Sedation

Sedation can be rather severe and cause patients to sleep 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 most 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 in part 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). Some medications can be activating (akathisia) and sedating at the same time [3]. I tell all patients that antipsychotics used to be called “major tranquilizer” and that they may feel tired when taking them. It is a patient’s responsibility to pay attention if their medication impairs their ability to drive.

Weight Gain and Metabolic Side Effects

Weight gain has always been a problem for patients taking antipsychotics, but the second-generation antipsychotics have turned the spotlight even more on this particular side effect. In 1999, a very influential meta-analysis of weight gain propensity of antipsychotics showed that not all antipsychotics are created equal when it comes to weight gain [4]. Clozapine and olanzapine had 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 weight neutral in this analysis, which did not include aripiprazole and quetiapine; molindone which is no longer available was associated with weight loss. In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), olanzapine led to a weight gain of 2 lbs per months, risperidone and quetiapine had comparable weight gains of 0.5 lbs per month, whereas patients assigned to ziprasidone or perphenazine lost weight [5]. In 2009, the Schizophrenia Patient Outcomes Research Team (PORT) guidelines [6] provided the following helpful ranking of weight gain liability (from highest to lowest risk): clozapine = olanzapine > low-potency first-generation antipsychotics > risperidone = paliperidone = quetiapine > mid-potency first-generation antipsychotics > high-potency antipsychotics = aripiprazole = ziprasidone. A more recent meta-analysis of weight gain in first-episode patients found weight gain for all antipsychotics except ziprasidone [7]. Note that not all newer antipsychotics were available for this analysis. Among more recently approved antipsychotics, lurasidone [8], brexpiprazole [9], and cariprazine appear to have excellent metabolic safety profiles [10].

Antipsychotic-induced weight gain is undesirable not only for reasons of esthetics but because of the many medical complications that are associated with being overweight or obese. Metabolic derangement is most critical: 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. The relevance of the metabolic syndrome lies in its predictive value for cardiovascular disease and diabetes, making it all the more worrisome that four out of ten patients in the CATIE cohort, for example, had the metabolic syndrome [11]. The typical patient develops diabetes as a late complication, in the setting of creeping but steady weight gain and increasing insulin resistance. It is intra-abdominal (central) fat that is responsible for the metabolic derangements: it matters where fat is deposited, and not all obese patients based on BMI calculations have the same metabolic risk. The pear-shaped abdomen seen in many chronic schizophrenia patients is the outward sign of central obesity and an ominous sign. One surrogate measure of metabolic risk is waist circumference which better reflects abdominal fat deposition than absolute weight. Waist circumference is the best anthropomorphic marker of insulin resistance for clozapine patients [12]. It is for this reason that metabolic monitoring guidelines include waist circumference as a parameter to follow (see Chap. 25 for metabolic monitoring guidelines). Insulin resistance develops rapidly, within a few weeks of treatment, with more pronounced effects of olanzapine compared to risperidone or aripiprazole [13]. Note that in patients treated with high-risk antipsychotics, particularly olanzapine and clozapine, insulin resistance can also develop in the absence of clinical obesity [14], and patients can present with diabetic ketoacidosis as the first clinical sign of a metabolic problem. Clozapine and olanzapine also have the highest risk for increasing triglycerides (one of the parameters of the metabolic syndrome). Very high triglycerides increase the risk for pancreatitis, although no clear cutoff value exists.

See Chap. 25 for details regarding guideline-based weight and metabolic monitoring.

Hyperprolactinemia and Sexual Side Effects

Recall from medical school that the prolactin inhibitory factor (PIF) turned out to be dopamine. Consequently, dopamine antagonists (i.e., antipsychotics) can increase prolactin. The first-generation antipsychotics and those second-generation antipsychotics with tight D2-binding predictably lead to hyperprolactinemia; antipsychotics with loose D2-binding and the partial agonist antipsychotics are considered “prolactin-sparing” (see Fig. 15.1).

For those patients who have symptoms attributable to hyperprolactinemia, I would first check the prolactin level and then consider switching to a prolactin-sparing antipsychotic. If the hyperprolactinemia is higher than you are comfortable with (e.g., above 100 ng/mL) or does not resolve after switching to a prolactin-sparing antipsychotic, further work-up will be necessary to make sure your patient does not have a prolactinoma [18]. Visual field testing and brain imaging may be needed. In cases where it is clinically necessary to continue a prolactin-elevating antipsychotic (e.g., a first-generation long-acting injectable), adding aripiprazole will normalize prolactin levels.

