Demoralization in Schizophrenia: A Pathway to Suicidal Ideation?

Introduction: Individuals with schizophrenia are at increased risk for suicide, and the Demoralization Hypothesis states that non-delusional awareness of one's social, cognitive, or occupational deterioration elicits depression and hopelessness. Both depression and hopelessness are established risk factors for suicide and are features of schizophrenia. The present study investigated whether insight into one's schizophrenia yields suicidal ideation, specifically by way of thwarted belongingness and perceived burdensomeness, which are constructs related to demoralization and measured by the Interpersonal Needs Questionnaire (INQ). Methods: Three separate models explored the mediating role of INQ scores on suicidal ideation in 99 participants with schizophrenia. With suicidal ideation entered as the dependent variable and INQ scores entered as the mediator, the first model included insight as the independent variable, the second included cognitive functioning, and the third included cognitive deterioration post-illness-onset. Results: Consistent with our hypothesis, INQ scores related to suicidal ideation (B = .03, SE = .01, p < .001). However, neither insight, cognitive functioning, nor cognitive deterioration predicted INQ scores or suicidal ideation. Additionally, INQ scores did not mediate relationships with suicidal, ideation. Conclusion: Although INQ scores led to increased suicidal ideation, neither insight into illness, current cognitive functioning, nor shift in functioning led to increased INQ scores. Implications are discussed, and future directions are proposed.

Long-term effects of Roluperidone on negative symptoms of schizophrenia.

Roluperidone has antagonist properties for 5-HT2A, sigma2, α1A- and α1B-adrenergic receptors, but no dopaminergic binding affinities. In 2 randomized controlled trials (RCT), treatment improved negative symptoms of schizophrenia and social functioning among patients with moderate to severe negative symptoms. We report results of the protocol specified analysis of 2 open-label extension studies of 24 and 40 weeks investigating whether improvement of negative symptoms was sustained without significant adverse effects or worsening of psychosis. Following 12-week double-blind phase of both RCTs, patients were eligible to receive monotherapy roluperidone 32 mg/day or 64 mg/day for 24 weeks (trial 1) or 40 weeks (trial 2) in open-label extension study. Trial 1 included 244 patients of whom 142 entered 24-week open-label extension and trial 2 included 513 patients of whom 341 entered 40-week open-label extension. Trial 1 had PANSS negative factor score of Pentagonal Structure Model as primary outcome. Trial 2 had Marder Negative Symptoms Factor Score as primary outcome measure and Personal and Social Performance (PSP) Total score as secondary outcome. During open-label extensions, continued improvements in negative symptoms and on PSP were observed. Overall rate of symptomatic worsening requiring discontinuation of roluperidone and treatment with an antipsychotic was <10 %. Roluperidone was well tolerated with no meaningful changes in vital signs, laboratory values, weight gain, metabolic indices, or extrapyramidal symptoms. Results of 2 open-label extension trials support roluperidone as a treatment of negative symptoms and social functioning deficits in patients with moderate to severe negative symptoms of schizophrenia.

Remote Assessment of Negative Symptoms of Schizophrenia.

In contrast to the validated scales for face-to-face assessment of negative symptoms, no widely accepted tools currently exist for remote monitoring of negative symptoms. Remote assessment of negative symptoms can be broadly divided into 3 categories: (1) remote administration of an existing negative-symptom scale by a clinician, in real time, using videoconference technology to communicate with the patient; (2) direct inference of negative symptoms through detection and analysis of the patient's voice, appearance, or activity by way of the patient's smartphone or other device; and (3) ecological momentary assessment, in which the patient self-reports their condition upon receipt of periodic prompts from a smartphone or other device during their daily routine. These modalities vary in cost, technological complexity, and applicability to the different negative-symptom domains. Each modality has unique strengths, weaknesses, and issues with validation. As a result, an optimal solution may be more likely to employ several techniques than to use a single tool. For remote assessment of negative symptoms to be adopted as primary or secondary endpoints in regulated clinical trials, appropriate psychometric standards will need to be met. Standards for substituting 1 set of measures for another, as well as what constitutes a "gold" reference standard, will need to be precisely defined and a process for defining them developed. Despite over 4 decades of progress toward this goal, significant work remains to be done before clinical trials addressing negative symptoms can utilize remotely assessed secondary or primary outcome measures.

