Evidence-Based Reviews

Sedation with antipsychotics: Manage, don't accept adverse 'calming' effect

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Initiate the antipsychotic at a reasonable, not overly high dose, then use a nonantipsychotic to help control insomnia, anxiety, and agitation.



Manage, don’t accept adverse ‘calming’ effect

Sedation is a frequent side effect of antipsychotics, especially at relatively high doses. Antipsychotics’ sedative effects can reduce agitation in acute psychosis and promote sleep in insomnia, but long-term sedation may:

  • interfere with schizophrenia patients’ efforts to go to work or school or engage in normal socialization
  • prevent improvement from psychosocial training, psychiatric rehabilitation, and other treatments.

This article discusses how to manage acute psychosis without oversedation and ways to address persistent sedation and chronic insomnia with less-sedating antipsychotics or adjunctive medications.

Neurobiology or psychopharmacology?

Many patients experience only mild, transient somnolence at the beginning of antipsychotic treatment, and most develop some tolerance to the sedating effects with continued administration. Others may have persistent daytime sedation that interferes with normal functioning.

Sedation is especially common in elderly patients receiving antipsychotics. Compared with younger patients, older patients receiving the same doses of the same medications become more heavily sedated for longer periods of time. The resulting sedation can impair arousal levels during the day and increase the risk of falls.

Sedation can occur with first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), but it is seen more commonly and tends to be more severe with low-potency FGAs than with SGAs. Clinical challenges come with:

  • distinguishing between sedation and negative symptoms of schizophrenia such as avolition, amotivation, withdrawal, and anhedonia
  • determining whether an individual’s cognitive impairment is related to the antipsychotic’s sedative properties.

Because the treatments are different, it is important to try to distinguish negative symptoms and/or cognitive impairment related to schizophrenia’s neurobiology from sedation related to the antipsychotic. Ask patients if they nap during the day or just lie around, and if they want to do things but can’t:

  • If they want to do things but feel too tired, this likely is sedation caused by the antipsychotic. Treatment might be a dose reduction.
  • If they are not interested in doing things, the likely cause is negative symptoms. Treatment might be a medication such as a selective serotonin reuptake inhibitor.
  • If they want to do things but cannot organize themselves to be able to do them, this likely is cognitive impairment. Treatment might be cognitive training or remediation.

Efficacy and sedation

Antipsychotics are thought to exert their effect by antagonism of postsynaptic dopamine D2 and serotonin 5HT2A receptors and possibly other receptors in the brain. Four SGAs—risperidone, olanzapine, quetiapine, and ziprasidone—act as dopamine D2 and 5HT2A antagonists. Aripiprazole is a dopamine D2 partial agonist, serotonin 5HT1A partial agonist, and serotonin 5HT2A antagonist.1 Efficacy data comparing SGAs with each other and with FGAs vary, but all 5 of these SGAs have been shown to be effective antipsychotics.2-4 They also generally cause less sedation than FGAs.

Patients with acute exacerbation of psychosis often have insomnia and frequently report paranoia that “something” will happen to them while they sleep. When treating agitated patients, many clinicians consider calming effects and true antipsychotic effects to be one in the same, which is not correct. All available antipsychotics are, on average, equally effective in treating acute psychotic symptoms but vary considerably in the amount of sedation they produce. Studies of short-acting injectable SGAs, such as ziprasidone and aripiprazole, have shown that agitation and acute symptoms can be controlled without significant sedation.5,6

Antipsychotic effects are not immediate and historically were thought to occur over several weeks. Recent meta-analyses suggest, however, that some antipsychotic effects are evident within the first week of treatment.7,8 To avoid overmedication, therefore, it’s important to separate calming effects from antipsychotic effects.

Recommendations. Choose the initial antipsychotic based on its effectiveness in treating the underlying disease, rather than relying on side effects—such as sedation—to control disease manifestations. Without sedation, patients are better able to engage in therapy; participate in family, social, school, and work activities; and increase their chances of recovery.

Initiate the antipsychotic at or titrate to a reasonable, not overly high dose—such as:

  • olanzapine, 10 to 20 mg/d
  • risperidone, 3 to 6 mg/d
  • ziprasidone, 100 to 140 mg/d
  • quetiapine, 400 to 600 mg/d
  • aripiprazole, 15 mg/d.

Continue the patient on that dose, and use a nonantipsychotic such as a benzodiazepine to help control insomnia, anxiety, and agitation. Two to 4 weeks is generally adequate, but some patients may need the adjunctive therapy for several months. If you initiate a more sedating antipsychotic acutely, switching to a less sedating agent when the patient is stable and the illness is in remission may support adherence and improve outcomes.


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