Drugs used in the treatment of psychotic disorders: Based on their activity at neurotransmitter receptors, antipsychotics are classified as typical and atypical antipsychotics. Atypical antipsychotics generally have greater overall efficacy and a lower risk of movement disorders, but they carry a higher risk of metabolic syndrome.
I) Typical or conventional or first generation antipsychotics: Typical antipsychotics 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 when medication adherence is a problem. Typical antipsychotics can control the positive symptoms of schizophrenia but are not useful for treating negative symptoms.
Adverse effects of typical antipsychotics include sedation, anticholinergic effects (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, such as thioridazine and chlorpromazine, may cause retinal or corneal deposits, respectively. Movement disorders may be incapacitating, can lead to drug non-compliance, and include extrapyramidal symptoms such as acute dystonia, akinesia, bradykinesia, akathisia, and tardive dyskinesia.
Dystonia
Akathisia
Drug induced Parkinsonism
Tardive dyskinesia
II) Atypical or second generation antipsychotics: Atypical antipsychotics are more selective D2 blockers than typical antipsychotics and have lower affinity for the D2 receptor, so they cause fewer 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 because they do not cause extrapyramidal effects. However, they are associated with higher mortality in older patients with dementia. An 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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