A presentation for pharamcology postgraduates . Dosages for the drugs not mentioned but required in examination point of view.

1. PHARMACOTHERAPY OF
SCHIZOPHRENIA
Dr Prasheeta V Praviraj
2nd year Postgraduate
MD Pharmacology
Rangaraya Medical College
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2. CONTENTS
• Introduction
• Pathogenesis
• Dopaminergic system
• Pharmacologic agents
• Treatment of schizophrenia
• Non pharmacological therapy
• Screening methods
• Conclusion
• References
2

3. Introduction
• Schizophrenia is a chronic thought disorder that is
characterized by psychotic symptoms during acute
phase.
• Onset of disease : late teens or 20’s
Positive
symptoms
Negative
symptoms
Cognitive
symptoms
Delusions Affective flattening Thought disorder
Hallucinations Alogia Behavioural changes
Disorganized speech Avolition , Anhedonia
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4. Types
• Paranoid schizophrenia
• Diorganized type
• Catatonic
• Undifferentiated
• Residual
Diagnosis
• DSM-IV-TR
• ICD-10
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5. History
Emil kraeplin
“ Demetia precox”
Eugene bleuler
“Schizophrenia”
Kurt schneider
“ First rank
symptoms”
1950 : Reserpine & Chlorpromazine
1950-1970: rest of neuroleptics discovered
1959 : Clozapine
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History

6. Pathogenesis
 Genetic predisposition
• First degree relative(10%) ,
• monozygotic twin (50%) ,
• dizygotic twins(10%)
• Linkage of schizophrenia
to Chromosome 1,5,6,8,11,22
4
• Neuregulin 1
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7.  Environmental component
• Dysfunctional families
• Early Stressful life
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8.  Dopamine hypothesis
• Increased and dysregulated levels of dopamine
neurotransmission
1. Patients taking drugs increasing DA levels were
showing schizophrenia like symptoms. (amphetamine,
apomorphine, cocaine)
2. Chlorpromazine (D2 antagonists)was seen to decreases
the symptoms of Schizophrenia
3. Postmortem studies of schizophrenic patients showed
increase in DA receptors ,.
4. PET scan studies : Increased amphetamine induced
striatal DA release
5. Not all patients were responsive to Dopamine
antagonists . Also not all patients showed DA receptor
rise postmortem.
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9. • Serotonin hypothesis
1. 5HT2A & 5HT2c- hallucinations
LSD & Mescaline(serotonin agonists) were found to cause
hallucination .----- research of hallucinogen in
blood,urine,brain
2. Atypical antipsychotics – 5HT2A receptor blockade
Protype drug Clozapine and others were acting based on
serotonin receptor blocking action
3. 5HT2A receptors
i. Modulate the release of dopamine , NE ,glutamate , GABA ,
Ach (cortex,limbic region,striatum)
ii. Depolarisation of glutamate neurons
iii. Stabilization of NMDA receptors on post-synaptic neurons .
4. 5HT2C receptors
inhibit dopamine release
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10. • Glutamate hypothesis
• Phencyclididne & Ketamine :non competitive inhibitors
of NMDA receptors –cognitive impairment & psychosis
• Hypofunctioning of NMDA receptors located on
GABAergic interneurons leads to diminished inhibitory
influences on neuronal functions
• NMDA receptor ion channel requires glycine for full
activation .
Schizophrenia : glycine site of NMDA is not fully
saturated . ----- trials involving high doses of glycine
thus promoting glutaminergic activity
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11.  Minor hypothesis
• Norepinephrine : Anhedonia – selective neuronal degenration
within the NE reward neural system
• GABA : GABA has a regulatory effect on dopamine –it keeps
the release of dopamine in check . Thus loss of these
GABAergic neurons will lead to hyperactivity of
dopaminergic neurons.
• Neuropeptides : Subtance P , Neurotensin
• Ach, Nicotine : decrease in the muscarinic and nicotinic
receptors in postmortem studies.
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12. Dopamine receptors
Classes Mechanism Location
D1 family (D1,D5) Release cAMP by
activation of adenylyl
cyclase & stimulte
phosphatidyl inositol
Gs
D1- putamen
- Nucleus accumbens
- olfactory tubercle
D5 – hypothalamus
- hippocampus
D2 family (D2,D3.D4) Inhibit cAMP release
Block Ca2+ channels
Open K+channels
Gi
D2-substantia nigra
-striatum
- pitiutary
D3-midbrain
- nucleus accumbens
- hypothalamus
D4-frontal cortex
- medulla
- midbrain
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13. Dopaminergic Pathways
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Fig1 : Dopaminergic pathways
(Courtesy : Rang & Dale )

14. Anatomical Pathology
• Mesolimbic system
ventral tegmental area
projects to Nucleus Accumbens in ventral striatum
Amygdala and Hippocampus
Mesolimbic positive
Hyperactivity symptoms
[emotions , memory ]
• Mesocortical system
ventral tegmental area
cerebral cortex : prefrontal cortex
Mesocortical negative
Hyperactivity symptoms
[attention , planning, motivated behaviour]
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PET SCAN

