Antipsychotic Drug-Induced Somnolence: Incidence, Mechanisms, and Management

Abstract

Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.

Systematic analysis of protein targets associated with adverse events of drugs from clinical trials and post-marketing reports

“…The next most predictive associations concern various muscarinic acetylcholine receptors. In our study, the muscarinic receptor M2 is associated with somnolence (PPV=1.0, Table 1), which is in line with acetylcholine being important for wakefulness and the expected effects of M2 antagonism (32). In practice, somnolence is a common side effect of muscarinic acetylcholine M2 and M3 receptor antagonists such as oxybutynin and tolterodine (33)(34)(35).…”

Lurasidone in the Treatment of Bipolar Depression: Systematic Review of Systematic Reviews

“…No electrocardiogram abnormalities, not even significant increase in QT interval length, have been documented in comparison with placebo or active competitor(s) from the SGA class. Stating the lack of histamine H1 and muscarinic M1, as well as strong norepinephrine alpha-1 antagonist, activities, lurasidone has also lower propensity to induce somnolence compared to most of the available SGA alternatives [88]. On the contrary, akathisia and dystonia were important, relatively common, AEs.…”

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“…In our study, the discontinuation rate due to side effects was 23% and the most prominent side effects were extended sleep, early morning grogginess and dry mouth. The blockade of histamine 1 receptors and alpha1 receptors may play a major role in antipsychotic drug-induced sedation [35]. Because of sedation, in our study the starting dose was decreased from 50 mg to 25 mg/d and the up-titration was done more slowly.…”

“…Metabolic syndrome is another important side effect to consider for second generation antipsychotics including Quetiapine XR [34,36]. Hyperglycemia, hyperlipidemia, weight gain, and new-onset diabetes have all been reported in patients taking standard doses of Quetiapine [35,37]. In fact, current manufacturer guidelines for Quetiapine Fumarate (Seroquel®) recommend monitoring plasma glucose and lipid profiles in all patients with significant risk factors (e.g.…”