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psychiatry in internal medicine

1. Common reward pathway.
DA
n
N
A
D
o
p
a
m
i
n
e
Opioi
ds
Nico
tine
Canna
b
Glutamat
e
GABA
5HT

2. Reward pathway :VTA to NucAc
VTA
Nuc
Ac
PFC
A
m
yg
Explosive
release of DA

3. Motivation pathway:PFC to N.Ac
VTA
Nuc
Ac
PFC
A
m
yg
Glutamate
release

4. Craving:Amygdala to PFC/N.Ac
DA n
NA
PFC
A
m
yg
Glutamate release
(Weiss et al,2000)

5. Salience.
DA n
NA
PFC
A
m
yg

6. Addiction & its neurobiology
1.Initiation of
abuse
Reward
pathway
VTA→
NAc
Dopamine,
(Opioids,
Cannabds)
.
2.From abuse
to dependence
1.Motivation
& drive
Orbitofr.
cortex
Glutamate
2.Memory
& Learning
Amygdala
& Hippcm
Glutamate
3.ControlPrefrontal
cortex
Glutamate
■Neural plasticity-reinforces drug seeking behavior.

7. Addiction & its neurobiology
3.Mech of
Relapse
1.Cue
related
OFC, VTA
& N.Acc
Glutamat
e DA
2.Stress
related
Lateral &
Ventral TA
N.Adr,
DA,CRF
3.Drug
related
VTA &
N.Acc
DA
Glutamat
e

8. Rationale of interventions.
1.Decreasing the rewarding effects of
drugs:
■Decreasing the positive
reinforcement.
■Making drug taking unpleasant.
2.Decreasing the motivation or craving.
3.Preventing relapse.
4.Applying the genetic understanding.
5.No medication for specific indication of
“anticraving”. Controversial concept.

9. Rationale of interventions.
■Decreasing DA release.
■Inhibiting the excitatory glutamate.
■Enhancing the inhibitory GABA.
■Balancing Glutamate v/s GABA
■Regulating the 5HT neurotransmission.
(Koob, 2000)

10. 1. Decreasing the reward
■Through the opioid system.
■Naltrexone- Depot Intramuscular.
■Through the cannabinoid system.
■Rimonabant.

11. Decreasing the reward.
Rimonabant
DA
n
N
A
Opioid
s
Nico
tine
Canna
b
Glutamat
e
GABA
Decreased DA
release
Naltrexone

12. Decreasing the
reward-Rimonabant.
■Cannabinoids modulate the reinforcing
effects of alcohol.
■Endogenous cannabinoid agonists also
promote alcohol craving.
■CB1 receptor, antagonist, Rimonabant,
decreases alcohol consumption in
rodents.
■Under phase II human trial.

13. Decreasing the motiv/craving.
DA
n
N
A
Opioi
ds
Nico
tine
Canna
b
Glutamat
e
GABA

14. GABA & Glutamate.
■Alcohol enhances GABA and inhibits
glutamate.
■GABA-A, major receptor-most of alcohol’s
effects.
■Rx for withdrawal involves drugs acting on
it.eg: Gabapentin.
■GABA-B agonist, Baclofen also shown to
reduce craving and alcohol intake.
(Addolorato et al, 2002; Bonnet et al,2003)

15. Glutamate
■Alcohol reduces glutamate activity by
interacting with NMDA receptors.
■NMDA antagonist in treating alcohol
dependence.Eg: Memantine.
■AMPA-kainate receptors activity
reduction
■Increasing GABA.Eg:Topiramate.
(Bisaga et al, 2004, Johnson et al,
2003)

16. Serotonin
■Serotonin dysregulation asstd –disorders
of attention, motivation & emotion.
■Co-occuring mood disorders.
■Alcohol alters serotonin
neurotransmission.
■Medications to regulate the
dysequilibrium.
■5HT receptor antagonism, reuptake
inhibition.
■Variability in responses to treatment.

17. 2.Decreasing motiv/craving.
1.Acamprosate
2.Topiramate.
3.Gabapentin.
4.Ondansetron
5.Baclofen
6.Memantine
7.SSRIs.

18. 1.Acamprosate
■Blockade of Glutamate NMDA receptors .
■Activation of GABA receptors.
■Normalizes the ethanol altered GABA-A
recep.
■Calcium channel blockade-in withdrawal.
■It also modulates NMDA receptor subunit
expression.
■Acamprosate restores the imbalance in the
excitatory & inhibitory NTs, caused by alcohol.
(Littleton, 1995; Rammes et al, 2001)

19. Acamprosate-Efficacy.
■Reduces alcohol intake on various outcome
measures, and ameliorates withdrawal
symptoms
■Reduces the intensity of post cessation alcohol
craving on exposure to cues.
■Meta-anlayses show a significant but modest
effect on outcome.
■Better tolerated.
■Dose: 333 mg tabs Wt<60kg:1-1-2
>60 kg:1-2-2 or 2-2-2
(Kiefer et al,2003)

20. 2.Topiramate.
■Topiramate has actions both in the
GABAergic and glutaminergic systems.
■Decreases DA level both in the VTA & Nac,
modulates DA release in the reward pathway.
■Decreases drinks/day, no. of heavy drinking
days, percentage of days abstinent, and
interference due to drinking.
■Dose: 25 mg with wkly increase by 25-50 mg in
twice daily dosing, upto 100-150 mg.
(Johnson et al,2003)

21. Topiramate-efficacy
■Good for combination with other Rx that
demonstrate effect in a subset of
patients.
■Topiramate+Ondansetron/Naltrexone in
early onset alcoholics.
■Topiramate+SSRI for later onset Type A
alcoholics.
■Topiramate+mood stabilisers for pts
with comorbid affective disorders.

