The Impact of Histologic Subtypes on Clinical Outcomes After Radiation-Based Therapy for Muscle-Invasive Bladder Cancer.

PURPOSE: Outcomes of radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC) with histologic subtypes of urothelial cancer (HS-UC) are lacking. Our objective was to compare survival outcomes of pure urothelial carcinoma (PUC) to HS-UC after RT. MATERIALS AND METHODS: A multicenter retrospective study of 864 patients with MIBC who underwent curative-intent RT to the bladder for MIBC (clinical T2-T4aN0-2M0) between 2001 and 2018 was conducted. Regression models were used to test the association between HS-UC and complete response (CR) and survival outcomes after RT. RESULTS: In total, 122 patients (14%) had HS-UC. Seventy-five (61%) had HS-UC with squamous and/or glandular differentiation. A CR was confirmed in 69% of patients with PUC and 63% with HS-UC. There were 207 (28%) and 31 (25%) patients who died of metastatic bladder cancer in the PUC and HS-UC groups, respectively. There were 361 (49%) and 58 (48%) patients who died of any cause in the PUC and HS-UC groups, respectively. Survival outcomes were not statistically different between the groups. The HS-UC status was not associated with survival outcomes in multivariable Cox regression analyses. CONCLUSIONS: In our study, HS-UC responded to RT with no significant difference in CR and survival outcomes compared to PUC. The presence of HS-UC in MIBC does not seem to confer resistance to RT, and patients should not be withheld from bladder preservation therapy options. Due to low numbers, definitive conclusions cannot be drawn for particular histologic subtypes.

Do larger cuff sizes with artificial urinary sphincter placement increase the risk of leakage after placement?

INTRODUCTION: To determine whether larger artificial urinary sphincters (AUS) cuff sizes of ≥ 5.0 cm have an impact on urinary incontinence after AUS implantation as compared to cuff sizes ≤ 4.5 cm. MATERIALS AND METHODS: A retrospective chart review of AUS implants performed at our institution from 1991 to 2021. Medical records were reviewed for demographics including body mass index (BMI), cause of incontinence, pelvic radiation, valsalva leak point pressure (VLPP), degree of leakage preoperatively and at 1-year post-AUS surgery, AUS revisions, erosion rate and the need for adjunct medication postoperatively. RESULTS: A total of 110 patients were included in the analysis. Of these, 44 patients had an AUS cuff size of ≥ 5.0 cm and 66 patients had a cuff size ≤ 4.5 cm. After AUS implantation at 1 year both groups had a median pad use of 1 pad per day. Lastly, the erosion rate was higher in the ≤ 4.5 cm cuff group (7.7% vs. 2.4%) but this was not statically significant. In all cases (6 patients) of cuff erosion, each patient had been radiated. CONCLUSION: AUS cuff sizes of ≥ 5.0 cm do not appear to have a negative impact on the degree of incontinence at 1-year post AUS as compared to those with cuff sizes ≤ 4.5 cm. The erosion rate was higher in those with cuffs ≤ 4.5 cm but was not statistically significant. This would suggest that at AUS implantation, the surgeon should choose a larger cuff if there is any doubt especially in those with radiation.

Anti-vaccination attitudes are associated with less analytical and more intuitive reasoning.

Online anti-vaccination rhetoric has produced far reaching negative health consequences. Persons who endorse anti-vaccination attitudes may employ less analytical reasoning when problem solving. Considering limitations in previous research, we used an online web-based survey (n = 760; mean age = 47.69; 388 males, 372 females) to address this question. Analytical reasoning was negatively correlated with anti-vaccination attitudes (r = -.18, p < .0001). This relationship remained significant after statistically controlling for potential confounders, including age, sex, education, and religiosity (r = -.16, p < .0001). We hope that elucidating the cognitive, non-information-based aspects of anti-vaccination attitudes will help to guide effective educational interventions aimed at improving public health in the future.

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia.

OBJECTIVE: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics. METHODS: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. RESULTS: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: ß = -.38, t = -2.48, P = .01; left: ß = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (ß = -.43, t = -0.26, P = .03). CONCLUSION: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit.

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.

Incidence of Antipsychotic-Associated Side Effects: Impact of Clinician Versus Patient Ratings and Change Versus Absolute Scores.

