Foundation of Addiction Medicine 2019

AUDIT-C 3 items
1998
Less time

Identifies heavy
drinking

101

102

103

AUDIT

104

AUDIT

105

106

Self-administered, diagnostic
screening instrument

Assessing and monitoring depression
severity.

PHQ-9 Less than 5 min and easily scored by
the clinician.

Administered repeatedly, to reflect
improvement or worsening of
depression in response to treatment.

Good diagnostic validity

107

PHQ-9 half the length of
many other
depression measures

comparable
sensitivity and
specificity

9 criteria DSM-IV
depressive disorders

108

109

110

Using the For initial diagnosis:
instrument
• Patient completes PHQ-9 Quick Depression
Assessment.

• If there are at least 4 ^s in the shaded section
(including Questions #1 and #2), consider a
depressive disorder. Add score to determine
severity.

Consider Major Depressive Disorder

• if there are at least 5 ^s in the shaded section
(one of which corresponds to Question #1 or
#2)

Consider Other Depressive Disorder

• if there are 2-4 ^s in the shaded section (one of
which corresponds to Question #1 or #2)

111

From Kroenke K, Spitzer RL, Psychiatric Annals 2002;32:509-521

112

Neurobiology of Addictive
Disorders

Centre for
Addiction
Medicine

Dr. Vivek Benegal

Professor of Psychiatry, Centre for Addiction
Medicine, National Institute of Mental Health

and Neurosciences, Bangalore

113

Contents

1. What is addiction?
2. Why do people use addictive substances/

behaviors?
3. Why do people find it difficult to stop?
4. Who is at high risk? Why?
5. How can we use our knowledge to help

persons with addiction and their families?

114

What is Addiction?

• Scientific study of addictive behavior started in the
1930s. People addicted to drugs were thought to be
morally flawed and lacking in willpower.

• Those views shaped society’s responses to drug abuse,
treating it as a moral failing rather than a health
problem

• Led to an emphasis on punitive rather than
preventative and therapeutic actions.

• Intervention led by criminal/ quasi-religious/self help

115

What is Addiction?

• Recent scientific research: addiction is a chronic
disease that affects both brain and behavior.

• Addiction is a chronic but treatable medical
condition involving changes to circuits involved in
reward, stress, and self-control

• Neurobiological abnormalities identified --can be
targeted with therapeutic intervention and
improved addiction treatments through the
healthcare system

• Reduced stigma???

116

What is Addiction?

• The initial decision to take drugs is typically
voluntary.

• But with continued use, a person's ability to exert
self-control can become seriously impaired

• Impairment in self-control is the hallmark of
addiction. Loss of control + Salience

• Brain imaging studies show physical changes in
brain areas-critical for judgment, decision-making,
learning and memory, and behavior control.
Explains compulsive nature of addiction.

117

WHY DO PEOPLE USE ADDICTIVE
SUBSTANCES/ OR INDULGE IN
ADDICTIVE BEHAVIORS?

118

Different drugs-different mechanisms;
BUT….

THC’s chemical structure is similar to the brain
chemical anandamide. Similarity in structure
allows drugs to be recognized by the body and
to alter normal brain communication.

119

All known addictive drugs activate brain reward regions

-with sharp increases in the release of dopamine

120

Drugs Increase Dopamine in the Reward Circuit

• Dopamine is a neurotransmitter
present in regions of brain that
regulate movement, emotion,
motivation, and feelings of pleasure.

• Typically, increases in response to
natural rewards –food, sex

• All drugs over stimulate the system ,
produce euphoric effects, which
strongly reinforce the behavior of
drug use—teaching user to repeat it.

• Most drugs of abuse target the
brain’s reward system by flooding it
with dopamine.

121

Drugs of abuse activate the same brain areas that are activated
by natural rewards, only they activate them more strongly.

Breiter et al., 1998

122

Stimulant-dependent DA
increases in the striatum are
associated with the feeling of

“high.”

