Antipsychotics with focus on atypical antipsychotic drugs.

1. ANTIPSYCHOTICS
Dr. Manjeeta Gupta
Department of Pharmacology
MIMER Medical College
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2. Psychotic disorders (psychosis):
 Severe psychiatric illness with distortion of thought and
perception.
 Classification of psychotic disorders:
 Schizophrenia
 Schizoaffective disorder – disorder of both thought and mood
 Delusional disorder – includes paranoid psychosis
 Substance-induced psychotic disorder – use/withdrawal of
amphetamines, cocaine, alcohol, LSD
 Cognitive disorder — organic brain syndrome

3. Schizophrenia
Split mind
– Highly disabling Chronic (relapsing & remitting) disorder of
thought
– Characterised by acute psychotic episodes
• Typical feature – loss of touch with reality
& selective attention deficit
• Prevalence – 1% of population
• Risk: 10% →1st degree relatives
10% → Dizygotic twins
50% → Monozygotic twins
• Onset in adolescence/early adulthood

4. Schizophrenia
—Split mind
—Highly disabling chronic (relapsing and remitting) disorder
of thought
—Characterised by acute psychotic episodes
• Typical feature – loss of touch with reality
& selective attention deficit.
• Prevalence – 1% of population
• Risk — 10% in 1st degree relatives
10% in Dizygotic twins
50% in Monozygotic twins
• Onset in adolescence/early adulthood

5. Etiology – unclear
Genetic: No single schizophrenia gene
Neuregulin – 1 (NRG – 1 mis-sense mutation)
Dsybindin
DISC-1
DAAO activator (G72)
Environmental: Aberrant intrauterine brain development
(infections, hypoxia?)
– Cannabis consumption in adolescence
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6. Dysbindin (??, located pre and post synaptically, glutamate neurotransmission?)
COMT (catechol-o-methyl transferase)
Neuregulin1 (transmembrane protein many isoforms)
Disc1 (neuronal migration, maturation, neurite outgrowth)
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7. Positive Symptoms
Hallucinations
Delusions
Disorganized Thought
Catatonia
Negative Symptoms
Blunted emotions
Anhedonia
Social withdrawal
Cognition
Attention
Memory
Mood Symptoms
Loss of motivation
Loss of insight
Demoralization
Suicide
Schizophrenia - symptoms
FUNCTION

8.  Hydrotherapy: “The pouring of cold water in a stream, from
a height of at least four feet onto the forehead, is one of the
most certain means of subsiding violent, maniacal
excitement”... wrote an anonymous physician in the early
1800’s.
 Dr Egas Moniz – Prefrontal lobectomy
 In 1947, French surgeon Laborit discovered Promethazine
used as anti-histaminic, had a calming effect on patients
 In 1953, Delay & Denikar used Laborit’s observation to
modify Promethazine structure into first effective anti-
psychotic medication, Chloropromazine
 In-patients at Mental Hospitals dropped by 1/3rd.
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History

10. Impact of Antipsychotics

11. Dopamine Hypothesis
 Repeated administration amphetamine, induces psychosis
resembling positive symptoms of schizophrenia
 Carlson (1963) first proposed that drugs such as chlorpromazine &
haloperidol alleviate schizophrenic symptoms by blocking DA
receptors & thereby ↓ DA function
 These antipsychotic medications, have been the main stay for
treatment for nearly 50 years, have in common their ability to block
D2 receptors.

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 ↑ DA receptor density (Post-mortem, PET)
 ↑ Homovanillic acid (HVA) in plasma, urine & CSF
1.Mesolimbic – ↑ activity of D2 receptor →
Positive symptoms
2.Mesocortical – ↓ activity of D1 receptors →
Negative symptoms

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15. Dopamine tract Innervation Function D-antagonist effects
Mesolimbic
Limbic areas,
Nucleus accumbens
Arousal, memory,
stimulus processing,
behavior, spontaneity,
motivation, assertively,
self-confidence
Psychosis relief
Mesocortical
Cortex – frontal and
prefrontal
Communication,
cognition, social
functions and stress
response
Psychosis relief
Nigrostriatal
Caudate nucleus,
Putamen
Extrapyramidal system
and movement
coordination
Movement disorders
Tubero
infundibular
Pituitary gland
Prolactin secretion
regulation
Hyperprolactineamia,
galactorhea,
gynecomastia
Dopaminergic systems in CNS

16. Serotonin Hypothesis
 Correlation between DA affinity & antipsychotic efficacy has become
weaker as a result of recently developed atypical antipsychotic
medications that also show substantial affinity for 5HT2 receptors
 The role of 5-HT in schizophrenia is based on the findings of LSD a
central 5-HT agonist , produces hallucinations and sensory disturbances
similar to psychosis.
 Atypical neuroleptics like clozapine and olanzapine are potent 5-HT2A
agonists.

