The treatment response for the negative symptoms of schizophrenia is not ideal, and the efficacy of antidepressant treatment remains a matter of considerable controversy. This systematic review and meta-analysis aimed to assess the efficacy of adjunctive antidepressant treatment for negative symptoms of schizophrenia under strict inclusion criteria.

A systematic literature search (PubMed/Web of Science) was conducted to identify randomized, double-blind, effect-focused trials comparing adjuvant antidepressants with placebo for the treatment of negative symptoms of schizophrenia from database establishment to April 16, 2025. Negative symptoms were examined as the primary outcome. Data were extracted from published research reports, and the overall effect size was calculated using standardized mean differences (SMD).

A total of 15 articles, involving 655 patients, were included in this review. Mirtazapine (N = 2, n = 48, SMD −1.73, CI −2.60, −0.87) and duloxetine (N = 1, n = 64, SMD −1.19, CI −2.17, −0.21) showed significantly better efficacy for negative symptoms compared to placebo. In direct comparisons between antidepressants, mirtazapine showed significant differences compared to reboxetine, escitalopram, and bupropion, but there were no significant differences between other antidepressants or between antidepressants and placebo. No publication bias for the prevalence of this condition was observed.

These findings suggest that adjunctive use of mirtazapine and duloxetine can effectively improve the negative symptoms of schizophrenia in patients who are stably receiving antipsychotic treatment. Therefore, incorporating antidepressants into future treatment plans for negative symptoms of schizophrenia is a promising strategy that warrants further exploration.

Schizophrenia is a chronic severe mental illness affecting 24-million people globally, associated with a life expectancy 15 years shorter than the general population. Approximately 70% of people with schizophrenia experience auditory verbal hallucinations (AVHs), i.e. ‘hearing voices’. Current treatment approaches remain unsuccessful in up to 30% of cases.

This systematic review and meta-analysis evaluated randomised controlled trials (RCTs) of non-pharmacological treatments for AVHs in schizophrenia spectrum disorders, assessing emerging treatment effectiveness and identifying research gaps.

A literature search was performed between 2013-2024 across five databases: PubMed, Embase, PsycINFO, Medline, and Web of Science. The meta-analysis included 45 studies based on predefined criteria and bias assessment. Effect sizes (Hedge’s g) were calculated using a random effects model with 95% confidence intervals. The study followed PRISMA guidelines and was pre-registered (PROSPERO ID: CRD42024598615).

Our sample included 2,314 patients and fourteen interventions. The overall mean effect size was -0.298 (95% CI, [-0.470, -0.126]), representing a medium, statistically significant effect. Subgroup analyses revealed medium, statistically significant effects for both AVATAR therapy and cognitive behavioural therapy (CBT). Conversely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) showed small, non-significant effects.

AVATAR therapy has the strongest evidence for treating AVHs, highlighting the need for large-scale RCTs and integration into treatment guidelines. CBT requires methodological standardisation. Acceptance and commitment therapy shows promise but needs further high-quality RCTs. Non-invasive brain stimulation techniques require additional trials before clinical implementation.

Insight assessment in psychosis remains challenging in practice-oriented research.

To develop and validate a proxy measure for insight based on information from electronic health records (EHR). For that purpose, we used data on the Scale to Assess Unawareness of Mental Disorder (SUMD) and data from EHR notes of patients in an early psychosis intervention programme (Programa de Atención a Fases Iniciales de Psicosis, Santander, Spain).

Junior and senior clinicians examined 134 clinical notes from 106 patients to explore criterion and content validity between SUMD and a clinician-rated proxy measure, using three SUMD items.

In terms of criterion validity, SUMD scores correlated with the proxy (r = 0.61, P < 0.001), even after adjusting for the following confounders: type of psychotic disorder, clinical remission status and rater experience (r = 0.58, P < 0.001); and the proxy predicted good insight status (odds ratio 20.95, 95% CI 7.32–59.91, P < 0.001). Regarding content validity, the three main SUMD subscores correlated with the proxy (r = 0.55–0.60, P < 0.005). There were no significant differences in age, gender or other clinical variables, i.e. discriminant validity, and the proxy significantly correlated with validated psychometric instruments, i.e. external validity. Intraclass correlation coefficient (i.e. interrater reliability) was 0.88 (95% CI 0.59–1.00, P < 0.05).

