Although all atypicals increase serum triglycerides to some degree, severe hypertriglyceridemia occurs predominantly with clozapine and olanzapine.24 Both drugs have favorable efficacy profiles, and the mechanism of their antipsychotic activity may include altering the various lipid pools.
For example, studies have found that decreased triglyceride levels correlate with hostility and psychological distress.25 Increased triglycerides have been theorized to enhance membrane fluidity, which in turn may augment presynaptic reuptake of serotonin and diminish postsynaptic serotonin activity.26 In other words, elevated triglyceride levels could play a role in atypical antipsychotic-mediated inhibition of serotonin transmission. It is not yet known whether lipid-lowering drugs might alter atypicals’ efficacy.
Table 2
RECOMMENDED METABOLIC MONITORING OF PATIENTS TAKING ATYPICAL ANTIPSYCHOTICS
| Every visit | Check weight Check blood pressure |
| Every 3 months | Fasting blood glucose Fasting triglycerides Fasting cholesterol |
Metabolic monitoring
Managing mental illness concurrently with weight gain, diabetes, and hypertriglyceridemia is a challenge. In our clinic, we try to diminish the atypicals’ adverse metabolic effects by monitoring a few basic parameters and taking preventive measures (Table 2).
We routinely screen patients for diabetes symptoms by asking questions about changes in belt size (a sign of weight change), urinary frequency, and thirst (Table 3). We also document baseline weight, blood glucose (Table 4), blood chemistry, and lipid levels, with routine follow-up throughout therapy and greatest scrutiny during the first months of a new treatment.
Patients who cannot control their weight with lifestyle modifications (Table 5) may require a lipid-lowering medication—a “stain” and/or fibrate (such as gemfibrozil)—or, if those measures are ineffective, a switch to another antipsychotic. Hyperlipidemia and hyperglycemia may be reduced substantially when patients discontinue the aggravating medication.27
Although discontinuing or switching medications may reduce metabolic side effects, the hazard of psychotic decompensation is substantial. Achieving an antipsychotic effect is extremely difficult for most patients, and one should not discontinue an effective treatment without seriously considering the consequences. Antipsychotic efficacy should never be sacrificed in the pursuit of a regimen with more benign side effects. Consider switching to an atypical with a more moderate effect on weight, however, if weight gain would likely lead to noncompliance. Even the most effective treatment will not work if a patient never takes it.
Table 3
5 SCREENING QUESTIONS TO MONITOR FOR METABOLIC AND SEXUAL SIDE EFFECTS
|
Table 4
DIAGNOSTIC CRITERIA FOR DIABETES
| • Symptoms of diabetes (such as polyuria, polydipsia, or unexplained weight loss) plus nonfasting plasma glucose (PG) >200 mg/dL (11.1 mmol/L) |
| OR |
| • Fasting plasma glucose >126 mg/dL (7.0 mmol/L) |
| OR |
| • 2-hour PG >200 mg/dL during an oral glucose tolerance test |
| Source: American Diabetes Association |
Cardiac toxicity
QTc prolongation. Atypical antipsychotics—like their typical counterparts—cause QTc prolongation to varying degrees. On an ECG, the QT interval corresponds to cardiac depolarization and repolarization phases. The QT interval—which changes naturally with the time of day, stressors, and heart rate—is commonly corrected for heart rate to yield QTc.28 If QTc is prolonged beyond a certain threshold, repolarization can occur simultaneously with early depolarization. The consequence may be ventricular arrhythmias, such as torsades de pointes, which can degenerate into ventricular tachycardia, fibrillation, and even death.
All the atypicals are thought to prolong QT intervals to some degree by reducing the flow of repolarizing K+ currents, ultimately making the myocardium more excitable.29 Although there is no specific threshold above which torsades de pointes will occur, it appears there is no significant risk of developing arrhythmias below a QT interval of 500 msec.30 In fact, because the atypicals behave like type IIIa antiarrhythmics, they will overdrive the ventricle and suppress other emergent ventricular arrhythmias. Notwithstanding the FDA’s scrutiny of ziprasidone, no data indicate that this agent is disproportionately toxic.
Clinical precautions. Overall, atypicals cause only a modest increase in the QT interval. Ziprasidone and quetiapine appear to have somewhat more pronounced effects, with ziprasidone prolonging the QT interval on average about 20 msec.31 These mean increases are clinically irrelevant in most patients, but use caution when treating patients who:
- have pre-existing heart disease that is known to be associated with ventricular arrhythmias
- are taking other medications that prolong QT through the same mechanism
- have historically had idiosyncratic sensitivities to prolonged QT.32
Bradycardia, electrolyte imbalances, and endocrine disorders—which themselves increase QTc—also might make an individual more susceptible to the consequences of subtle QT prolongation.29
Managing patients at risk. In our clinic, we assess patients for risk of QT prolongation by inquiring about a family history of cardiac disease or a personal history of arrhythmia, syncope, or near syncope. In at-risk patients, we: