A systematic review and meta-analysis of neuroimaging studies examining synaptic density in individuals with psychotic spectrum disorders.

BACKGROUND: Psychotic disorders have long been considered neurodevelopmental disorders where excessive synaptic pruning and cortical volume loss are central to disease pathology. We conducted a systematic review of the literature to identify neuroimaging studies specifically examining synaptic density across the psychosis spectrum. METHODS: PRISMA guidelines on reporting were followed. We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science and The Cochrane Library from inception to December 8, 2023, and included all original peer-reviewed articles or completed clinical neuroimaging studies of any modality measuring synaptic density in participants with a diagnosis of psychosis spectrum disorder as well as individuals with psychosis-risk states. The NIH quality assessment tool for observational cohort and cross-sectional studies was used for the risk of bias assessment. RESULTS: Five studies (k = 5) met inclusion criteria, comprising n = 128 adults (psychotic disorder; n = 61 and healthy volunteers; n = 67 and specifically measuring synaptic density via positron emission tomography (PET) imaging of the synaptic vesicle glycoprotein 2 A (SV2A). Three studies were included in our primary meta-analysis sharing the same outcome measure of SV2A binding, volume of distribution (VT). Regional SV2A VT was reduced in psychotic disorder participants in comparison to healthy volunteers, including the occipital lobe (Mean Difference (MD)= -2.17; 95% CI: -3.36 to -0.98; P < 0.001 ), temporal lobe (MD: -2.03; 95% CI: -3.19 to -0.88; P < 0.001 ), parietal lobe (MD:-1.61; 95% CI: -2.85 to -0.37; P = 0.01), anterior cingulate cortex (MD= -1.47; 95% CI: -2.45 to -0.49; P = 0.003), frontal cortex (MD: -1.16; 95% CI: -2.18 to -0.15; P = 0.02), amygdala (MD: -1.36; 95% CI: -2.20 to -0.52, p = 0.002), thalamus (MD:-1.46; 95% CI:-2.46 to -0.46, p = 0.004) and hippocampus (MD= -0.96; 95% CI: -1.59 to -0.33; P = 0.003). CONCLUSIONS: Preliminary studies provide in vivo evidence for reduced synaptic density in psychotic disorders. However, replication of findings in larger samples is required prior to definitive conclusions being drawn. PROSPERO: CRD42022359018.

Depression in caregivers of patients with schizophrenia: a scoping review.

PURPOSE: Caregivers play a vitally important role in the lives of people with schizophrenia. However, their mental health can often be overlooked. In recent years, with increasing attention to mental health and wellness, common mental illness such as depression in caregivers of people with schizophrenia has received renewed attention. The purpose of this review was to consolidate and synthesize recent literature on (1) the prevalence of depression in caregivers of people with schizophrenia, (2) factors associated with depression in caregivers of people with schizophrenia, and (3) interventions that target depression in caregivers of people with schizophrenia. METHODS: A systematic search focusing on literature published between 2010 and 2022 was done to retrieve relevant articles from the following databases: Ovid MEDLINE, Ovid EMBASE, and Ovid Psych INFO. RESULTS: Twenty-four studies met inclusion criteria and were included in the review. Nine evaluated the prevalence of depression, 18 evaluated factors associated with depression in caregivers, and 6 examined interventions targeting depression. The prevalence of depression and depressive symptoms in samples of caregivers ranged between 12 and 40% across the studies. Females, especially mothers of people with schizophrenia, were more likely to experience depression, followed by younger caregivers. Several factors, including gender, interpersonal relationships, social support, stigma, literacy, and financial constraints, were identified as factors associated with depression in caregivers. Several interventions like yoga, emotional training, and psychoeducation were evaluated, and they showed a significant reduction in the level of depression and depressive symptoms experienced by the caregiver population. CONCLUSIONS: Depression in caregivers in this clinical population may be widespread and warrants further study. There are promising interventions that can target depression in caregivers. Well-designed longitudinal studies may help identify caregivers at risk of developing depression and further inform targets for intervention.

Metformin for the prevention of clozapine-induced weight gain: A retrospective naturalistic cohort study.

