Drugs used for the treatment of psychosis

1. Antipsychotics
Dr. M. Ahsan, MBBS, MD

2. Learning Outcomes….
• Classify antipsychotic drugs
• Describe the mechanism of action of typical and atypical
antipsychotics
• Describe the pharmacokinetics & clinical actions of antipsychotics
• Describe the therapeutic uses and adverse effects of antipsychotics
• Identify the cautions and precautions related to use of antipsychotics

3. Schizophrenia
• Type of chronic psychosis characterized by:
Delusions
hallucinations (auditory commonly)
disturbances in thought
• Onset in late adolescence or early adulthood
• Genetic component
• Dysfunction of the mesolimbic or mesocortical dopaminergic
neuronal pathways

4. Antipsychotic drugs
• Antipsychotic drugs are primarily
used to treat schizophrenia, but
they are also effective in other
psychotic and manic states
not curative
do not eliminate the chronic
thought disorder
decrease the intensity of
hallucinations and delusions
permit the person with
schizophrenia to function in a
supportive environment

5. Antipsychotics
• First generation (low potency)
Chlorpromazine
Thioridazine
• First generation (high potency)
Fluphenazine
Haloperidol
Loxapine
Molindone
Perphenazine
Pimozide
Prochlorperazine
Thiothixene
Trifluperazine

6. Antipsychotics
• Second generation (atypical
antipsychotics)
Risperidone
Ziprasidone
Paliperidone
Iloperidone
Lurasidone
Olanzapine
Quetiapine
Clozapine
Asenapine
• Third generation
Aripripazole
Brexipiprazole
Cariprazine

7. First generation antipsychotics
• Also called conventional/typical antipsychotics
• Competitive blocker of dopamine D2 receptors
• More likely to be associated with extrapyramidal symptoms
(EPS)……especially haloperidol
……less likely with chlorpromazine (binds less potently)
No one drug is clinically more effective than the other

8. Second generation antipsychotic drugs
• Also called atypical antipsychotics
• Lower incidence of EPS
• High risk of metabolic adverse effects (diabetes, hypercholesterolemia,
weight gain)
• Block serotonin and dopamine receptors
• Used as first line drugs for schizophrenia
• More efficacious than first generation drugs

9. Mechanism of action
• Dopamine antagonism:
• All the 1st generation and most of the 2nd generation receptors block
D2 receptors in the brain and the periphery
• Serotonin receptor blocking activity:
• Most 2nd generation agents block 5-HT receptors (esp. 5-HT2A)

10. Mechanism of action
• Clozapine: has high affinity for D1, D4, 5-HT2, M and α receptors, but
weak D2 receptor antagonist
• Risperidone/ Olanzapine: blocks 5-HT2A receptor to a greater extent
than D2
• Aripiprazole/Brexipiprazole/Cariprazine: partial agonists at D2 and 5-
HT1A, antagonist at 5-HT1A
• Quetiapine: weak blocker of D2 and 5-HT2A (low risk of EPS is due to
relatively short period of time that it bind to D2 receptor)
• Pimavanserin: inverse agonist of 5-HT2A; antagonist of 5-HT2C
…..indicated for psychosis associated with Parkinson’s ds

11. Mechanism of action
The antipsychotic action
is due to blockade at
dopamine and/or
serotonin receptors.
However, many agents
also block cholinergic,
adrenergic, and
histaminergic
receptors……resulting in
undesirable side effects

12. Actions
• Antipsychotic effects
• Extrapyradimal effects
• Antiemetics effects
• Anticholinergic effects
• Other effects

13. Antipsychotic actions
• Hallucinations and delusions (positive symptoms) are reduced
....… by blocking dopamine receptors in the mesolimbic system
• Calming effect and reduce spontaneous physical movement
• Do not depress the intellectual functioning
• Motor incoordination is minimal
• Improvement take several days to weeks to occur
…therapeutic effects are related to secondary changes in corticostriatal pathways.
 Negative effects (blunted affect, anhedonia,
apathy)
 Impaired attention
 Cognitive impairment
 Not improved by typical
antipsychotics….
 Improved by atypical
antipsychotics (clozapine)

14. Extrapyramidal Actions
Due to chronic treatment:
Dystonias (sustained contraction of muscles leading to twisting
distorted postures)
Parkinson-like symptoms
Akathisia (motor restlessness)
Tardive dyskinesia (involuntary movements of the tongue, lips, neck,
trunk, and limbs)
• Caused by blocking of dopamine receptors in the nigrostriatal
pathway
• Atypical antipsychotics exhibit a lower incidence of these symptoms

