Evaluation of Sexual Function With Adjunctive Lumateperone in Patients With Major Depressive Disorder

Major depressive disorder (MDD) is one of the most burdensome illnesses worldwide, reducing quality of life due to the disorder itself as well as related comorbidities.^1–3 Approximately 68% of patients with MDD are affected by comorbid sexual dysfunction (SD),^4–6 with validated questionnaires demonstrating a higher prevalence than that seen with spontaneous reports. While a common adverse effect of antidepressant therapies (ADTs), SD is one of the most underreported adverse effects in clinical trials and clinical practice.^5,6

SD and MDD are bidirectionally linked, with SD increasing risk of MDD, while MDD and its treatment being a cause of SD.^7–11 Comorbid SD spontaneously resolves in only 5%–30% of cases,⁴ but adequate MDD treatment can improve sexual functioning, particularly sexual desire, in some patients.^10,12 However, ADT can induce or worsen SD.^4,6,13–15 Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are associated with increased prevalence of SD,^16–19 with SSRI-induced incidence believed to be as high as 80%.¹⁰ A study in patients with MDD treated with 1 ADT in primary care showed that 36%–43% of those on SSRIs or venlafaxine had Changes in Sexual Functioning Questionnaire (CSFQ; a validated measure of SD)^20–22 Total scores indicative of SD; lower rates (<25%) were seen with the norepinephrine-dopamine reuptake inhibitor bupropion.²³ This may support a class effect, as the serotonergic inhibition of the dopaminergic and noradrenergic pathways is involved in sexual desire and arousal.^23–26

Sexual adverse effects typically emerge early in the course of ADT,²⁷ are a primary cause of treatment discontinuation in patients, contribute to nonadherence,^10,27–29 and are associated with poor quality of life.³⁰ In a study of the SSRI paroxetine, onset of SD occurred in the first 2 weeks of treatment in patients with MDD without baseline SD.³¹ Accommodation to serotonin reuptake inhibitor–induced SD occurs in 6–12 months in <10% of patients.³²

To manage treatment-emergent SD linked to SSRI and SNRI use in patients with MDD, clinicians may consider lowering the medication dose, introducing adjunctive treatments such as dopamine-enhancing agents (eg, bupropion) or serotonin-targeting therapies (eg, buspirone), switching to an alternative ADT associated with less SD, or recommending nonpharmacologic interventions.^{12,13,33–36} Switching ADT because of sexual adverse effects is common and appears to be supported by indirect comparisons of clinical trial data,^9,37,38 although few randomized trials have explored the effectiveness of this strategy for maintaining effective treatment of depression.³⁴ Importantly, SD may also be associated with risk of depression relapse.^13,39 Therefore, novel, effective MDD treatments that improve depression symptoms with minimal sexual adverse effects are needed.

Lumateperone is an atypical antipsychotic for the treatment of schizophrenia, depressive episodes associated with bipolar I or II disorder as monotherapy and as adjunctive therapy with lithium or valproate, and MDD as adjunctive therapy to ADT.⁴⁰ Lumateperone modulates several key neurotransmitters implicated in serious mental illness.^41,42 Specifically, lumateperone is a potent serotonin 5-HT_2A receptor antagonist, a dopamine D₂ receptor presynaptic partial agonist and postsynaptic antagonist, a D₁ receptor–dependent indirect modulator of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) currents, and a serotonin reuptake inhibitor.^41,42 This novel mechanism of action may be efficacious in MDD due to the involvement of glutamate in depression and the effects of lumateperone on the glutamatergic system.⁴³

The efficacy of adjunctive lumateperone 42 mg/day + ADT in patients with MDD with inadequate ADT response has been demonstrated in the phase 3, randomized, double-blind, placebo-controlled clinical trial Study 502 (NCT05061706).⁴⁴ Lumateperone 42 mg adjunctive to ADT significantly improved depressive symptoms and disease severity compared with placebo adjunctive to ADT, as measured by both clinician- and patient-rated outcomes. In this analysis of Study 502, the impact of lumateperone 42 mg+ ADT on sexual functioning, as measured by the CSFQ 14-item version (CSFQ-14), was assessed.