This SUMD-based proxy measure was shown to have good to excellent validity and reliability, which may offer a reliable and efficient alternative for assessing insight in real-world clinical practice, EHR-based research and management. Future studies should explore its applicability across different healthcare contexts and its potential for automation, using natural language-processing techniques.

The functional outcome of patients with psychotic disturbances is associated with several overlapping premorbid, societal, neuropsychological, and clinical factors. Extracting the factors associated with functional outcomes is important for designing effective mental health interventions.

In a naturalistic prospective European multicentre study, we analysed the effects of sociodemographic, preadmission, admission, and postadmission precursors on functional outcomes in 296 patients with recent-onset psychosis (ROP) and 262 patients at clinically high risk of psychosis (CHR-P). Functioning was assessed with the Global Assessment of Functioning—symptoms and deficits version—at baseline and at the 9- and 18-month follow-ups.

In the overall sample, male sex, childhood adversities, poor sociability, scholastic problems, neurocognitive deficits, and greater severity of baseline and follow-up symptoms were associated with poor functional outcomes. In contrast, a favourable work/educational situation and preadmission treatment for nonpsychotic disorders were associated with better functional outcomes. Among ROP patients, neurocognitive deficits and the severity of baseline and follow-up affective and psychotic symptoms were strongly associated with functional outcomes. Among CHR-P patients, premorbid sociability, previous treatment for affective disorders, and follow-up affective symptoms played more significant roles.

To improve functioning in patients in the early stages of psychosis, several factors should be considered, such as sex, childhood adversities, psychosocial development, baseline neurocognitive deficits, work/educational situation, clinical presentations, and follow-up symptoms. Personalized and integrated treatment and rehabilitation measures should be actively continued beyond the first admission period, with a particular focus on addressing both baseline and follow-up affective disturbances.

Developmental trauma increases psychosis risk in adulthood and is associated with poor prognosis and treatment response. It has been proposed that developmental trauma may give rise to a distinct psychosis phenotype. Our aim was to explore this by systematically reviewing neuroimaging studies of brain structure and function in adults with psychosis diagnoses, according to whether or not they had survived developmental trauma. We registered our search protocol in PROSPERO (CRD42018105021).

We systematically searched literature databases for relevant studies published before May 2024. We identified 31 imaging studies (n = 1,761 psychosis patients, n = 1,775 healthy controls or healthy siblings).

Developmental trauma was associated with global and regional differences in gray matter; corticolimbic structural dysconnectivity; a potentiated threat detection system; dysfunction in regions associated with mentalization; and elevated striatal dopamine synthesis capacity.

These findings warrant further research to elucidate vulnerability and resilience mechanisms for psychosis in developmental trauma survivors.

Dissociative experiences are common transdiagnostically, and particularly prevalent in psychosis. Such experiences have long been under-recognised in routine clinical practice, despite evidence that dissociation is related to clinical complexity and increased risk of self-harm and suicidality. Adopting a symptom-specific, targeted approach to conceptualisation and intervention for dissociation may help improve outcomes.

The evidence base for psychological treatments targeting dissociation is building, but training and guidance for clinicians remains sparse. This review outlines a preliminary approach to the treatment of a subtype of dissociative experience (felt sense of anomaly dissociation), based on emerging research evidence and clinical practice. The guidance is tailored to the context of psychosis, and may also have broader clinical relevance.

We present symptom-specific guidance for clinicians, including factors to consider in the assessment, formulation, and intervention for felt sense of anomaly dissociation in the context of psychosis, and reflections on process issues. We present a cognitive behavioural model, where affect-related changes are interpreted as an internal threat, driving a maintenance cycle of catastrophic appraisals and safety behaviours. Using this formulation, evidence-based therapy techniques familiar to most readers can then be applied.

It is important for clinicians to consider dissociation. As well as generating new avenues for translational intervention research, we anticipate that the novel insights and specific advice outlined here will be of use to professionals working with dissociation in psychosis (and beyond). Encouragingly, we demonstrate that widely used, evidence-based skills and techniques can be employed to address distress arising from dissociation.

The rate at which psychosis drugs can be reduced in dose remains unclear. Anecdotal reports exist of people experiencing worsening of mental state before their next dose of long-acting injectable antipsychotic. No research has previously explored this phenomenon, but understanding this may advise on the rate of receptor occupancy change that provokes the emergence of psychotic symptoms.

Exploring the relationship between psychotic symptoms and variations in plasma concentration (and calculated receptor occupancy) of long-acting injectable antipsychotics.

