to 52 weeks. Controversy arises from the judgement as to
and although licensed in the USA, this remained an experi- whether these benefits are ‘cost-effective’. A 2006 National
mental drug in the UK. Several AChEIs have, however, now Institute for Health and Clinical Excellence guideline (NICE
been widely licensed. 2006) concluded acetylcholinesterase inhibitors were only
cost-effective in disease of ‘moderate’ severity (MMSE 10-20),
Donepezil and galantamine are reversible inhibitors of cen- a somewhat bizarre conclusion that, following judicial review,
tral acetylcholinesterase, with little effect on peripheral butyr- was (marginally) modified. Demonstrable benefits from cogni-
ylcholinesterase, while rivastigmine inhibits both enzymes. tive enhancers are undoubtedly slight with no impact on disease
Galantamine further enhances acetylcholine synaptic activity progression, but some of the discrepancy in perception (apart
by modulating nicotinic receptors. Donepezil, also active at from the unjustified optimism of patients and carers) may
nicotinic sites, upregulates the a-7 isotype which has been pro- lie with limitations in assessing those specific domains where
posed as part of a neuroprotective ‘package’ (Takada-Takatori benefits maximally impact, such as the executive disorders
et al 2008). All are readily absorbed, rivastigmine and galan- that may underlie functional decline (Behl et al 2008). There
tamine more rapidly (Tmax <2 hours) than donepezil (Tmax are as yet unconfirmed reports that rivastigmine may have ben-
3–5 hours). The former two compounds have low protein efits in the dementia of Parkinson’s disease. The Cochrane
binding (<40%), while binding is high for donepezil. review of memantine suggests small beneficial effects on