22. 3.Baclofen.
■GABA(B) receptor agonist-approved as
an antispasmodic medication.
■Blocks effect of alcohol on GABA
synapses.
■GABAmimetic action-decreasing
hyperexcitability during withdrawal.
■In pts with glutamate-GABA imbalance.
(Colombo et al,2004)

23. Baclofen- Efficacy.
■Reduced voluntary alcohol intake in
alcohol-preferring rats.
■Reduced alcohol craving and intake in
alcoholics.
■Rapid suppression of withdrawal symptoms.
■Outpatient detoxification.
■Reduces compulsion to drink in Early onset
but not in Late onset alcoholism.
■Dose: 10 mg tabs, titrated upto 50 mg/day in
thrice daily dosing.
(Flannery et al,2004; Addolorato et al,2002)

24. 4.Ondansetron
■Serotonin-3 (5-HT3) antagonist
approved for treatment of nausea.
■5-HT3 antagonists attenuated effects of
alcohol and other addictive drugs
through indirect regulation of DA
release in mesocorticolimbic areas.
■5-HT deficiency in the early-onset
subtype.
(Johnson et al,2000)

25. Ondansetron-Efficacy.
■Efficacious in early onset(<25 yrs), but
not in late onset alcoholics.
■Reduced drinking and an increased
number of abstinent days.
■Improvements in symptoms of
depression, anxiety and hostility.
■Dose: 4 mg/day in twice daily dosing.
(Johnson et al,2000)

26. 5.SSRIs ??
■Preclinical studies- reduced levels of
serotonin asstd with alcoholism,
indicating a biological predisposition.
■Chronically, SSRIs reduce 5-HT levels,
thereby reciprocally enhancing DA
function and substituting for alcohol’s
rewarding effects.
■Animal studies- SSRIs reduced alcohol
consumption in a dose dependent
fashion.

27. SSRIs- Efficacy??
■Was hypothesized to be helpful in Type
B alcoholics.
■Pts with early onset and sociopathic
profiles indicative of 5-HT
abnormalities.
■Studies disproved this, contrarily Type A
alcoholics fared better, and Type B had a
poorer outcome.
(Kranzler et al,:Pettinati et al,2001& 2003)

28. Sertraline
■Differential effect with Type II & I
alcoholics.
■With Type II- an increased alcohol
intake vs those on placebo.
■With Type I- significant increase in
abstinence rates, with benefit observed
even 6m after treatment.
■Dose: 200mg/day
(Pettinati et al, 2000)

29. 6.Gabapentin
■Influences the synthesis of GABA and
glutamate.
■For insomnia associated with alcohol
dependence, in protracted withdrawals.
■Ongoing trial of Naltrexone+Gabapentin
during initial period of abstinence.
■Efficacy in withdrawal state??
(Karam-Hage et al,2000)

30. 7.Bupropion
■Through the DA & NA-ergic systems
■In comorbid nicotine dependent pts, as a
smoking cessation aid.
■Unpublished case reports of decreased
pleasure & alcohol intake.
■No controlled trials.

31. 8.Memantine.
■NMDA antagonist- decreases
glutamatergic neurotransmission.
■Shown to decrease alcohol craving
before the administration of alcohol but
not after it in moderate drinkers.
■Open label pilot study- dosage of 20
mg/day- reduces drinking.
(Farmington et al,2005; Bisaga et al, 2004)

32. Combination pharmacotherapy
■Addiction is not a homogenous disease.
■Multiple brain sites & circuits are involved.
■Thus,treatment must target multiple sites.
■Or, be an optimal combination of medications.
■Eg:
■Acamprosate+Disulfiram
■Acamprosate+Naltrexone.
■Acamprosate+SSRIs.
■Naltrexone+Disulfiram
■Naltrexone+Ondansetron.

33. In specific subgroups.
1.Pts actively drinking:
1.Naltrexone,
2.Acamprosate,
3.Topiramate,
4.Gabapentin,
5.SSRIs,
2.For amelioration of withdrawal symptoms:
1.Acamprosate
2.Baclofen,
3.Gabapentin,
4.Memantine

34. In Type II & I.
■Type II
■For early onset dependence
■Polysubstance abuse.
■Externalizing symptoms
■Family history positive
■Type I
■Late onset dependence.
■Slowly developing
■Family history negative

Ondansetron,
Naltrexone
Baclofen

Sertraline,
Acamprosate

35. Current status.
■FDA approved for long term treatment in
alcoholism
■Oral and depot injectable Naltrexone.
■AcamprosateDisulfiram.
■FDA approved for other indications, but not
for alcoholism. In phase II trials for
alcoholism.
■TopiramateSSRIs
■OndansetronBupropion
■BaclofenGabapentin
■In phase I trials
■MemantineRimonabant
■KudzuDopamine 3 antagonists