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19. Glutamate Hypothesis
 Preclinical as well as clinical studies provide evidence of
hypofunction of NMDA receptors as a primary, or at least, a
contributory process in the pathophysiology of schizophrenia
 Several clinical trials with agents that act at the glycine modulatory
site on the NMDA receptor have revealed consistent reductions in
negative symptoms and variable effects of cognitive and positive
symptoms
 These studies also provide evidence that suggests the effects of
clozapine on negative symptoms and cognition may be through
activation of the glycine modulatory site on the NMDA
receptor.

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21. Classification
Typical /Classical Antipsychotics
1. Phenothiazines
Aliphatic side chain: Chlopromazine, Triflupromazine
Piperidine side chain: Thioridazine
Piperazine side chain: Trifluoperazine, Fluphenazine
2. Butyrophenones: Haloperidol, Trifluperidol
Penfluridol
3. Thioxanthenes: Flupenthixol
4. Other heterocyclics: Pimozide, Loxapine
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Low potency

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23. Chlopromazine
 Prototype drug
 Has D1 + D2 + α1, + H1 + 5-HT2A receptors blocking
property
 Potent local anaesthetic (irritant action)
 Only helpful for positive symptoms
 Highly plasma & tissue bound
 Variable t1/2 - 18-30 hrs
 Cumulative effect seen (OD maintenance dose)
 Metabolised by CYP2D6
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24.  S/E: Marked EPS, Sedation, postural hypotension, reflex
tachycardia, ↑ prolactin release, ↓ GH, ADH, ACTH &
gonadotropins secretion
 Lowers seizure threshold
 Mild obstructive jaundice can occur, reversible on stopping
treatment
 Urticarial skin reactions are common but usually mild
 Excessive sensitivity to ultraviolet light may also occur
 Weight gain, impaired glucose tolerance, ↑serum TGs & QTc
prolongation also seen
 Tolerance develops to sedation & hypotension
 Dose: 100-800 mg oral
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27. Triflupromazine
• Aliphatic side chain phenothiazine
• More potent than CPZ
• Use: Antiemetic
• S/E: acute muscle dystonia in children
• Dose: 50-200 mg oral
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28. Thioridazine
• Low potency phenothiazine
• Marked central anticholinergic action
• Lowest incidence of EPS
• S/E: Cardiac arrythmias, sexual dysfunction
• Dose: 100-400 mg oral
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29. Trifluoperazine
Fluphenazine
• High potency piperzine side chain phenothiazine
• Minimum autonomic actions
• Marked EPS
• Dose: 2-20 mg oral(Trifluoperazine)
1-10 mg oral(Fluphenazine)
 Fluphanazine decanoate → given as depot
intramuscular injection → ↑ compliance
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30. Haloperidol
• Potent antipsychotic
• Marked EPS
• Fewer autonomic effects, Less epileptogenic
• Does not cause weight gain
• Uses: Acute schizophrenia
Huntington’s disease
Gilles de la tourette’s syndrome
• Metabolised by CYP3A4 & CYP2D6
• Dose: 2-20 mg oral
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31. Trifluperidol
• More potent than haloperidol
• Similar actions
• Dose: 1-8 mg oral
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32. Penfluridol
• Long acting neuroleptic
• Uses: Chronic schizophrenia
Affective withdrawal
Social maladjustment
Dose: 20-60 mg oral
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33. Flupenthixol
• Marked EPS
• Infrequently used now a days
• Uses: Schizophrenia with other psychosis
• Dose: 3-15 mg oral
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34. Pimozide
• Selective DA antagonist
• Little α or cholinergic blocking action
• Long t1/2 - 48-60 hrs
• Uses: Maintenance therapy
Gilles de la tourette’s syndrome
Ticks
• S/E: Arrythmias
• Dose: 2-6 mg oral
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35. Loxapine
• Dibenzoxapine derivative
• MOA similar to CPZ
• Rapid & short acting
• Dose: 20-50 mg oral
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36. ARRIVAL OF ATYPICAL
ANTIPSYCHOTIC
• “German psychiatrists in the early 1960s opposed the
theory that EPS and antipsychotic efficacy were linked.
Their work led to introduction of Clozapine, an
antipsychotic with no EPS.”
• Clozapine was briefly marketed and quickly withdrawn
for two reasons:
– The embarrassment of not having any EPS, and
– Agranulocytosis
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37. Atypical antipsychotics
MARTA (multi acting receptor targeted agents)
• Clozapine, Olanzapine, Quetiapine
SDA (serotonin-dopamine antagonists)
• Risperidone, Ziprasidone, Paliperidone, Lurasidone,
sertindole
Selective D2/D3 antagonists
• Sulpiride, Amisulpiride
Other newer drugs
• Aripiprazole, Zotepine, Asenapine

