This document discusses the history and development of atypical antipsychotic medications. It begins with an overview of the serendipitous discoveries that led to the development of early antipsychotics like chlorpromazine in the 1950s. It then covers the development of second-generation atypical antipsychotics from the 1990s onward, including clozapine, risperidone, olanzapine, quetiapine, and others. The rest of the document details the mechanisms of action, therapeutic indications, side effect profiles, and dosing of various atypical antipsychotics.

1. Atypical Antipsychotics
DR.MURUGAVEL.V
Junior resident
Institute of Mental Health
Chennai

2. ’30s ’40s ’50s ’60s ’70s ’80s ‘90 s ’00s
ECT
Chlorpromazine
Haloperidol
Fluphenazine
Thioridazine
Loxapine
Perphenazine
Second-generation
antipsychotics
Clozapine
Risperidone
Olanzapine
Quetiapine
Ziprasidone
Aripiprazole
Next-generation
The history of antipsychotic drug development

3. The history of antipsychotic drug development
• Often based on chance findings that bear little relationship to
the intellectual background driving observation.
• In 1891, Paul Ehrlich observed the antimalarial effects of
methylene blue, a phenothiazine derivative.
• Later, the phenothiazines were developed for their
antihistaminergic properties.
• In 1951, Laborit and Huguenard administered the aliphatic
phenothiazine, chlorpromazine, to patients for its potential
anesthetic effects during surgery.
• thereafter, Hamon et al. and Delay et al. extended the use of
this treatment in psychiatric patients and serendipitously
uncovered its antipsychotic activity.

4. The history of antipsychotic drug development
• Between 1954 and 1975,
about 15 antipsychotic drugs
were introduced in the United
States and about 40
throughout the world.
• Thereafter, there was a hiatus
in the development of
antipsychotics until the
introduction of clozapine
treatment in the United States
in 1990 opened the era of
"atypical" antipsychotic drugs.

5. Classic and commonly
used terms
Proposed terms by WPA
Neuroleptics or
Typical antipsychotics
First generation
antipsychotics
Atypical antipsychotics
(serotonin – dopamine
antagonists)
Second generation
antipsychotics
Dopamine partial
agonists
( aripiprazole )
Third generation
antipsychotics

6. WHY THEY ARE ‘ATYPICAL’ ?
LOWER RISK OF EPS
SPECTRUM OF ACTION
 Higher ratio of serotonin : dopamine receptor blockade
 Appear more specific for mesolimbic than striatal dopamine
system
DIFFERENT SIDE EFFECT PROFILE

7. characteristics
• Low D2 receptor blocking effects
• Reduced risk of extrapyramidal side effects.
HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine
QuetiapineQuetiapine ZiprasidoneZiprasidone
5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonis
Casey 1994Casey 1994
Atypical Antipsychotics In Vivo Binding Affinities

8. RECEPTOR OCCUPANCY RECEPTOR AFFINITY

9. Differences among Antipsychotic Drugs
• Clozapine
– binds more to D4, 5-HT2, α1, and histamine H1 receptors
than to either D2 or D1 receptors
• Risperidone
– about equally potent in blocking D2 and 5-HT2 receptors
• Olanzapine
– more potent as an antagonist of 5-HT2 receptors
– lesser potency at D1, D2, and α1 receptors
• Quetiapine
– lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors

10. Differences among Antipsychotic Drugs
• Clozapine, olanzapine and quetiapine
– potent inhibitors of H1 histamine receptors
– consistent with their sedative properties
• Aripiprazole
– partial agonist effects at D2 and 5-HT1A receptors

11. Classification
MARTA (multi acting receptor targeted agents)
• clozapine, olanzapine, quetiapine
SDA (serotonin-dopamine antagonists)
• risperidone, ziprasidone, sertindole
Selective D2/D3 antagonists
• sulpiride, amisulpiride

12. Available drugs (only 10 are FDA Approved)
 Amisulpride
 Aripiprazole
 Asenapine
 Blonanserin
 Clotiapine
 Clozapine
 Iloperidone
 Lurasidone
 Mosapramine
 Olanzapine
 Paliperidone
 Perospirone
 Quetiapine
 Remoxipride
 Risperidone
 Sertindole
 Sulpiride
 Ziprasidone
 Zotepine

13. Therapeutic indications
Schizophrenia and schizoaffective disorder – acute and
chronic psychoses- first line treatment all SGA’s except
clozapine
Mood disorders
 acute mania- all SGA’s except clozapine
 acute bipolar depression- quetiapine,fluoxetine
combination
 Maintanence therapy-
aripiprazole,olanzapine,quetiapine
 Adjunctive therapy in treatment depression-
olanzapine,fluoxetine combination

