Pharmacotherapy of Psychosis (Schizophrenia). Dopaminergic projections in the brain. Positive and negative symptoms. Typical and atypical antipsychotics. Partial dopamine agonists. Refractory Schizophrenia Pimavanserin: Parkinson's disease psychosis

1. Pharmacotherapy of
Psychosis
Dr Pranav Sopory
All India Institute of Medical Sciences
New Delhi
Mob: +91 9999491690
Email: pranav.sopory@gmail.com
LinkedIn: www.linkedin.com/drsopory
Self-portrait of a patient with Schizophrenia

2. Contents
• Introduction to Psychosis
• Major Dopaminergic Pathways
• Typical Antipsychotics (FGA) & Adverse Effects
• Atypical Antipsychotics (SGA) & Adverse Effects
• Adherence to Antipsychotics
• Phases of Treatment
• Newer Agents

3. What is psychosis?
• Psychosis is a symptom of an underlying mental disorder.
• Components:
1. Delusions (false beliefs)
2. Hallucinations (seeing or hearing things that others do not see or hear)
3. Incoherent speech and behavior that is inappropriate for the situation.
• Characteristic: Loss of insight
• Psychotic disorders are associated with:
1. Sleep problems
2. Social withdrawal
3. Lack of motivation
4. Difficulties carrying out daily activities.
https://www.nhs.uk/conditions/psychosis/

4. Psychotic disorders (DSM-V)
1. Mood disorders (major depression or mania) with psychotic features
2. Substance-induced psychosis
3. Dementia with psychotic features
4. Delirium with psychotic features
5. Delusional disorder
6. Schizophrenia (Prevalence in India : 2-3/1000)

5. Major Dopaminergic Projections
Goodman & Gilman’s The Pharmacological Basis of Therapeutics; 13th Edition,
Figure 13-11
1. Mesolimbic
2. Mesocortical
3. Nigrostriatal
4. Tuberoinfundibular

6. Case I
• A person quarrels and hits his neighbour. The next day he starts
feeling that he is being followed by the police who may arrest him.
He also feels that his neighbour is controlling him through radio
waves. He later suspects that his neighbour has transformed into a
demon. There are continuous voices commenting his each and
every action.

7. Mesolimbic Pathway
• MLP: VTA → NA
• Reward/ Addiction Pathway
• ↑ ↑ DA: Overactive MLP
Positive Symptoms:
1. Hallucinations & delusions
2. Disorganized thought & speech
3. Bizarre behaviors
Ventral Tegmental Area (VTA)
Nucleus Accumbens (NA)

8. 1. Typical Antipsychotics (FGA)
Goodman & Gilman’s The Pharmacological Basis of Therapeutics; 13th Edition,
Table 16-1
GENERIC NAME
ORAL DOSAGE (mg/d)
ACUTE PSYCHOSIS MAINTENANCE
1ST EPISODE CHRONIC 1ST EPISODE CHRONIC
PHENOTHIAZINES
Chlorpromazine 200-600 400-800 150-600 250-750
Perphenazine 12-50 24-48 12-48 24-60
Trifluoperazine 5-30 10-40 2.5-20 10-30
Fluphenazine 2.5-15 5-20 2.5-10 5-15
OTHER FGA
Loxapine 15-50 30-60 15-50 30-60
Thiothixene 5-30 10-40 2.5-20 10-30
Haloperidol 2.5-10 5-20 2.5-10 5-15
General PD property: STRONG D2 BLOCKADE
Structural Classifn: phenothiazines and others (thioxanthines, butyrophenones, diphenylpiperidines)

9. 1. Typical Antipsychotics (FGA)
• 1933, France: Promethazine (anti-histaminic)
• Sedative side-effects noted & used as a pre-op ‘calming agent’
• 1950: Chlorpromazine developed and marketed as anti-anxiety pill.
• 1952, USA: 38 psychotic patients administered chlorpromazine.
• Results: ↓ delusional and hallucination episodes
• 1955: Chlorpromazine approved in USA for treatment of psychosis
Ban TA. Fifty years chlorpromazine: a historical
perspective. Neuropsychiatr Dis Treat. 2007

10. D1 receptor subfamily
D2 receptor subfamily
• D1
• D5
• D2
• D3
• D4
(Gs)
(Gi)

11. Nigrostriatal Pathway
Substantia Nigra (SN)
• NSP: SN → Striatum (C+P)
• Coordination of movement
• ↓ ↓ DA:
• Extrapyramidal symptoms (EPS)
• FGA > SGA