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cognition in Alzheimer’s across the severity range up to 6 P450 system and responses to individual drugs and drug com-
months (McShane et al 2006). binations. P450 enzymes are of two types: mitochondrial,
which mediate steroid synthesis; and microsomal, which medi-
The demographic ‘time-bomb’ heralding dramatic increases ate the oxidative metabolism of exogenous compounds.
in dementia and the limited results from current strategies have Although predominantly sited in the liver, they are widely
directed considerable endeavour towards new drug develop- distributed, including in gut wall and brain.
ment. Patients with rheumatoid arthritis have lower rates of
Alzheimer’s disease, though interest in the role of anti- Cytochrome P (CY-P) isoforms are characterised according
inflammatory agents in the management of dementias has to a genetic format, where the first number refers to the gene
waned. However, because of the strong association between family, followed by the gene subfamily letter and finally the
brain cholesterol and generation of b-amyloid peptide gene number itself, e.g. CYP-2-D-6. Over 30 CYP enzymes
(Michikawa 2003), interest has grown in the use of lipid- have been identified, with many still to be characterized
lowering statins, though benefits remain to be established. (Ketter et al 1995; Ereshefsky et al 1996) but in humans, four
Some developments are likely in novel delivery systems for cur- appear to be the most important – CYP1A2, CYP2C (compris-
rent drugs, such as transnasal formulations with enhanced brain ing 2C9/10 and 2C19), CYP2D6 and CYP3A3/4 (Fig. 11.9A).
penetrance (Hanson & Frey 2008) and transdermal patches (Win- Most psychotropic drugs utilize the 2D6 system, while the
blad & Machado 2008), but entirely new departures involve mod- importance of the CYP3A3/4 system lies in it being the most
ifying the formation and elimination of pathological elements, such abundant, especially in intestinal mucosa. The activity of these
as tau and amyloid protein by, amongst other things, targeting over- enzymes is determined genetically and striking interindividual
activity/expression of GSK-3 (Martinez & Perez 2008). differences in drug levels and tolerabilities of many psychotro-
pic agents can to some extent be attributed to polymorphisms
From a protracted and shaky start, cognitive enhancement within these systems, especially the CYP2D6 genotype. These
is now an extremely active area within psychopharmacology, result from the combination of ‘wild’ alleles (which possess
with the likelihood of such drugs becoming ‘life-style’ agents, normal metabolic activity) and/or ‘mutant’ alleles, which may
as well as therapies for defined illnesses. be characterized by decreased or absent metabolic capacity
(Vandel 2003). The exact combination of polymorphisms in
Drug interactions any individual determines their capacity to metabolise drugs
which utilize that system – i.e. whether they are ‘poor’, ‘inter-
Increasing polypharmacy, of prescribed as well as over- mediate’, ‘rapid’ (‘extensive’), or ‘ultra-rapid’ metabolisers –
the-counter medicines (including ‘natural’ remedies), makes which has a bearing on dose–response relationships for both
drug interactions increasingly likely. Most encountered in psy- efficacy and tolerability. About 7% of Caucasians can be charac-
chiatric practice do not, fortunately, have serious conse- terised as ‘poor’ (as opposed to ‘extensive’) metabolisers of drugs
quences but even these may delay or obstruct target effects undergoing oxidative metabolism via 2D6, while the
or increase the likelihood of non-target ones. As we have seen, corresponding figure for Orientals is only 1% (Bertilsson 1995).
rarely some can be fatal. On the other hand, 15–20% of South Asians exhibit 2C19
polymorphisms, which are only evident in 3–5% of Caucasians.
Interactions are of two kinds. In pharmacodynamic interac-
tions, a target action is magnified or diminished on the basis of In addition to one’s individual enzyme ‘endowment’, these
the action of a second drug operating on the same target. These systems may be inhibited or induced by exogenous substances,
can produce responses that are quantitatively excessive but respectively delaying or accelerating metabolism of drugs
recognisable (e.g benzodiazepines and alcohol) or strikingly dif- utilising that system as its substrate. Thus, broad understanding
ferent qualitatively from those of either drug alone (e.g. the of those drugs which are metabolised by P450 enzymes and
hypertensive crises with MAOIs, where the second ‘drug’ is a some of the commoner inhibitors and inducers can be helpful
food constituent). Pharmacokinetic interactions result when one in predicting patterns of interaction of clinical relevance
drug produces an alteration, usually quantitative, in the target (Fig. 11.9B). One might for example predict that smokers will
action of a second drug by altering its absorption, distribution attain substantially lower blood levels of clozapine than non-
and especially its metabolism or elimination. smokers on comparable doses, which is the case (Rostami-Hod-
jegan et al 2004); or that fluoxetine, a potent inhibitor of the
As far as psychotropic drugs are concerned, pharmacody- CYP2D6 isoenzyme and less so of the CYP3A3/4 group, would
namic interactions are in general the more serious but pharma- produce elevations in the blood levels of other psychotropics
cokinetic interactions are not uncommon. The efficacy of most such as tricyclics, certain antipsychotics (eg haloperidol) and
psychotropics correlates poorly or not at all with blood levels benzodiazepines such as alprazolam. It may in addition increase
and the relationships with tolerability are only slightly more carbamazepine levels. It can also be recommended that fluvox-
secure, so these have traditionally been seen as rarely produc- amine, which inhibits both the 3A3/4 and 1A2 groups, should
ing problems of significance to routine practice. This may, not be coadministered with theophylline (or aminophylline) or
however, be complacent. Detailed understanding of the bases alprazolam in view of the high levels of the latter drugs that
of such interactions may throw light on important clinical are likely to ensue. Caution would also be indicated with cloza-
issues, such as differences in response rates and patterns of pine. Combinations of tricyclics with potent inhibitors of
tolerability. Occasionally it may prevent potentially toxic CYP2D6 should be avoided, as tricyclics are dependent on this
elevations in blood levels. for their hydroxylation. The combination of a tricyclic (desipra-
mine) with paroxetine or fluoxetine can result in a three- to
The disciplines of pharmacogenetics and pharmacoge-
nomics have increased understanding of the cytochrome

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A

Substrate CYP1A2 CYP2D6 CYP2C9 CYP2C19 CYP3A3/4

Antidepressants Tertiary amine Tertiary and Tertiary amine Tertiary amine
Antipsychotics tricyclics tricyclics
tricyclics secondary (N-demethylation) (N-demethylation)
(Es)citalopram (Es)citalopram
(N-demethylation) tricyclics Moclobemide Sertraline
Sertraline O-desmethylvenlafaxine
Mirtazapine (hydroxylation) (Fluoxetine) (Fluoxetine)
Norfluoxetine
Fluoxetine Aripiprazole (Reboxetine)
(Clozapine)
Venlafaxine (Olanzapine) Clozapine
Quetiapine
(O-demethylation) Aripiprazole
Sertindole
Mirtazapine (Haloperidol)