14. Other indications:
 Exhibits outwardly aggressive and violent behaviour
 Autistic spectrum disorder
 Tourettes syndrome
 Huntington’s disease
 Lesch Nyhan Syndrome
 Along with methylphenidate/dextroamphetamine in
children with ADHD.
 Psychosis secondary to head trauma, dementia,
treatment resistant
 Decreases the risk of suicide and water intoxication in
patients with schizophrenia

15. Common Side Effects
• Extra pyramidal symptoms
• Orthostatic hypotension
• Sedation
• Weight gain
• Metabolic syndrome
• QT prolongation
• Anti cholinergic side effects
• Hyper prolactinemia
• Sexual dysfunction
• Increased risk of Pneumonia

16. Extra pyramidal side effects (EPS):
Risperidone > Olanzapine = Ziprasidone > Quetiapine > Aripiprazole =
Clozapine

17. Orthostatic hypotension
Definition
fall in systolic blood pressure of at
least 20 mm Hg or diastolic blood
pressure of at least 10 mm Hg
when a person assumes a standing
position.
Treatment
changing the dose of the
medication or stopping it entirely.
Clozapine > > Quetiapine,
Risperidone > Ziprasidone,
Olanzapine, Aripiprazole

18. SEDATION
Due to histaminergic
receptor (H1) blockade in
CNS
Clozapine > > Olanzapine,
Quetiapine > Risperidone,
Ziprasidone, Aripiprazole

19. WEIGHT GAIN
Clozapine = Olanzapine > Quetiapine, Risperidone >
Ziprasidone, Aripiprazole
Suggested
mechanisms were
• 5 HT 2C antagonism,
• H 1 blockade
• Hyperprolactinemia
and
• Increased serum
leptin.

20. Metabolic effects
Weight gain over 1 year (kg)
aripiprazole 1
amisulpride 1.5
quetiapine 2 – 3
risperidone 2 – 3
olanzapine > 6
clozapine > 6

21. METABOLIC SYNDROME
DIABETES MELLITUS
How they cause??
 5 HT 2A/2C antagonism
 Increased plasma lipids
 Weight gain
 Leptin resistance
Most sensitive test to detect is
Oral Glucose tolerance test.
High Risk with
CLOZAPINE>OLANZAPINE>>RISPERIDONE>QUETIAPINE
Low risk with
ARIPIPRAZOLE,AMISULPIRIDE

22. METABOLIC SYNDROME (contd)
DYSLIPIDEMIA
Raise in triglycerides levels are
more common than serum
cholesterol.
Treated with
 Fibrates
 Statin
 Dietary & life style modification
HYPERTENSION
Posibly due to alpha 2 antagonism
Slow,steady rise over a period of
time
 clozapine

23. Insulin resistance
• Prediabetes (impaired fasting glycaemia) has
~ 10% chance / year of converting to Type 2
diabetes
• Prediabetes plus olanzapine has a 6-fold
increased risk of conversion
• If olanzapine is stopped 70% will revert back
to prediabetes

24. Stroke in the elderly
• Risperidone and olanzapine associated with
increased risk of stroke when used for behavioural
control in dementia
• Risperidone 3.3% vs 1.2% for placebo
• Olanzapine 1.3% vs 0.4% for placebo
• However, large observational database studies
– Show no increased risk of stroke compared with typical
antipsychotics or untreated dementia patients

25. QT PROLONGATION
Blockade of potassium channels
Causing torsades des pointes and
sudden cardiac death
High effect
• Any intravenous antipsychotic
• Haloperidol
• Sertindole
• Amisulpride
• Chlorpromazine
• Quetiapine
• Ziprasidone
No effect on QT interval
• Aripiprazole
• SSRI’s
• Carbamazepine
• Valproate
• BZD’s

26. Clozapine > Olanzapine > others

28. HYPER PROLACTINEMIA
Risperidone,amisulpiride
Normal values:
Male 0-20 ng/dl
Female 0-25 ng/dl
Level around 30-50 ng/dl
• Reduced libido
• infertility
Level around >100 ng/dl
• Galactorrhea
• Amenorrhea
Rule out a prolactinoma if levels >118
ng/dl

29. HYPER PROLACTINEMIA
Non prolactin elevating
antipsychotics
Aripiprazole
Ziprasidone
Olanzapine
Clozapine
Quetiapine

30. SEXUAL DYSFUNCTION
result from decreased dopaminergic activity centrally and alpha
adrenergic blockade peripherally.
Risperidone>olanzapine>quetiapine>aripiprazole