METHODS

Study Design and Patients

This post hoc analysis of SD was based on data from Study 502, a phase 3, randomized, double-blind, placebo-controlled trial that included patients with MDD with inadequate response to ADT. Detailed methods for Study 502 have been previously published.⁴⁴ Briefly, the study consisted of a screening period (up to 2 weeks), a 6-week double-blind treatment period, and a 1-week safety follow-up period. Participants were randomized 1:1 to oral lumateperone 42 mg+ADT or placebo +ADT once daily.

Eligible male and female patients (aged 18–65 years) met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnostic criteria for MDD, as confirmed by the Mini-International Neuropsychiatric Interview.^44,45 Participants had inadequate response to 1 or 2 courses of ADT in the current depressive episode, defined as <50% improvement with ≥6 weeks of ADT monotherapy, as confirmed by the Antidepressant Treatment Response Questionnaire. Participants were experiencing a major depressive episode, defined as Montgomery-Åsberg Depression Rating Scale (MADRS) Total score ≥24,⁴⁶ and had Clinical Global Impression–Severity score ≥4⁴⁷ and Quick Inventory of Depressive Symptomatology−Self Report 16-item score ≥14⁴⁸ at screening and baseline; duration of the current major depressive episode was ≥8 weeks but ≤18 months prior to screening.

Exclusion criteria included a lifetime psychiatric diagnosis other than MDD (eg, schizophrenia, schizoaffective disorder, bipolar disorder, other psychotic disorders) and alcohol/substance use disorders within 6 months.

The study protocol complied with the Declaration of Helsinki and Good Clinical Practice guidelines and was approved by an institutional review board or ethics committee/government agency; written informed consent was obtained from study participants.

Assessments

The primary endpoint was the change from baseline to Day 43 in MADRS Total score in the modified intent-to-treat (mITT) population. Sexual function was evaluated in post hoc analyses, based on changes in CSFQ-14 Total score in the intent-to-treat (ITT) population. Changes from baseline to Day 43 in CSFQ-14 domain scores (pleasure, desire/frequency, desire/ interest, arousal/excitement, and orgasm/completion) were also evaluated. Higher CSFQ-14 Total scores indicate better sexual functioning; CSFQ-14 Total scores ≤41 in female patients and ≤47 in male patients are categorized as SD. Changes or differences of 2 or 3 points in the CSFQ-14 Total score vs placebo are considered clinically meaningful.^{7,22,34,49,50}

Statistical Analysis

Analyses were conducted in the ITT population and in subgroups by baseline SD (CSFQ-14 Total score ≤41 for female patients and ≤47 for male patients), sex (female vs male), and age (<45 vs ≥45 years). The ITT population was defined as all randomized patients who received ≥1 dose of study treatment and had a baseline MADRS Total score.

Details of the primary statistical analysis are included in the Supplementary Materials.

This post hoc analysis was exploratory, and results are therefore descriptive rather than confirmatory; no adjustment for multiplicity was applied. All reported P values are nominal and should be interpreted descriptively.

RESULTS

Patient Population

All 480 randomized patients received adjunctive treatment and were included in the ITT population (lumateperone +ADT, n=242; placebo +ADT, n=238); 89.4% of patients completed treatment. Baseline demographics and disease characteristics were similar between treatment groups (Supplementary Table 1). The mean age of the study population was 46 years, and the majority of patients were women (69.6%) and White (95.4%). During double-blind treatment, the most commonly administered ADTs were SSRIs (lumateperone +ADT, 66.1%; placebo +ADT, 60.5%), followed by SNRIs (lumateperone+ ADT, 27.7%; placebo +ADT, 33.6%). Most patients (82.5%) met the criteria for SD at baseline (women, 85.0%; men, 76.7%).