Duloxetine

Trazodone

Clozapine Risperidone
Olanzapine Olanzapine
Aripiprazole
Sertindole
Haloperidol
Perphenazine
Chlorpromazine

Sedative/hypnotics Diazepam Diazepam
(N-demethylation) (N-demethylation and
Phenobarbital hydroxylation)
Hexo- and mepho-barbital Flunitrazepam
Alprazolam
Clonazepam
Midazolam
Donepezil
Galantamine
(N-oxide-galantamine)

AChEIs Galantamine
(O-desmethyl-galantamine)

Miscellaneous Caffeine Atomoxetine Warfarin Methadone Carbamazepine
Propranolol Beta-blockers (major isomer) Diphenhydramine Methadone
Paracetamol Chlorpheniramine Phenytoin Omeprazole Ca channel antagonists
Theophylline Codeine Tolbutamide Lansoprazole Statins (atorva-/lova-/
Melatonin (demethylation to morphine) Chlorpropamide Phenytoin simva-)
Frovatriptan Dextromethorphan Rosiglitazone Propranolol Ethosuximide
Zolmitriptan Dihydrocodeine Celecoxib R-warfarin (less active Sildenafil
Rasagiline Diphenhydramine Diclofenac isomer) Quinidine
lc antiarrhythmics Ibuprofen Erythromycin
Metoclopramide Indomethacin Immunosuppressants
Promethazine Naproxen (ciclasporin, etc.)
Tramadol Fluvastatin Chemotherapeutic agents
Tamoxifen Rosuvastatin (cyclophosphamide,
Valsartan tamoxifen, etc.)
Protease inhibitors

Fig. 11.9 (A) Psychotropic drug interactions: some substrates of cytochrome P450 isoforms.

(Continued)

four-fold increase in plasma desipramine levels, whereas coad- Psychotropics with little or no participation in P450-
ministration with sertraline, a weaker inhibitor, produces only mediated metabolism include sulpiride, amisulpride, riva-
modest increases in desipramine levels. stigmine and memantine. Most drugs have several potential
metabolic pathways and even now the necessary details of
A further example is bergamottin, a constituent of grape- oxidative metabolism are still not known for the majority,
fruit juice, which inhibits the CYP3A3/4 system on which, so clinically it is not yet possible to apply information
for example, ciclosporin (cyclosporin), a number of calcium on those drugs that do utilise the P450 system in a mathe-
channel antagonists and buspirone depend for metabolism, matical way. This is nonetheless an area of increasing
resulting in significant elevations in blood levels and compro- importance.
mised tolerability.

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B CYP1A2 CYP2D6 CYP2C9 CYP2C19 CYP3A3/4
Inhibitors
Strong Fluvoxamine Quinidine Fluvoxamine Fluvoxamine Azole antifungals
Paroxetine Fluoxetine (e.g. ketoconazole)
Weak Naringenin Fluoxetine Cimetidine Protease inhibitors
Inducers (grapefruit juice) Ritonavir Disulfiram (e.g. saquinavir)
Norfluoxetine Metronidazole Oxcarbazine Macrolide antibiotics
Caffeine Sertraline Phenytoin Modafinil (e.g. erythromycin)
Cimetidine Desmethylsertraline Fluoxetine Bergamottin (grapefruit
Ciprofloxacin Fluvoxamine Valproic acid Isoniazid juice)
Ethinyl oestradial Venlafaxine (Depakote) Fluvoxamine
Moclobemide Moclobemide Norfluoxetine
Haloperidol Fluoxetine
Perphenazine Sertraline
Bupropion Desmethylsertraline
Erythromycin Paroxetine
Ketoconazole Venlafaxine
Duloxetine Hyperforin (St John’s Wort)
Reboxetine (high dose) Trazodone
Quinidine
Cimetidine
Diltiazem
Verapamil
Escitalopram
Dexamethazone

Cigarettes Resistant to induction Barbiturates Barbiturates Carbamazepine
(? nicotine) Phenytoin Carbamazepine Phenobarbital
Carbamazepine Carbamazepine Phenytoin Phenytoin
Barbiturates Griseofulvin Primidone Topiramate
Omeprazole St John’s Wort Rifampicin Primadone
Ritonavir St John’s Wort Rifampicin
NNRTIs* Modafinil
Dexamethasone
NNRTIs (e.g. efavirenz)
Cafestol (unfiltered coffee)

Fig. 11.9—Cont’d (B) Psychotropic drug interactions: some inhibitors and inducers of cytochrome P450 isoforms.
*Non-nucleoside reverse transcriptase inhibitors.

