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Background and hypothesis Several studies suggest that raloxifene, a selective estrogen receptor modulator, improves symptoms and cognition in post-menopausal women with Schizophrenia-Spectrum Disorders (SSD). We aimed to assess the effects of adjunctive raloxifene in women and men with SSD. Study design This parallel, randomized, double-blind, placebo-controlled trial included adult SSD patients across the Netherlands and Belgium. Participants were stratified by age, sex, and global functioning and randomly assigned 1:1 to 12-week add-on raloxifene or placebo. Primary outcomes were symptom severity at 6, 12, and 38 weeks and cognition at 12 and 38 weeks, as measured with the Positive and Negative Syndrome Scale and the Brief Assessment of Cognition in Schizophrenia, respectively. Intention-to-treat analyses were performed using linear mixed-effect models. Study results We assessed 261 patients for eligibility, of which 102 (28% female) were assigned to raloxifene (n  = 52) or placebo (n  = 48). Although we found no main effect of raloxifene, secondary sex-specific analysis showed that in women, raloxifene had beneficial effects on negative symptoms at week 6 (LSM −2.92; adjusted P  = 0.020) and week 12 (LSM −3.12; adjusted P  = 0.030), and on working memory at week 38 (LSM 0.73; adjusted P  = 0.040), while having negative effects on working memory at week 38 in men (LSM −0.53; adjusted P  = 0.026). The number of adverse events was similar between groups. Conclusions Our results do not support the use of raloxifene in patients with SSD in general, but suggest female-specific beneficial effects of raloxifene on negative symptoms and working memory. Our findings encourage further research on sex-specific pharmacotherapeutic treatment. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits may be characteristic for only a subgroup of first-episode psychosis (FEP) and the link with clinical and functional outcomes is less profound than previously thought. This study aimed to identify cognitive subgroups in a large sample of FEP using a clustering approach with healthy controls as a reference group, subsequently linking cognitive subgroups to clinical and functional outcomes. Methods: 204 FEP patients were included. Hierarchical cluster analysis was performed using baseline brief assessment of cognition in schizophrenia (BACS). Cognitive subgroups were compared to 40 controls and linked to longitudinal clinical and functional outcomes (PANSS, GAF, self-reported WHODAS 2.0) up to 12-month follow-up. Results: Three distinct cognitive clusters emerged: relative to controls, we found one cluster with preserved cognition (n = 76), one moderately impaired cluster (n = 74) and one severely impaired cluster (n = 54). Patients with severely impaired cognition had more severe clinical symptoms at baseline, 6- and 12-month follow-up as compared to patients with preserved cognition. General functioning (GAF) in the severely impaired cluster was significantly lower than in those with preserved cognition at baseline and showed trend-level effects at 6- and 12-month follow-up. No significant differences in self-reported functional outcome (WHODAS 2.0) were present. Conclusions: Current results demonstrate the existence of three distinct cognitive subgroups, corresponding with clinical outcome at baseline, 6- and 12-month follow-up. Importantly, the cognitively preserved subgroup was larger than the severely impaired group. Early identification of discrete cognitive profiles can offer valuable information about the clinical outcome but may not be relevant in predicting self-reported functional outcomes. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Throughout the life stages of women with schizophrenia-spectrum disorders (SSD), lower estrogen levels are associated with more severe disease course. At perimenopause in the mid-forties, estrogen levels decline to remain persistently low after menopause. This period is hypothesized to increase relapse risk and reduce antipsychotic effectiveness in preventing relapse. Study Design The cohort of persons with schizophrenia/schizoaffective disorder was identified from Finnish nationwide registers (N = 61 889) and stratified by sex and age <45 vs. ≥45 years. Hospitalizations for psychosis were defined per 5-year age group during the follow-up 1996–2017. Risk of psychosis hospitalization (Adjusted Hazard Ratio, aHR) was assessed using within-individual design, by comparing antipsychotic monotherapy use to nonuse periods in the same individuals for seven dose categories in defined daily doses (DDDs/day). Results Starting at age 45–50, women were consistently more often hospitalized for psychosis than their male peers. Women ≥45 had significantly higher aHRs than women <45 at antipsychotic monotherapy >0.6 DDDs/day, and than men at >1.1 DDDs/day. This female-specific age-dependent decrease in effectiveness was present for clozapine doses >0.6 DDDs/day, olanzapine doses >1.4 DDDs/day, and for specific doses of quetiapine (0.9–1.1 DDDs/day) and risperidone (0.6–0.9 DDDs/day). Conclusions While younger women have a lower risk of relapse and generally need a lower antipsychotic dose to prevent rehospitalization than men, antipsychotic effectiveness declines in women after the age of 45. Starting in mid-forties, older women with SSD should be regarded as a vulnerable group that deserve special attention. [ABSTRACT FROM AUTHOR]

