Verbal memory (VM) is one of the most affected cognitive domains in first-episode psychosis (FEP) and is a robust predictor of functioning. Given that healthy females demonstrate superior VM relative to males and that female patients show less-severe illness courses than male patients, this study examined whether normative sex differences in VM extend to FEP and influence functioning. Four hundred and thirty-five patients (299 males, 136 females) with affective or nonaffective psychosis were recruited from a catchment-based specialized FEP intervention service and 138 nonclinical controls (96 males, 42 females) were recruited from the same community. One of the two neurocognitive batteries comprising six cognitive domains (VM, visual memory, working memory, attention, executive function, processing speed) were administered at baseline. In patients, positive and negative symptoms were evaluated at baseline and functioning was assessed at 1-year follow-up. Patients were more impaired than controls on all cognitive domains, but only VM showed sex differences (both patient and control males performed worse than females), and these results were consistent across batteries. In patients, better baseline VM in females was related to better functioning after 1 year, mediated through fewer baseline negative symptoms. Supplemental analyses revealed these results were not driven by affective psychosis nor by age and parental education. Thus, normative sex differences in VM are preserved in FEP and mediate functioning at 1-year follow-up via negative symptoms. This study highlights the importance of investigating sex effects for understanding VM deficits in early psychosis and suggests that sex may be a disease-modifying variable with important treatment implications.

Background Given the increasing acceptability and legalization of cannabis in some jurisdictions, clinicians need to improve their understanding of the effect of cannabis use on mood disorders. Objective The purpose of this task force report is to examine the association between cannabis use and incidence, presentation, course and treatment of bipolar disorder and major depressive disorder, and the treatment of comorbid cannabis use disorder. Methods We conducted a systematic literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials from inception to October 2020 focusing on cannabis use and bipolar disorder or major depressive disorder, and treatment of comorbid cannabis use disorder. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was used to evaluate the quality of evidence and clinical considerations were integrated to generate Canadian Network for Mood and Anxiety Treatments recommendations. Results Of 12,691 publications, 56 met the criteria: 23 on bipolar disorder, 21 on major depressive disorder, 11 on both diagnoses and 1 on treatment of comorbid cannabis use disorder and major depressive disorder. Of 2,479,640 participants, 12,502 were comparison participants, 73,891 had bipolar disorder and 408,223 major depressive disorder without cannabis use. Of those with cannabis use, 2,761 had bipolar disorder and 5,044 major depressive disorder. The lifetime prevalence of cannabis use was 52%–71% and 6%–50% in bipolar disorder and major depressive disorder, respectively. Cannabis use was associated with worsening course and symptoms of both mood disorders, with more consistent associations in bipolar disorder than major depressive disorder: increased severity of depressive, manic and psychotic symptoms in bipolar disorder and depressive symptoms in major depressive disorder. Cannabis use was associated with increased suicidality and decreased functioning in both bipolar disorder and major depressive disorder. Treatment of comorbid cannabis use disorder and major depressive disorder did not show significant results. Conclusion The data indicate that cannabis use is associated with worsened course and functioning of bipolar disorder and major depressive disorder. Future studies should include more accurate determinations of type, amount and frequency of cannabis use and select comparison groups which allow to control for underlying common factors.

Objectives Late‐onset bipolar disorder (LOBD) represents a significant subgroup of bipolar disorder (BD). However, knowledge for this group is mostly extrapolated from small studies in subjects with early/mixed age of illness onset. In this global sample of older adults with BD (OABD: ≥50 years old) we aim to characterize the sociodemographic and clinical presentation of LOBD (≥40 years at BD onset) compared to early‐onset BD (EOBD: <40 years at BD onset). Methods The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data on 437 older age bipolar disorder participants. We compared LOBD versus EOBD on depression, mania, functionality, and physical comorbidities. Exploratory analyses were performed on participants with BD onset ≥50 years old. Results LOBD (n = 105) did not differ from EOBD (n = 332) on depression, mania, global functioning, nor employment status (p > 0.05). Late‐onset bipolar disorder was associated with higher endocrine comorbidities (odds ratio = 1.48, [95%CI = 1.0,12.1], p = 0.03). This difference did not remain significant when subjects with BD onset ≥50 years old were analyzed. Limitations This study is limited by the retrospective nature of the variable age of onset and the differences in evaluation methods across studies (partially overcame by harmonization processes). Conclusion The present analysis is in favor of the hypothesis that LOBD might represent a similar clinical phenotype as classic EOBD with respect to core BD symptomatology, functionality, and comorbid physical conditions. Large‐scale global collaboration to improve our understanding of BD across the lifespan is needed.