Pregnancy and lactation Meta-analysis of published data suggested that first trimester
exposure to low-potency phenothiazines imparts a small
Most psychotropics can produce fetal maldevelopment when increased risk of organ dysgenesis (additional risk: 4 per
administered to pregnant laboratory animals and the trans- 1000 live births) though recent studies have failed to find
lation of such data to humans led initially to considerable any increased risk (Yonkers et al 2004). No specific risk can
concern. This is reflected in the conservative recommenda- be attributed to high potency antipsychotics or tricyclics.
tions usually offered by clinicians and the British National Provisional evidence with newer antipsychotics suggests no
Formulary. Systematic clinical evaluation has, however, been increased teratogenic risk though exposed neonates may be
sparse (Altshuler et al 1996). The issue is complicated by large for gestational age (Newham et al 2008).
potentially confounding environment/life style (e.g. greater
smoking prevalence) and other factors that increase obstetric While tricyclics appear safe for use throughout pregnancy,
risk in psychiatric patients and the fact that discontinuation including first trimester (Simon et al 2002), the position of
of medications can be associated with striking relapse risks SSRIs remains contentious. It is suggested that in utero expo-
(Viguera et al 2007). sure is associated with an increased risk of earlier delivery
(Simon et al 2002), low birth weight for gestational age and
Recent appraisals agree that in general psychotropic drugs neonatal respiratory distress (Oberlander et al 2006), though
are relatively safe to use during pregnancy (Einarson 2009). these findings have been challenged. One study, as yet unrepli-
cated, found an increased risk of the potentially fatal

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Clinical psychopharmacology CHAPTER 11