There are significant differences between men and women in the efficacy and tolerability of antipsychotic drugs. Here, we provide a comprehensive overview of what is currently known about the pharmacokinetics and pharmacodynamics of antipsychotics in women with schizophrenia spectrum disorders (SSDs) and translate these insights into considerations for clinical practice. Slower drug absorption, metabolism and excretion in women all lead to higher plasma levels, which increase the risk for side-effects. Moreover, women reach higher dopamine receptor occupancy compared to men at similar serum levels, since oestrogens increase dopamine sensitivity. As current treatment guidelines are based on studies predominantly conducted in men, women are likely to be overmedicated by default. The risk of overmedicating generally increases when sex hormone levels are high (e.g. during ovulation and gestation), whereas higher doses may be required during low-hormonal phases (e.g. during menstruation and menopause). For premenopausal women, with the exceptions of quetiapine and lurasidone, doses of antipsychotics should be lower with largest adjustments required for olanzapine. Clinicians should be wary of side-effects that are particularly harmful in women, such as hyperprolactinaemia which can cause oestrogen deficiency and metabolic symptoms that may cause cardiovascular diseases. Given the protective effects of oestrogens on the course of SSD, oestrogen replacement therapy should be considered for postmenopausal patients, who are more vulnerable to side-effects and yet require higher dosages of most antipsychotics to reach similar efficacy. In conclusion, there is a need for tailored, female-specific prescription guidelines, which take into account adjustments required across different phases of life. [ABSTRACT FROM AUTHOR]

Aim: There is an ongoing debate regarding the optimal timing of discontinuation of antipsychotic drugs for patients with first episode psychosis. Although most guidelines recommend maintenance therapy for at least 1 or 2 years after reaching remission, study results indicate that early discontinuation may be beneficial for at least a subsample of patients. To date, little is known about which medication strategies are applied in patients recovering from a first psychotic episode. In this study, we examined the beliefs and practices of clinicians on medication discontinuation. Methods: We performed a survey among 50 experienced Dutch psychiatrists to assess how often specific treatment strategies have been applied in the past 12 months, as well as their knowledge and expectations with respect to medication discontinuation. Results: Psychiatrists estimated that, after remission, they continued medication at the same dose for at least 12 months in 51.2% of cases, continued in a reduced dose in 33.8% of cases and discontinued medication in 9.1% of cases after 4.4 months of remission on average. Although the medication is discontinued in only a relatively small proportion of patients, almost half of all clinicians (45.9%) used this strategy at least once in the past 12 months. Conclusions: There is substantial practice variation in antipsychotic medication strategies after remission from a first psychotic episode. Future research on long‐term effects of early medication discontinuation can guide clinicians in making evidence‐based decisions when treating first‐episode patients. [ABSTRACT FROM AUTHOR]

Background: Cognition is commonly affected in brain disorders. Non-invasive brain stimulation (NIBS) may have procognitive effects, with high tolerability. This meta-analysis evaluates the efficacy of transcranial magnetic stimulation (TMS) and transcranial Direct Current Stimulation (tDCS) in improving cognition, in schizophrenia, depression, dementia, Parkinson's disease, stroke, traumatic brain injury, and multiple sclerosis. Methods: A PRISMA systematic search was conducted for randomized controlled trials. Hedges' g was used to quantify effect sizes (ES) for changes in cognition after TMS/tDCS v. sham. As different cognitive functions may have unequal susceptibility to TMS/tDCS, we separately evaluated the effects on: attention/vigilance, working memory, executive functioning, processing speed, verbal fluency, verbal learning, and social cognition. Results: We included 82 studies (n = 2784). For working memory, both TMS (ES = 0.17, p = 0.015) and tDCS (ES = 0.17, p = 0.021) showed small but significant effects. Age positively moderated the effect of TMS. TDCS was superior to sham for attention/vigilance (ES = 0.20, p = 0.020). These significant effects did not differ across the type of brain disorder. Results were not significant for the other five cognitive domains. Conclusions: Our results revealed that both TMS and tDCS elicit a small trans-diagnostic effect on working memory, tDCS also improved attention/vigilance across diagnoses. Effects on the other domains were not significant. Observed ES were small, yet even slight cognitive improvements may facilitate daily functioning. While NIBS can be a well-tolerated treatment, its effects appear domain specific and should be applied only for realistic indications (i.e. to induce a small improvement in working memory or attention). [ABSTRACT FROM AUTHOR]

A corrigendum related to an error in the original article regarding the statement about women's stomachs being less acidic compared to men's and how it affects the absorption of antipsychotic drugs.

