psychiatry in internal medicine

1. Typical (First Generation)
antipsychotics : Problems
• Extrapyramidal symptoms
• Tardive dyskinesia
• Neuroleptic induced dysphoria
• Negative symptoms produced / exacerbated
• Memory/ cognitive problems
• Treatment refractoriness
• Poor quality of life

8. ATYPICAL (Second Generation)
ANTIPSYCHOTICS
• No / minimal EPS
• No / minimal ↑ in prolactin
• Reduce negative symptoms
• 5HT2
& D2
receptor antagonism

9. ATYPICAL ANTIPSYCHOTICS :
Mechanism of Action
• Antipsychotic efficacy : 60-80% D2
receptor
blockade (clozapine/ quetiapine-different)
• Fast-off theory (Loose binding, fast release)
Low EPS/ TD/ ↑ prolactin
• EPS avoided : ? 5-HT blockade

10. CLOZAPINE

11. • Pharmacokinetics
➢ Peak : 2 hours
➢ t½ (elimination) : 12 hours
➢ Extensive first pass metabolism
• Plasma monitoring useful

12. Adverse Effects
• Sialorrhea
• Anticholinergic effects
• CVS effects
• Weight gain / hyperglycemia
• Urogenital effects
• NMS
• EPS

13. • Leukopenia and Agranulocytosis (1-2%,
max. in first 3 months potentially fatal)
• Seizures (3-4%, >500 mg/d; dose-related,
grand mal type)

14. Uses
a) Schizophrenia
- Treatment resistant
- Treatment intolerant (severe EPS/TD)
- Negative symptoms
- Cognitive symptoms (verbal fluency,
not executive functioning)
- Suicidality
- Childhood onset

15. b) Schizoaffective disorder (esp. manic
features)
c) Aggression (psychosis, dementia)
d) Affective disorder (treatment resistant mania,
psychotic depression)
e) Parkinsonism (Dopaminomimetic psychosis,
tremors)
f) ‘Dual diagnosis’ patients

16. Risperidone

17. Pharmacokinetics
• Peak : 3 hours
• Hepatic metabolism
• Metabolite similar to parent compound
• t½ = 22 hours

18. Adverse effects
• EPS (dose dependent, <haloperidol)
• Hyperprolactinemia
• Weight gain
• NMS
• O-C symptom emergence/exacerbation
• CVS (QTc prolongation, bradycardia)
• Urogenital effects

19. Utility / Efficacy
A) Schizophrenia
- First episode
- Cognitive symptoms (working memory)
- Negative symptoms
- Depressive symptoms
B) Schizoaffective disorder
C) Dementia
D) Delirium
E) Affective disorder (acute mania,
prophylaxis, psychotic depression)
F) ? ‘Dual diagnosis’ patients

20. Olanzapine

21. Pharmacokinetics
• Peak : 5 hours
• t½ = 31 hours
• High protein binding
• Weak hepatic enzyme effect

22. Adverse effects
• Sedation
• Hypotension
• Weight gain (Max. of all Atypicals)
• Hyperglycemia
• EPS/NMS
• ? QTc prolongation

23. Utility / Efficacy
a) Schizophrenia - Negative symptoms
- Depressive symptoms
- COS
- Cognitive symptoms
b) First episode psychosis
c) Parkinsonism
d) Dementia
e) Affective disorders

24. Ziprasidone

25. • Pharmacokinetics
- Peak = 2-6 hrs
- t½ = 3-10 hrs
- extensive hepatic metabolism
• Low affinity for H1
receptors
• Inhibits 5-HT & NE uptake

26. Adverse Effects
• Somnolence
• Dizziness
• QTc prolongation
• Nausea

27. Utility / Efficacy
a) Schizophrenia - Positive symptoms
- Negative symptoms
- Depressive symptoms
b) Schizoaffective disorder

28. Quetiapine

29. Pharmacokinetics
• Rapid absorption
• t½ = 6 hrs (steady state ~ 2 days)
• CYP3A4 metabolism
• Linear pharmacokinetics
• Reduced clearance in renal / hepatic
dysfunction and elderly

30. Pharmacodynamics
• D2
receptor occupancy = 30-41% (lower for
striatum)
• 5-HT2A
receptor occupancy = 57-74%
32% (striatum)
• D2
/D3
receptor occupancy
60% (temporal cortex)

31. Adverse effects
• Commonest – headache, somnolence,
dizziness
• Lenticular opacities (rare, 6-12 mths of
treatment)
• Thyroid : ↑ TSH
• Liver Functions: ↑ AST (reversible,
transient, first 3 weeks)
• Seizures : 0.8% prevalence
• Orthostatic hypotension / tachycardia

32. • EPS : minimal; no dose – dependent
increase
• Hyperprolactinemia : absent
• Weight gain : minimal
• Hyperglycemia / DM : minimal
• QTc prolongation : absent / minimal

33. Utility / Efficacy
a) Schizophrenia :
- Positive symptoms (at higher doses; c.f. HPL)
- Negative symptoms (c.f. HPL)
- Cognitive symptoms (significant, memory/ attention/
executive functions)
- Depressive symptoms
- Aggressive symptoms (±)
- Late onset schizophrenia
- Childhood onset schizophrenia
b) Dementia (aggression > psychosis, better functional
status, especially Alzheimer’s/ Lewy Body)

34. c) Mood disorders
- Mania/ Bipolar disorders (including RCAD)
- Psychotic depression (?)
- Unipolar depression/ dysthymia
(adjunct with SSRI)
d) OCD (treatment refractory, augmentor)
e) PTSD
f) Autism
g) Personality disorders (ASPD/BPD, for
aggression)
h) Delirium
i) Parkinsonism (dopaminomimetic psychosis)
j) ‘Dual diagnosis’ patients (stimulants / alcohol)

