Adjunctive lumateperone improved sexual function rather than worsening it

Design

Prespecified sexual-function analysis of a 6-week phase 3 randomised, double-blind, placebo-controlled trial

Population

480 adults with major depressive disorder and inadequate response to one or two antidepressants; 82.5 per cent with baseline sexual dysfunction

Primary outcome

Changes in Sexual Functioning Questionnaire 14-item total score at day 43

Effect

Least squares mean difference 2.7 (effect size 0.38, P < 0.0001) overall; 3.1 in those with baseline dysfunction; 3.5 in women (P < 0.0001), 1.9 in men (P = 0.08)

Sexual dysfunction is one of the commonest reasons an antidepressant regimen is abandoned, and adding an antipsychotic is usually expected to make it worse. This prespecified analysis of a phase 3 trial measured it directly. Four hundred and eighty adults with major depressive disorder and inadequate response to one or two antidepressants - MADRS total 24 or more, Clinical Global Impression severity 4 or more - were randomised to six weeks of lumateperone 42 mg plus their antidepressant, or placebo plus antidepressant, with sexual function assessed on the 14-item Changes in Sexual Functioning Questionnaire.

Eighty-two and a half per cent had sexual dysfunction at baseline, which is the first number worth carrying away. At day 43 the lumateperone group improved more than placebo on the total score (least squares mean difference 2.7, effect size 0.38, P < 0.0001). The improvement was concentrated in those who had dysfunction at baseline (difference 3.1, effect size 0.42) with no change in those who did not - so this is not a drug improving function in people who were fine. In women the difference was 3.5 (effect size 0.47, P < 0.0001); in men it was 1.9 and did not reach significance (P = 0.08). Both sexes improved significantly in the pleasure and arousal domains.

The authors note that improvement in depression may itself explain part of the sexual improvement, which is likely and does not diminish the practical point. The reason to change something is the absence of the expected harm: for a patient whose main objection to augmentation is what it will do to sexual function, this trial says that objection does not apply to this agent. And the 82.5 per cent baseline figure is the reminder that the question should be asked before the drug is chosen, not after the complaint arrives.

• Ask about sexual function before choosing an augmentation agent; four in five of these patients already had a problem.
• Do not warn patients that lumateperone augmentation will worsen sexual function; it did not in this trial.
• Note the men's result did not reach significance, so the confident statement applies to women.
• Remember six weeks is short; nothing here describes function on longer treatment.
• Use a brief standardised measure rather than an open question, which under-detects this reliably.

The statistics, in plain English

An effect size of 0.38 is small to moderate, and the result that matters most is the absence of worsening rather than the size of the improvement. The men's difference of 1.9 with P = 0.08 is a null result in a smaller subgroup, not evidence of no effect in men - 112 men with baseline dysfunction is too few to settle it. Because depression itself improved on active treatment, part of the sexual improvement is likely to be a consequence of that rather than an independent drug effect; this analysis cannot separate the two.

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