Sedation can be rather severe and lead to an inability to take the medication, as well as sleeping most of the day. For patients who have a problem with negative symptoms, this adds insult to injury. Clozapine, olanzapine, and quetiapine are clearly rather sedating for many patients, whereas aripiprazole and ziprasidone can lead to insomnia and are often poorly tolerated by chronic patients who have gotten used to the ataractic effects of their antipsychotic. Sedation depends on the degree to which histamine receptors are blocked by the antipsychotic.

With patients who have a “hangover” in the morning from a high nightly antipsychotic dose, you can try splitting up the dose or lowering the total daily dose. Short of changing the antipsychotic, coffee in the morning is sometimes sufficient (I think this is as effective as and safer than prescription stimulants or modafinil).

Weight gain has always been a problem for patients taking psychotropics, but the second-generation antipsychotics have turned the spotlight even more on this issue. A very influential meta-analysis of weight gain propensity of antipsychotics has shown that not all antipsychotics are created equal when it comes to weight gain liability (Allison et al., 1999). Clozapine and olanzapine pose the biggest liability for weight gain, estimated to be more than 4 kg in 10 weeks of treatment, compared to 2 kg with risperidone. Ziprasidone was weightneutral in this analysis, which did not include aripiprazole and quetiapine; molindone was associated with weight loss. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), olanzapine led to a weight gain of 2 lb per month,
risperidone and quetiapine had comparable weight gains of 0.5 lb per month, whereas patients assigned to ziprasidone or perphenazine lost weight.

As weight and body fat increases, insulin resistance increases, which can lead to a cluster of metabolic findings known as metabolic syndrome (syndrome X), that is, impaired glucose tolerance, hypertension, and dyslipidemia (see WELL CARD Metabolic Syndrome in Appendix C for more details). The relevance of the metabolic syndrome lies in its predictive value for cardiovascular disease and diabetes, making it all the more worrisome that 4 of 10 patients in CATIE had the metabolic syndrome (McEvoy et al., 2005). The typical patient develops diabetes as a late complication, in the setting of creeping but steady weight gain and increasing insulin resistance. Note, however, that in patients treated with second-generation antipsychotics, insulin resistance can develop in the absence of clinical obesity (Henderson et al., 2005), and patients can present with diabetic ketoacidosis as the first clinical sign of a metabolic problem. As a result, all second-generation antipsychotics carry a class warning about the possibility of diabetes and the need for clinical monitoring. Despite the class warning, the risk is not the same for all antipsychotics, and psychiatry’s most effective antipsychotics, clozapine and olanzapine, carry the highest liability for the development of diabetes (American Diabetes Association, 2004). Clozapine and olanzapine also have the highest risk for increasing triglycerides (one of the parameters of the metabolic syndrome and a risk factor for pancreatitis if levels are very high). (See Chapter 21 for details on monitoring.)