Schizophrenia: Side Effects of Novel Antipsychotic Agents

Side Effects of Novel Antipsychotic Agents

One of the most significant advantages of the newer antipsychotic agent is the relatively less risk of developing EPS and TD. How-ever, treatment emergent substantial weight gain is a harbinger for long-term health consequences and frequently an important reason for noncompliance with medication. According to a meta-analysis done by Allison and colleagues (1999), clozapine and olanzapine are associated with a weight gain of about 10 lb over 10 weeks and ziprasidone was among the agents with the lowest weight gain at an average of 1 lb over the same period. Risperi-done and quetiapine are intermediate with approximately 5 lb. Patients with schizophrenia, independent of the use of antipsy-chotic agents, are at higher risk of developing diabetes mellitus relative to the general. The data from Patient Outcome Research Team (PORT) suggest that the rate of diabetes mellitus and obesity amongst patients with major mental illness was substan-tially higher even before the advent of the novel antipsychotic drugs. This was more so in women and nonwhite population. Thakore and colleagues (2002) investigated visceral fat distri-bution in drug-naïve and drug-free patients with schizophrenia. Compared with controls, patients with schizophrenia had central obesity and signficantly higher levels of plasma cortisol. Thus patients with schizophrenia are at a higher risk to develop major medical problems even before they are exposed to antipsychotic medications. However, this risk has been exacerbated with the introduction of the novel antipsychotic agents as seen by the dra-matic rise in number of published cases and reports of signifi-cant hyperglycemia associated with the use of these medications, particularly olanzapine and clozapine and to a lesser extent with quetiapine and risperidone. The risk of antipsychotic-induced weight gain and secondary diabetes with clozapine and olanza-pine may result from changes in glucose metabolism and insu-lin resistance induced by these agents. In approximately 40% of the cases of hyperglycemia, insulin resistance appears to occur even in absence of significant weight gain raising some interest-ing questions about how these medications may interact with the insulin-glycemic control. Unfortunately, in the case of clozapine, the risk of developing abnormal glucose and diabetes mellitus appears to be cumulative over the years as reported by Henderson and colleagues (2000). There are no effective countermeasuresavailable to help with weight gain and hyperglycemia. The sub-stantial increased risk to the health of patients with schizophrenia due to these effects is worrisome and an important shortcoming of these efficacious and important medications.

Amongst the novel agents, risperidone, due to its potent dopamine D₂ blockade, remove the inhibitory dopaminergic tone in the tuberoinfundibular neurons resulting in significant increase in prolactin levels. This increase in prolactin is significantly more than usually seen with the typical antipsychotic agents. It is likely that the serotonin system is also involved along with dopamine in raising the prolactin levels. Clozapine and quetiapine on the other hand, are less potent at the D₂ receptors and thus are unlikely to cause prolactin elevations. In some individuals, these elevations of prolactin lead to amenorrhea, galactorrhea, gynecomastia and may possibly decrease bone mineral density. Ziprasidone and olanzapine, within the therapeutic dose range, do not cause sig-nificant increases in prolactin levels.

Cases of sudden death while receiving clozapine therapy (in physically healthy young adults with schizophrenia) from myocar-ditis and cardiomyopathy led to a black box warning from FDA.