This longitudinal study monitored mental state variation within dosing cycles of people taking depot flupentixol and zuclopenthixol. The Positive and Negative Syndrome Scale (PANSS) monitored global mental state changes, and was stratified into domains according to a five-factor model. Plasma assays at maximal and minimal concentrations allowed prediction of striatal D2 occupancy from published data. We examined correlations between receptor occupancy and the emergence of psychotic symptoms.

Preliminary results from ten participants with psychotic disorders suggest that global mental state deterioration may correlate with increased rate of D2 occupancy reduction. Increased rate of D2 occupancy reduction led to deterioration in ‘positive’ (r = 0.637 [CI: 0.013, 0.904], P = 0.047) and ‘resistance’ (r = 0.726 [CI: 0.177, 0.930], P = 0.018) PANSS clinical domains at minimal concentrations. PANSS score differences were not related to absolute reduction in D2 occupancy.

Our novel observational study design has been demonstrated to be feasible and practicable. Faster reductions in D2 occupancy may increase the risk of increased positive psychotic symptoms and irritability. Slower reductions may minimise this effect. Further recruitment is required before this can be confirmed.

Some psychotic experiences in the general population show associations with higher schizophrenia and other mental health-related polygenic risk scores (PRSs), but studies have not usually included interviewer-rated positive, negative and disorganised dimensions, which show distinct associations in clinical samples.

To investigate associations of these psychotic experience dimensions primarily with schizophrenia PRS and, secondarily, with other relevant PRSs.

Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort participants were assessed for positive, negative and disorganised psychotic experience dimensions from interviews, and for self-rated negative symptoms, at 24 years of age. Regression models were used to investigate associations between psychotic experience dimensions and schizophrenia and other PRSs (2500+ participants for each analysis).

Against expectation, none of the positive, negative or disorganised dimensions was associated with schizophrenia PRS. In secondary analysis, self-rated negative symptoms were associated with higher depression (β = 0.10 [95% CI 0.06–0.15]), anxiety (β = 0.09 [95% CI 0.04–0.13]), neuroticism (β = 0.11 [95% CI 0.06–0.15]) and autism (β = 0.09 [95% CI 0.05–0.13]) PRSs (all P < 0.001); and first-rank delusions were nominally associated with higher schizophrenia PRS (odds ratio 7.35 [95% CI 2.10–25.77], P = 0.002), although these experiences/symptoms were rare.

Positive, negative and disorganised psychotic experiences are probably not strongly associated with polygenic liability to schizophrenia in this general population cohort of young adults. Self-rated negative symptoms may indicate social withdrawal/low motivation due to higher polygenic liability to affective disorders or autism, and first-rank delusions may indicate higher polygenic liability to schizophrenia, but these findings require independent confirmation.

Psychological therapy (PT) along with antipsychotic medication is the recommended first line of treatment for first-episode psychosis (FEP). We investigated whether ethnicity, clinical, pathways to care (PtC) characteristics, and access to early intervention service (EIS) influenced the offer, uptake, and type of PT in an FEP sample.

We used data from the Clinical Record Interactive Search-First Episode Psychosis study. Inferential statistics determined associations between ethnicity, clinical, PtC, and PT offer/uptake. Multivariable logistic regression estimated the odds of being offered a PT and type of PT by ethnicity, clinical and PtC characteristics adjusting for confounders.

Of the 558 patients included, 195 (34.6%) were offered a PT, and 193 accepted. Cognitive behavioral therapy (CBT) (n = 165 of 195; 84.1%) was commonly offered than group therapy (n = 30 of 195; 13.3%). Patients who presented via an EIS (adj. OR = 2.24; 95%CI 1.39–3.59) were more likely to be offered a PT compared with those in non-EIS. Among the patients eligible for an EIS, Black African (adj. OR = 0.49; 95%CI = 0.25–0.94), Black Caribbean (adj. OR = 0.45; 95%CI = 0.21–0.97) patients were less likely to be offered CBT compared with their White British counterparts. Patients with a moderate onset of psychosis (adj. OR = 0.34; 95%CI = 0.15–0.73) had a reduced likelihood of receiving CBT compared with an acute onset.

Accessing EIS during FEP increased the likelihood of being offered a PT. However, treatment inequalities remain by ethnicity and clinical characteristics.

