Schizophrenia Bulletin最新文献

Background: Motivational deficits have a major impact on the quality of life of patients with schizophrenia (SCZ) and respond poorly to antipsychotic medication. However, the underlying mechanisms, which cannot be accessed through conventional questionnaire-based scoring, remain largely unknown. This study aims to identify dysfunctional mechanisms that generate motivation deficits in patients with SCZ.

Study design: Behavioral tests were combined with computational modeling to elucidate motivational deficits in 35 patients with SCZ compared to 35 matched healthy controls (HC). All participants performed a comprehensive set of behavioral tasks, including preference tasks in which participants rated and chose between various hypothetical effort costs and expected outcomes (rewards or punishments), and performance tasks in which they adjusted motor or cognitive effort production to the outcome at stake.

Study results: Preference tasks (likability ratings and binary choices) revealed a significantly greater aversion to hypothetical effort costs in patients relative to HC, with no significant difference in the sensitivity to reward or punishment. Performance tasks (grip and Stroop) confirmed a greater aversion to cognitive effort (but not motor effort), and additionally uncovered a lower sensitivity to expected outcomes (both rewards and punishments).

Conclusions: In contrast to what was observed in other clinical populations, results were not consistent across behavioral tasks. The observed pattern highlights the complexity of motivational deficits in patients with SCZ, which may not be reducible to a single underlying mechanism. The most consistent finding was an increased aversion to cognitive effort, which may underlie the apathy manifested by most patients with SCZ.

Background and hypothesis: Estrogen affects drug metabolism for specific antipsychotics, which may produce sex differences in serum levels, especially over the menopausal transition. Here, we explore sex differences in concentrations of four commonly used antipsychotics: clozapine, olanzapine, aripiprazole, and quetiapine and examined how these vary across age groups, including postmenopause (>55).

Study design: Antipsychotic concentrations of 44 378 serum samples drawn between January 2016 and October 2024 were analyzed. Samples were provided by 6147 unique adult men and women for clozapine (n = 34 761 samples, 26% female), olanzapine (n = 5114, 27% female), aripiprazole (n = 3171, 37% female), and quetiapine (n = 1332, 50% female). To investigate the effect of sex and age on antipsychotic concentrations, we employed linear mixed-effects models and pairwise contrasts by dividing the samples in 6 groups according to sex and age (<45, 45-55, and >55 years).

Study results: We found higher concentrations in women compared to men for clozapine (P < .001), and olanzapine (P < .001), but not for quetiapine or aripiprazole. Young women (<45) showed higher levels of clozapine (P = .004) and olanzapine (P < .001) than men, but older women did not. Clozapine levels were higher in women <45 and 45-55 compared to women >55 years (all P < .05). For olanzapine, aripiprazole, and quetiapine concentrations differences between female age groups were absent.

Conclusions: We found sex differences in olanzapine and clozapine concentrations, which were most pronounced until 45 years of age. Our findings suggest that monitoring antipsychotic levels may add clinical value and underscore the need for sex-specific prescription guidelines for olanzapine and clozapine.

Background and hypothesis: Shared clinical features and genetic factors in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) have led to the hypothesis of common pathophysiological mechanisms. This study aims to elucidate aberrant transdiagnostic structural covariance patterns across these disorders employing a multivariate analytical approach.

Study design: Structural magnetic resonance imaging data were acquired from a sample of 704 subjects, comprising 244 healthy controls, 119 first-episode treatment-naïve SCZ individuals, 159 BD individuals, and 182 treatment-naïve MDD individuals. Seed-based partial least squares correlation analysis was applied to construct structural covariance networks (SCNs) across 6 predefined functional networks: the default mode network (DMN), dorsal attention network (DAN), frontoparietal control network (FPCN), somatomotor network (SMN), ventral attention network (VAN), and visual network. Network seeds were selected based on functional network definitions. Spatial distributions of SCNs were calculated, and individual network integrity indices were derived as measures of SCN strength. Group comparisons of network integrity were performed using multiple t-tests to identify network-specific alterations across the diagnostic groups.