35. Drug Formulations Dose range
(therapeutic)
Maximum
dose
Clozapine Tablet, Acute
parenteral
250-450 mg/day 600 mg/day
Risperidone Tablet, Liquid, ?
Long acting
parenteral
2-6 mg/day 12 mg/day
Olanzapine Tablet, ?Acute
parenteral
10-20 mg/day 40 mg/day
Ziprasidone Capsule, ?Acute
parenteral
80-160 mg/day 320 mg/day
Quetiapine Tablet 150-750 mg/day 800mg/day

36. ATYPICAL (THIRD GENERATION)
ANTIPSYCHOTIC
• Most recent addition to the
class of ‘Atypical
antipsychotics’
• Quinilinone derivative
ARIPIPRAZOLE

37. PHARMACODYNAMICS AND
MECHANISM OF ACTION
• Effect on Dopamine
- Partial dopamine agonist
- Works as a ‘Dopamine system stabilizer’
- Antagonist activity in hyperdopaminergic
areas (mesolimbic pathway)
- Agonist activity in hypodopaminergic areas
(mesocortical pathways)
- Referred to as ‘Goldilocks’ antipsychotic
(Burris et al,2002)

38. ……..Pharmacodynamics
contd.
• Effects on serotonin
-Partial agonist at 5 HT-1a receptors
-Antagonist at 5 HT-2a receptors
• Others
-Modest affinity at alpha-adrenergic and
H-1 receptors
Jordan et al,2002; Keck et al, 2003

39. IMPLICATIONS
• Partial D-2 agonism and 5 HT-2
antagonism: Low risk of EPS and
Tardive Dyskinesia
• 5HT-1a partial agonism:Antidepressant,
anxiolytic effect
• Low effect on H-1 and Alpha-1
receptors: Low risk of sedation, weight
gain and hypotension

40. PHARMACOKINETICS
• Bioavailability: 87%
• Mean Tmax: 3 hrs; Mean T1/2: 75 hrs
• Protien-binding: 99%
• Metabolism: CYP 2D6, CYP 3A4
• Active metabolite: Dehydroaripiprazole
• Administration of food: Delays T max by 3
hrs, no effect on absorption
Mallikarjun et al, 2000

41. DOSAGE/ ADMINISTRATION
• Initial and target dose 15 mg/d, no
titration required
• Higher doses do not produce greater
results
• Dose escalation from (30-90 mg/d) does
not affect tolerability
• No dose adjustment required in special
populations
• Can be administered once daily with/
without food

42. EFFECTS ON MAJOR
SYSTEMS
System Symptom/ sign Incidence
1) Nervous system Tremors/
somnolence
> placebo,
subsides
quickly
2) GI system Nausea; vomiting;
dyspepsia;
constipation
> placebo,
subsides to 1%
in 1 week
3) Movement disorders EPS, tardive
dyskinesia
~placebo,
Lesser than
haloperidol
Pigott et al, 2002; Kuzawa et al 2001

43. 2nd
Generation Antipsychotic
Medication- SGAMs
New Drugs:
• Dopamine receptor partial agonist:
Iloperidone, apomorphine, preclamol
• Serotonin-receptor modulators:
● Pipamerone: selective 5HT2
/ dopamine
antagonist
● MDL 100, 907 pure 5HT2A
antagonist
● ORG 5222: 5HT2A
5HT 2c,
5HT 6, 7,
antagonist and 5HT1d
agonist

44. 2nd
Generation Antipsychotic
Medication- SGAMs
New Drugs:
NMDA Receptors agonists:
• High dose of glycine: improvement in
–ve
• d-serine: improvement in –ve,
psychosis and cognitive functioning
• D-cycloserine: improvement in –ve
when added to conventional
antipsychotic
• CX516: improves attention, memory

45. 2nd
Generation Antipsychotic
Medication- SGAMs
New Drugs:
• Sigma Receptor Antagonists:
Rimacozole, tiosperone, panamesine
(EMD 57444), Eliprodil, (SL 8207),
SR-31742
• Polysaturated Fatty Acids: Omega -3
fatty acids, improvement in both +ve
and –ve symptoms and abnormal
movements

46. ATYPICAL ANTIPSYCHOTICS
Utility !
• Schizophrenia – positive symptoms +++
• Schizophrenia – negative symptoms +
• Schizophrenia – cognitive impairments ++
• Schizophrenia – affective symptoms +
• Schizophrenia – treatment resistance ++
• First line for first episode psychosis +++
• First line for EPS/TD/Akathisia ++

47. ATYPICAL ANTIPSYCHOTICS
Utility !
• First line for Parkinsonism and
psychosis +++
• Elderly with psychotic disorders +
• Children
• Delirium +
• Mood disorders +
• Dementia (aggression) ++

48. • Cost effectiveness
• Quality of Life
• Compliance
• EPS
ATYPICAL ANTIPSYCHOTICS
Utility ?

49. ATYPICAL ANTIPSYCHOTICS
Harm !
• Weight gain
• Hyperglycemia
• Hyperlipidemia
• QTc prolongation
• Seizures
• Agranulocytosis

50. • Controlled trials : few
• Long term trials : minimal
• Across culture trials : absent
• Head to head comparison with first
generation antipsychotics : few
• Head to head comparison between second
generation antipsychotics : few
• Trials with ‘at risk’ (elderly, children, women
in reproductive age group) population :
minimal
ATYPICAL ANTIPSYCHOTICS
Problems !