31. Increased susceptiblity to pneumonia
60% more risk in elderly population
Highest in the first week of treatment
Seen only with SGA’s
Possible mechanisms:
• Sedation
• Drymouth
• Effects on immune response

32. Type Manifestations Mechanism
Autonomic
nervous
system
Loss of accommodation, dry mouth,
difficulty urinating, constipation
Muscarinic cholinoceptor blockade
Orthostatic hypotension, impotence,
failure to ejaculate
Alpha adrenoceptor blockade
Central
nervous
system
Parkinson's syndrome, akathisia,
dystonias
Dopamine receptor blockade
Tardive dyskinesia
Supersensitivity of dopamine
receptors
Toxic-confusional state Muscarinic blockade
Endocrine
system
Amenorrhea-galactorrhea, infertility,
impotence
Dopamine receptor blockade
resulting in hyperprolactinemia
Other Weight gain
Possibly combined H1 and 5-HT2
blockade

33. RISPERIDONE
 Benzisoxazole
 Undergoes first pass metabolism
 Peak plasma level levels – 1 hr (parent compound) ,
3 hrs for metabolite
 Combined half life 20 hrs (once daily dosing)
 Antagonist of serotonin 5HT2A, dopamine D2, α1, α2
adrenergic histamine H1 receptors.

34. Side effects
 Weight gain
 Anxiety
 Nausea
 Dizziness, hyperkinesias, somnolence,
 Vomiting
 Rhinitis
 Erectile dysfunction

35.  Dosages – Initially 1-2 mg/day , raised to 4 mg/
day
 Only SDA available in depot formation IM
injection every 2 weeks (25mg,50mg or 75 mg)
 Drug interactions – Paroxetine and Fluoxetine
(blocks the formation of
RISPERIDONE’S active metabolite)
 RISPERIDONE + SSRI – significant elevation of
prolactin - galactorrohea and breast
enlargement

36. OLANZAPINE
 85% absorbed from the GI tract
 40% is inactivated by first pass metabolism
 Peak concentration - 5hrs
 Half life - 31 hrs
 5HT2A ,D1, D4, α1 ,5HT1A , muscarinic M1 through M5
and H1 receptors

37. SIDE EFFECTS
 Weight gain
 Somnolence
 Dry mouth
 Dizziness
 Constipation
 Dyspepsia
 Increased appetite
 Akathisia
 tremor

38.  Periodic assessment of “blood sugar” and
“transaminase”.
 Increased stroke among patients with dementia
 DOSAGES – initial dose for treatment of psychosis –
5-10 mg , acute mania- 10-15 mg.
 Start 5-10 mg , raise to 10 mg per day
 30-40 mg in treatment resistant cases.

39. • Drug interactions
– FLUVOXAMINE and CIMETIDINE – increases
– CARBAMAZEPINE and PHENYTOIN - decreases

40. QUETIAPINE
 DIBENZOTHIAZEPINE
 Rapidly absorbed from GI tracts
 Peak plasma concentration – 1-2 hrs
 Steady half life – 7 hrs (2- 3 dosing per day)
 lower-potency compound with relatively similar
antagonism of 5-HT2, D2, α1, and α2 receptors .

41. Side effects
 somnolence, postural hypotension and dizziness –
most common side effect.
 Least likely to cause extra pyramidal side effects. –
used in Parkinsonism who develop DOPAMINE
AGONIST induced psychosis.
 Moderate weight gain
 Small rise in heart rate , constipation and transient
rise in liver transaminases can occur.

42. • DOSAGES – available in 25, 50 and 200 mg.
• Schizophrenia – target of 400 mg/ day
• Mania & BPD – 800 & 300 mg respectively
• Insomnia – 25- 300 mg at night

43. ZIPRASIDONE
 BENZOTHIAZOLYL PIPERAZINE
 Peak plasma concentration- 2-6 hrs
 Terminal half life at steady state – 5-10 hrs
 Bioavailability doubles when taken along with food.
 Blocks 5HT2A and D2 receptors , antagonist 5HT1D,
5HT2C, D3,D4,α1 and H1 receptors.

44. Agonist activity at 5HT1A receptor
Serotonin reuptake inhibitor
Nor epinephrine reuptake inhibitor
SIDE EFFECTS:
 somnolence, headache, dizziness , nausea , light
headedness, prolongation of QTc interval.
 avoided in patients with cardiac arrythmias.