Efficacy Outcomes

The primary endpoint was met with lumateperone +ADT, with significantly greater MADRS Total score improvement from baseline to Day 43 vs placebo +ADT in the mITT population (lumateperone +ADT, n=232; placebo +ADT, n=237; least squares mean difference [LSMD] vs placebo +ADT, −4.5; effect size [ES], −0.56; P<.0001); improvements in the CGI-S score (LSMD, −0.5; ES, −0.51; P<.0001) and QIDS-SR-16 Total score (LSMD, −2.2; ES, −0.45; P <.0001) were also significant. ⁴⁴

Lumateperone + ADT provided statistically significant, clinically meaningful (2-or 3-point difference).^{7,22,34,49,50} improvement in CSFQ-14 Total score at Day 43 vs placebo+ADT in the ITT population (LSMD, 2.7; ES, 0.38; P <.0001) (Figure 1) in this post hoc analysis.

Lumateperone+ADT significantly improved CSFQ-14 Total score at Day 43 vs placebo +ADT in patients with SD at baseline (lumateperone+ADT, n=198; placebo +ADT, n= 198) (Figure 2), in this exploratory subgroup analysis. In this post hoc analysis, in women with SD at baseline (lumateperone +ADT, n=142; placebo +ADT, n= 142), lumateperone +ADT demonstrated significant improvement in CSFQ-14 Total score at Day 43 (baseline mean: lumateperone+ADT, 28.7; placebo +ADT, 28.5; change at Day 43: LSMD, 3.8; ES, 0.50; P<.0001). In men with SD at baseline (lumateperone+ADT, n=56; placebo+ADT, n=56), the CSFQ-14 Total score showed a numerical improvement at Day 43 (baseline mean: lumateperone+ADT, 38.3; placebo +ADT, 37.2; change at Day 43: LSMD, 2.2; ES, 0.36; P=.0975). In patients without SD at baseline, CSFQ-14 Total score remained unchanged at Day 43 (baseline mean: lumateperone+ADT, 50.1; placebo +ADT, 49.1; change at Day 43: LSMD, −0.4; ES, −0.10; P=.7266).

In this post hoc analysis, a similar proportion of patients with normal sexual functioning at baseline retained it at the end of treatment with lumateperone+ADT and placebo +ADT (74.4% in both groups) (Supplementary Table 2). Among those with normal sexual functioning at baseline, a slightly lower proportion of patients receiving lumateperone+ADT shifted to SD compared with placebo +ADT (20.9% vs 25.6%). Additionally, among patients with sexual dysfunction at baseline, a greater proportion receiving lumateperone+ADT improved to normal sexual function compared with placebo +ADT (26.3% vs 15.2%).

CSFQ-14 Total score significantly improved with lumateperone+ADT vs placebo+ADT from baseline to Day 43 in women (LSMD, 3.5; ES, 0.47; P <.0001) (Figure 3), meeting the criteria for clinically meaningful improvement (defined as a difference of ≥2 points). In men, numerical improvements in CSFQ-14 Total score from baseline to Day 43 were observed (LSMD, 1.9; ES, 0.33; P=.0791), which did not meet the criteria for clinical meaningfulness.

A significant improvement in CSFQ-14 Total score from baseline to Day 43 with lumateperone+ADT vs placebo+ADT was observed in both younger (<45 years; LSMD, 3.0; ES, 0.41; P<.05) and older (≥45 years; LSMD, 3.0; ES, 0.43; P<.001) patient subgroups (Supplementary Figure 1).

Analysis of change from baseline in CSFQ-14 Total score by antidepressant class is presented in the Supplement (Supplementary Figure 2).

Improvements with lumateperone+ADT were statistically significant across all CSFQ-14 domain scores at Day 43 vs placebo+ADT (Figure 4). This included improvements in pleasure (LSMD, 0.3; ES, 0.39; P<.0001), desire/frequency (LSMD, 0.3; ES, 0.24; P<.05), desire/interest (LSMD, 0.7; ES, 0.39; P<.0001), arousal/excitement (LSMD, 0.6; ES, 0.28; P<.01), and orgasm/completion (LSMD, 0.7; ES, 0.33; P<.001).

Lumateperone+ ADT significantly improved outcomes, with both sexes showing significant changes from baseline in pleasure and arousal/excitement. Statistically significant improvements in desire/frequency, desire/interest, and orgasm/completion were observed in women only, with numerical improvements observed in men for these domains (Figure 5). Analysis of CSFQ-14 Total and domain score distributions at baseline showed no evidence of substantial ceiling or floor effects (Supplementary Table 3).