15. PHARMACOLOGIC AGENTS-
• CLASSICAL or TYPICAL NEUROLEPTICS
PHENOTHIAZI
NES
THIOXANTHE
NES
BUTYROPHEN
ONES
MISCELLANEOUS
i)Aliphatic side
chain
:Chlorpromazine
Flupenthixol Haloperidol Pimozide
ii)Piperadine
moiety
:Thioridazine
Thiothixene Benperidol Penfluridol
iii)Piperazine
moiety : -
Trifuoperazine
- Perphenazine
- Fluphenazine
Zuclopenthixol Droperidol* Molindone
Domperidone* Loxapine
Sulpiride ,
Amisulpride
Remoxipride
Metoclopramide
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16. • NOVEL or ATYPICAL ANTIPSYCHOTICS
• GLUTAMINERGIC ANTIPSYCHOTICS
Clozapine
Olanzapine
Sertindole
Asenapine
Risperidone
Ziprasidone
Paliperidone
Aripiprazole
Quetiapine
Zotepine
Glycine transporter 1
inhibitor
mGlu receptor agonists
Bitopertin : Phase 2 trials (-) Pomaglumetad methionil : Phase
2 trial (+/-)
Sarcoserine(-/+)
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17. PHARMACOKINETICS
Absorption & distribution :Highly lipid soluble and
protein bound
• Large volume of distribution
• Prolonged occupancy of D2 receptor
Metabolism : oxidation , demethylation , cytochromes
P450 enzymes
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18. PHARMACODYNAMICS
DRUG RECEPTOR
Chlorpromazine D2=α1>5HT2=D1=M1
Thioridazine α2>D2=5HT2=M1>D1
Flupenthixol D2=5HT2>α1=D2
Haloperidol D2>α1>5HT2>D1
Sulpiride D2>D3>D4
Pimozide D2>5HT2>D2
Molindone D2>5HT2A
NEUROLEPTICS
18