Feasibility and pilot efficacy results from the multisite Cognitive Remediation in the Schizophrenia Trials Network (CRSTN) randomized controlled trial.

BACKGROUND: The true benefit of pharmacologic intervention to improve cognition in schizophrenia may not be evident without regular cognitive enrichment. Clinical trials assessing the neurocognitive effects of new medications may require engagement in cognitive remediation exercises to stimulate the benefit potential. However, the feasibility of large-scale multisite studies using cognitive remediation at clinical trials sites has not been established. METHOD: 53 adult patients with DSM-IV schizophrenia from 9 university-affiliated sites were randomized to a cognitive remediation condition that included the Posit Science Brain Fitness auditory training program with weekly Neuropsychological and Educational Approach to Remediation (NEAR) "bridging groups" or a control condition of computer games and weekly healthy lifestyles groups. Patients were expected to complete 3 to 5 one-hour sessions weekly for 40 sessions or 12 weeks, whichever came first. The primary outcomes were feasibility results as measured by rate of enrollment, retention, and completion rate of primary outcome measures. The study was conducted from July 2009 through January 2010. RESULTS: During a 3-month enrollment period, 53 (of a projected 54) patients were enrolled, and 41 (77%) met criteria for study completion. Thirty-one patients completed all 40 sessions, and all patients completed all primary outcome measures. Preliminary efficacy results indicated that, after 20 sessions, patients in the cognitive remediation condition demonstrated mean MATRICS Consensus Cognitive Battery composite score improvements that were 3.7 (95% CI, 0.05-7.34) T-score points greater than in patients in the computer-games control group (F(1,46) = 4.16, P = .047). At the end of treatment, a trend favoring cognitive remediation was not statistically significant (F(1,47) = 2.26, P = .14). CONCLUSION: Multisite clinical trials of cognitive remediation using the Posit Science Brain Fitness auditory training program with the NEAR method of weekly bridging groups at traditional clinical sites appear to be feasible. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00930150.

Development of a brief scale of everyday functioning in persons with serious mental illness.

We developed and tested the validity of a brief scale to assess everyday functioning in persons with serious mental illness. A sample of 434 adults with schizophrenia or schizoaffective disorder were administered the University of California, San Diego, Performance-Based Skills Assessment (UPSA), which assesses functional skills in 5 areas of life functioning (eg, finances and planning). Through use of factor analysis, we developed the UPSA-Brief, which consists of 2 subscales (communication and financial) from the original UPSA. UPSA-Brief scores were correlated with cognitive functioning, symptoms of psychosis, age, and education. We further tested the sensitivity and specificity of the UPSA-Brief for predicting residential independence using receiver-operating characteristic (ROC) curves. Finally, sensitivity to change was assessed through comparison of 2 interventions for improving UPSA-Brief scores. UPSA-Brief scores were highly correlated with scores on the full version of the UPSA (r = .91), with overall cognitive functioning (r = .57), and with negative symptoms (r = -.32). The discriminant validity of the UPSA-Brief was adequate (ROC area under the curve [AUC] = 0.73; 95% confidence interval [CI]: 0.67-0.78), with greatest dichotomization for the UPSA-Brief at a cutoff score of 60. The UPSA-Brief was significantly better than the Dementia Rating Scale, Positive and Negative Syndromes Scale positive, and Positive and Negative Syndromes Scale negative at predicting residential independence (all P values < .05). Participants receiving a behavioral intervention also improved significantly compared with a support condition (P = .023). The UPSA-Brief has adequate psychometric properties, predicts residential independence, is sensitive to change, and requires only 10-15 minutes to administer. Therefore, the UPSA-Brief may be a useful performance-based functional outcome scale.