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39. CLOZAPINE (1989)
• 1st Atypical antipsychotic
• Selectively blocks D4 receptors & has weak D2 blocking property
• Also blocks α1 + α2 receptors & more strongly blocks 5-HT2
receptors in cortex
• In addition has significant H1 blocking property
• Useful for positive and negative symptoms and refractory cases
• t1/2 -12 hrs
• In 2002 FDA approved this drug for reducing suicidal risk in
schizophrenia.
• Used as RESERVE DRUG in RESISTANT
SCHIZOPHRENIA

40. Side effects
• Least extrapyramidal side effects
• Major limitation is Agranulocytosis in 1-2 %
• MC in 6th – 18th week of therapy
• Risk ↑ when co-administered with carbamazepine, reversible on
stopping drug (CYP3A4)
• Orthostatic hypotension, sedation, weight gain, ↑ heart rate,
paradoxical hypersalivation & ↑ risk for seizures (2-3%)

41. • Precipitates Diabetes, Myocarditis, urinary incontinence
• Metabolised by CYP1A2, CYP2C19 & CYP3A4
• Interactions with SSRIs and valproic acid ↑ Clozapine levels
• Dose: 100-300 mg oral

42. OLANZAPINE (1996)
• Similar to clozapine ( blocks almost all receptors)
• Broad spectrum efficacy covering Schizo-affective
disorders & Mania
• Also used in children with developmental CNS disorders
& Tourette’s syndrome
• t1/2 : 24 – 30 hrs
• Lesser EPS
• Metabolised by CYP1A2 & glucuronyl transferase
• Dose related lowering of seizure threshold
• Avoid in elderly with Hypertension → risk of CVA

43. •Weight gain – MC side effect.
•↑ in glycosalated Hb, total cholesterol & triglycerides
• No agranulocytosis reported
•Dose: 2.5-20 mg oral
•Resperidone & Olanzapine → useful in calming agitated or
aggressive patients with dementia

44. RISPERIDONE (1994)
• Blocks selective D2 + 5-HT2 + α1+ α2 + H1 receptors
• Effective for positive & negative symptoms (controversial)
• Extrapyramidal side effects low (can occur at high doses)
• Uses: Schizophrenia (including adolescent schizophrenia)
Schizoaffective disorder
Mixed & manic states associated with bipolar disorder
Irritability in people with autism

45. Side effects : sedation, weight gain, ↑ BP, orthostatic
hypotension.
•↑ prolactin levels
•May cause anxiety/agitation & ↑ risk of
stroke in elderly
•Dose: 2-8 mg oral
•Can be given as depot IM (for chronic cases)

46. QUETIAPINE (1997)
• Less potent than risperidone
• Given BD due to short half life – 6hrs
• Blocks 5HT1A + 5HT2 + D2 + α1 + α2 + H1 receptors in brain
• Minimal EPS & ↑ prolactin levels
• Metabolised by CYP3A4
• Not useful for negative symptoms
• Used in Acute mania/Bipolar disorder (maintenance therapy)
• Dose: 50- 400 mg oral

47. • S/E: sedation, orthostatic hypotension, weight gain, cataract
formation, priapism , hyperventilation, hyperglycemia, peripheral
oedema.
• Anticholinergic side effects (like older drugs & Clozapine)
• Urinary incontinence & QTc prolongation can also occur

48. ZIPRASIDONE
• Combined D2 + 5-HT 2A/2C + H1+ α1
blocking property
• Also antagonist at 5HT1D & agonist at 5HT1A
• In addition has anxiolytic & antidepressant
properties(inhibit NA & 5HT reuptake)
• T1/2 - 8 hrs, BD dosing
• Efficacy rated equivalent to Haloperidol
• Uses: Schizophrenia
Mania
• Dose: 40- 160 mg oral
• Parental forms available

49. • Less weight gain & ↑ blood sugar
• Less EPS & hyperprolactinaemia
• Nausea & vomiting MC side effects
• Dose related QTc prolongation → Cardiac
Arrythmias.