• DA increases MPH-reduced binding of [11C]raclopride dose-dependently in the striatum, where it
induced by different competes with DA for binding to DA D2 receptors (D2R).
classes of drugs
within the ventral
striatum, are linked
to the subjective
experience of
euphoria (or high)
during intoxication.

Volkow et al (2010) Bioessays; 32(9): 748–755

123

High, but brief, bursts of dopamine are required for
addiction

• Speed with which drug enters, acts upon, and leaves the brain (i.e. its
pharmacokinetic profile) plays a fundamental role in determining its
reinforcing effects.

• Every drug of abuse (cocaine, MPH, meth-amphetamine, and nicotine) exhibits the
same profile when the administration is intravenous, i.e., peak levels in
the human brain are reached within 10 min and this fast uptake is
associated with the “high”.

• Making sure that an addictive drug enters the brain as slowly as possible
should be an effective way of minimizing its reinforcing potential, hence
its abuse liability.

Volkow et al (2010) Bioessays; 32(9): 748–755124

WHY DO PEOPLE FIND IT DIFFICULT TO
STOP?

LONG LASTING BRAIN Changes OCCUR due to persistent drug use

125

Drugs more addictive than natural rewards?

• Just as we turn down volume on a radio that is too loud, brain of
repeated drug user adjusts by producing fewer neurotransmitters
in the reward circuit, or reducing number of receptors that can
receive signals.

• As a result, ability to experience pleasure from naturally
rewarding (i.e., reinforcing) activities is also reduced.

• So, drug user eventually feels flat, without motivation, lifeless,
depressed, and unable to enjoy things previously pleasurable.

• Needs to keep taking drugs to experience even a normal level of
reward—which only makes the problem worse, like a vicious cycle.

• Need to take larger amounts of the drug to produce the familiar
high—an effect known as tolerance.

126

Changes due to persistent drug use

• Drugs change brain of addicts in complex and
persistent ways…..far outlast other changes
associated with tolerance and withdrawal.

• Most important of these is a ‘sensitization’ or
hypersensitivity to the incentive motivational
effects of drugs and drug-associated stimuli
----Incentive sensitization theory of addiction (Robinson & Berridge, 1993)]

• INCREASE IN DRUG WANTING

127

What happens with repeated exposure

• Like LEARNING
• Neurochemical changes→Epigenetic

modifications→ Long lasting structural and
functional neuroadaptations
• Salience—Loss of control– Withdrawal

– Rapid reinstatement/Relapse –Use despite harm

HARM CAN HAPPEN W.O ADDICTION→ HARMFUL USE

128

Changes….

Neuro-adaptive mechanisms
within specific brain-circuits
mediate this transition from –
• occasional, controlled drug

use to..

• loss of behavioral control
over drug-seeking and
drug-taking that defines
chronic addiction

Drug addiction has been conceptualized as a disorder that moves from
impulsivity to compulsivity in a collapsed cycle of addiction comprised of
three stages: preoccupation/anticipation, binge intoxication, and
withdrawal/negative affect (Koob, 2004)

129

130

131

132

∆FosB Sensitizes Drug Responses by Altering the
Structure of Nucleus Accumbens Neurons

Expansion of neuron’s
dendritic tree (increased
dendritic spines) after
chronic drug (cocaine)
exposure observed in nuc
accumbens and prefrontal
cortex.

Similar to those observed
in long-term potentiation
during learning --long-lived
sensitized responses to
drugs of abuse or
environmental cues.

133

Epigenetic regulation and dendritic spine plasticity

• All drugs of abuse 134
alter structural
connectivity of
neurons in the
reward and other
circuitry

• Effect most
evident in changes
in the number,
shape and size of
dendritic spines
on medium spiny
neurons (MSNs) in
the nucleus
accumbens (NAc)

From: Robinson & Nestler(2011)Nature Reviews Neuroscience 12, 623-637

Experimentation

135

Experimentation
Regular Use - Tolerance

136

Experimentation
Regular Use - Tolerance

Loss of Control

137

Experimentation

Regular Use - Tolerance

Loss of Control
Salience – Craving -

Withdrawal

138

Experimentation

Regular Use - Tolerance

Loss of Control
Salience – Craving -

Withdrawal
Use despite HARM
Attempts to Abstain → Relapse

139

WHO IS AT HIGH RISK? WHY?

