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.

Movement disorders caused by antipsychotics

Dystonia

• Description: Painful, involuntary contractions of antagonistic muscle groups that lead to twisting, sustained, repetitive motions or abnormal postures. It most commonly affects the head, face, and neck. It may present as life-threatening laryngospasm, oculogyric crisis, torticollis, etc. Occurs within hours to days of initiating therapy.
• Treatment: Anticholinergics like benztropine as prophylaxis; in emergencies, use intramuscular biperiden or diphenhydramine, or benzodiazepines like lorazepam; sos intubation.

Akathisia

• Description: A feeling of restlessness and tension that may compel near-constant motion or, rarely, suicide. Starts after days to weeks of therapy.
• Treatment: Propranolol, mirtazapine, cyproheptadine, 5HT2 antagonists mianserin and ritanserin, 5HT1 agonist zolmitriptan, benztropine in some cases, parenteral diazepam, clonazepam or lorazepam in emergencies, Vit B6.

Drug induced Parkinsonism

• Description: Bradykinesia, rigidity, tremors, etc. Starts after days to months of therapy.
• Treatment: Decrease dose of antipsychotic, change to new drug, benztropine, amantadine.

Tardive dyskinesia

• Description: Involuntary athetoid or choreiform movements of the lower face, extremities, and/or trunk muscles. It presents with grimacing, puckering, lip smacking, tongue movements, and excessive blinking. It may persist after stopping the medication and may be permanent. Seen months or years after therapy.
• Treatment: Switch to new drug. Valbenazine and tetrabenazine, which are vesicular monoamine transporter inhibitors. Clonazepam, Ginkgo biloba, Vit B6, E. Stimulation of the globus pallidus.

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