persistent pulmonary hypertension of the newborn (Chambers pharmacokinetic changes accompanying gestation must be con-
et al 2006). However, it is clear that infants exposed to SSRIs sidered. There is little point in agreeing a delicately balanced
in late gestation have a three-fold increased risk of developing decision and, in effect, running risks without maximising ben-
a ‘neonatal behavioural syndrome’ following delivery (Moses- efits. In general, blood levels of therapeutic agents fall as preg-
Kolko et al 2005), comprising a combination of CNS, respira- nancy progresses from a combination of altered absorption,
tory and GI signs that usually fade over the first 2 weeks of plasma volume expansion (cf. lithium), reduction in plasma
life. No fatalities have been recorded but some infants require binding proteins, diminished hepatic flow, CYP changes
special support. Thus, there are sufficient questions to urge mediated by alterations in steroid hormones and increased
caution in the use of SSRIs in pregnancy until the position is renal filtration and excretion (Sit et al 2008). With fluoxetine,
clarified. this can result in a 50% reduction in blood levels at 36/37
weeks compared to the first 8 weeks (Heikkinen et al 2003).
No drug has undergone greater reappraisal in recent years Thus, to avoid symptom ‘breakthrough’ in the second half of
than lithium. In the 1970s a Register of Lithium Babies pregnancy, doses may need to be increased then tapered
collected data from Denmark, Canada and the USA on preg- 2 weeks prior to delivery to minimise the risks of withdrawal
nancy outcomes for babies exposed to lithium in utero. effects in the infant.
Although reporting high rates of congenital – especially car-
diovascular – abnormalities, even the first report noted that The lipophilic properties of the great majority of psycho-
abnormality was less common than might have been expected tropic agents results in secretion in breast milk. However,
from animal data. Latterly, the Register provided data on 225 the large apparent volume of distribution of such drugs
babies, in whom the prevalence of birth defect was 11% (gen- means that the fraction of a maternal dose that is available
eral population 2%), 18 of the 25 having cardiovascular for secretion in breast milk is small. The levels attained are
abnormalities and 6, Ebstein’s Anomaly (Weinstein 1976). also dependent on the lipid content of the milk sample,
This work was highly influential in attributing to lithium a being as a rule higher in later expressed (or hind-) milk,
unique teratogenic risk but the nature of data collection (vol- with its higher fat content, than in initial (or fore-milk) sam-
untary reporting) held a powerful inherent bias – uneventful ples. Formal study of the passage of maternal psychotropic
pregnancies were less likely to be reported. Subsequently, the drugs to breast-fed infants has been slight and differences
risk of Ebstein’s anomaly with first trimester lithium exposure in drug assay methodologies makes comparisons difficult.
was calculated at 0.05–0.1%, indicating a 20- to 40-fold increase Evidence to date suggests that for mothers receiving most
over the population risk (Yonkers et al 2004) though others of the major classes of psychotropics the decision to
have argued that with such a rare disorder the question of breast-feed can, in terms of safety, be left to them (Yoshida
whether there is an increased risk, far less its magnitude, can- & Kumar 1996). In view of immaturity of the liver, breast-
not be determined at present (Giles & Bannigan 2006). What feeding should be contraindicated with babies born prema-
is clear, however, is that earlier data grossly inflated any risk. turely or who have neonatal illness.
Current reviews suggest that lithium during pregnancy is asso-
ciated with a small increased relative risk for all congenital There is a suggestion from a single case report that doxe-
abnormalities (approximately 1.2), while for all cardiovascular pin may cause infant toxicity (Matheson et al 1985) but
abnormalities it is in the region of 3.5 (Giles & Bannigan other tricyclics, although transferred, appear to be asso-
2006). In more recent animal studies in which doses are kept ciated with very low or undetectable levels in infants. On
to those comparable to therapeutic use in humans, lithium is the evidence to date, SSRIs also appear safe. Antipsychotics
devoid of demonstrable teratogenic effects (Giles & Bannigan do attain measurable levels in breast-fed infants and isolated
2006). ‘Lithium babies’ tend to be heavier at birth (Yonkers reports of acute dystonic episodes and ‘restlessness’ with
et al 2004). standard drugs have appeared. However, in general these
too seem relatively safe, though information on newer drugs
First trimester exposure to carbamazepine is associated is insufficient to allow for recommendations. Despite its
with a 0.5–1% risk of neural tube defects and greater inci- teratogenicity, there is no evidence that carbamazepine need
dences of craniofacial defects ( 11%), fingernail hypoplasia be contraindicated postnatally (Yoshida & Kumar 1996),
( 26%) and developmental delay ( 20%) (Jones et al a position probably similar for valproate (Eberhard-Gran et al
1989). Teratogenicity is enhanced when carbamazepine is 2006). Care should be exercised with benzodiazepines, as they
combined with valproate. The risk of neural tube deficits is may impair suckling from neonatal sedation and contribute to a
substantially greater with valproate (5–9%) relating to its ‘floppy’ baby.
use between 17 and 30 days’ gestation and to dose (Yonkers
et al 2004). Lumbrosacral fusion deficits are the most com- The one proscription is probably lithium, which is readily
mon. Valproate also imparts 2% risk of hypospadias to male secreted. One study found that trough levels of lithium in
fetuses. Finally, although data are contaminated, first trimes- maternal serum, milk and infant serum all fell by approxi-
ter exposure to benzodiazepines may be associated with a mately half – 0.76 to 0.35 to 0.16 mmol/l, respectively – and
slight increase in oral cleft abnormalities (OR ¼ 1.79, 1.13– infant tolerability was good (Viguera et al 2007). However,
2.82) (Dolovich et al 1998). Any drug with sedative proper- because of immaturity of regulatory mechanisms, these may
ties should be avoided in the prenatal period as this may com- represent a greater pharmacological impact than comparable
plicate delivery. levels in adults, so while the consensus for avoiding breast-
feeding with lithium has been challenged (Linden & Rich
If the decision is taken with the patient to continue treat- 1983; Viguera et al 2007), an alternative during the period of
ment with psychotropics during pregnancy, the effects of breast-feeding would still seem prudent advice.

287

Companion to Psychiatric Studies

It is further reassuring that so far there is no evidence that undue influence being brought to bear from psychopharmacol-
exposure of the neonate to psychotropics produces any detect- ogy. The issue then becomes a ‘gut’ one – whether as a matter
able early developmental/learning delays (Altshuler et al of principle mothers, or clinicians, have reservations about
1996), though the question has only been systematically exposing the immature brain to centrally acting drugs of diverse
evaluated in relation to tricyclics (Yoshida et al 1997). and pervasive pharmacological actions. Placed in terms of such
imponderables, it is likely most individuals would still opt for
Thus, overall the evidence is that the decision to breast-feed avoidance.
can in most instances be left to individual mothers, without

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