Real-world cognitive--and metacognitive--dysfunction in schizophrenia: a new approach for measuring (and remediating) more "right stuff".

While the role of impaired cognition in accounting for functional outcome in schizophrenia is generally established by now, the overlap is far from complete. Moreover, little is known about the potential mechanisms that bridge between cognition and functional outcome. The aim of this article is to aid in closing this gap by presenting a novel, more ecologically valid approach for neuropsychological assessment. The new approach is motivated by the view that metacognitive processes of self-monitoring and self-regulation are fundamental determinants of competent functioning in the real world. The new approach incorporates experimental psychological concepts and paradigms used to study metacognition into current standard neuropsychological assessment procedures. Preliminary empirical data that support and demonstrate the utility of the new approach for assessment, as well as remediation efforts, in schizophrenia are presented and discussed.

Neuropsychological performance in schizotypal personality disorder: importance of working memory.

BACKGROUND: Cognitive deficits consistently have been reported in schizophrenia patients and in patients with schizotypal personality disorder. For this study, the authors wanted to identify which of the domains of cognitive impairment represent "core" deficits of schizophrenia, comparing subjects with schizotypal personality disorder to two comparison groups: healthy volunteers and patients with personality disorders unrelated to schizophrenia. METHOD: Three groups completed a neuropsychological battery: patients with DSM-III-R schizotypal personality disorder (N=82); patients with DSM-III-R personality disorders unrelated to schizophrenia (i.e., a personality disorder other than schizotypal, schizoid, or paranoid [N=44]); and healthy volunteers (N=63). The battery included the California Verbal Learning Test, Trailmaking Test parts A and B, the Dot test of working memory, the Stroop Color and Word Test, the Paced Auditory Serial Addition Test, the WMS visual reproduction test, and the WAIS-R vocabulary and block design. RESULTS: Normative standards for performance that controlled for age, gender, and education were created from the scores of the healthy volunteers. Overall, schizotypal personality disorder patients performed significantly worse than the healthy volunteers and those with personality disorders unrelated to schizophrenia. Specifically, patients with schizotypal personality disorder demonstrated impaired performance on the Paced Auditory Serial Addition Test, WMS visual reproduction test, Dot test, and California Verbal Learning Test. In addition, in a regression analysis, performance on the Paced Auditory Serial Addition Test demonstrated the largest effect size. Indeed, it accounted for unique variance above and beyond all other cognitive measures, since controlling for Paced Auditory Serial Addition Test performance abolished group differences across all other measures. CONCLUSIONS: Patients with schizotypal personality disorder demonstrated moderate cognitive impairment compared with healthy volunteers (significant for seven out of 11 measures). These differences reached statistical significance for tasks of working memory, episodic memory, and delayed recall. Working memory performance accounted for the group differences. This study supports the view that working memory represents a core deficit of schizophrenia spectrum disorders.

Klinefelter's syndrome (XXY) as a genetic model for psychotic disorders.

Males with an extra-X chromosome (Klinefelter's syndrome) frequently, although not always, have an increased prevalence of psychiatric disturbances that range from attention deficit disorder in childhood to schizophrenia or severe affective disorders during adulthood. In addition, they frequently have characteristic verbal deficits. Thus, examining brain magnetic resonance imaging (MRI) scans of these individuals may yield clues to the influence of X chromosome genes on brain structural variation corresponding to psychiatric and cognitive disorders. Eleven adult XXY and 11 age matched XY male controls were examined with a structured psychiatric interview, battery of cognitive tests, and an MRI scan. Ten of eleven of the XXY men had some form of psychiatric disturbance, four of whom had auditory hallucinations compared with none of the XY controls. Significantly smaller frontal lobe, temporal lobe, and superior temporal gyrus (STG) cortical volumes were observed bilaterally in the XXY men. In addition, diffusion tensor imaging (DTI) of white matter integrity resulted in four regions of reduced fractional anisotropy (FA) in XXY men compared with controls, three in the left hemisphere, and one on the right. These correspond to the left posterior limb of the internal capsule, bilateral anterior cingulate, and left arcuate bundle. Specific cognitive deficits in executive functioning attributable to frontal lobe integrity and verbal comprehension were noted. Thus, excess expression of one or more X chromosome genes influences both gray and white matter development in frontal and temporal lobes, as well as white matter tracts leading to them, and may in this way contribute to the executive and language deficits observed in these adults. Future prospective studies are needed to determine which gene or genes are involved and whether their expression could be modified with appropriate treatments early in life. Brain expressed genes that are known to escape inactivation on extra-X chromosomes would be prime candidates.