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Hippocampal circuitry and related cortical connections are altered in first episode psychosis (FEP) and are associated with verbal memory deficits, as well as positive and negative symptoms. There are robust sex differences in the clinical presentation of psychosis, including poorer verbal memory in male patients. Consideration of sex differences in hippocampal-cortical circuitry and their associations with different behavioral dimensions may be useful for understanding the underlying pathophysiology of verbal memory deficits and related symptomatology in psychosis. Here, we use a data-driven approach to simultaneously capture the complex links between sex, verbal memory, symptoms, and cortical-hippocampal brain metrics in FEP. Structural magnetic resonance imaging and behavioral data were acquired from 100 FEP patients (75 males, 25 females) and 87 controls (55 males, 32 females). Multivariate brain-behavior associations were examined in FEP using partial least squares to map sociodemographic, verbal memory, and clinical data onto brain morphometry. The analysis identified two sex-dependent patterns of verbal memory, symptoms, and brain structure. In male patients, verbal memory deficits and core psychotic symptoms were associated with both increased and decreased frontal and temporal cortical thickness and reductions in CA2/3 hippocampal subfield and fornix volumes. In female patients, fewer negative/depressive symptoms were associated with a more attenuated cortical thickness pattern and more diffuse reductions in hippocampal white matter regions. Taken together, the results contribute towards better understanding the underlying pathophysiology of psychosis by highlighting the unique contribution of specific hippocampal subfields and surrounding white matter and their connections with broader cortical networks in a sex-dependent manner.

Background Verbal memory (VM) is one of the most affected cognitive domains in individuals with a first episode of psychosis (FEP). In the general population, there are well-documented sex differences in VM such that males perform worse than females. This has implications for understanding cognitive deficits in psychosis given that male patients present with more severe negative symptoms and poorer functional outcomes, both of which are associated with cognitive deficits. There lacks, however, a clear understanding of how VM deficits might contribute to males’ poorer functioning. From a neuroanatomical perspective, VM relies on a network of brain regions, including the hippocampus (HC) as an important hub in the acquisition of new information. Interestingly, many of the brain regions that differ between males and females, including the HC, show structural abnormalities in psychosis. Thus, consideration of sex differences may be essential for better characterizing and understanding brain alterations in psychosis and their effects on cognition. The aims of the current research were to: (1) evaluate whether the propensity for poorer functional outcomes among FEP males is mediated by sex differences in VM; and (2) investigate whether HC volume mediates the effect of sex on VM. Methods 137 FEP (90 males, 47 females) and 81 controls (55 males, 26 females) completed a VM task (Wechsler Memory Scale or CogState Research Battery) and a structural MRI scan (1.5 Tesla). Patients were additionally assessed for negative symptoms (Scale for the Assessment of Negative Symptoms) at baseline and functioning (Social and Occupational Functioning Assessment Scale) at 1-year follow-up. Performance of the matched control group was used as normative data to derive VM z-scores. HC volumes were computed for each subject and hemisphere using the MAGeT brain algorithm. Mediation analyses were conducted using the PROCESS macro with SPSS. The behavioral model (‘sex VM negative symptoms functioning’) was performed in patients only, controlling for education; the imaging model (‘sex HC volume VM’) was performed in both groups and additionally controlled for age and total brain volume. Significance was assessed at 95% confidence intervals. Results The effect of sex on functioning at 1-year follow-up was fully mediated by verbal memory capacity and negative symptoms (β=0.54, CI=[0.12, 1.12]. Importantly, neither VM nor negative symptoms alone mediated the relationship between sex and functioning at 1-year follow-up. Left and right HC volumes, which were larger in males than in females in both groups, demonstrated a suppression effect on the relation between sex and verbal memory in patients (left HC: β=-0.21, CI=[-0.39, -0.07]; right HC: β=-0.24, CI=[-0.45,-0.09]), but not in controls (left HC: β=0.04, CI=[-0.14, 0.24]; right HC: β=0.06, CI=[-0.13,0.25]). Discussion This study reveals that sex differences in VM are robust and influence functioning through negative symptoms in FEP. Given that males are typically overrepresented in psychosis samples, it is possible that male patients chiefly contribute to associations between negative symptoms and neurocognitive impairments observed in previous studies in which sex was not explicitly examined. Further, our results suggest that the role of the HC in memory may be differentially affected by sex. This second model was specific to FEP, indicating that certain structure-function relationships are not consistent between patients and controls. Overall, such findings highlight the need to consider sex differences when developing personalized treatment plans and highlight neurocognitive deficits as a promising avenue for treatment.