OBJECTIVE: Clozapine is presently the sole antipsychotic with an indication for treatment-resistant Schizophrenia, but is associated with significant weight gain and other metabolic aberrations. This retrospective chart review aimed to evaluate the effectiveness of adjunctive metformin in preventing clozapine-induced weight gain. METHODS: We conducted a retrospective chart review of patients newly initiated on clozapine at the Centre for Addiction and Mental Health in Canada, from November 2014 to April 2021. Our primary outcome was body weight at 6 and 12 months after clozapine initiation. Other metabolic parameters served as secondary outcomes. RESULTS: Among 396 patients (males: 71.5%, mean age: 42.8 years) initiated on clozapine, 69 were on metformin or prescribed it ≤3 months after clozapine initiation. The clozapine+metformin group demonstrated less weight gain compared with the clozapine-only group at 6 months (clozapine+metformin: -0.15 kg [SE = 1.08] vs. clozapine-only: 2.99 kg, SE = 0.54) and 12 months after clozapine initiation (clozapine+metformin: -0.67 kg, SE = 1.22 vs. clozapine-only: 4.72 kg, SE = 0.67). Adaptive changes were also observed for fasting glucose (F = 3.10, p = 0.046) and triglycerides (F = 8.56, p < 0.001) in the clozapine+metformin group compared with clozapine only. CONCLUSION: In this large retrospective naturalistic cohort study, co-prescription of clozapine and metformin was associated with less weight gain and related metabolic dysfunction at 6 and 12 months after initiation versus clozapine alone. These findings provide evidence for the effectiveness of metformin in preventing clozapine-induced weight gain; larger randomized controlled trials are needed to confirm these results.

Distinct profiles of psychological and neuropsychological functions underlying goal-directed pursuit in schizophrenia.

OBJECTIVES: Several components are known to underlie goal-directed pursuit, including executive, motivational and volitional functions. These were explored in schizophrenia spectrum disorders in order to identify subgroups with distinct profiles. METHODS: Multiple executive, motivational and volitional tests were administered to a sample of outpatients with schizophrenia spectrum diagnoses (n = 59) and controls (n = 63). Research questions included whether distinct profiles exist and whether some functions are impacted disproportionately. These questions were addressed via cluster analysis and profile analysis, respectively. RESULTS: Some such functions were significantly altered in schizophrenia while others were unaffected. Two distinct profiles emerged, one characterized by energizing deficits, reduced reward sensitivity and few subjective complaints; while another was characterized by markedly increased punishment sensitivity, intact reward sensitivity and substantial subjective reporting of avolitional symptoms and boredom susceptibility. CONCLUSION: These findings highlight the importance of considering distinct patterns of strengths and deficits in functions governing goal-directed pursuit in schizophrenia that demarcate identifiable subtypes. These distinctions have implications for treatment, assessment and research.

Investigating the predictors of happiness, life satisfaction and success in schizophrenia.

BACKGROUND: Previous studies have suggested that, despite marked functional impairments, remitted first episode patients with schizophrenia report levels of well-being that are comparable to healthy controls. The aim of the current study was to specifically evaluate self-reported happiness, life satisfaction and success in individuals with schizophrenia beyond their first-episode of psychosis, and to investigate the impact of symptoms and functioning on these subjective experiences. METHODS: Fifty-one schizophrenia patients and 56 matched healthy controls participated in the study. Factor scores were computed to compare happiness and life satisfaction and success (LSS) between groups. Hierarchical multiple regression analyses were conducted to investigate the predictive value of symptoms and functional impairments on patients' subjective reports of happiness and LSS. RESULTS: Schizophrenia participants endorsed lower levels of LSS compared to healthy controls, with no significant group differences in self-reported happiness. For patients with schizophrenia, motivation deficits and depressive symptoms predicted reductions in both happiness and LSS. CONCLUSIONS: Patients with schizophrenia do not report significant reductions in their subjective experience of happiness, but do endorse lower levels of life satisfaction and success. Further, the absence of a robust link between poor functioning and lower happiness or LSS serves to reaffirm the notion that functional status does not dictate whether an individual with schizophrenia experiences a sense of happiness, satisfaction or success in life.

Neurocognitive impairment in the deficit subtype of schizophrenia.