Correlates of insight in first episode psychosis.

Impaired insight is common in schizophrenia and may be related to poor treatment adherence. Few studies have examined the clinical and neurocognitive correlates of insight in early schizophrenia. Early course schizophrenia, schizoaffective, and schizophreniform disorder patients (n=535) were studied. The Positive and Negative Symptom Scale (PANSS) was used to assess psychopathology, and a broad range of neuropsychological functions was assessed. Using hierarchical stepwise multiple regression analyses, we examined the association of clinical, neurocognitive, and premorbid measures with the level of insight. Impaired insight was associated with overall symptomatology, including positive, negative, and general psychopathology and with deficits in cognitive functioning. In descending order of robustness, the significant variables were PANSS general psychopathology (p<0.0001), Rey Auditory Verbal Learning Test (p<0.0004), Clinical Global Impression (p<0.005), PANSS positive (p<0.007), and premorbid adjustment-general subscale (p=0.02). Among the PANSS general psychopathology items, unusual thought content was most robustly associated with impaired insight (p<0.00000). Insight impairment is very common in early schizophrenia, and appears to be associated with a broad range of psychopathology and deficits in multiple cognitive domains. These observations suggest that deficits in insight may be related to a generalized dysfunction of neural networks involved in memory, learning, and executive functions.

Neuropsychological performance in schizotypal personality disorder: evidence regarding diagnostic specificity.

BACKGROUND: Individuals with schizotypal personality disorder (SPD) share cognitive deficits with schizophrenic patients, suggesting that these deficits represent a core feature of the schizophrenia spectrum. We investigated the neuropsychological profile in SPD patients compared with two comparison groups: healthy volunteers (HV) and patients who met criteria for another non-schizophrenia spectrum personality disorder (NSS). METHODS: We tested 48 DSM-III-R SPD patients, 22 NSS and 32 HV on a neuropsychologic battery that included the California Verbal Learning Test (CVLT), Trail Making A and B, the DOT test of working memory, the Stroop Color-Word Interference, the Paced Auditory Serial Addition Test (PASAT), the Wechsler Memory Scale Visual Reproduction Test (WMSV-R), and the Wechsler Adult Intelligence Scale vocabulary and block design. RESULTS: Normative standards for performance were created using the HV group. SPD patients performed significantly worse compared with HVs; specifically, SPD patients demonstrated impaired performance on the PASAT and the WMSV-R immediate and delayed recall compared to HV. Moreover, SPD patients were impaired in the PASAT and the WMSV-R immediate condition compared with the NSS group. The NSS patients did not differ from HV on any of the cognitive tasks. The interpersonal factor of the schizotypal symptoms inversely correlated with the PASAT score (r = -.32, p <.006). CONCLUSIONS: Compared with HVs, SPD patients demonstrate modest cognitive impairment. These differences reached statistical significance for the PASAT (an auditory working memory task), and the WMSV-R immediate and delayed recall (a learning-recall test). In contrast, performance of NSS patients did not differ from that of HVs. The types of deficits observed in SPD patients are qualitatively similar to but milder than those seen in patients with schizophrenia.