45. • Dosages – 20,40, 60 ,80 mg.
• IM comes single use daily 20mg/ml vial
• Oral ziprasidone initiated at 40 mg a day.
• Efficacy in the range of 80-160 mg/day.
• High as much as 240 mg are being used.

46. Clozapine
 DIBENZODIAZEPINE
 Rapidly absorbed
 Plasma level – 2 hrs
 Steady state – less than one week if twice daily
dosing is used.
 Half life – 12 hrs
 Antagonist of 5HT2A , D1,D3,D4 and α receptors.

47. Conventional antipsychotic:
90% of striatal D2 receptor
occupied
Clozapine occupies only 20-67% of D2
receptors
Relatively low potency as a D2 receptor antagonist.

48. • Special indications
– patients with severe tardive dyskinesia.
– Patients prone to develop EPS
– Treatment resistant schizophrenia
– Severe treatment resistant mania
– Severe psychotic depression
– Idiopathic Parkinson’s disease
– Huntington’s disease
– Suicidal patients with schizophrenia and schizoaffective
disorder.
– Pervasive developmental disorder
– Autism of childhood
– OCD (rarely)

49. Side effects
– Sedation
– Dizziness
– Syncope
– Tachycardia
– Hypotension
– ECG changes
– Fatigue
– Weight gain
– constipation
– Anticholinergic
effects
– SIALORROHEA
– AGRANULOCYTOSIS
– SEIZURES
– MYOCARDITIS

50. Clozapine-associated seizures occur most often at
doses greater than 600 mg /day.

51. AGRANULOCYTOSIS
 Leucocyte and differential blood count normal before
starting
 Monitor counts every week for 6 months, then at least
2 weeks once for 1 year
 At least Q 4 weeks after count stable for 1 year (for 4
more weeks after discontinuation)
 If leucocyte count < 3000/mm3, or if ANC < 1500/mm3,
discontinue immediately and refer to hematologist
 Patient should report immediately symptoms of
infection, esp. flu-like illness (fever, sore throat)

52. Dosages
– Initial dosage is 25 mg one or 2 times daily
although conservative initial dosage is 12,5 mg
daily.
– Raised gradually to 25 mg a day for every 2-3 days
to 300 mg divided doses
– 900 mg can be used.
– Plasma conc greater than 350 ng/mL is likely hood
for better response.

53. Drug interactions
 Clozapine + (carbamazepine, phenytoin,
propulthiouracil, sulfonamides, captopril) causes
bone marrow suppression.
 Clozapine+ Lithium – increases the risk of
seizures, confusion and movement disorders.
 Clozapine+ Paroxetine – precipitate clozapine
associated neutropenia.

54. Amisulpiride
 Half life 12 hours
 Bioavailablity 48 %
 Primarily a D2,D3 antagonist
 Antidepressant effect due to 5HT7 blockade
 Used in treating schizophrenia,bipolar disorder
 Also in dysthymia

55. Side effects
 Extrapyramidal side effects
 Insomnia
 Hypersalivation
 Nausea
 Headache
 Hyperactivity
 Anxiety
 Vomiting
 Hyperprolactinaemia
Very less chances of causing
• sedation
• Tardive dyskinesia
• Blood dyscrasias

56. Amisulpride's use is contraindicated in
 Phaeochromocytoma
 Concomitant Prolactin dependent tumours e.g. Prolactinoma,
Breast cancer
 Movement disorders (e.g. Parkinson's disease and dementia with
lewy bodies)
 Lactation
 Children before the onset of puberty
 Amisulpride should not be used in conjunction with drugs that
prolong the QT interval and Torsades de Pointes is common in
overdose.
 TCAs are very dangerous
 Amisulpride is moderately dangerous
 SSRIs are modestly dangerous.

57. ARIPRIPAZOLE
 QUINOLONE DERIVATIVE
 Well absorbed reaching peak levels of 3- 5 hrs
 Half life is about 75 hrs

58. Other SDA’s
• Bifeprunox - partial dopamine agonist.
– Treatment of schizophrenia
– GI side effects are most common.
• Paliperidone – major active metabolite of
risperidone.
– Recommended dose of 6mg per day with 3-12
mg/day.

59. SGA vs FGA
NO EVIDENCE OF
BENEFIT OF SGA’S OVER
FGA’S IN
IMPROVEMENT OF
NEGATIVE SYMPTOMS
CLOZAPINE HAS SHOWN
CLEAR UTILITY IN
TREATMENT RESISTANT
SCHIZOPHRENIA

60. Conclusion
Good clinical practice
involves using both
types of medication at
different times,
depending on the
specific needs of the
patient.

61. THANK YOU