While treatment non-adherence is a well-established relapse risk factor, broader contributors require investigation. Studying chronic, high-risk schizophrenia cohorts in real-world lower middle-income country (LMIC) settingsremains methodologically challenging.

To explore multidimensional factors moderating treatment trajectories in individuals with chronic schizophrenia at high risk of relapse, comparing relapsers and non-relapsers in a real-world LMIC setting.

In this 12-month prospective naturalistic study, 56 clinically stable adults with chronic schizophrenia (≥2 relapses within 3 years), receiving long-acting injectable and/or oral antipsychotics were followed up monthly. Relapse was defined as worsening psychotic symptoms requiring re-hospitalisation. Linear mixed-effects models examined trajectories of Positive and Negative Syndrome Scale (PANSS) total and factor domains (positive, negative and disorganised) and tested group*time*moderator interactions for neurological soft signs (NSS), quality of life (QOL), aberrant salience, anxiety, resilience, self-esteem, social adversity and childhood trauma.

Twenty-three participants (41%) relapsed; overall attrition was 59%, with 21% of discontinuations relapsing. Most relapses (87%) involved non-adherence and substance misuse. No group*time interaction effects were found for PANSS domains. Poorer overall QOL (F(4, 31 = 4.0), p = 0.009) was associated with worse negative symptom trajectory in the relapse group, while more pronounced NSS was associated with worse positive symptom trajectory in the non-relapse group (F(2, 23 = 8.4), p = 0.002).

Conducting longitudinal research in chronic, high-risk schizophrenia populations in LMICs is challenging. Although exploratory and hypothesis-generating, QOL and NSS may represent clinically meaningful moderators of treatment course and potential targets for intervention and future research.

Impaired social functioning substantially affects the quality of life of patients with schizophrenia; however, it remains unclear whether the factors associated with social functioning differ according to relapse frequency. This study aimed to examine the differences in these factors among Japanese outpatients with schizophrenia, stratified by relapse frequency.

This nationwide cross-sectional study, the Multicenter Treatment Survey and Assessments for Schizophrenia in Psychiatric Clinics (MUSASI), was conducted in 330 psychiatric clinics in Japan between September and October 2023. A total of 10,081 patients diagnosed with schizophrenia-related disorders were analyzed. Patients were categorized as nonrelapsers, low-frequency relapsers (1–2 relapses), or high-frequency relapsers (≥3 relapses). Social functioning was assessed using the Social and Occupational Functioning Assessment Scale, with scores ≥61 defined as high functioning.

This study included 3,670 nonrelapsers, 4,428 low-frequency relapsers, and 1,983 high-frequency relapsers. Overall, 55.8% (n = 5,631) of patients were classified as having high social functioning. Across all groups, employment, shorter periods of instability during the past year, lower Clinical Global Impression–Severity scores, and fewer negative symptoms were significantly associated with higher social functioning. Group-specific associations were also observed: in nonrelapsers and low-frequency relapsers, positive symptoms and medication-related factors were relevant, whereas in low- and high-frequency relapsers, marital history was associated, and in high-frequency relapsers, the absence of tardive dyskinesia emerged as a factor.

Factors associated with social functioning differed according to relapse frequency, highlighting the need for relapse frequency-based, stratified intervention strategies.

Pharmacological efforts to treat anorexia nervosa (AN) have predominantly repurposed medications that treat conditions with overlapping symptoms and yielded generally disappointing results. Despite limited empirical support, SSRIs are often prescribed to patients with AN. Whether SSRIs are effective in a subgroup of individuals with AN, such as those with depression, is not known.

A secondary analysis of a randomized trial of fluoxetine versus placebo for relapse prevention in AN was conducted. Participants (n = 92) were weight-restored women with AN who completed the Beck Depression Inventory (BDI) at the time of randomization. BDI scores were dichotomized to reflect moderate/severe depression (BDI > 20, n = 26). A Cox Proportional Hazards model estimated the association of the level of depression, medication, and their interaction with time to relapse. Mixed effects models examined the effects of medication on symptom trajectories in high versus low depression groups and whether depression severity modified the effect of the drug on symptom trajectory.

There was a significant interaction between medication and depression severity in time to relapse (hazard ratio = 0.46, 95% CI: [0.25, 0.85], p = .01). Depression severity modified the effect of fluoxetine on the time course of symptoms of depression (β = −0.27, 95% CI: [−0.42,-0.12], p = 0.001) and bulimia (β = −0.15, 95% CI: [−0.25,-0.05], p = 0.004) in the twelve month follow-up period.

Fluoxetine was more effective than placebo in reducing relapse among more depressed, weight-restored individuals with AN. These results require replication but provide support for the use of antidepressant medication for patients with AN who remain depressed following weight restoration.

The optimal duration for maintaining antidepressant treatment in individuals with obsessive-compulsive disorder (OCD) who achieve symptom stabilization remains unclear.