Study results: Structural covariance patterns exhibited spatial distributions akin to those of functional networks. Network integrity showed common reductions across all 3 disorders in DMN, DAN, and FPCN, while BD showed specific reductions in the SMN, and both BD and MDD showed reductions in the VAN. Furthermore, there was a significant correlation between individualized network integrity and clinical and cognitive manifestations.

Conclusions: Our results highlight the potential of the integrity of SCNs as transdiagnostic biomarkers.

Background: Early psychosis and schizophrenia-spectrum disorders are life-altering conditions, frequently associated with persistent impairments in functioning. Although evidence-based interventions exist, treatment outcomes remain variable. Self-Determination Theory (SDT) posits that autonomy-supportive environments facilitate positive outcomes; however, mediators of this association have been understudied in treatment settings of this clinical population.

Study design: Data were drawn from the Recovery After an Initial Schizophrenia Episode-Early Treatment Program study, a multisite, cluster-randomized controlled trial comparing NAVIGATE (n = 223; 78% male; Mage = 23.18), a coordinated specialty care intervention informed by SDT principles, to community care (CC; n = 180; 66% male; Mage = 23.08). Structural equation modeling was used to test whether perceived autonomy support from healthcare providers predicted overall functioning indirectly through recovery-oriented psychological growth. Models were evaluated separately by treatment condition and by study year, adjusting for baseline group differences.

Study results: Model fit indices indicated adequate fit (RMSEA≤.05, CFI > .95, SRMR<.08, TLI > .95). Among NAVIGATE participants, perceived autonomy support at 3 months predicted functioning at 12 months via recovery-oriented psychological growth processes at 6 months (ß = 1.41, SE = 0.73, abps = 0.063, 95%CI, 0.32-3.05); this indirect effect remained significant at Year 2. Significant full mediation effects were observed. No indirect effects were detected in the CC group.

Conclusions: Treatment programs that emphasize autonomy-supportive principles, such as NAVIGATE, lead to improved functional outcomes by fostering recovery-oriented psychological growth. These findings highlight the relevance of SDT in clinical practice, providing a framework to optimize treatment outcomes by cultivating autonomy-supportive environments.

Background: The antipsychotic aripiprazole is mainly metabolized by the cytochrome P450 (CYP) 2D6. The main objective of this study was to evaluate the influence of CYP2D6 phenotypes on aripiprazole plasma levels and treatment duration.

Design: 466 patients treated with aripiprazole for up to 12 months and with at least one aripiprazole plasma level in steady-state condition were selected. CYP2D6 genotypes and phenoconversion to poor metabolizer status due to strong CYP2D6 inhibition were considered. Aripiprazole plasma level-to-dose ratios and treatment duration up to discontinuation, defined as switching to another psychotropic drug and/or stopping the follow-up, were analyzed using robust linear models and Cox regression, respectively. Akaike variable selection was applied.

Results: CYP2D6 poor metabolizers (genetically determined n = 19 and phenoconverted, n = 52) showed higher aripiprazole concentration-to-dose (P < .001) and aripiprazole plus dehydroaripiprazole concentration-to-dose (P < .001) ratios when compared to normal metabolizers (n = 255). CYP2D6 extreme metabolizers (ie, poor and ultrarapid metabolizers) had higher risk of treatment discontinuation versus intermediate and normal metabolizers after 3, 6, and 12 months of treatment (HR: 2.08, 1.75, 1.59, respectively; P = .013, P = .019, and P = .047, respectively). For a pharmacogenetic-guided treatment, the number of patients needed to genotype to prevent 1 patient from aripiprazole discontinuation was 15.

