Typical Antipsychotics & Schizophrenia

These are first generation antipsychotics. The modern era in the pharmacologic treatment of schizophrenia began in the 1950s with the discovery of chlorpromazine (Thorazine®). By the late 1960s and 1970s, researchers had theorized that chlorpromazine and other typical antipsychotics worked by blocking D2 receptors in the mesolimbic pathway.

Through this action, typical antipsychotics can be dramatically effective in improving the positive symptoms of psychosis, often within several weeks. Furthermore, 50% or more of patients who discontinue treatment relapse within 6 months. However, because of the adverse effects associated with these drugs, many patients are unable to adhere to therapy, leading to a cycle of treatment initiation, discontinuation, relapse, and hospitalization. While some variability may occur in patient response, there appear to be no clinical differences in the efficacy of these agents.

What are the typical Antipsychotics available in the US?

• Thorazine(chlorpromazine, GSK)
• Prolixin (fluphenazine, Geneva)
• Haldol (Haloperidol, Ortho-Mc Neil)
• Compazine(prochlorperazine, GSK)
• Stelazine(trifluoperazine, GSK)
• Trilafon (perphenazine, Schering)
• Serentil (mesoridazine, Boehringer Ingelheim)
• Navane (thiothixene, Pfizer)
• Moban (Molindone, Enda Labs)
• Loxitane(loxapine, Watson)
• Mellaril(Thioridazine, Mylan)

What are the Adverse Effects Associated with Typical Antipsychotics?

As known, in addition to the mesolimbic pathway, three other key dopaminergic pathways in the brain are the mesocortical, nigrostriatal, and tuberoinfundibular pathways. By blocking dopamine receptors in these pathways, typical antipsychotics can cause a number of adverse effects. While some side effects can be directly attributed to the blockade of D2 receptors in dopaminergic pathways, the mechanisms underlying other side effects is unclear. By blocking D2 receptors in the mesocortical pathway, where dopamine may already be deficient in people with schizophrenia, typical antipsychotic agents can actually cause or worsen negative and cognitive symptoms. Blocking D2 receptors in the nigrostriatal pathway can produce EPS. The incidence varies, but EPS are believed to occur in as many as 50% to 75% of patients who take typical antipsychotics.

In addition, long-term blockade of D2 receptors in this pathway can produce tardive dyskinesia (TD), an often irreversible movement disorder that causes quick, jerky limb movements (called dancing, or choreiform movements). As many as 32% of patients who take typical antipsychotics for 5 years, and 68% of those who take them for 25 years, develop TD. Blocking D2 receptors in the tuberoinfundibular pathway can cause the pituitary gland to release excess prolactin into the blood (hyperprolactinemia). Hyperprolactinemia is associated with amenorrhea in women, as well as sexual dysfunction, breast enlargement, and galactorrhea in both men and women. The condition may also cause other adverse effects, including interference with fertility (especially in women), accelerated demineralization of bones in postmenopausal women, and weight gain.

Antipsychotics may cause a rare but potentially fatal complication called neuroleptic malignant syndrome. This condition can result in extreme muscle rigidity, high fever, coma, and even death. Other side effects that may occur (and which vary depending on the particular agent) include:

• dry mouth, blurred vision, constipation, and cognitive blunting (anticholinergic effects)
• weight gain and drowsiness (which may be attributed to antihistaminergic effects)
• cardiovascular effects, such as orthostatic hypotension (which is possibly due to blockade of alpha1 adrenergic receptors) and QTC prolongation
• diabetes (certain typical antipsychotics have been associated with treatment-emergent diabetes)
• lipid abnormalities (increases in triglycerides; decreases in HDL cholesterol without associated increases in total cholesterol)
• seizures