Schizophrenia is a heterogeneous disorder characterized by numerous diverse signs and symptoms. Individuals with prominent, persistent, and idiopathic negative symptoms are thought to encompass a distinct subtype of schizophrenia. Previous work, including studies involving neuropsychological evaluations, has supported this position. The present study sought to further examine whether deficit patients are cognitively distinct from non-deficit patients with schizophrenia. A comprehensive neurocognitive battery including tests of verbal memory, vigilance, processing speed, reasoning, and working memory was administered to 657 patients with schizophrenia. Of these, 144 (22 %) patients were classified as deficit patients using a proxy identification method based on severity, persistence over time, and possible secondary sources (e.g., depression) of negative symptoms. Deficit patients with schizophrenia performed worse on all tests of cognition relative to non-deficit patients. These patients were characterized by a generalized cognitive impairment on the order of about 0.4 standard deviations below that of non-deficit patients. However, when comparing deficit patients to non-deficit patients who also present with negative symptoms, albeit not enduring or primary, no group differences in cognitive performance were found. Furthermore, a discriminant function analysis classifying patients into deficit/non-deficit groups based on cognitive scores demonstrated only 62.3 % accuracy, meaning over one-third of individuals were misclassified. The deficit subtype of schizophrenia is not markedly distinct from non-deficit schizophrenia in terms of neurocognitive performance. While deficit patients tend to have poorer performance on cognitive tests, the magnitude of this effect is relatively modest, translating to over 70 % overlap in scores between groups.

Motivational deficits in major depressive disorder: Cross-sectional and longitudinal relationships with functional impairment and subjective well-being.

BACKGROUND: Many individuals with major depressive disorder present with prominent motivational deficits; however, the effect of these symptoms on functional outcomes in the illness remains unclear. METHOD: Individuals with major depression who participated in the Sequenced Treatment Alternatives to Relieve Depression study were included in the present investigation (N=1563). Motivational deficits were evaluated using a derived measure from the Hamilton Depression Rating Scale, while functioning was assessed using the Work and Social Adjustment Scale. Subjective outcomes were also evaluated using the Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: After treatment with citalopram, over 70% of participants continued to experience some degree of motivational deficits. These deficits were significantly associated with greater functional impairments both globally and in each domain of functioning evaluated. These symptoms were also linked to worse subjective outcomes such as overall life satisfaction and quality of life. Change in the severity of motivational deficits over time was significantly linked with changes in outcome. Motivational deficits continued to demonstrate a significant association with outcomes, even after controlling for potentially confounding variables such as duration of depressive episode and severity of other depressive symptoms. CONCLUSIONS: Motivational deficits are significantly linked to the functional impairment present in many people with major depression, just as they are in other psychiatric illnesses such as schizophrenia. A greater understanding of the underlying mechanisms of these motivational deficits in particular, beyond other depressive symptoms, is critical to the development of strategies aimed at enhancing functional recovery and improved subjective well-being.

Relationship between symptomatic improvement and overall illness severity in patients with schizophrenia.

BACKGROUND: Whether improvement on ratings of global illness severity is differentially associated with improvement in specific symptom domains in patients with schizophrenia is not well understood. The present study examined the independent relationships between improvement in specific symptom clusters and change in global impressions of illness severity. METHODS: This study included 589 patients with chronic schizophrenia who were assessed at baseline and after 6 months of antipsychotic treatment. Both clinicians and patients completed the Clinical Global Impressions-Severity of Illness Scale (CGI-S). Symptom severity was assessed using factor scores derived from the Positive and Negative Syndrome Scale. RESULTS: Change in illness severity ratings made by the clinician and those made by the patient demonstrated moderate overlap. Nearly half of the patients were evaluated as clinically improved during the 6-month period, as rated by the clinician, with less than a third of patients experiencing a reduction in illness severity as determined by both the clinician and themselves. Improvements in clinician-rated CGI-S scores were most strongly associated with reduction in positive symptom severity. In contrast, change in patient-rated CGI-S scores was not linked to reduction in positive symptoms but rather to improvement in depressive and anxiety symptoms. This latter finding remained in a subsample of patients with relatively preserved insight into illness, suggesting that lack of insight cannot account for these findings. Finally, reduction in positive symptoms beyond 2 to 3 points was found to be clinically meaningful. CONCLUSIONS: In conclusion, change in overall illness severity, as determined by clinicians, is not necessarily interchangeable with patients' view of improvement of their own clinical status. Moreover, changes in the 2 evaluations of illness severity are associated with changes in different symptom domains.

Motivation and Social Cognition in Patients with Schizophrenia.