This systematic review and pairwise meta-analysis of double-blind randomized placebo-controlled trials (DBRPCTs) compared antidepressant maintenance and antidepressant discontinuation groups in terms of relapse rate at each DBRPCT study endpoint (primary outcome), OCD symptom improvement, all-cause discontinuation, and adverse event-related discontinuation. Furthermore, relapse rates at 4, 8, 12, 16, 20, and 24 weeks were compared between the groups. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated. The absolute risk reduction (ARR) and number needed to treat to benefit (NNTB) for relapse rates were also estimated.

Nine trials (n = 1084; mean age: 32.8 years; proportion of males: 53.3%) were included. The antidepressant maintenance group had lower relapse rates at each DBRPCT study endpoint (RR [95% CI] = 0.53 [0.42–0.68]; ARR = 21.0%; NNTB = 5) and lower all-cause and adverse event-related discontinuation rates than the antidepressant discontinuation group. The maintenance group also exhibited lower relapse rates at 4 weeks (RR [95% CI] = 0.47 [0.31–0.70]; ARR: not significant; NNTB: not significant), 8 weeks (0.42 [0.31–0.57]; 12.0%; 8), 12 weeks (0.43 [0.32–0.56]; 18.0%; 6), 16 weeks (0.41 [0.32–0.52]; 25.0%; 4), 20 weeks (0.43 [0.34–0.53]; 26.0%; 4), and 24 weeks (0.42 [0.33–0.52]; 27.0%; 4) than the discontinuation group. Moreover, the maintenance group outperformed the discontinuation group regarding OCD symptom improvement.

Individuals with OCD may benefit from continued antidepressant treatment, provided that it is well tolerated.

Cannabis use is linked to treatment non-adherence and relapses in psychotic disorders. Antipsychotic medication is effective for relapse prevention in primary psychoses, but its effectiveness after cannabis-induced psychosis (CIP) remains unclear.

To examine the effectiveness of antipsychotic medication for relapse prevention following the first clinically diagnosed CIP.

A cohort of 1772 patients (84.1% men) with incident CIP was identified from the Swedish National Patient and Micro Data for Analyses of Social Insurance registers. The primary outcome was hospitalisation due to any psychotic episode. Drug use data were collected from the Prescribed Drug Register and modelled into drug use periods using the PRE2DUP method. A within-individual Cox regression model was used to study the risk of outcomes during the use of different oral or long-acting injectable (LAI) antipsychotics compared with non-use.

The mean age at first diagnosis was 26.6 years (s.d. = 8.3). Of the cohort, 1343 (75.8%) used antipsychotics and 914 (51.3%) experienced psychosis hospitalisation during the follow-up. Any antipsychotic use was associated with a decreased risk of psychosis hospitalisation (adjusted hazard ratio (aHR) 0.75; 95% CI 0.67–0.84). Specific antipsychotics associated with decreased risk included aripiprazole LAI (aHR 0.27; 95% CI 0.14–0.51), olanzapine LAI (aHR 0.28; 95% CI 0.15–0.53), clozapine (aHR 0.55; 95% CI 0.34–0.90), oral aripiprazole (aHR 0.64; 95% CI 0.45–0.91), antipsychotic polytherapy (aHR 0.74; 95% CI 0.63–0.87) and oral olanzapine (aHR 0.81; 95% CI 0.69–0.94).

In particular, LAIs, clozapine and oral aripiprazole were associated with a decreased risk of psychosis relapse following CIP. Prescribers should consider using more LAIs for better treatment outcomes after CIP.

Many studies have highlighted the detrimental effect of childhood maltreatment (CM) on depression severity and the course of illness in major depressive disorder (MDD). Yet our understanding of how CM influences the dynamic symptom change throughout a patient’s trajectory remains limited. Hence, we investigated the impact of CM on depression severity in MDD with a focus on various treatment phases during inpatient treatment and after discharge (1 or 2 years later) and validated findings in a real-world setting.

We used longitudinal data from a cohort study sample (n = 567) and a clinical routine sample (n = 438). CM was measured with the Childhood Trauma Questionnaire (CTQ), and depression severity was assessed using Beck’s Depression Inventory (BDI). The long-term clinical trajectory was assessed using the Life Chart Interview.

Our analyses revealed that CM significantly increased depression severity before, during, and after inpatient therapy in both samples. Although CM was associated with higher depression severity at the beginning of inpatient treatment and lower remission rates upon discharge, no discernible impact of CM was evident on the relative change in symptoms over time during inpatient treatment. CM consistently predicted higher relapse rates and lower rates of full remission after discharge during long-term follow-up in both samples.

Our findings affirm the link between CM and the development of more severe and persistent clinical trajectories within real-world clinical settings. Furthermore, conventional psychiatric treatments may not lead to comparable outcomes for individuals with a history of CM, underscoring the necessity for tailored therapeutic interventions.