The long-term effects of (asymptomatic) elevation of prolactin are unclear. However, prolactin-induced hypoestrogenemia can lead to osteoporosis, and I would consider monitoring (in collaboration with the patient’s primary care doctor) bone density in premenopausal women with antipsychotic-induced amenorrhea [19]. For some women, hormone replacement therapy should be considered. An observed increased breast cancer risk in female patients with schizophrenia has raised concerns about antipsychotic-induced prolactin elevation as prolactin plays a role in mammary carcinogenesis [20]. However, most patients have other breast cancer risk factors (nulliparity, obesity, diabetes, smoking) that are probably more relevant. This is similar to patients with osteoporosis who have risk factors other than hyperprolactinemia that would need to be taken into account as well [21].

Many patients struggle with loss of libido as a function of dopamine blockade and hyperprolactinemia [22]. Sexual side effects of antipsychotics are usually missed as nobody (I am guilty myself) ever asks but simply assumes patients to be “asexual,” particularly your middle-aged and older, chronic patient [23]. This is untrue: patients with schizophrenia are sexually active, and this means that female patients can get pregnant and that all patients are at risk for sexually transmitted disease, including human immunodeficiency virus (HIV). It is worthwhile not to assume anything, so you should have a discussion about sexual topics with your patients, regardless of age. Simply ask: “Are you sexually active?” and take it from there. Erectile dysfunction from antipsychotics might respond to a trial of sildenafil [24].

Priapism is a potentially serious adverse reaction to antipsychotics with prominent alpha-1 blockade: risperidone, olanzapine, and clozapine [25]. Warning signs are prolonged erections that last several hours.

Cardiac Toxicity

Although rare, antipsychotics, particularly thioridazine (no longer on the market), have been implicated in sudden death since the introduction of antipsychotics. Pimozide, sometimes touted as the best treatment for delusional disorder, has calcium channel-blocking properties and should only be used if you can monitor the ECG. Personally, I never used thioridazine (or its metabolite mesoridazine) much or pimozide because safer options that are as effective are available. Many emergency departments avoid droperidol because of (an admittedly controversial) black-box warning about QTc prolongation. Intravenous haloperidol should only be used if ECG monitoring is possible. Unfortunately, newer antipsychotics do not appear to be safer with regard to the risk for sudden death than older antipsychotics [26].

Antipsychotics can cause arrhythmias via prolongation of the action-potential phase of the cardiac cycle, by delaying ventricular repolarization and thereby increasing the risk for lethal ventricular arrhythmias, such as torsades de pointes (TdP) [27]. This effect on repolarization is reflected in a prolonged QT interval on the ECG which is a precondition for the development of torsades. Since the QT interval is inversely correlated with the heart rate, it needs to be heart-rate corrected. A common method for a corrected QTc interval uses the Bazett formula, which is calculated by dividing the QT interval by the square root of the R-R interval [28] although other corrections are available.

The propensity to prolong the QTc interval is different for different antipsychotics and tied to their potency to block particular potassium channels. Ziprasidone went through the FDA-approval process when the issue of antipsychotics and QTc prolongation had become a concern. As a result, the company that makes ziprasidone had to conduct a trial that directly compared the propensity of ziprasidone to increase QTc at peak levels with several other antipsychotics. Thioridazine came out as the clear winner (or loser, if you will), increasing QTc by 36 ms, followed by ziprasidone which demonstrably increased QTc by about 20 ms. Other antipsychotic showed less QTc prolongation. It is reassuring that QTc prolongation greater than 500 ms is very rare with ziprasidone [29] and that there is no dose-related QTc prolongation with ziprasidone [30]. The latter is important because it suggests that blocking the metabolism of ziprasidone should not increase cardiac risk beyond the small, expected QTc prolongation. It is further reassuring that the modest QTc prolongation with ziprasidone appears to not translate into a higher risk of sudden death when compared to other antipsychotics. After ziprasidone was approved, a large cohort study of almost 20,000 patients (named ZODIAC, for Ziprasidone Observational Study of Cardiac Outcomes) that randomized participants to either ziprasidone or olanzapine found no difference between those two treatments with regard to serious cardiac events [31]. This trial confirmed the observation of a very low yet increased risk of sudden death for schizophrenia patients. ZODIAC is a good example of a “large simple trial” that focuses on detecting small differences between outcomes that are important in routine clinical care [32]. Quetiapine and iloperidone are newer antipsychotics that prolong the QTc interval in a dose-dependent manner. The evidence, however, for clinically meaningful QT prolongation with most classes of psychiatric agents remains minimal [27].

I would nevertheless prefer a baseline ECG in all my patients. True, the measurement of the QTc interval is fraught with measurement errors, and its predictive value for important clinical end points is imperfect, as seen in ZODIAC above [33]. However, ECG monitoring is the only way to identify patients at higher risk for sudden cardiac death from an arrhythmia on the basis of QTc prolongation. The threshold for QTc interval screening with follow-up ECG monitoring should be lower in patients on polypharmacy or patients from special populations (e.g., methadone patients [34]). The most important risk-reducing intervention may be a careful search for risk factor for QT prolongation before prescribing psychiatric medications [27].

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