12. Adverse EffectsSpasm of
muscles of
tongue, face,
neck and back
Subjective and
objective restlessness.
No anxiety or agitation
Acute Dystonia
1-5 days
Akathisia
5-60 days
Bradykinesia, rigidity,
variable tremor, mask
facies, shuffling gait
Parkinsonism
5-30 days
Elderly at risk
Perioral tremor
(? Late variant
of
parkinsonism)
Rabbit syndrome
Months to years
Extreme rigidity, fever,
unstable blood pressure,
myoglobinemia
Neuroleptic
Malignant Syndrome
Weeks to months

13. Tuberoinfundibular Pathway
Pituitary Gland
• TIP: Hypothalamus → Anterior Pituitary
• Inhibition of Prolactin release
• ↓ ↓ DA: by FGA > SGA
Hyperprolactinemia
1. Galactorrhea & amenorrhea (F)
2. Sexual dysfunction or infertility (M+F)
Hypothalamus
M/c cause of non-adherence in young males
SCZ onset: M/c in adolescent males

14. Management of Side effects
• zc
REACTION Rx
Acute Dystonia Antiparkinsonian agents
(Diphenhydramine 25-50 mg IM or Benztropine 1-2mg IM
Akathisia Reduce dose or change drug.
Clonazepam.
Propranolol (low dose: 20-80 mg/d) more effective than
antiparkinsonian agents
Parkinsonism Dose reduction.
Change medication.
Antiparkinsonian agents.
Neuroleptic Malignant Syndrome Stop antipsychotic immediately.
Supportive Care.
Dantrolene & Bromocriptine.
Rabbit Syndrome Antiparkinsonian agents often helps
Hyperprolactinemia Rapid reversal on stopping antipsychotic.
Reduce dose or change drug. Goodman & Gilman’s The Pharmacological Basis of
Therapeutics; 13th Edition, Table 16-5

15. Case II
• A 24-year-old football player has been discharged after treatment of
a psychotic episode. While his hallucinations, delusions, and
paranoia have subsided, he is demonstrating marked cognitive
impairment. He has difficulty reading the newspaper, hardly speaks
to his family members, stays locked-up in his room for days and
doesn’t enjoy playing football anymore.
? Treat with Typical Antipsychotics

16. Mesocortical Pathway
• MCP: VTA → Cortex
• Cognition
• ↓ ↓ DA: Inactive MCP
Negative Symptoms:
1. Flat affect
2. Anhedonia
3. Alogia
VTA
BAD PROGNOSIS

17. SGA: 5-HT2A>>D2 (Precise mechanism remains unclear!)
Mauri MC, Paletta S, Maffini M, et al. Clinical pharmacology of
atypical antipsychotics: an update. EXCLI J. 2014
Receptor Action Proposed Effect Clinical Effect
5-HT2A Strong Antagonist ↑ Neocortical DA ↓ Negative Symptoms
5-HT1A Partial Agonism ? ↓ Negative Symptoms
↓ Anxiety
5-HT2C Strong Antagonist ? ~same~
D2 Weak antagonist Same as Atypical ↓ Positive Symptoms
D2
5-HT2A
HIGH LOWFGA SGA
BLOCKADE

18. SGA: Differential D2 action
1. Fast-off-D2 Effect
• SGA: Lower affinity than DA
Seeman P. Clozapine, a fast-off-D2 antipsychotic.
ACS Chem Neurosci. 2014
Beaulieu JM et al., The Akt-GSK-3 signaling cascade in the
actions of dopamine. Trends Pharmacol Sci. 2007
G-protein-mediated signaling
β-Arrestin-2-mediated signaling
(Akt-GSK3)
FGA: Inhibit both pathways with similar efficacy
SGA: Inhibit cAMP-independent mainly
Explains ↓ EPS associated with SGA
2. cAMP-independent mechanisms

19. Classification of SGA
Classfn Receptor Affinity Drugs
SDA:
Serotonin-Dopamine Antagonists
(5-HT2A and D2) Risperidone and
Paliperidone (metabolite)
Ziprasidone
Iloperisone
Lurasidone
MARTA:
Multi-Acting Receptor Targeted
Antipsychotics
(SDA + M1, H1, 5-HT1A, 5-HT1C) Clozapine
Olanzapine
Quetiapine
Asenapine
D2/D3 receptor antagonists D2 and D3 Amisulpride
Partial D2 Agonism (3rd GEN.*) D2 Aripiprazole
General PD property: D2 BLOCKADE essential for antipsychotic effect !
Classification: based on Receptor affinity