Additional post hoc analyses were conducted to examine the relationship between changes in depressive symptoms and sexual function. A correlation analysis demonstrated a moderate association between the change from baseline in MADRS Total score and CSFQ-14 Total score at Day 22 (r =−0.262) and Day 43 (r =−0.378). A mixed-effects model for repeated measures analysis assessed change from baseline in CSFQ Total score with change in MADRS Total score as a covariate. After adjusting for improvements in depressive symptoms, the effect of adjunctive lumateperone on the CSFQ-14 Total score was not statistically significant (P=.09). Finally, an exploratory analysis further indicated that approximately 66.2% of the treatment effect on CSFQ-14 Total score was mediated through changes in MADRS Total score (depressive symptoms).

DISCUSSION

This post hoc analysis of the phase 3, randomized, double-blind, placebo-controlled Study 502 demonstrated that adjunctive lumateperone treatment improves sexual functioning as measured by the CSFQ score vs placebo +ADT in patients with MDD with inadequate response to ADT. These results expand on the primary analysis, in which lumateperone+ADT improved overall depression (MADRS Total score) vs placebo +ADT.⁴⁴

In this post hoc analysis, lumateperone +ADT was associated with significant improvement in sexual functioning at Day 43 vs placebo+ADT in the overall ITT population, per CSFQ-14 Total score. A 2-to 3-point change in CSFQ Total score has been suggested as clinically meaningful based on prior comparative studies of ADT with differing effects on sexual functioning; therefore, the observed LSMD of 2.7 points is consistent with modest improvement in sexual functioning.³⁴ At baseline, when treated with ADT alone, 82.5% of patients met the criteria for SD, with a higher proportion of women (85.0%) than men (76.7%) experiencing SD. This is aligned with previous studies in this setting, in which a similarly high proportion of patients (>80%) had preexisting SD before treatment initiation.⁵⁰ The difference in incidence between men and women at baseline also aligns with previous findings in a post hoc analysis of a phase 4 trial in patients with MDD receiving treatment with ADTs (vilazodone and citalopram).⁷

Significant improvements in CSFQ-14 Total score with lumateperone+ADT vs placebo +ADT were observed in the subgroup of patients who reported SD at baseline in this exploratory analysis, with over 25% of patients with SD at baseline having normal sexual function at the end of the double-blind treatment period. Improved sexual functioning during MDD treatment may reflect overall symptom improvement.⁷ Additionally, compared with placebo +ADT, fewer patients treated with lumateperone+ADT shifted from sexual functioning at baseline to sexual dysfunction at the end of treatment, and a greater proportion of patients with sexual dysfunction at baseline improved to normal sexual function. The pharmacologic profile of lumateperone differs from that of other atypical antipsychotics, which may be relevant to its effects on sexual functioning; however, the exact mechanisms underlying these differences were not assessed in this study.⁵¹

In the subgroup of patients without baseline SD, CSFQ-14 Total score remained stable throughout the treatment period. A shift analysis showed that approximately 75% of these patients retained normal sexual function at the end of treatment. These findings suggest no evidence of worsening sexual function over the 6-week treatment period; long-term effects were not assessed. In contrast, commonly used antidepressants such as the SSRIs paroxetine and sertraline⁵² and the SNRI venlafaxine,⁵³ as well as atypical antipsychotics such as risperidone and olanzapine,⁵⁴ have been associated with treatment-emergent SD in patients with normal baseline sexual function.

Women had statistically significant improvements in CSFQ-14 Total score from baseline to Day 43, whereas in the male population, numerical improvement did not reach statistical significance. These exploratory findings should be interpreted cautiously given the post hoc nature of the analyses, lack of adjustment for multiple comparisons, and the relatively small sample size in men; although it is possible that the magnitude of benefit differs by sex, conclusions cannot be drawn on this result in men. However, these results are consistent with clinical trials of the atypical antipsychotics brexpiprazole and aripiprazole adjunctive to ADT in the treatment of MDD, in which women showed significant improvements in sexual functioning, while men had numerical, nonsignificant improvements.^55,56 Although antipsychotics generally demonstrate comparable efficacy in men and women as adjunctive therapy in MDD,^55,56 some agents in this class have been associated with elevated prolactin levels, which may contribute to SD.^57,58 These adverse effects are more pronounced in women than in men, but more common in men than in women.^57,58 Across clinical studies in patients with MDD, bipolar disorder, and schizophrenia, lumateperone+ADT was not associated with increases in prolactin levels.^44,59–66