There is a substantial body of literature on environmental risk associated with schizophrenia. Most research has largely been conducted in Europe and North America, with little representation of the rest of the world; hence generalisability of findings is questionable. For this reason, we performed a mapping review of studies on environmental risk for schizophrenia spectrum disorders, recording the country where they were conducted, and we linked our findings with publicly available data to identify correlates with the uneven global distribution. Our aim was to evaluate how universal is the ‘common knowledge’ of environmental risk for psychosis collating the availability of evidence across different countries and to generate suggestions for future research identifying gaps in evidence.

We performed a systematic search and mapping of studies in the PubMed and PsycINFO electronic databases reporting on exposure to environmental risk for schizophrenia including obstetric complications, paternal age, migration, urbanicity, childhood trauma, and cannabis use and subsequent onset of schizophrenia spectrum disorders. This search focused on articles published from the date of the first available publication until 31 May 2023. We recorded the country where they were conducted. We downloaded publicly available data on population size, measures of wealth, medical provisions, research investment, and of quality research outputs per country and performed regression analyses of each predictor with the number of studies and recruited cases in each country.

We identified 308 publications that included a sample size of 445,000 patients with schizophrenia spectrum disorders. The majority were conducted in northern Europe and North America, with large parts of the world totally unrepresented. In the associations between the number of environmental risk studies for schizophrenia with potential predictors, we found that neither population nor wealth or research investment were strong predictors of research outputs in the field. Interestingly, the stronger correlations were found for number of researchers per population and for indicators of top-end scientific achievements, such as number of Nobel laureates per country.

Our results demonstrate a gap of knowledge due to the underrepresentation of studies on environmental risk of schizophrenia spectrum disorders in large parts of the world. This has implications not only in the generalisability of any findings from research conducted in the Northern hemisphere but also in our ability to progress in efforts to make causal inferences about biological pathways to schizophrenia. These findings reinforce the need to focus research on populations that are underrepresented in research and underserved in health care.

During puberty, sex-specific processes shape distinct mental health outcomes. However, research on puberty and psychosis has been limited, and the findings are conflicting.

To explore how puberty status and timing and oestradiol levels influence psychotic experiences and whether they interact with genetic and exposomic vulnerabilities to schizophrenia in female adolescents.

We analysed data from female participants in the Adolescent Brain Cognitive Development Study at baseline (n = 5673) and two annual follow-up assessments. Psychotic experiences were assessed using the Prodromal Psychosis Scale and puberty status with the Pubertal Development Scale. Age at menarche and salivary oestradiol concentration were recorded. Exposomic vulnerability to schizophrenia (ES-SCZ) and polygenic risk score for schizophrenia (PRS-SCZ) were calculated. Longitudinal mixed logistic regression models were used to test associations of psychotic experiences with hormone levels and puberty status. Age of menarche was analysed using second follow-up data.

Earlier menarche (odds ratio 0.68, 95% CI: 0.59 to 0.78) and higher oestradiol concentration (odds ratio = 1.08, 95% CI: 1.01 to 1.16) were associated with greater likelihood of psychotic experiences, as were mid-pubertal (odds ratio 1.41, 95% CI: 1.18 to 1.69) and late to post-pubertal (odds ratio 2.23, 95% CI: 1.74 to 2.86) compared with pre-pubertal stage. ES-SCZ and PRS-SCZ were associated with greater likelihood of psychotic experiences. No significant interactions of puberty factors with ES-SCZ or PRS-SCZ were detected.

Physical and hormonal puberty factors have critical roles in development of psychosis. The absence of interaction effects could be attributed to the age range of the cohort. Further research during follow-ups is essential.

The environment shapes the risk of psychosis. In particular, urbanicity, deprivation or inequality, migrant density and cannabis availability may not only influence psychosis incidence, but also the characteristics of individuals who arrive at clinical services. This study examined how socioeconomic factors influence the incidence and characteristics of cases of First-Episode Psychosis (FEP).

We analysed prospective data collected from the FEP early detection programme of Emilia-Romagna, a high-income Italian region. Participants were 1240 individuals aged 18–35 years, who presented at the public healthcare services for a FEP. Exposures were derived from area-level data of 331 municipalities. We used population density, socioeconomic deprivation, educational deprivation, economic inequality, migrant density (proportion of migrants), frequent cannabis use (proportion of people aged 15–19 years old who reported frequent cannabis use). Outcome measures were FEP incidence (cases/100 000 inhabitants at risk per year) and characteristics (age of onset, migrant status, unemployment, substance use, treatment lag [DUP], family and resource problems). We reviewed pertinent literature, and formulated a Directed Acyclic Graph to present causal assumptions and provide adjustment sets for Bayesian spatial and multilevel models of social causation. To compare the effects of different exposures, we computed Average Marginal Effects and report the outcome changes that correspond to one standard deviation change of the exposure, incidence rate ratios (IRR) or odds ratios (OR).

