Drugs used in the treatment of psychotic disorders: Based on their activity on neurotransmitter receptors, antipsychotics can be classified as typical and atypical antipsychotics. Atypical antipsychotics have overall greater efficacy and decreased risk of movement disorders, but they carry greater risk of metabolic syndrome.
I) Typical or conventional or first generation antipsychotics: They act primarily by blocking D2 dopamine receptors. They include chlorpromazine, thioridazine, trifluoperazine, haloperidol, fluphenazine, loxapine, thiothixene and pimozide. Long acting intramuscular formulations are available for haloperidol, perphenazine, fluphenazine and chlorpromazine. Long acting forms are especially useful for patients in whom compliance is a problem. Typical antipsychotics can control positive symptoms of schizophrenia but are not useful to treat negative symptoms.
Adverse effects of typical antipsychotics include sedation, anticholinergic effects like dry mouth and constipation, orthostatic hypotension, cognitive defects, dystonia, muscle stiffness, tremors, galactorrhea and elevated prolactin levels, seizures, movement disorders and metabolic syndrome (less likely). Some drugs like thioridazine and chlorpromazine may cause retinal or corneal deposits respectively. Movement disorders may be incapacitating and lead to drug non-compliance and include extrapyramidal symptoms like acute dystonia, akinesia, bradykinesia , akathisia and tardive dyskinesia.
Dystonia
Akathisia
Drug induced Parkinsonism
Tardive dyskinesia
II) Atypical or second generation antipsychotics: They are more selective D2 blockers than typical antipsychotics and have lesser affinity to the D2 receptor compared to typical antipsychotic drugs, hence cause less extrapyramidal adverse effects. They also block serotonin 5HT2A receptors. They are effective in treating both positive and negative symptoms of schizophrenia. They include clozapine, olanzapine, aripiprazole, asenapine, brexpiprazole, cariprazine, ziprasidone, risperidone, lurasidone, quetiapine etc. Second generation drugs are preferred as they do not cause extrapyramidal effects. However they are associated with higher mortality in older patients with dementia. Advantage of clozapine is high efficacy. Aripiprazole, olanzapine and risperidone are available in long acting injectable formulations.
Adverse effects of clozapine include sedation, hypotension, tachycardia, weight gain, metabolic syndrome, glucose intolerance, sialorrhea and rare but potentially fatal agranulocytosis. WBC count has to be monitored regularly with clozapine therapy. Major adverse effects of second generation drugs include metabolic syndrome, weight gain and dyslipidemias. Blood glucose and lipid levels should be monitored.
Antipsychotics that may prolong QTc
Thioridazine
Haloperidol
Olanzapine
Risperidone
Ziprasidone
Neuroleptic malignant syndrome
Potentially fatal adverse effect of antipsychotics (all classes), metoclopramide, promethazine, amoxapine, droperidol, tetrabenazine and diatrizoate or abrupt cessation of levodopa, rarely lithium
Develops few days to weeks after starting therapy
Marked by fever, autonomic instability, rigidity and altered mental status. Diaphoresis, dysphagia, tremors, incontinence, confusion, coma, mutism, varied features
Leukocytosis, raised CPK (rhabdomyolysis)
Immediately stop offending drug, shift to ICU
Administer dantrolene (skeletal muscle relaxant), bromocriptine (D2 agonist), ECT in refractory cases
Cooling measures, electrolyte correction, hydration
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