Background: Cognitive impairment is a core symptom of patients with schizophrenia, yet substantial heterogeneity in the degree of impairment exists within and between diagnoses of the schizophrenia spectrum, leading to sub-optimal understanding of the general and individual pathology of schizophrenia. By means of a cluster-analytic approach, individuals are grouped based on profiles of traits regardless of specific diagnoses. As this approach has already proven itself in decreasing cognitive heterogeneity within specific psychotic disorders, we investigated the structure of cognitive heterogeneity within a broader spectrum of psychotic disorders by including a large sample of schizophrenia patients and healthy individuals. Methods: An agglomerative hierarchical clustering analysis was performed using cognitive data (patients n = 324, healthy controls n = 40). All patients were diagnosed with a DSM-IV-TR diagnosis of schizophrenia (SZ), schizoaffective (SZA) or schizophreniform (SZP) disorder or another psychotic disorder/psychosis not otherwise specified (PNOS). To measure cognitive function, the composite Z-score was calculated, based on six cognitive domains as defined by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: Four clusters emerged from the clustering analysis, gradually and significantly distinguishable in cognitive impairment. The first cluster (n=50) contained relatively intact individuals, the second cluster (n=122) consisted of individuals with minimal to mild cognitive impairment, the third cluster (n=114) contained individuals with moderate cognitive impairment and individuals with most severe cognitive impairment were placed in the fourth cluster (n=78). All six cognitive domains show similar differences between clusters. While symptom severity and educational attainment show the same classification patterns as the neurocognitive profiles do, cluster assignment was not affected by illness duration and antipsychotic intake. Discussion: Results confirm that data-driven formed groups based on the clustering of neurocognitive profiles contain less cognitive heterogeneity compared to predefined diagnostic groups. Our results demonstrate that clustering patients with a schizophrenia spectrum disorder based on their neurocognitive profile decreases cognitive heterogeneity within the formed groups, creating more meaningful groupings and findings accentuate a cognitive continuum irrespective of a specific diagnosis, providing insight into the underlying pathology of clinical manifestation of schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotic effectiveness in preventing relapse declines around menopausal age in women with schizophrenia or schizoaffective disorder (SSD). It is not known whether systemic menopausal hormone therapy (MHT) can help to prevent psychosis relapse., Methods: A within-subject study design was used to study the effectiveness of MHT in preventing relapse in a Finnish nationwide cohort of women with SSD between 40 and 62 years of age who used MHT during follow-up (1994-2017). Hazard ratios adjusted for age and psychotropic drug use were calculated for psychosis relapse as main outcome and any psychiatric hospitalization as secondary outcome., Results: The study population comprised 3,488 women using MHT. Use of MHT was associated with a 16% lower relapse risk (adjusted hazard ratio [aHR]=0.84, 95% CI=0.78-0.90) when compared to non-use. Stratified by age, MHT was associated with decreased relapse risks when used between ages 40-49 (aHR=0.86, 95% CI=0.78-0.95) and ages 50-55 (aHR=0.74, 95% CI=0.66-0.83), but not between ages 56-62 (aHR=1.11, 95% CI=0.91-1.37). Similar effectiveness was found for estrogen alone or combined with fixed or sequential progestogens (aHRs between 0.79 and 0.86), transdermal and oral formulations (aHRs 0.75-0.87), and for most specific formulations (aHRs 0.75-0.85), except tibolone (aHR=1.04, 95% CI=0.75-1.44) and formulations with dydrogesterone (aHR=1.05, 95% CI=0.85-1.30). Similar results were observed with any psychiatric hospitalization as outcome measure., Conclusions: The findings underscore the potential value of MHT in preventing psychosis relapse among women with SSD of menopausal age. These findings translate clinical evidence on the neuroprotective effects of estrogens to real-world settings, encompassing a group of women for whom current antipsychotic treatment options may be insufficient., Competing Interests: Dr. Taipale, Dr. Tanskanen, and Prof. Tiihonen have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. Prof. Tiihonen has been a consultant/advisor to and has received honoraria from: Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Orion, Otsuka, Mediuutiset, Sidera, and Sunovion. Dr. Taipale reports personal fees from Gedeon Richter, Janssen, Lundbeck and Otsuka. Dr. Sommer has received speaker fees from Otsuka and a charity grant from Janssen unrelated to this project. The remaining authors report no financial relationships with commercial interests.

Schizophrenia-spectrum disorders (SSD) are highly heterogeneous in risk factors, symptom characteristics, and disease course outcome. Although speech anomalies have long been recognized as a core symptom of SSD, speech markers are an unexplored source of symptom heterogeneity that may be informative in recognizing relevant subtypes. This study investigated speech heterogeneity and its relation to clinical characteristics in a large sample of patients with SSD and healthy controls. Speech samples were obtained from 142 patients with SSD and 147 healthy controls by means of open-ended interviews. Speech was analyzed using standardized open-source acoustic speech software. Hierarchical clustering was conducted using acoustic speech markers. Symptom severity was rated with the Positive and Negative Syndrome Scale, and cognition was assessed with the Brief Assessment of Cognition for Schizophrenia. Three speech clusters could be distinguished in the patient group that differed regarding speech properties, independent of medication use. One cluster was characterized by mild speech disturbances, while two severely impaired clusters were recognized (fragmented speakers and prolonged pausers). Both clusters with severely impaired speech had more severe cognitive dysfunction than the mildly impaired speakers. Prolonged pausers specifically had difficulties with memory-related tasks. Prolonged pausing, as opposed to fragmented speaking, related to chronic active psychosis and refractory psychotic symptoms. Based on speech clustering, subtypes of patients emerged with distinct disease trajectories, symptomatology, and cognitive functioning. The identification of clinically relevant subgroups within SSD may help to characterize distinct profiles and benefit the tailoring of early intervention and improvement of long-term functional outcome. (PsycInfo Database Record (c) 2022 APA, all rights reserved).