BackgroundIntegrity of hippocampal subfield structure and associated limbic circuitry subserves various memory processes, a domain that is impaired in psychosis and an important predictor of functional outcome. We use a novel atlas that encapsulates both hippocampal subfields and surrounding white matter (WM), forming the ‘memory circuit’, to assess volumes with high-resolution MRI, and microstructure with quantitative T1 (qT1). Our aims were to examine 1) group by time interactions on memory measures and the memory circuit, and 2) explore the relationships between the chosen memory measures and limbic structures, informed by results from 1), in a longitudinal sample of first episode of psychosis (FEP) patients.MethodsNineteen FEP and 20 controls with baseline and 3-month follow-up data were included. Logical Memory and Visual Reproduction Subscales of the Weschler Memory Scale, and MRI scans on a 3T scanner were collected. High-resolution T2-weighted images (0.64 mm3) were input to the MAGeT Brain algorithm to obtain volumes of hippocampal subfields and surrounding WM, defined by fimbria, alveus, fornix, and mammillary bodies. Mean qT1 values for each hippocampal subfield and WM structure were sampled from MP2RAGE (1 mm3) qT1 maps. Linear mixed models were used to assess group by time interactions on memory measures, volumes and qT1. To begin, total hippocampal volumes and WM structure for each hemisphere were examined using a Bonferroni correction for multiple comparisons, followed by post-hoc tests of individual subfields and WM structures. Linear models were then used to assess relationships between baseline memory and change in anatomical measures of interest in FEP. Models controlled for sex, education, age, and brain volume.ResultsSignificant group by time interactions emerged on bilateral mean WM qT1 (left: F1,65=9.3, p=.003; right: F1,65=10.6, p=.002), where it was found that within the FEP group, qT1 (relaxation time in ms) increased over the 3-month follow-up period. Looking at WM structures separately, the interaction was driven by qT1 changes in fimbria, fornix, and mammillary bodies bilaterally (p’s<.05). No significant group by time interactions were found with respect to volumes or memory, although a trend-like group by time interaction on right fornix volume was found (F1,64=5.6, p-uncorrected=.02). Finally, brain-behaviour relationships were explored, restricting our anatomical measure of interest to mean qT1 values within bilateral WM. Although no tests passed correction for multiple comparisons, there was a trend association between better delayed recall of Visual Reproduction and decreases in qT1 of combined WM on the right hemisphere (F1,11=3.72, p=.08), driven by changes in qT1 of the right fornix (F1,11=4.4, p=.06).DiscussionThis study reveals significant microstructural changes in WM output circuitry of the hippocampus shortly after a FEP. Specifically, increases in qT1 were found within fimbria, fornix, and mammillary bodies bilaterally. Given that T1 relaxation times are typical...