15. Antiemetic Actions
Block D2 receptors on chemoreceptor trigger zone (CTZ)…….leading to
antiemetic action
(except aripiprazole and thioridazine)
Atypical antipsychotic drugs are not used as antiemetics
Used for nausea due
to:
Vertigo
Motion sickness
Cancer chemotherapy

16. Antimuscarinic Actions
• Some of the neuroleptics, particularly thioridazine, chlorpromazine,
clozapine, and olanzapine, produce anticholinergic effects:
Blurred vision
Dry mouth (exception: clozapine increase salivation)
Confusion
Constipation and urinary retention
The anticholinergic property may actually assist in reducing the risk of
EPS with these agents

17. Actions of Antipsychotics
• Orthostatic hypotension…..due to alpha receptor blockade
• Poikilothermia….due to alteration of temperature-regulating
mechanisms
• Increased prolactin release….due to D2 blockade in pituitary
(Atypical neuroleptics are less likely to produce prolactin elevations)
• Sedation…. H1-histamine receptor blockade due to chlorpromazine,
olanzapine, quetiapine, and clozapine.
• Sexual dysfunction
• Weight gain….with 2nd generation agents

18. Therapeutic uses
• Schizophrenia
Traditional antipsychotics are most effective in treating positive
symptoms of schizophrenia (delusions, hallucinations, thought
processing, and agitation)
Atypical antipsychotics with 5-HT2A receptor blocking activity may be
effective in many patients who are resistant to the traditional agents
Clozapine is reserved for the treatment of refractory patients (10-20% cases),
because its use is associated with bone marrow suppression, seizures and orthostasis

19. Therapeutic uses
• Prevention of severe nausea and vomiting
• As tranquilizers to manage agitated and disruptive behavior secondary to
other disorders.
• Treatment of chronic pain with severe anxiety (used along with opioids)
• Chlorpromazine is used to treat intractable hiccups..
• Pimozide is indicated for treatment of the motor and phonic tics of
Tourette's disorder (Risperidone & haloperidol are also commonly
prescribed for this tic disorder)
• Risperidone & Aripiprazole is now approved for the management of
disruptive behavior and irritability secondary to autism

20. Therapeutic uses
• Management of manic and mixed symptoms of bipolar disorder
• Lurasidone and quetiapine are used for bipolar depression
• Paliperidone is used for schizoaffective disorder
• Also used as adjunctive drugs for refractory depression

21. Pharmacokinetics
• Variable absorption through oral route
• Absorption is unaffected by food
• Readily pass into the brain, have a large volume of distribution, bind
well to plasma proteins, and are metabolized to many different
substances, usually by the cytochrome P450 system in the liver
Long acting injectable (LAI) formulations: Fluphenazine decanoate,
haloperidol decanoate, risperidone microspheres, paliperidone palmitate
are LAIs
Act for 2 – 4 weeks (some for 6-12 weeks)
Used to treat outpatients who are non-adherent to medications

22. Adverse effects
• Extrapyramidal effects
Occur after weeks to months
Treated with central anticholinergics
(benztropine)
• Tardive dyskinesia
Occurs after months or years of treatment
Resolves after prolonged holiday from
antipsychotics but may be irreversible
Valbenazine and Deutetrabenazine is used for
management (vesicular monoamine
transporter inhibitors)
• Neuroleptic malignant syndrome
Potentially fatal reaction
Fever, muscle rigidity, altered mental status, unstable
BP, myoglobinemia
Supportive therapy (Dantrolene may be used)
• Others:
Drowsiness, confusion
Antimuscarinic side effects
Orthostatic hypotension
Depression of hypothalamus leading to amenorrhoea,
galactorrhoea, infertility
Weight gain
Abnormal glucose and lipid profiles

23. Cautions & Contraindications
• All antipsychotics may lower the seizure threshold
• Increased risk of seizure from alcohol withdrawal
• All of the atypical antipsychotics also carry the warning of increased
risk for mortality when used in elderly patients with dementia-related
behavioral disturbances and psychosis
• There can be worsening of mood and suicidal ideation when used for
mood disorders….monitoring required

24. Thank you for being patient!!

25. References
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.
• Clinical Medicine: A Textbook for Medical Students & Kumar PJ
and Clark ML (8th ed.); Elsevier Saunders
• Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a
review. British Medical Bulletin. 2015;114(1):169–179