140

Association between age at initiation of alcohol use and lifetime dependence

SOURCE: 2001–2002 National Epidemiologic Survey on Alcohol and Related Condition1s41

Quantity x FrequencyCAsusorcriaetinont bdertiwnekeinnaggesaet ivnietiarittioyn pofraelcdoihcotleusde abnyd laifegtiemeadteopennsdeentce

(Andaman & Nicobar2008)

Benegal et al, 2009

142

http://www.teen-safe.or Earlier the Use…Greater the Risk
g

Teens more susceptible to becoming marijuana-dependent than adults.

If you smoke marijuana at age 21, your chances of becoming
marijuana-dependent are 4%.

If you smoke marijuana at age 13, your chance of becoming
marijuana-dependent is four times greater, up to 17%.

143

Earlier the onset of use- greater the neuroadaptation
Early drinking →Freezes brain -prolonged neuroadaptations

In young, a dose
of alcohol
changes activity
of neurons in
hippocampus,
(memory and
learning).

Same dose had little or no effect in adult !!

Tapert et al, 2005 144

Greater impulsivity & risk-taking

1. Subcortical limbic structures, e.g.
hippocampus & amygdala, mature during
adolescence, at a relatively faster pace
than the prefrontal cortex (PFC)

2. PFC is the later structures to mature, and

development of PFC structural and

functional connectivity continues into late

adolescence and early adulthood http://users.loni.usc.edu/~thompson/DEVEL/dynamic.html

3. PFC development and connectivity parallel the appearance of adult executive
functions.

4. An immature PFC, along with more developed limbic regions, may lead to an
imbalance or disruption of top-down control, which is thought to underlie
particular adolescent-typical behavior such as impulsivity and risk taking

145

Why do adolescents take drugs?

Seen in the context of adolescent brain changes

To fit in Peer affiliation more important than parental
controls! Evolutionary benefits. Brain changes –
social cognition, social skills

To feel good Negative mood states and emotional lability of
adolescence

To feel Psychological dysregulations – developmental +
better transdiagnostic vulnerabilities (Externalizing
spectrum temperament / disorders)

To do better Psychological dysregulations; Social Strain

To Greater Impulsivity – Poor frontal brakes
experiment

WHY ARE ADOLESCENTS AT HIGHER RISK? 146

Who is at Greater Risk

• > Impulsive –Novelty ADOLESCENTS- MATURING
seeking→ Early BRAIN
experimentn
ADOLESCENTS-
• Difficulty sustaining EXTERNALIZING
motivation←→Boredom TEMPERAMENTS
> MATURATIONAL DELAY
• Higher mood reactivity+
mood recognition

• >Peer affiliation needs –
marginalised/
stigmatized

147

High Risk for Addictive Disorders

Family Loading “Converted” 1. Inability to
psychopathologi sustain
Early onset of use attention
cal states:
Exposures to Bipolar-ASPD 2. Low
Developmental Stress boredom
Externalizing threshold
temperament
3. Impulsivity
4. Poor error

monitoring
5. Emotional

reactivity

REWARD
DEFICIT
STATE

148

Externalizing disorders

Mood disorders Conduct dis → Attention
Antisocial Deficit
Psychoses Emotionally Personality Aut Sp
Unstable Disorder Disorder→ Dis
Adult ADD

Addictive disorders

Depression & Anxiety Disorders

Internalizing disorders

149

HR subjects : smaller volumes in critical brain regions responsible

for “adult functions”

Differences in brain
volume on MRI
between Low risk
and High risk subjects
(ROI & VBM)

Gray Matter Region

L & R Superior frontal gyrus
L & R ant. cingulate gyrus
L & R amygdala
R Hippocampal gyrus
R parahippocampal gyrus
Right & L Thalamus
Right cerebellum

Benegal et al (2007) Addiction Biology 150