Social cognition, referring to one's ability to perceive and process social cues, is an important domain in schizophrenia. Numerous studies have demonstrated that patients with schizophrenia have poorer performance on tests assessing social cognition relative to healthy comparison participants. However, whether variables such as motivation are related to performance on these tests in patients with schizophrenia is unclear. One thousand three-hundred and seventy-eight patients with schizophrenia completed the Facial Emotion Discrimination Task as a measure of emotional processing, a key facet of social cognition. Level of motivation was also evaluated in these patients using a derived measure from the Quality of Life Scale. The relationship between motivation and task performance was examined using bivariate correlations and logistic regression modeling, controlling for the impact of age and overall severity of psychopathology, the latter evaluated using the Positive and Negative Syndrome Scale. Motivation was positively related to performance on the social cognition test, and this relationship remained significant after controlling for potential confounding variables such as age and illness severity. Social cognition was also related to functioning, and the relationship was mediated by level of motivation. The present study found a significant relationship between motivation and performance on a test of social cognition in a large sample of patients with schizophrenia. These findings suggest that amotivation undermines task performance, or alternatively that poor social cognitive ability impedes motivation. Future studies evaluating social cognition in patients with schizophrenia should concurrently assess for variables such as effort and motivation.

The Effects of Video Games on Cognition and Brain Structure: Potential Implications for Neuropsychiatric Disorders.

Video games are now a ubiquitous form of entertainment that has occasionally attracted negative attention. Video games have also been used to test cognitive function, as therapeutic interventions for neuropsychiatric disorders, and to explore mechanisms of experience-dependent structural brain changes. Here, we review current research on video games published from January 2011 to April 2014 with a focus on studies relating to mental health, cognition, and brain imaging. Overall, there is evidence that specific types of video games can alter brain structure or improve certain aspects of cognitive functioning. Video games can also be useful as neuropsychological assessment tools. While research in this area is still at a very early stage, there are interesting results that encourage further work in this field, and hold promise for utilizing this technology as a powerful therapeutic and experimental tool.

Values in First-Episode Schizophrenia.

OBJECTIVE: Functional impairment continues to represent a major challenge in schizophrenia. Surprisingly, patients with schizophrenia report a level of happiness comparable with control subjects, even in the face of the prominent functional deficits, a finding at odds with evidence indicating a positive relation between happiness and level of functioning. In attempting to reconcile these findings, we chose to examine the issue of values, defined as affectively infused criteria or motivational goals used to select and justify actions, people, and the self, as values are related to both happiness and functioning. METHODS: Fifty-six first-episode patients in remission and 56 healthy control subjects completed happiness and values measures. Statistical analyses included correlations, analysis of variance, structural equation modelling, and smallest space analysis. RESULTS: Results indicated that patients with schizophrenia placed significantly greater priority on the value dimensions of Tradition (P = 0.02) and Power (P = 0.03), and significantly less priority on Self-direction (P = 0.007) and Stimulation, (P = 0.008). CONCLUSIONS: Essentially, people with schizophrenia place more emphasis on the customs and ideas that traditional culture or religion provide in conjunction with a decreased interest in change, which is at odds with the expectations of early adulthood. This value difference could be related to functional deficits. To this point, we have assumed that people hold to the same values that guided them before the illness' onset, but this may not be the case. Our study indicates that values differ in people with schizophrenia, compared with control subjects, even early in the illness and in the face of symptomatic remission.

Subtyping Schizophrenia by Treatment Response: Antipsychotic Development and the Central Role of Positive Symptoms.

We have recently proposed a model for subtyping schizophrenia based on antipsychotic (AP) treatment response. Evidence suggests that APs, both old and new, are comparable in terms of efficacy; however, one AP, clozapine, is uniquely effective in one subgroup of patients (that is, those with treatment-resistant schizophrenia [TRS]). This permits us to subdivide schizophrenia into 3 specific groups: AP responsive, clozapine responsive, and clozapine resistant. Here, we integrate this model with current criteria related to TRS and ultraresistant schizophrenia, the latter referred to in our model as clozapine resistant. We suggest several modifications to existing criteria, in line with current evidence and practice patterns, particularly emphasizing the need to focus on positive symptoms. While APs can favourably impact numerous dimensions related to schizophrenia, it is their effect on positive symptoms that distinguishes them from other psychotropics. Further, it is positive symptoms that are central to AP and clozapine resistance, and it is these people that place the greatest demands on acute and long-term inpatient resources. In moving AP development forward, we advocate specifically focusing on positive symptoms and capitalizing on the evidence we have of 3 subtypes of psychosis (that is, positive symptoms) based on treatment response, implicating 3 distinguishable forms of underlying pathophysiology. Conversely, pooling these groups risks obfuscating potentially identifiable differences. Such a position does not challenge the importance of dopamine D2 receptor blockade, but rather highlights the need to better isolate those other subgroups that require something more or entirely different.

