Treatment Comparison: Somnolence/Sedation With Dopamine Partial Agonists vs D2 Receptor Antagonists

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CONFERENCE REPORTER

In a recent study, investigators compared rates of somnolence/sedation with dopamine partial agonists vs D2 receptor antagonists in the adjunctive treatment of major depressive disorder (MDD) and the treatment of acute schizophrenia. Data were presented at the 2025 American Society of Clinical Psychopharmacology Annual Meeting in Scottsdale, AZ.¹

Somnolence/sedation are both adverse effects associated with the use of some atypical antipsychotics in the treatment of MDD and schizophrenia. They disrupt sleep quality, can interfere with daily functioning, and negatively impact overall quality of life.^2-5 The risk of somnolence/sedation can play a large role in influencing patient and provider decisions regarding atypical antipsychotic treatment.^6-8

Atypical antipsychotics can be categorized as either dopamine partial agonists, which act as functional agonists or antagonists depending on the surrounding levels of endogenous dopamine, or dopamine D2 receptor antagonists (eg, quetiapine), which act as pure antagonists at these receptors.⁹ However, the relative rates of somnolence/sedation associated with dopamine partial agonists vs D2 receptor antagonists in MDD or schizophrenia are unclear. Investigators sought to better understand these rates by conducting 2 independent meta-analyses that used studies identified by prior systematic literature reviews.

The adjunctive MDD meta-analysis included randomized, double-blind, placebo-controlled, phase 2 and 3 trials with a randomization phase ≥6 weeks evaluating atypical antipsychotics approved by the US Food and Drug Administration for the adjunctive treatment of MDD in adults. The trials that were included assessed somnolence as a binary outcome.

The schizophrenia meta-analysis included double-blind, randomized, controlled trials with a randomization phase ≥4 weeks evaluating atypical antipsychotics for the treatment of acute schizophrenia in adults. The trials that were included trials assessed somnolence/sedation as a binary outcome. Excluded from the analysis were study populations with first episode schizophrenia, predominant negative symptoms, or refractory disease. In studies that reported both somnolence and sedation, the outcome with the highest number of events was reported.

Investigators then used Bayesian network meta-analyses (NMAs) to evaluate the treatment effect of dopamine partial agonists and D2 receptor antagonists on somnolence in MDD or somnolence/sedation in schizophrenia. Statistical assessments of heterogeneity were based on model fit comparisons between fixed- and random-effects models using the deviance information criterion (DIC). For schizophrenia, which used a random-effects model, another statistical measure (Ƭ2) was calculated.

For MDD, investigators included 10 studies, then used a fixed-effects model for analysis, due to a lower DIC compared with the random-effects model (40.4 vs 41.8, respectively). The odds of experiencing somnolence were 72% less for patients taking dopamine partial agonists compared with those taking D2 receptor antagonists (OR [95% CrI], 0.28 [0.13, 0.59]).

For schizophrenia, investigators included 50 studies. The odds of experiencing somnolence/sedation were 57% less for patients taking dopamine partial agonists compared with those taking D2 receptor antagonists (OR [95% CrI], 0.43 [0.26, 0.73]).

There was low to moderate heterogeneity observed for the random-effects model on somnolence/sedation (Ƭ2=0.14), which suggests that the variability among study results is relatively low. Investigators concluded that dopamine partial agonists may be less likely to cause somnolence in MDD or somnolence/sedation in schizophrenia compared with D2 receptor antagonists.

References

1. Nabulsi N, Ta J, Haile F, et al. Indirect treatment comparison of somnolence or sedation with dopamine partial agonists versus D2 receptor antagonists in major depressive disorder and schizophrenia. Poster presented at: 2025 American Society of Clinical Psychopharmacology Annual Meeting; May 27-30, 2025; Scottsdale, AZ. Accessed May 29, 2025.

2. Valencia Carlo YE, Saracco-Alvarez RA, Carlo VAV, et al. Adverse effects of antipsychotics on sleep in patients with schizophrenia. Systematic review and meta-analysis. Front Psychiatry. 2023;14:1189768.

3. Spielmans GI, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. Focus (Am Psychiatr Publ). 2016;14(2):244-265.

4. Hofstetter JR, Lysaker PH, Mayeda AR. Quality of sleep in patients with schizophrenia is associated with quality of life and coping. BMC Psychiatry. 2005;5:13.

5. Takaesu Y, Kanda Y, Nagahama Y, et al. Delayed sleep-wake rhythm is associated with cognitive dysfunction, social dysfunction, and deteriorated quality of life in patients with major depressive disorder. Front Psychiatry. 2022;13:1022144.

6. Ng-Mak D, Poon JL, Roberts L, et al. Patient preferences for important attributes of bipolar depression treatments: a discrete choice experiment. Patient Prefer Adherence. 2018;12:35-44.

7. Jorgensen TR, Emborg C, Dahlen K, et al. Patient preferences for medicine administration for acute agitation: results from an internet-based survey of patients diagnosed with bipolar disorder or schizophrenia in two Nordic countries. Psychol Health Med. 2018;23(1):30-38.

8. Doane MJ, Boeri M, Vass C, et al. Preferences for attributes of oral antipsychotic treatments: results from a discrete-choice experiment in respondents with schizophrenia or bipolar I disorder. BMC Psychiatry. 2024;24(1):605.

9. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs. 2004;18(4):251-267.