A significant improvement in CSFQ-14 Total score from baseline to Day 43 was observed with lumateperone +ADT vs placebo +ADT in all patients regardless of age in this post hoc analysis. Previous research has indicated that ADT-associated SD is commonly reported in older adults, likely due to age-related physiological changes such as reduced sex hormone levels, vascular problems, and the presence of comorbid medical conditions.^58,67,68 Some studies have reported associations between age and SD,^27,69 suggesting that age and related health factors may influence sexual functioning outcomes during ADT treatment. Additionally, in older women, menopause may be associated with changes in sexual function and response to ADT, potentially due to declining estrogen levels.^58,68

Treatment with lumateperone +ADT was associated with improvements across all CSFQ-14 domain scores vs placebo +ADT. Although the study included twice as many women as men, which may have contributed to the observed differences in sexual functioning, both sexes showed improvements from baseline in pleasure and arousal/excitement, while improvements in desire/frequency, desire/interest, and orgasm/completion were significant only in women. However, because clinically meaningful change thresholds have not been established for CSFQ-14 domains, these results should be interpreted as exploratory.

SD may be linked to performance anxiety, often presenting as premature ejaculation and reduced sexual satisfaction in men, and as impaired desire, arousal, sexual activity, and satisfaction in women.^33,70 Moreover, experiencing SD (eg, inability to climax or loss of sensation) may also lead to frustration, lowered self-esteem, and relationship strain contributing to emotional blunting.^71,72 However, research also suggests that physiological impairments, such as difficulties with arousal and orgasm, are directly linked to ADT use, particularly SSRIs.^10,27,72 Some atypical antipsychotics, such as risperidone, have been associated with sexual adverse effects, including reduced sexual desire and orgasmic dysfunction following treatment.^54,73 Overall, these findings describe sexual functioning outcomes with lumateperone+ADT in patients with MDD, addressing both physiological and emotional dimensions of sexual health.

Post hoc analyses showed that improvements in sexual functioning were moderately associated with improvements in depressive symptoms. After adjusting for MADRS Total score, the treatment effect on CSFQ-14 Total score was no longer significant, and mediation analysis suggested that the effect on sexual function was largely related to improvements in mood. These findings suggest that improvement in depressive symptoms, which were observed for the primary efficacy outcome, may also be associated with improvement in sexual functioning. These results are consistent with prior literature suggesting that adequate treatment may be associated with improvement in sexual functioning.¹²

The strengths of this post hoc analysis include a large study population, the inclusion of patients with and without baseline SD, and the use of a validated sexual function scale, the CSFQ-14, to assess sexual functioning over time.

A limitation of this study is the short-term duration (6 weeks), which may not have captured the long-term effects of lumateperone on sexual functioning. Due to the post hoc, exploratory nature of the analyses, no adjustments for multiplicity were performed, and P values are nominal. Improvement in depressive symptoms may also have contributed to improved sexual function. Additionally, SD was assessed using self-reported measures, which can be influenced by personal bias, recall inaccuracy, or reluctance to disclose sensitive information. Sexual activity and partnership were not assessed, which may limit the interpretation of these sexual functioning data. Furthermore, the study population comprised predominantly White patients and a relatively small population of men (∼30%), which may have resulted in the analyses in the male population being underpowered. Therefore, the results may not be generalizable to the wider population of patients with MDD. This may limit interpretation of the findings in real-world clinical settings.

In summary, this post hoc analysis of the phase 3 Study 502 demonstrated that lumateperone 42 mg+ ADT significantly improved SD compared with placebo + ADT, as measured by the CSFQ-14 Total score, in patients with MDD with inadequate response to ADT. Significant improvements in sexual function with lumateperone 42 mg + ADT were observed across multiple patient subgroups, including those with baseline SD, women, and both younger and older adults, as well as across individual CSFQ-14 domains. In patients without baseline SD, no evidence of worsening sexual function was observed over the 6-week treatment period.