19. Figure 2 : receptor action of antipsychotics
(Courtesy:Lippincott)
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20. • ATYPICAL ANTIPSYCHOTICS
DRUG RECEPTOR SELECTIVITY
Clozapine 5HT2A=D4>α1=D1=D2=H1=M1
Olanzepine 5HT2A>D4>α1=D1=D2=H1=M1
Risperidone 5HT2A>D4=D2=α1=H1=M1
Quetiapine Α1>5HT2A=D2=M1
Aripiprazole D2=5HT1A>5HT2A>α1=H1
Ziprasidone 5HT2A>D2=α1=H1
Asenapine 5HT2A>D2=D3=D4>α2=α1
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21. Figure 3:Correlation between the clinical potency and affinity for
dopamine D2 receptors among antipsychotic drugs
(Courtesy: Rang & Dale )
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22. Adverse effects
• Behavioural effects
- “pseudodepression”:drug induced akinesia
- Sedation : depresses sensory inputs to RAS
(Phenothiazines, Thioxanthenes , Clozapine ,
Quetiapine, Olanzepine)
- Toxic confusional states : antimuscarinic
effect(Phenothiazines , Clozapine, Olanzepine)
• Neurologic effects
- Parkinson’s syndrome
Rx: antimuscarinic drugs (never Levodopa)
amantidine , selegiline
- Akathisia : uncontrollable restlessness
- Acute dystonic reaction : spastic retrocollis / torticollis
Rx : Sedative antihistaminics
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23. • Neurolept-Malignant Syndrome
life threatening rare disorder has been observed in patients
extremely sensitive to extra pyramidal S/E
- initial symptom: muscle rigidity
- fever , stress leucocytosis , autonomic instability
- increase myoglobin , creatinine kinase
-MOA: Central mechanisms – usual DA receptor blockade in
EP & hypothalamic site
Peripheral mechanism – Neuromuscular system
Rx : Discontinuation of neurolept
Supportive therapy
- Cold sponging
- Dantrolene
- Diazepam
- Bromocriptine(dopamine agonist)
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24. • Rabbit syndrome (Perioral syndrome)
- longterm S/E
- Rx: anticholinergic antiparkinsonian drugs
• Tardive Dyskinesia
- Late occuring syndrome of Choreoathetoid movement,
oro-buccal - lingual dyskinesia
- MOA: longterm DA receptor blockade
New DA receptor synthesis (striatal nerve cells)
Supersensitive to small amounts of DA
Relative cholinergic deficiency
Ultimate dec in GABA release Involuntary
movements
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25. Rx:(1) Decrease dopaminergic overactivity- Decrease dose: not
effective
(2) Increase cholinergic overactivity- Stop antiparkinsons
drug . Choline / Lecithine – poor results , high doses
(3)Increase GABA activity along with “neurolept-holidays”:
Diazepam [30-40mg/day]
(4) Substitution of atypical neuroleptic: Clozapine ,
Olanzepine
• Autonomic Side effects
- α blockade : Postural Hypotension & Tachycardia
Loss of libido & Delayed ejaculation
- Antimuscarinic : dryness of mouth , constipation , urinary
retention
Clozapine- paradoxical hypersalivation
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26. • Metabolic & Endocrine effects :
- Weight gain : All typical antipsychotics
Clozapine , Olanzepine (max)
Ziprasidone (least )
Aripiprazole (no gain)
- Diabetes mellitus : Clozapine , Olanzepine (max)
- Hyperlipidaemia : Clozapine , Olanzepine (max)
- Hyperprolactinaemia :
Males - Loss of libido , Impotence , Infertility .
Females – Amenorrhea , Galactorrhea , Osteoporosis
“pseudopregnancy”
Rx: Dose decrease
Switch to aripiprazole
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27. • Toxic / Allergic reactions :
- Agranulocytosis immune reaction
- Cholestatic jaundice 6th-18th week
- Skin eruptions reversible reaction
• Ocular complications
- corneal deposits
- retinal deposits = retinitis pigmentosa (thioridazone)
:800mg/d
• Cardiac complications
- ventricular arrhythmias : thioridazone
- myocarditis : clozapine
- sudden death
• Use in pregnancy: Cat ‘C’
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28. • Tolerance and Dependence
-Tolerance : Sedative & Autonomic side effects
- No drug seeking behaviour
- Withdrawal : Clozapine – rapid & severe relapse
Other drugs :relapse will take 5-6 months
• Others (phenothiazine)
- jaundice
- photosensitivity
- epileptogenic effects
- poikilothermic effects(impaired hypothalamic
thermoregulatory centre)
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29. Drug interactions
DRUG EFFECTS
Antacids Decreases absorption
Anticholinergics Increases anticholinergic effects
Alcohol More sedation
Barbiturates Decreased antipsychotic effect but more sedation
Carbamazepine &
Phenytoin
Lowering seizure threshold
Lithium Enhanced neurotoxicity
Oral contraceptive Potentiate hyperprolactinaemia
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30. TREATMENT
Acute phase
(4-8weeks)
Stabilization
Phase
(6months)
Maintenance
phase
Agitated behaviour : Benzodiazepenes (CI : elderly ,
brain damage , sedated )
Psychotic behaviour : high potency antipsychotics
Lorazepam + Haloperidol
Lorazepam + Risperidone(newer antipsychotics)
ECT/Clozapine
Medication which helped in acute remission is
continued for 6 months
Clinical parameters are monitored
Educate patient
Minimise the risk of relapse
Depot formulations ; Fluphenazine decanoate
Haloperidol decanoate
1st episode : 1-2 years
Recurrent : 5 years
Severe & Recurrent : indefinitely
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31. Investigations
BASELINE INVESTIGATIONS
Pregnancy test
Vital signs , Body weight
Toxicology screening
ECG/EEG
Complete blood count
MONITORING INVESTIGATIONS
Weight monitoring
FBS/RBS
Lipid profile
Hb1Ac
Prolactin level
ECG
Complete blood count (Clozapine)
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32. Resistant schizophrenia
• Failure to respond to two or more antipsychotics
in the optimum dosage and duration
• Rx : - Clozapine
- Psychotherapy
- Electroconvulsive therapy
- Repetitive transcranial magnetic stimulation
CLOZAPINE:
1) Treatment of resistant schizophrenia
2) Risk reduction of recurrent suicidal behaviour
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33. Non pharmacological therapy
• Psychotherapy
• Family education
• Self help groups
• Skills training
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34. Screening methods
Behavioural models Based on Pharmacological antagonism
Innate behaviour of golden hamster Amphetamine stereotypy in rats
Pole climbing avoidance in rats Apomorphine stereotypy in rats
Self stimulation of brain in rats Apomorphine climbing in rats
Catalepsy in rats Inhibition of jumping in mice
Phencyclidine induced bizarre of
locomotion and stereotypy
Phencyclidine induced social withdrawal
test
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In-vitro & Ex-vivo
3H prazosin competition binding alpha 1 adrenoceptors
In-vivo methods

35. CONCLUSION
• Pathophysiology of schizophrenia is not fully understood
which limits rational drug development
• Discovery of typical antipsychotics has led to the
formation of dopamine hypothesis
• Assuming glutamate hypothesis is the best explanation
provided till now further research in this direction may
yield new therapeutics replacing the current day drugs .
• Despite much research , schizophrenia remains a
scientific mystery and a personal disaster for the patient
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36. REFERENCE
• Kaplan & Sadocks;Schizophrenia;Synopsis of Clinical
Psychiatry; 10th edition ; Chapter 10;Pg 158-177
• Charles De Battista; Antipsychotic agents and lithium ; Basic
and clinical pharmacology ; Katzung trevor;13th edition ;
Chapter 29 ;Pg490-502;
• Mary A Gutierrez & Glen L Stimmel , Schizophrenia ,
Textbook of Therapeutic , Eric T .Herfinadale , Dick R
Gourley. 8th edition; Pg 1432
• David G Standart et.al ;Pharmacology of Dopaminergic
neurotransmission;Principles of pharmacolgy-The
pathophysiologic basis of disease ; 3rd edition ; Chapter 13 ; Pg
195-201
• HL Sharma & KK Sharma;Antipsychotic drugs;Principlesof
Pharmacology ; 2nd edition;Pg 451-460
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37. THANK YOU
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