OBJECTIVE: This study aimed to compare (1) the detection rates of antipsychotic-associated side effects between clinician and patient ratings and (2) differences as a function of change and absolute score definitions. METHODS: Data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (N = 1460) were analyzed. In this trial, 18 adverse events were systematically and concurrently assessed by clinicians and patients using a 4-point severity scale ranging from 0 (absent) to 3 (severe). The incidence of antipsychotic-associated side effects was calculated according to 2 definitions: change score (ie, higher score on the scale versus baseline) and absolute score (a score of 2 or 3 on the scale). In addition, patient and clinician concurrent detection rates were examined. RESULTS: The differences in incidence of antipsychotic-associated side effects between clinician and patient ratings were as small as 5.7% across the 2 definitions. The incidence of all side effects across clinician and patient ratings was approximately 2 times higher when using the change versus absolute score definition. Among the side effects detected by patients, 11 side effects were identified more frequently by clinicians, with 14.3% to 30.2% differences when using the change versus absolute score definition. Conversely, there was no difference of 10% or greater in patient or clinician concurrent detection rate on any item when using the absolute versus change score definition. CONCLUSIONS: Our findings suggest that patient ratings are in line with clinician ratings and that the change score definition may be superior for the assessment of antipsychotic-associated side effects in clinical studies.

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.

Reduced insulin sensitivity is related to less endogenous dopamine at D2/3 receptors in the ventral striatum of healthy nonobese humans.

BACKGROUND: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [(11)C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. METHODS: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [(11)C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. RESULTS: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). CONCLUSION: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

Positive symptoms are associated with clinicians' global impression in treatment-resistant schizophrenia.

Previous investigations on the relationship between global rating measures and symptoms have not considered the additional role of functioning. In this naturalistic study, we examined the relationship between symptom domains and functioning on Clinical Global Impression scales for severity (CGI-S) and improvement (CGI-I) in a sample of patients with schizophrenia assessed to be treatment resistant. Participants were patients with a diagnosis of schizophrenia or schizoaffective disorder who failed 2 prior antipsychotic trials and were considered candidates for clozapine. They were assessed on the 18-item Brief Psychiatric rating Scale (BPRS), Social Occupational Functioning Assessment Scale (SOFAS), and CGI-S at baseline. A subset of patients was followed up at 6 weeks after initiation of clozapine and assessed on the CGI-I. The independent effects of symptom domains and functioning on the CGI scales were examined via multivariate regression models. Brief Psychiatric rating Scale positive factor (P < 0.001) and SOFAS (P < 0.001) scores were significant determinants of CGI-S at baseline. Multivariate models suggested that relative change measures had a better fit for the CGI-I compared to absolute change measures (R = 0.72 vs R = 0.61, respectively). Improvements in BPRS positive (P < 0.001) and affect (P = 0.002) factors and SOFAS (P = 0.030) scores were significant determinants of CGI-I. Ratings of 1 and 2 on the CGI-I corresponded to a mean relative change in the BPRS total of 65% and 41%, respectively. Positive symptoms were a key determinant of clinicians' impression of severity and improvement in this study. Although psychosocial functioning played a large part in determining severity, it was not as significant in the assessment of improvement.

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.

The Effect of Clozapine on Hematological Indices: A 1-Year Follow-Up Study.

Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and is linked to a need for mandatory hematological monitoring. Besides agranulocytosis, other hematological aberrations have resulted in premature termination in some cases. Considering clozapine's role in immunomodulation, we proceeded to investigate the impact of clozapine on the following 3 main hematological cell lines: red blood cells, platelets, white blood cells (WBCs), and its differential counts. Data were extracted from patients initiated on clozapine between January 2009 and December 2010 at a single hospital. Patients with a preclozapine complete blood count, who were receiving clozapine during the 1-year follow-up period, were included in the present investigation. Counts of red blood cells, platelets, WBC, and its differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils were extracted and trajectories plotted. One hundred one patients were included in this study and 66 remained on clozapine at the end of 1 year. There was a synchronized but transient increase in WBC, neutrophils, monocytes, eosinophils, basophils, and platelets beginning as early as the first week of clozapine treatment. There were no cases of agranulocytosis reported in this sample, and five developed neutropenia. A spike in neutrophils immediately preceded the onset of neutropenia in three of the five. The cumulative incidence rates were 48.9% for neutrophilia, 5.9% for eosinophilia, and 3% each for thrombocytosis and thrombocytopenia. Early hematological aberrations are visible across a range of cell lines, primarily of the myeloid lineage. These disturbances are transient and are probably related to clozapine's immunomodulatory properties. We do not suggest discontinuing clozapine as a consequence of the observed aberrations.

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.

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.

BACKGROUND AND OBJECTIVE: The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC. METHODS: Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation. KEY FINDINGS AND LIMITATIONS: Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42). CONCLUSIONS AND CLINICAL IMPLICATIONS: There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.