What does schizophrenia teach us about antipsychotics?

OBJECTIVE: To examine how advances in our understanding of schizophrenia have shaped thinking about antipsychotics (APs) and their role in treatment. METHOD: Three specific developments in the field of schizophrenia are highlighted: advances in knowledge related to the earliest stages of schizophrenia, specifically the prodrome; reconceptualization of schizophrenia as an illness of multiple symptom domains; and greater clarification regarding the efficacy of clozapine and a new generation of APs. RESULTS: Evidence indicating that negative and cognitive symptoms are present during the prodrome suggests that intervention at the time of first-episode psychosis constitutes late intervention. The limited efficacy of APs beyond psychosis argues against a magic bullet approach to schizophrenia and for polypharmacy that is symptom domain-specific. Clozapine's unique, but limited, efficacy in treatment resistance supports subtyping schizophrenia based on treatment response. CONCLUSIONS: Advances in our understanding of schizophrenia have important implications regarding the current use of APs, expectations regarding response, and future drug development.

Clinical and functional outcomes in people with schizophrenia with a high sense of well-being.

Optimal outcome in schizophrenia is thought to include remission of symptoms, functional recovery, and improved subjective well-being. The present study examined the characteristics of individuals with schizophrenia who report being satisfied with their life in general. Individuals with schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness study were included in the present analysis. Approximately half of the individuals evaluated reported a high level of life satisfaction, even while many concurrently described themselves as at least moderately ill and experiencing moderate-severe symptoms and manifested severe functional deficits. Of all individuals evaluated, only about 1% experienced what was considered to be optimal outcome. Individuals with schizophrenia are able to experience a high level of life satisfaction, despite experiencing severe illness and functional deficits. Those involved in care should be aware that life satisfaction as an outcome is not necessarily associated with symptom remission and superior functioning.

Antipsychotic dosing: found in translation.

In the field of schizophrenia research, as in other areas of psychiatry, there is a sense of frustration that greater advances have not been made over the years, calling into question existing research strategies. Arguably, many purported gains claimed by research have been "lost in translation," resulting in limited impact on diagnosis and treatment in the clinical setting. There are exceptions; for example, we would argue that different lines of preclinical and clinical research have substantially altered how we look at antipsychotic dosing. While this story remains a work in progress, advances "found in translation" have played an important role. Detailing these changes, the present paper speaks to a body of evidence that has already shifted clinical practice and raises questions that may further alter the manner in which antipsychotics have been administered over the last 6 decades.

Daily activity patterns in remitted first-episode schizophrenia.

BACKGROUND: Impairment in community functioning is characteristic of many individuals with schizophrenia. Despite a wealth of literature documenting such functional impairments, how patients spend their time on a daily basis and the types of activities they engage in remains less clear. The present investigation set out to examine the daily activity patterns of remitted first-episode patients with schizophrenia. METHODS: Twenty-eight first-episode schizophrenia patients in symptomatic remission and twenty-eight age-, gender-, and education-matched healthy comparison subjects participated in the present study. The Day Reconstruction Method (DRM) was employed to evaluate daily life activities, while the Social and Occupational Functional Assessment Scale was used to for assessment of community functioning. Psychopathology was assessed using the Positive and Negative Syndrome Scale, depressed mood using the Calgary Depression Scale for Schizophrenia, and clinical insight using the Schedule for the Assessment of Insight. Neurocognition was also evaluated with the Brief Assessment of Cognition in Schizophrenia. RESULTS: First-episode schizophrenia patients experienced marked impairment in functioning, despite being in symptomatic remission. Patients and controls did not differ in the number of activities reported throughout their day. However, first-episode schizophrenia patients had significantly shorter days than comparison subjects and spent significantly less time engaged in non-passive (i.e., effortful) activities, which was related to poorer functional status. CONCLUSIONS: Individuals with first-episode schizophrenia and in symptomatic remission demonstrate decreased levels of non-passive activities and poorer functional outcomes. A better understanding of the underlying factors is very likely critical to the development of strategies aimed at enhancing functional recovery in schizophrenia.