These findings indicate that lumateperone 42 mg+ADT did not worsen sexual functioning, with additional analyses showing that it is unlikely to be associated with treatment-related SD. These results support its potential as an effective, well-tolerated adjunctive therapy in patients with MDD with inadequate ADT response.

Article Information

Published Online: September 2, 2026. https://doi.org/10.4088/JCP.26m16387
© 2026 Physicians Postgraduate Press, Inc.
Submitted: February 18, 2026; accepted June 29, 2026.
To Cite: Clayton AH, Earley WR, Kozauer SG, et al. Evaluation of sexual function with adjunctive lumateperone in patients with major depressive disorder.
J Clin Psychiatry 2026;87(3):26m16387.
Author Affiliations: University of Virginia School of Medicine, Charlottesville, Virginia (Clayton); Former Employee of Intra-Cellular Therapies, A Johnson & Johnson company, Bedminster, New Jersey (Kozauer); Intra-Cellular Therapies, A Johnson & Johnson company, Bedminster, New Jersey (Earley, Mo, Edwards, Durgam).
Corresponding Author: Anita H. Clayton, MD, Univ Virginia, 2955 Ivy Road, Northridge Suite 210, Charlottesville 22901, VA 22903 ([email protected]).
Author Contributions: Drs Clayton, Earley, Kozauer, Mo, Edwards, and Durgam participated in study design and study conduct. All authors participated in data analysis/interpretation and writing/critical review and approved the final manuscript for publication.
Financial Disclosure: Drs Mo, Edwards, Earley, and Durgam are full-time employees of Intra-Cellular Therapies, a Johnson & Johnson company. Dr Kozauer is a former employee of Intra-Cellular Therapies, a Johnson & Johnson company. Dr Clayton has received grant funding from Janssen, Neumora Therapeutics, Neurocrine Biosciences, Otsuka, Relmada Therapeutics, Reunion Neuroscience, S1 Biopharma; has received consulting fees from AbbVie, Inc., ACCUMIN, Actinogen, AdhereTech, Axsome Therapeutics, Biogen, Inc., Initiator Pharma, Intra-Cellular Therapies Inc., Janssen Research & Development, LLC, LiveNova PLC, MycoMedica Life Sciences, PBC, Neumora Therapeutics, Inc., Neurocrine Biosciences, P/S/L Group Services, Reunion Neuroscience, S1 Biopharma, Seaport Therapeutics, Sertsei Pharmaceuticals, Inc., Vella Bioscience, Inc; has received royalties/copyright from Ballantine Books/Random House, Changes in Sexual Functioning Questionnaire, Guilford Publications; and may hold shares or restricted stock units in Mediflix LLC and S1 Biopharma.
Funding/Support: This study was funded by Intra-Cellular Therapies, a Johnson & Johnson company, Bedminster, New Jersey.
Role of the Funder: Intra-Cellular Therapies, a Johnson & Johnson company, was responsible for the design, analysis, interpretation, and publication of this study.
Previous Presentation: Presented as a poster at the European College of Neuropsychopharmacology (ECNP) Annual Congress; October 11–14, 2025; Amsterdam, the Netherlands.
Acknowledgments: The authors thank all study investigators, research staff, and patients for their participation. Medical writing support was provided by Keri Ramessar, PhD, of Nucleus Global, an Inizio company, and funded by Intra-Cellular Therapies, a Johnson & Johnson company.
Supplementary Material: Available at Psychiatrist.com.

Clinical Points

• Sexual dysfunction in major depressive disorder (MDD) is underreported and can be worsened by first-line treatments (eg, SSRIs/SNRIs). Therefore, treatments with minimal sexual adverse effects are needed.
• Adjunctive lumateperone 42 mg improves depressive symptoms without worsening sexual function, suitable for patients with MDD with inadequate antidepressant therapy response seeking to avoid sexual dysfunction as an adverse effect of treatment.