Conclusion: CYP2D6 poor metabolism was associated with increased aripiprazole and aripiprazole plus dehydroaripiprazole concentrations-to-dose. CYP2D6 extreme phenotypes were associated with increased risk of treatment discontinuation over 1 year of treatment. This finding supports the applicability of pre-emptive CYP2D6 genotyping, which is expected to decrease aripiprazole adverse events and inefficacy that would probably lead to treatment discontinuation.

Background and hypothesis: Identifying the nature of mitochondrial perturbations in brain regions dysfunctional in schizophrenia (SZ) and bipolar disorder (BP) is essential to decipher their disease processes. Employing "threshold-free" analytical approaches that evaluate patterns of gene expression differences and functional pathway enrichment can inform the shared and distinct aspects of SZ and BP disease processes. We hypothesized that transcriptomic signatures will be concordant, selectively within brain regions affected in both disorders.

Study design: SZ and BP transcriptomic signatures were evaluated in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), 2 regions that mediate different functions and are differentially affected by the disorders. Rank-rank hypergeometric overlap and gene-set enrichment analysis, 2 complementary analytical approaches that incorporate multiple quantitative measures to identify patterns of gene expression differences, were applied for transcriptome-wide and Gene Ontology "Mitochondria" (GO_Mito) analysis.

Study results: SZ disease effects were highly concordant across the DLPFC and ACC; findings reflected lower oxidative phosphorylation (OXPHOS) and greater translational repression. BP disease effects were weakly concordant across the DLPFC and ACC. Cross-diagnostic comparisons revealed transcriptomic concordance predominately within the ACC, especially for OXPHOS genes.

Conclusions: The SZ and BP disease effects on biological processes, particularly OXPHOS, are similar within the ACC but not the DLPFC. The overall constellation of findings in SZ was highly consistent with protective cellular responses that re-establish homeostasis after pathogenic insults. Together, these findings provide key insight into the potential substrates of DLPFC and ACC dysfunction that is associated with cognitive and affective dysregulation, respectively, in SZ and BP.

Background: Second-generation antipsychotics (SGAs) are widely prescribed for psychiatric disorders but frequently cause sexual dysfunction, particularly in women-a side effect often underrecognized. This study assessed the association between SGAs and female sexual dysfunction using the US Food and Drug Administration Adverse Event Reporting System (FAERS).

Study methods: We analyzed FAERS data from Q1 2004 to Q4 2023, identifying female sexual dysfunction cases using predefined MedDRA Preferred Terms. Nine SGAs were included: aripiprazole, quetiapine, olanzapine, risperidone, paliperidone, lurasidone, brexpiprazole, asenapine, and ziprasidone. Disproportionality analyses were conducted using frequentist (ROR, PRR) and Bayesian (BCPNN, MGPS) methods. Results were stratified by symptom type and prolactin-related drug effects.

Study results: A total of 11 786 reports were identified, peaking in 2017. Women aged 19-41 years accounted for the largest subgroup (n = 4787, 40.6%). Antipsychotics accounted for 9 of the top 50 drugs linked to sexual dysfunction, with aripiprazole, quetiapine, and olanzapine most frequently reported. Aripiprazole was strongly associated with compulsive sexual behavior (ROR: 296.23) and hypersexuality. Risperidone and paliperidone were linked to decreased libido and anorgasmia. Prolactin-elevating drugs were associated with older age, intramuscular use, and more serious outcomes.

Conclusion: This pharmacovigilance study highlights significant associations between specific SGAs and female sexual dysfunction. Disproportionality signals vary by drug, symptom type, and prolactin-related mechanisms. Clinicians should consider sexual side effects in treatment decisions and monitor patients accordingly. Further prospective studies are warranted.

Background and hypothesis: Altered cortical folding is a well-established finding in schizophrenia spectrum disorders (SSD). Patients with SSD have been hypothesized to exhibit an accelerated decline in age-related cortical folding, quantified with the local gyrification index (LGI). Here, we assessed longitudinal and cross-sectional LGI differences in patients with chronic SSD relative to healthy controls across 13 years.