Having a relapse of schizophrenia or recurrent psychosis is feared by patients, can cause social and personal disruption and has been suggested to cause long-term deterioration, possibly because of a toxic biological process.

To assess whether relapse affected the social and clinical outcomes of people enrolled in a 24-month randomised controlled trial of antipsychotic medication dose reduction versus maintenance treatment.

The trial involved participants with a diagnosis of schizophrenia or recurrent, non-affective psychosis. Relapse was defined as admission to hospital or significant deterioration (assessed by a blinded end-point committee). We analysed the relationship between relapse during the trial and social functioning, quality of life, symptom scores (Positive and Negative Syndrome Scale) and rates of being in employment, education or training at 24-month follow-up. We also analysed changes in these measures during the trial among those who relapsed and those who did not. Sensitivity analyses were conducted examining the effects of ‘severe’ relapse (i.e. admission to hospital).

During the course of the trial, 82 out of 253 participants relapsed. There was no evidence for a difference between those who relapsed and those who did not on changes in social functioning, quality of life, symptom scores or overall employment rates between baseline and 24-month follow-up. Those who relapsed showed no change in their social functioning or quality of life, and a slight improvement in symptoms compared to baseline. They were more likely than those who did not relapse to have had a change in their employment status (mostly moving out of employment, education or training), although numbers changing status were small. Sensitivity analyses showed the same results for those who experienced a ‘severe’ relapse.

Our data provide little evidence that relapse has a detrimental effect in the long term in people with schizophrenia and recurrent psychosis.

Late-life depression (LLD) is characterized by repeated recurrent depressive episodes even with maintenance treatment. It is unclear what clinical and cognitive phenotypic characteristics present during remission predict future recurrence.

Participants (135 with remitted LLD and 69 comparison subjects across three institutions) completed baseline phenotyping, including psychiatric, medical, and social history, psychiatric symptom and personality trait assessment, and neuropsychological testing. Participants were clinically assessed every two months for two years while receiving standard antidepressant treatment. Analyses examined group differences in phenotypic measure using general linear models. Concurrent associations between phenotypic measures and diagnostic groups were examined using LASSO logistic regression.

Sixty (44%) LLD participants experienced a relapse over the two-year period. Numerous phenotypic measures across all domains differed between remitted LLD and comparison participants. Only residual depressive symptom severity, rumination, medical comorbidity, and executive dysfunction significantly predicted LLD classification. Fewer measures differed between relapsing and sustained remission LLD subgroups, with the relapsing group exhibiting greater antidepressant treatment intensity, greater fatigue, rumination, and disability, higher systolic blood pressure, greater life stress and lower instrumental social support. Relapsing group classification was informed by antidepressant treatment intensity, lower instrumental social support, and greater life stress.

A wide range of phenotypic factors differed between remitted LLD and comparison groups. Fewer measures differed between relapsing and sustained remission LLD subgroups, with less social support and greater stress informing vulnerability to subsequent relapse. This research suggests potential targets for relapse prevention and emphasizes the need for clinically translatable relapse biomarkers to inform care.

To compare time to relapse in patients with major depressive disorder (MDD) stabilised on antidepressant treatment (ADT) + brexpiprazole who were randomised to continued adjunctive brexpiprazole or brexpiprazole withdrawal (switch to placebo).

This Phase 3, multicentre, double-blind, placebo-controlled, parallel-arm, randomised withdrawal study enrolled adults with MDD and inadequate response to 2–3 ADTs. All patients started on adjunctive brexpiprazole 2–3 mg/day (Phase A, 6–8 weeks). Patients whose symptoms stabilised (Phase B, 12 weeks) were randomised 1:1 to adjunctive brexpiprazole or adjunctive placebo (Phase C, 26 weeks). The primary endpoint was time to relapse in Phase C. Depression rating scale score changes were secondary endpoints.

1149 patients were enrolled and 489 patients were randomised (ADT + brexpiprazole n = 240; ADT + placebo n = 249). Median time to relapse was 63 days from randomisation in both treatment groups for patients who received ≥1 dose. Relapse criteria were met by 22.5% of patients (54/240) on ADT + brexpiprazole and 20.6% (51/248) on ADT + placebo (hazard ratio, 1.14; 95% confidence interval, 0.78–1.67; p = 0.51, log-rank test). Depression scale scores improved during Phases A–B and were maintained in Phase C. Mean weight increased by 2.2 kg in Phases A–B and stabilised in Phase C.

Time to relapse was similar between continued adjunctive brexpiprazole and brexpiprazole withdrawal; in both groups, ∼80% of stabilised patients remained relapse free at their last visit. Adjunctive brexpiprazole therapy was generally well tolerated over up to 46 weeks, with minimal adverse effects following brexpiprazole withdrawal.

ClinicalTrials.gov identifier: NCT03538691. Funding: Otsuka, Lundbeck.