20. 18F PET-DOPA: D2 Occupancy and Behavioral Effects
D2 blockade:
• 65%: Anti-psychosis
• 72%: Hyperprolactinemia
• 80%: EPS
• 90%: NMS
Positron Emission Tomography in Schizophrenia: A New
Perspective, J Nucl Med April 2010 vol. 51 no. 4 511-520
Schizophrenia patient
Healthy volunteer

21. 3. Partial D2 receptor agonist: Third Generation
Dopamine
Dopamine +
Haloperidol
Aripiprazole
Dopamine +
Aripiprazole
Aripiprazole, Brexipiprazole, Cariprazine
}
• Antipsychotic activity requires:
80-95 % D2 occupancy.
25%
• Intrinsic D2 activity: 25%
• Sufficient postsynaptic signal to
remain below EPS threshold
• Better adherence than other drugs

22. Adherence to antipsychotics
• Highest rate of non-adherence among all chronic illnesses
• 75% over 2 year course*
Causes:
• Intolerable S/E
• Lack of insight
• Persistent residual disease
Leads to psychotic relapse
Management?
*Leucht S et al., Antipsychotic drugs versus placebo for relapse prevention in schizophrenia:
a systematic review and meta-analysis. Lancet. 2012 Jun 2;379(9831):2063-71.
Least tolerable: Haloperidol- Max. EPS

23. Depot preparations available in India
Grover S et al., Clinical Practice Guidelines for Management of Schizophrenia.
Indian J Psychiatry. 2017
Name of antipsychotic Dosage (mg) Timing (weeks)
Zuclopenthixol decanoate 200 4
Paliperidone palmitate 234 initially followed by
117 monthly
4
Fluphenazine decanoate 12.5-50 2
Haloperidol decanoate 50 4
Risperidone depot 25-50 2
Olanzapine pamoate 210-405 4
Diluent:
Decanoate: Oil-based (sesame/ coconut)
Water-based: palmitate, pamoate

24. Phases of treatment
I. ACUTE PHASE (F.E.P)
• Completely florid symptoms of psychosis
• High R/o harm to family members
• Parenteral adm. of antipsychotics with ↑ sedative action
• Lasts 4-6 weeks
II. CONTINUATION PHASE (Aim-based)
• Prevention of relapses
• Lasts 1 yr. (after F.E.P.), 5yrs (S.E.P.), Life-long (aggressive/suicidal)
III. MAINTENANCE/STABLE PHASE (Goal based)
• Improve functioning
• Improve QoL
D2 blockade achieved within hours
Clinically noticeable difference >2 weeks
PANS scoring possible
Mousavi SG et al., Onset of action of atypical and typical antipsychotics in the
treatment of acute psychosis. J Res Pharm Pract. 2013

25. Receptor Potency (Ki values)
FGA D2 5HT2A M1 A1A A1B H1
SGA
Goodman & Gilman’s The Pharmacological Basis of Therapeutics; 13th Edition,
Table 16-2
Ki: inhibitory constant
Smaller Ki: Greater binding affinity and smaller dose of drug needed for activity

26. Adverse Effects:
Monoamine Receptor Affinity
1. D2
2. H1
3. M1
4. ⍺1
Non-monoamine Receptor Affinity
1. Adverse Metabolic Effects
2. Adverse Cardiac Effects
3. Other Adverse Effects
Depends on receptor affinity

27. Non-dopaminergic Side Effects
Receptor Side-Effect Comments
H1
Sedation & weight gain Highest risk
FGA: Chlorpromazine
SGA: Clozapine, Quetiapine
Useful: Agitated patients (acute psychosis)
M1
Blurred vision, constipation Highest risk: Clozapine
⍺1
Orthostatic hypotension Rx with fludrocortisone
 Seen mostly in WEAK D2 blockers: FGA and SGA

28. Tolerance and Physical Dependence
• Loss of efficacy to antipsychotics doesn’t develop
• Antipsychotics are NOT addictive
• Tolerance to non-dopaminergic effects develop (H1, M1, ⍺1)
Chronic D2 blockade:
• Some patients develop postsynaptic supersensitivity: D2
High receptors
• On sudden withdrawal: Emergent Dyskinesia / Tardive Dyskinesia
Time: months to years
Risk proportional to D2 blockade
Rx: VMAT2 inhibitors
Valbenazine, Tetrabenazine
Orofacial dyskinesia
Widespread choreoathetosis
↑ activity in Nigrostriatal Pathway
Highest R/o Elderly: missed drug