50. PALIPERIDONE
• Also known as 9-hydroxyrisperidone
• DA antagonist
• Given orally or as Depot preparation (IM)
• Uses: Mania
Maintenance for bipolar disorder (at low
dose)
Schizophrenia
Schizoaffective disorder

51. • Primary active metabolite of risperidone
• MOA - unknown
• Antagonist effect at α1 & α2 adrenergic + H1receptors
• Also binds with DA & 5HT receptors
• Like risperidone, its possible use is
in people with Autism and Asperger
syndrome
• S/E: Restlessness, EPS
including involuntary
movements, tremors &
muscle stiffness
• Not approved for treatment of
dementia-related psychosis due
to ↑ death rate

52. SERTINDOLE (1995)
• Initially there were some poorly supported arguments
about improved negative symptom reduction
• Low risk for EPS, no sedation & very mild prolactin
elevation (major advantages)
• S/E: rhinitis, ↓ ejaculatory volume, orthostatic
hypotension, tachycardia & weight gain
• Concern about sudden cardiac death due to cardiac
arrhythmia led to its voluntary removal in 1998

53. SULPIRIDE
•Lesser EPS , sedation & autonomic S/E than
haloperidol
• S/E: Gynaecomastia (↑ prolactin)
• Dose : 400- 800mg oral

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AMISULPRIDE
• Congener of sulpiride
• High affinity for D2 + D3 & low affinity for
5HT2 receptors
• Long & better acting, safer
• Less EPS
• Less sedation & weight gain
• Hyperprolactinemia similar to typical
neuroleptics
• QTc prolongation seen
• t1/2 - 12 hrs
•Dose : 200- 400mg oral

55. Aripiprazole
• Partial agonist at D2 & 5HT1A, antagonist at 5HT2 receptors
• Longest half life – 3 days !!
• Metabolised by CYP3A4 & CYP2D6
•Dose needs to be halved in patients on ketoconazole/quinidine
& doubled with carbamazepine
• Frequent S/E: nausea, dyspepsia, constipation & light
headedness
• Weight gain, ↑ BP, prolongation of QTc interval
• Uses: Schizophrenia
Mania & Bipolar illness
Dose : 10-15mg once daily (max: 30mg /day)

56. Zotepine
• Has D2 + D1 + 5HT2 + α1 + H1 receptor blocking
property
• Also inhibits NA reuptake
• Useful for both positive & negative symptoms
• Less EPS, least sedation
• t1/2 -14 hrs
• Use: Schizophrenia
• Dose: 25-100 mg oral
• S/E: Weakness, headache & postural hypotension
• Also hyperprolactinemia, weight gain, cardiac arrythmia,
hyperglycemia, lowers seizure threshold,
dyslipidemia

57. ASENAPINE
• Given sublingually BD (5-10mg)
• S/E: Sedation, oral hypoesthesia, postural
hypotension, NMS
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58. HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine
QuetiapineQuetiapine ZiprasidoneZiprasidone
5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist)
Casey 1994Casey 1994
Atypical Antipsychotics In Vivo Binding Affinities

59. Schizophrenia
Schizoaffective disorders
Acute control of mania
Gilles de la Tourette’s syndrome
Autism & Asperger’s syndrome
Huntington’s chorea
Intractable hiccups
Indications for antipsychotics

60. ANTIPSYCHOTIC DRUG - SCREENING METHODS
IN VITRO AND EX VIVO MODELS
H Prazosin Competition Binding for alpha 1 adrenoceptors
IN VIVO MODELS
Catelepsy in Rodents
Inhibition of Amphetamine induced Stereotypy in Rats
Inhibition of Apomorphine induced sterotypy in Rats
Phenycylidine induced Bizzare pattern of Locomotor activity and stereotypy
Phenycylidine induced social withdrawal measured in the social interaction test
Conditioned avoidance reflex in Rats
Neurodevelopmental Models
Genetic Models
Single unit recording of A9 and A10 Midbrain Dopaminergic Neurons
Extrapyramidal side effects Primed Monkey Model
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62. References
1.
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