Negative Symptoms Track Functioning, and Their Change Is Hard to Attribute
A decrease in negative-symptom scores on treatment is easy to read as a sign that the drug is working. How much of that change can be attributed to treatment depends on what it is compared with and how it was measured. The question matters because greater severity of negative symptoms, such as avolition and anhedonia, has been associated with poorer functioning and health-related quality of life across 68 mostly cross-sectional studies.1 Xanomeline-trospium studies track these symptoms with two clinician-rated scores from the Positive and Negative Syndrome Scale (PANSS): the PANSS negative subscale and the PANSS Marder negative factor score, each scored from 7 to 49.2 In pooled 5-week trials, the negative subscale decreased 3.0 points on treatment, against 1.3 points on placebo;2 and in a year-long trial with no placebo group it decreased 0.8 points.3 Real-world data from a patient registry and a prescriber survey describe who starts the drug and why; neither has reported on negative-symptom outcomes.4,5
How much of that change can be attributed to treatment depends on what it is compared with and how it was measured.
Against Placebo, the 5-Week Difference Was 1.7 Points
In a post hoc analysis, Kaul and colleagues pooled the three EMERGENT trials in inpatients with an acute exacerbation to provide sufficient statistical power for subgroup analyses.2 The negative subscale decreased 3.0 points on treatment and 1.3 points on placebo, a difference of −1.7 points (95% confidence interval [CI], −2.4, −1.0; P < .0001), with separation observed beginning at Week 3. The Marder negative factor score difference was −2.0 points.2 Both were secondary outcomes.2 Adverse events occurred in 67.9% on treatment and 51.3% on placebo, most often nausea and constipation.6 Horan and colleagues note that, during an acute exacerbation, improvement in negative-symptom scores can be difficult to distinguish from improvement in other symptom domains.7 The 1.7-point difference describes short-term change (i.e., 5 weeks) during acute illness and does not establish the corresponding effect in stable illness.
Over a Year, With No Placebo Group, Scores Fell About 1 Point
EMERGENT-5, an open-label safety trial, followed 566 psychiatrically stable outpatients switched from another antipsychotic.3 Over 52 weeks, the negative subscale decreased 0.8 points and the Marder negative factor score decreased 1.1 points; both started from lower baselines than in the acute trials.2,3 Efficacy was not tested statistically, and only 277 participants (48.9%) completed the year-long study.3 Adverse events occurred in 82.3%, most often nausea, vomiting, and constipation, and 17.7% stopped the drug because of an adverse event.3 Without a placebo arm, the authors note, it can be hard to tell whether effects reflect the drug or other factors, such as symptom fluctuation.3 The year-long change therefore cannot isolate the contribution of treatment.
Negative-Symptom Score Change by Study Setting
Pooled EMERGENT-1, EMERGENT-2, and EMERGENT-3 trials (n=640) and the open-label EMERGENT-5 trial (N=566)
| Setting | Measure | Baseline score, mean ± SD |
Change from baseline, LS mean (SE) or mean ± SD |
LS mean difference (95% CI) |
| Pooled EMERGENT-1, -2, -32 Week 5; inpatients; double-blind; xanomeline-trospium vs placebo |
PANSS negative subscale | Treatment: 22.7 ± 3.8 Placebo: 22.6 ± 4.0 |
Treatment: -3.0 (0.3) Placebo: -1.3 (0.3) |
-1.7 (-2.4, -1.0) |
| PANSS Marder negative factor score | Treatment: 22.4 ± 4.5 Placebo: 22.3 ± 4.6 |
Treatment: -3.8 (0.3) Placebo: -1.8 (0.3) |
-2.0 (−2.8, -1.2) | |
| EMERGENT-53 Week 52; psychiatrically stable outpatients; open-label; xanomeline-trospium only |
PANSS negative subscale | 17.7 ± 4.0 | -0.8 ± 4.4 | No placebo group |
| PANSS Marder negative factor score | 16.9 ± 4.3 | -1.1 ± 4.5 | No placebo group | |
| CI = confidence interval; LS = least squares; PANSS = Positive and Negative Syndrome Scale; SD = standard deviation; SE = standard error. Scores range from 7 to 49; lower scores indicate less severe symptoms. Sources: Kaul et al.2; Kaul et al.3 |
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Prescribers Cite Functioning More Often Than Negative Symptoms
Practice data show how the drug is being used, not how negative symptoms respond. The observational RESKU registry, presented at Psych Congress 2026, has reported baseline data only: 19 of 29 adults (65.5%) started xanomeline-trospium in an outpatient setting, and 62.1% started it primarily because current treatment was not working.4 In a prescriber survey also presented at Psych Congress 2026, 37 of 100 prescribers chose the drug mainly for overall functioning or quality of life, and 15 for negative symptoms.5 The survey included 81 psychiatrists, and the completion rate was 9.2%; nurse practitioners and physician assistants were underrepresented.5 More prescribers cited functioning or quality of life than negative symptoms, but neither data set measured whether these outcomes changed.5
Whether Treatment Drives Negative-Symptom Improvement Remains Unclear
Negative symptoms such as avolition and anhedonia are linked with poorer functioning and quality of life, so improving them may matter in patients’ daily lives.1 With xanomeline-trospium, negative-symptom scores have decreased in clinical trials, but evidence that the decrease reflects treatment comes only from short-term studies during acute illness.2,3 More research is needed to understand how much negative-symptom improvement is attributable to the medication, whether it holds in stable illness, and whether it carries through to better functioning and quality of life.
Financial support was provided by Bristol Myers Squibb. Psychiatrist.com independently developed the content and maintained final editorial control.
References
- Chan A, Lu A, Menon T, et al. Association between negative symptoms and health-related quality of life and functional outcomes in persons with schizophrenia: a systematic review. Schizophr Res. 2026;288:95-103. doi:10.1016/j.schres.2025.12.019
- Kaul I, Sawchak S, Claxton A, et al. Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-controlled, EMERGENT trials. Schizophrenia (Heidelb). 2024;10:102. doi:10.1038/s41537-024-00525-6
- Kaul I, Claxton A, Chaturvedi S, et al. Long-term efficacy, safety, and tolerability of xanomeline and trospium chloride in schizophrenia: a 52-week, open-label trial (EMERGENT-5). Schizophr Res. 2026;288:86-94. doi:10.1016/j.schres.2025.12.015
- Correll CU, Selvaraj V, Nucifora FC Jr, et al. Real-world patient baseline characteristics at xanomeline-trospium chloride initiation in adults with schizophrenia in routine clinical practice: participants enrolled in the RESKU registry. Poster 80 presented at: Psych Congress 2026; September 15-19, 2026; New Orleans, LA.
- Melnick I, Palaia J, Zhong Y, et al. Experiences of xanomeline/trospium chloride prescribing: a cross-sectional survey of healthcare providers. Poster Psych 41 presented at: Psych Congress 2026; September 15-19, 2026; New Orleans, LA.
- Kaul I, Claxton A, Sawchak S, et al. Safety and tolerability of xanomeline and trospium chloride in schizophrenia: pooled results from the 5-week, randomized, double-blind, placebo-controlled EMERGENT trials. J Clin Psychiatry. 2025;86(1):24m15497. doi:10.4088/JCP.24m15497
- Horan WP, Targum SD, Claxton A, et al. Efficacy of KarXT on negative symptoms in acute schizophrenia: a post hoc analysis of pooled data from 3 trials. Schizophr Res. 2024;274:57-65. doi:10.1016/j.schres.2024.08.001