Study design: The sample comprised patients with SSD (mean baseline age = 41.28 years) and healthy controls (mean baseline age = 41.56 years), with magnetic resonance imaging acquisitions at baseline (103 SSD patients and 99 controls) and follow-up after 5 (50 SSD patients and 57 controls) and 13 years (42 SSD patients and 60 controls). T1-weighted images were processed with the longitudinal pipeline in FreeSurfer. Spatiotemporal linear mixed-effects models were used to test for longitudinal and cross-sectional case-control differences in LGI, as well as the impact of symptom severity and antipsychotic medication dose among patients.

Study results: Although cross-sectional LGI was lower in patients in extensive frontal, parietal, and occipital regions, we observed no significant differences in longitudinal trajectories between patients and controls after FDR correction. Medication dose was linked cross-sectionally to lower LGI of the anterior cingulate, orbitofrontal cortex, and postcentral gyrus.

Conclusion: In the longest longitudinal study on cortical folding in SSD patients to date, we found no evidence for accelerated progressive decline in cortical folding. Rather, chronic SSD appears to be characterized by a state of stable hypogyria relative to healthy controls, consistent with the interpretation of LGI as a marker of early gyrification disturbances in SSD.

Background and hypothesis: Estrogens play a neuroprotective role in schizophrenia spectrum disorders (SSD), and evidence suggests that perimenopausal estrogen decline is associated with symptom exacerbation and increased relapse risk in women with SSD. Hormone replacement therapy (HRT) may mitigate these effects, but clinical and epidemiological data on its use in women with SSD remain limited.

Study design: We conducted a case series of 5 women (aged 47-53 years) with SSD in perimenopause or postmenopause, who were treated with individualized HRT regimens (transdermal or oral estradiol with oral, vaginal, or intrauterine progestogens) in a psychosis outpatient clinic. The women were monitored for 3 months for psychiatric stability, tolerability, side effects, and menopausal symptoms, using clinical observation and self-report.

Study results: All 5 women tolerated HRT well, with no serious adverse effects. Three women reported notable improvements in mood, energy, and social functioning. Negative symptoms improved in 4 women, and 1 woman with active positive symptoms experienced partial symptom reduction. Three women reported relief of menopausal symptoms (eg, sleep disturbance, vasomotor symptoms, and joint pain), which was perceived as beneficial to mental stability. All patients continued HRT beyond follow-up.

Conclusions: Hormone replacement therapy appears feasible and acceptable for women with SSD before and after the menopausal transition, with potential benefits for mood and functional improvement and high tolerability. Individualized approaches and safety considerations are essential. This approach may be integrated into routine psychiatric care, though larger studies with standardized outcomes are needed.

Cognitive impairment is a prominent feature of psychosis-spectrum disorders that impedes functional recovery. Globally, clinical guidelines recommend that evidence-based treatments, including cognitive remediation and cognitive compensation, are offered to people with psychosis with cognitive impairment. Clinical guidelines also recommend that, where possible, family is involved in the mental health treatment of their loved ones more broadly. Nevertheless, there is little guidance on how to assist family members with understanding and addressing the cognitive health needs of people with psychotic disorders. This is despite a demonstrable relationship between this symptom domain and caregiver burden as well as a clear need for greater professional supports from the perspectives of consumers and carers. In this article, we highlight the impact of cognitive impairment in psychosis on caregiver outcomes and argue the need to increase efforts to promote knowledge about cognitive health among caregivers via cognition-specific psychoeducation and/or more active involvement in cognitive rehabilitation. We showcase some of the existing cognition-specific resources that are available to caregivers and propose areas in need of future research. We conclude this article by presenting several practical recommendations for how clinical teams can advance their support of family members caring for loved ones with psychosis and cognitive impairment when it is clinically appropriate to do so and the consumer their caregiving network are agreeable.