The exposures and incidence of FEP displayed heterogeneous spatial distribution, with no spatially organized pattern. Accordingly, incidence and characteristics were best modelled as non-spatial, three-level hierarchical models. The incidence of FEP was influenced by population density (IRR, 1.14; 95% CrI, 1.03; 1.29), educational deprivation (IRR, 1.15; 95% CrI, 1.02; 1.31) and frequent cannabis use (IRR, 1.31; 95% CrI, 0.98; 1.82), more than socioeconomic deprivation. Higher migrant density in an area shortened the DUP on average by 3.4 months (95% CrI, −1.122; 0.76), while an increase of cannabis use of one standard deviation increased the DUP of 12.9 months (95% CrI, −2.86; 6229). Socioeconomic deprivation increased the likelihood of FEP cases being substance users (OR, 1.12; 95% CrI, 1.01; 1.26), while population density decreased it (OR, 0.91; 95% CrI, 0.83; 1.00).

Area-level socioeconomic features affect both the incidence and the characteristics of FEP, including the probability of individual being migrants, substance users or having a different DUP. Educational deprivation may function as a proxy for culture- or cognitive-related factors. Area-level socioeconomic data may inform public healthcare strategies for early identification and availability of tertiary clinical services.

Defence behaviours – actions carried out to reduce perceived threat – are an important maintenance factor for persecutory delusions. Avoidance of feared situations and subtle in-situation behaviours reduce opportunities for new learning and are erroneously credited for the non-occurrence of harm; hence inaccurate fears are maintained. In contrast, exposure to feared situations whilst dropping defence behaviours – a key technique of cognitive therapy for paranoia – allows the discovery of new information concerning safety, thereby reducing persecutory delusions.

We aimed to develop for use in research and clinical practice a self-report assessment of paranoia-related defence behaviours.

A 64-item pool was developed from interviews with 106 patients with persecutory delusions, and completed by 53 patients with persecutory delusions, 592 people with elevated paranoia, and 2108 people with low paranoia. Exploratory and confirmatory factor analyses were used to derive the measure. Reliability and validity were assessed.

Two scales were developed: a 12-item avoidance scale and a 20-item in-situation defences scale. The avoidance scale had three factors (indoor spaces, outdoor spaces, and interactions) with an excellent model fit (CFI=0.98, TLI=0.97, RMSEA=0.04, SRMR=0.027). The in-situation defences scale had a 5-factor model (maintaining safety at home, mitigating risk, staying vigilant, preparing for escape, and keeping a low profile) with a good fit (CFI=0.95, TLI=0.94, RMSEA=0.046, SRMR=0.039). Both scales demonstrated good internal reliability, test–retest reliability, and construct validity.

The Oxford Paranoia Defence Behaviours Questionnaire is a psychometrically robust scale that can assess a key factor in the maintenance of persecutory delusions.

Second-generation antipsychotics (SGAs) are moderately effective treatments for psychotic disorders but are associated with significant weight gain and metabolic complications. These contribute to a nearly 20-year reduction in life expectancy for individuals with enduring psychotic illness. Weight gain can also negatively impact adherence, increase relapse risk, and worsen psychosocial outcomes.

To highlight the mechanisms underlying antipsychotic-induced weight gain (AIWG), examine pharmacological strategies for its prevention and treatment, and argue for the early use of metformin.

This perspective article synthesises current evidence on the pathophysiology of AIWG and evaluates the role of metformin in mitigating these effects.

Weight gain can occur rapidly after initiating antipsychotic treatment, particularly in young people and those prescribed antipsychotics for non-psychotic indications. Presentation and response to interventions vary. Of all pharmacological strategies, metformin has the most robust evidence for both prevention and treatment of AIWG. It is a well-tolerated, low-cost antihyperglycaemic agent with an established safety profile. Metformin should be considered early in the course of antipsychotic treatment for all individuals, regardless of diagnosis, to prevent clinically significant weight gain and reduce long-term health risks. Early intervention may improve adherence, reduce relapse, and enhance overall quality of life.