29. Adverse Metabolic Effects (68%: MetS)
Insulin resistance:
Chlorpromazine: Initially used pre-surgery for insulinoma
Risk: Clozapine > Olanzapine ……… Ziprasidone (least)
↓ risk: Aripiprazole, Brexipiprazole, Cariprazine (GG-13E)
Elevated Triglycerides:
Clozapine > Olanzapine > Quetiapine
Weight independent: occurs within the first 6 weeks
As insulin resistance worsened: ↑ lipolysis: ↑
triglyceridemia
End result:
Type-2 DM & CAD (risk ↑ 50%)
Papanastasiou E. The prevalence and mechanisms of metabolic syndrome in schizophrenia: a review.
Ther Adv Psychopharmacol. 2013;3(1):33-51.
Proposed mechanisms:
1. Alter HPA axis: Cushing’s Syndrome
(Meyer and Stahl, 2009)
2. Genetic predisposition: 23% MetS in Indian pop.
(Bajaj and Varma et al. 2013)
Risk factors:
Women, SGA, polypharmacy, age >40 years

30. Adverse Cardiac Effects: ↑QTc → TdP → SCD
Antipsychotics block IKr channel: ↑ QTc
Dose dependent effect
↑ R/o when given with CYP 2D6 & 3A4 inhibitors
 ↑ R/o: pts. with LQTS
US-FDA black box warning for use in Geriatric patients
Least R/o with Aripiprazole
Beach SR et al., QTc prolongation, torsades de pointes, and
psychotropic medications. Psychosomatics. 2013
Drugs with High R/o ↑ QTc at Therapeutic Doses
Drug Class Drug Name
FGA Thoiridazine (max.), Haloperidol, Chlorpromazine, Pimozide
SGA Ziprasidone, Iloperidone, Quetiapine

31. Other Adverse Effects
1. Seizures: Class label warning (USA)
• Dose dependant
• Clozapine (5%) > Loxapine….. Haloperidol (least)
2. Agranulocytosis: Clozapine
• Genotypes: HLA-B38/B39/B67 and HLA-DQB105
3. Photosensitivity: Chlorpromazine
• UV exposure: Changes structure of drug
• Body reacts to new antigen
• Allergic response of light-exposed skin
Wiciński M, Węclewicz MM. Clozapine-induced agranulocytosis/granulocytopenia: mechanisms and monitoring.
Curr Opin Hematol. 2018
↓GABA

32. Antipsychotics: Pharmacokinetics
1. Highly lipophilic: Accumulate in Brain
2. Short t1/2 (min to max: check table)
3. Biological t1/2 persists 24 hours: permit
OD dosage
4. Oral: High Absorption
• Concurrent Anticholinergic: Negligible
effect
• Exception: Asenapine
 FPM: >98%
 ODT only, F: 35%
Goodman & Gilman’s The Pharmacological Basis of
Therapeutics; 13th Edition, Table 16-5
5. Highly protein bound (acid-glycopr)
• Don’t displace albumin-bound drugs
6. Metabolized mainly by CYP2D6 &
CYP3A4
• Carbamazepine & Phenytoin C/I in pts
with Psychosis + Epilepsy
7. Safe in patients with Renal disease

33. Real World Effectiveness Studies (2009)
1. CATIE: Clinical Antipsychotic Trials of Intervention Effectiveness
2. CUtLASS: Cost Utility of the Latest Antipsychotic drugs in SCZ Study
Between [FGA Vs. SGA] & [Among SGAs*]
• Non-significant difference in terms of
1. Efficacy
2. Adherence
3. Side-effect profile
4. Cost-effectiveness
5. Improvement in QoL
Naber D, Lambert M. The CATIE and CUtLASS studies in schizophrenia: results and
implications for clinicians. CNS Drugs. 2009*except Clozapine
SGA as first line:
• ↓ EPS
• ↑ weight gain, hyperglycaemia and
dyslipidaemia.
(Lieberman JA et al., 2003; Schooler N
et al., 2005; Emsley RA et al., 2006)