An SMS text messaging intervention to improve clinical engagement in early psychosis: A pilot randomized-controlled trial.

Disengagement of youth with psychosis from Early Psychosis Intervention (EPI) services continues to be a significant barrier to recovery, with approximately one-third prematurely discontinuing treatment despite the ongoing need. The current pilot trial sought to evaluate the preliminary efficacy and feasibility of a weekly short message service (SMS) intervention to improve engagement in EPI services. This was a longitudinal single-blinded randomized control trial in which participants were assigned to receive either an active or sham SMS intervention over nine months. Sixty-one participants with early psychosis between the ages of 16 and 29 were enrolled, randomized, and received at least part of the intervention. Primary outcomes consisted of participant clinic attendance rates over the course of the intervention and clinician-rated engagement. Secondary measures included patient-rated therapeutic rapport, attitude toward medication, psychopathology, cognition, functioning, and intervention feedback from participants. Compared to the sham group, participants receiving the active intervention did not show improved appointment attendance rates; however, did exhibit some improvements in aspects of engagement, including improved clinician-rated availability, attitude toward medication, positive symptoms, avolition-apathy and social functioning. Thus, contrary to our hypotheses, digitally augmented care did not result in enhanced engagement in EPI services, as measured by clinic attendance, although with some indication that it may contribute to improved attitude toward medication and, potentially, medication adherence. Weekly SMS text messaging appeared to result in a pattern of engagement whereby individuals who were improving clinically attended appointments less often, possibly due to inadvertent use of the intervention to check in with clinicians. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04379349).

Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.

We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.

A systematic review of structural and functional magnetic resonance imaging studies on the neurobiology of depressive symptoms in schizophrenia spectrum disorders.

Depressive symptoms in Schizophrenia Spectrum Disorders (SSDs) negatively impact suicidality, prognosis, and quality of life. Despite this, efficacious treatments are limited, largely because the neural mechanisms underlying depressive symptoms in SSDs remain poorly understood. We conducted a systematic review to provide an overview of studies that investigated the neural correlates of depressive symptoms in SSDs using neuroimaging techniques. We searched MEDLINE, PsycINFO, EMBASE, Web of Science, and Cochrane Library databases from inception through June 19, 2023. Specifically, we focused on structural and functional magnetic resonance imaging (MRI), encompassing: (1) T1-weighted imaging measuring brain morphology; (2) diffusion-weighted imaging assessing white matter integrity; or (3) T2*-weighted imaging measures of brain function. Our search yielded 33 articles; 14 structural MRI studies, 18 functional (f)MRI studies, and 1 multimodal fMRI/MRI study. Reviewed studies indicate potential commonalities in the neurobiology of depressive symptoms between SSDs and major depressive disorders, particularly in subcortical and frontal brain regions, though confidence in this interpretation is limited. The review underscores a notable knowledge gap in our understanding of the neurobiology of depression in SSDs, marked by inconsistent approaches and few studies examining imaging metrics of depressive symptoms. Inconsistencies across studies' findings emphasize the necessity for more direct and comprehensive research focusing on the neurobiology of depression in SSDs. Future studies should go beyond "total score" depression metrics and adopt more nuanced assessment approaches considering distinct subdomains. This could reveal unique neurobiological profiles and inform investigations of targeted treatments for depression in SSDs.

Heterogeneity in functional connectivity: Dimensional predictors of individual variability during rest and task fMRI in psychosis.

BACKGROUND: Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. The aim of this study was to investigate the relationship between individual variability in functional connectivity during resting state and the performance of a social task and social and non-social cognition in a large sample of controls and individuals diagnosed with SSD. METHODS: Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global 'variability score'. Pairwise correlational distance was calculated as 1 - the correlation coefficient between a given pair of participants, and averaging distance from one participant to all other participants provided the mean correlational distance metric. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability. RESULTS: Group comparison between SSD and controls showed greater SSD MCD during rest (p = 0.00038), while no diagnostic differences were observed during task (p = 0.063). Hierarchical regression analyses demonstrated the persistence of a significant diagnostic effect during rest (p = 0.008), contrasting with its non-significance during the task (p = 0.50), after social cognition was added to the model. Notably, social cognition exhibited significance in both resting state and task conditions (both p = 0.01). CONCLUSIONS: Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes.