Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

OBJECTIVE: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD). METHODS: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data. RESULTS: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time. CONCLUSION: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Impaired insight into illness is unrelated to subjective happiness, success, and life satisfaction in schizophrenia.

BACKGROUND: Impaired insight into illness is a common feature of schizophrenia. Improved insight is associated with better treatment adherence and clinical outcomes. At the same time, improving insight has been suggested to increase depressive symptoms and diminish quality of life. The aim of this study was to examine the associations between impaired insight and degree of subjective happiness, perceived level of success, and life satisfaction in patients with schizophrenia spectrum disorders. METHODS: A total of 108 participants with schizophrenia or schizoaffective disorder were included. Data for this study were obtained from our group's previous investigation that examined the relationship between impaired insight and visuospatial attention. Insight into illness was measured by the VAGUS scale, which assesses general illness awareness, accurate symptom attribution, awareness of the need for treatment, and awareness of the negative consequences attributable to the illness. RESULTS: Our results revealed no association among the VAGUS average and subscale scores and degree of subjective happiness, perceived level of success, and life satisfaction. CONCLUSIONS: Our study suggests that insight into illness is not related to subjective happiness, life satisfaction, or perceived level of success in patients with schizophrenia, which is in contrast to previous reports that demonstrate an association between insight into illness and depression.

Real-World Utilization Patterns of Long-Acting Injectable Antipsychotics in Canada: A Retrospective Study.

Objective: The objective of this study was to analyze the real-world prevalence of long-acting injectable (LAI) antipsychotic use and determine when LAIs are being used in sequencing of antipsychotic medications among Canadian patients with schizophrenia. Methods: This was a retrospective, longitudinal cohort study using Canadian pharmacy prescription data between August 2005 and June 2017. Patients with inferred schizophrenia spectrum disorder were indexed on the date of their first antipsychotic prescription and analyzed for minimum 12 months to track lines of antipsychotic therapy and LAI utilization. Results: A total of 16,300 patients were identified for analysis. 48.2% and 46.0% of index antipsychotic prescriptions were prescribed by a general practitioner/family medicine doctor and psychiatrist, respectively. 1,062 (6.5%) patients used an LAI during the study period. Of those patients, 789 used an LAI within two years of index (74.3% of LAI users; 4.8% of all patients). The majority of LAI use (62.0%) occurred in the third line of therapy or later. 65.0% of patients had tried at least two therapy lines, and most patients reported gaps of six months to one year between treatment lines. Conclusion: Despite their potential to reduce relapse in schizophrenia by improving treatment adherence, this study shows LAIs continue to be under-utilized in Canada. When used, LAIs are positioned late in sequencing of antipsychotic medications, often not initiated until years after diagnosis. Continued preference for oral APs with poor adherence may be negatively impacting prognosis and exacerbating burden of schizophrenia. Efforts should be invested to understand barriers to LAI uptake and advocate for earlier, widespread use of LAIs.

The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey.

BACKGROUND: It is well established that the different antipsychotics used for schizophrenia symptoms differ substantially in their side effects. However, relatively little is known about the impact of these side effects on functioning from the patient's perspective. We aimed to understand how key side effects of second-generation antipsychotics impact the functioning and quality of life (QoL) of patients with schizophrenia. METHODS: This is a cross-sectional, web-based survey of patient-reported side effect burden of antipsychotic drugs in adults with schizophrenia. The survey was deployed in the United States, Canada, Australia, Spain, Italy, Norway, and Denmark. It included sociodemographic and clinical questions, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), and the Glasgow Antipsychotic Side-Effect Scale (GASS). Eight pre-defined key side effects classified as activating ("Shaky hands or arms," "Restlessness," and "Difficulty sleeping"), sedating ("Sleepy during the day", "Feeling drugged or like a zombie," and "Feeling dizzy/Fainted") or other side effects ("Problems enjoying sex" and "Gaining weight"), and additional questions related to impacts on function and quality of life were asked. RESULTS: In total, 435 participants (mean age: 38 years, 53.8% female) were included. The total Q-LES-Q-SF score indicated overall medium satisfaction with their quality of life (score of 44.3; possible range 14-70). The most prevalent side effects were "Sleepy during the day" (83.2%), "Difficulty sleeping" (74.7%), "Dry mouth" (63.9%), "Problems enjoying sex" (53.4%) and "Gaining weight" (52.4%). Women reported the side effects of "Sleepy during the day", "Problems enjoying sex" and "Gaining weight" more frequently than men. Key side effects impacted physical, social, occupational and psychological aspects of functioning. Patients with key side effects often felt frustrated by their experiences. Total Q-LES-Q-SF score showed a significant inverse correlation with the score of pre-defined groups of side effects indicating worse QoL in association with more severe key side effects in these patients. CONCLUSION: Stable patients with schizophrenia taking second-generation antipsychotics live with many side effects, including activating and sedating side effects, sexual side effects, and weight gain. Presence of these side effects is associated with substantial impacts across all aspects of daily functioning and lower quality of life and satisfaction.

Correction to: The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: a worldwide, cross-sectional, web-based survey.

[This corrects the article DOI: 10.1186/s12991-020-00292-5.].

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.

One-year symptom trajectories in patients with stable schizophrenia maintained on antipsychotics versus placebo: meta-analysis.

BackgroundAs definitions of relapse differ substantially between studies, in investigations involving data aggregation, total scores on clinical rating scales provide a more generalisable outcome.AimsTo compare total symptom trajectories for antipsychotic versus placebo treatment over a 1-year period of maintenance treatment in schizophrenia.MethodRandomised controlled trials with antipsychotic and placebo treatment arms in patients with stable schizophrenia that reported Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale total scores at more than one time point were included. Meta-regression analyses were employed using a mixed model.ResultsA total of 11 studies involving 2826 patients were included. Meta-regression analyses revealed significant interactions between group and time (PS<0.0001); both standardised total scores and per cent score changes remained almost unchanged in patients continuing antipsychotic treatment, whereas symptoms continuously worsened over time in those switching to placebo treatment.ConclusionsWhen considering long-term antipsychotic treatment of schizophrenia, clinicians must balance symptomatic and functional outcomes.

What Is the Place of Clozapine in the Treatment of Early Psychosis in Canada?

Research and development of early intervention (EI) services for first-episode psychosis have brought much-needed transformation of service delivery for this serious mental disorder to many jurisdictions. The effectiveness of the EI model of service delivery is contingent on timely access to all evidence-informed treatment interventions, including a rational approach to pharmacotherapy. In this perspective paper, we present a brief review of the well-established effectiveness of clozapine in patients who clearly show lack of response to regular antipsychotic therapy. We concentrate, in particular, on the need to identify eligibility for clozapine therapy very early on following failure of treatment on 2 antipsychotic medications. We suggest that attention to the low use of clozapine in the very early phase of treatment of psychosis may be of particular value, as the response to clozapine at this stage is likely to produce larger benefits in other domains of outcomes because of the greater retention of patients' personal and social agency.

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.

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.

Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice.

Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management.

Characterization and prediction of individual functional outcome trajectories in schizophrenia spectrum disorders (PREDICTS study): Study protocol.

Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.