34. Choosing an Antipsychotic:
1. Most Imp.: Avoidance of adverse effects based on patient and drug characteristics
2. Family H/o treatment
3. FGA for positive symptoms, SGA for negative symptoms: NOT ABSOLUTE
4. Medical comorbidity
5. Special population: Pediatric, geriatric, pregnancy & lactation
Grover S et al., Clinical Practice Guidelines for Management of Schizophrenia.
Indian J Psychiatry. 2017

35. Special population
1. Pediatric population
• Adolescent SCZ (13-17 yr): Aripiprazole, olanzapine, risperidone, quetiapine, lurasidone
• R/o Amenorrhea in girls & Gynaecomastia in boys (Amisulpride: Max. Hyperprolactinemia)
2. Geriatric population
• Highest risk: EPS & TD (25%)
• ↑ R/o CAD & SCD
• Amisulpride ( D2/D3# - Least action on α1, H1 or M1 ; Ki = 10,000): Safest
3. Pregnancy
• All drugs: lipophilic - cross the placenta
• R/o GDM, high birth weight & prematurity

36. Refractory Illness
a.k.a. Refractory Schizophrenia
Characteristic: Negative symptoms
• 30% pts. (after 4-5 weeks of Rx of Acute phase)
• 60% of these pts. respond with Clozapine
Newer Hypothesis:
• Resistant SCZ is another subset of SCZ.
Veerman SR et al., Memantine augmentation in clozapine-refractory schizophrenia: a
randomized, double-blind, placebo-controlled crossover study. Psychol Med. 2016
The Glutamate Hypothesis of
Schizophrenia:
NMDA Receptor mediated excitotoxicity at
Prefrontal cortex:
Neurodegeneration
Cognitive impairment and Negative symptom

37. Clozapine
• First US-FDA approved SGA (1989)
• Dose: 300-900 mg/day (Maintenance: Chronic Schizophrenia)
PK
• Peak plasma concentration: 2.5 hours
• t1/2 : 12 hours
• Multiple CYPs (1A2, 2C19, 3A4)
• C/I with Fluvoxamine (CYP#): ↑ serum conc. 10 fold
S/E
• Metabolic syndrome (80%)
• Seizures
• Sedation (40%)
• Agranulocytosis (2%) – immediate cessation (fatal)
Monitoring
• TDM: Plasma levels: 350-420 ng/ml (Done weekly in AIIMS – New Delhi)
• CBC + Diff: WBC> 3,500/mm3 ANC> 2,000/mm3

38. Nonpsychotic Uses
Obsessive Compulsive Disorder (OCD) Risperidone (Adjunct)
Generalized Anxiety Disorder (GAD) Risperidone (Monotherapy)
Tourette’s Syndrome Aripiprazole (First Line)
Autism Risperidone and aripiprazole (5-16 y.o.)

39. Parkinson Disease Psychosis (PDP)
• Incidence: 60%
• Risk not established with levodopa use.
• Psychosis not linked to dopaminergic pathways
• Rx: SGA (Clozapine & Quetiapine)
Kianirad Y, Simuni T. Pimavanserin, a novel antipsychotic for management of Parkinson's disease psychosis.
Expert Rev Clin Pharmacol. 2017
• Neuroimaging study:
Elevated 5-HT2A receptor binding density
in temporal and occipital lobe in PD pts.
with auditory & visual hallucination.

40. 4. 5-HT2A inverse agonist: Pimavanserin
Pimavanserin:
• Specific inverse agonist of 5-HT2A receptors
• Devoid of D2 receptor activity (The only antipsychotic)
• USFDA approved (2016) for PDP
Kianirad Y, Simuni T. Pimavanserin, a novel antipsychotic for management of Parkinson's disease psychosis.
Expert Rev Clin Pharmacol. 2017

41. Summary: Pharmacotherapy of Psychosis
1. First Generation (Typical Antipsychotics)
2. Second Generation (Atypical Antipsychotics)
3. Third Generation (Partial D2 Agonist)
4. 5-HT2A inverse agonist

42. Conclusion
Only 2 certainties in management:
1. Clozapine for resistant schizophrenia
2. Pimavanserin for PDP
Typical: ↑EPS, Atypical: ↑Metabolic syndrome
No drug is exclusively D2 selective
D2 blockade: essential for anti-psychotic action (except Pimavanserin)
Management should be patient specific, not generalized

43. Thank you very much.
1972 1974
John F. Nash
(Mathematician)
Nobel Prize winner
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Syd Barrett
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