Hyperdeactivation of the Default Mode Network in People With Schizophrenia When Focusing Attention in Space.

When studying selective attention in people with schizophrenia (PSZ), a counterintuitive but replicated finding has been that PSZ display larger performance benefits than healthy control subjects (HCS) by cues that predicts the location of a target stimulus relative to non-predictive cues. Possible explanations are that PSZ hyperfocus attention in response to predictive cues, or that an inability to maintain a broad attentional window impairs performance when the cue is non-predictive. Over-recruitment of regions involved in top-down focusing of spatial attention in response to predictive cues would support the former possibility, and an inappropriate recruitment of these regions in response to non-predictive cues the latter. We probed regions of the dorsal attention network while PSZ (N = 20) and HCS (N = 20) performed a visuospatial attention task. A central cue either predicted at which of 4 peripheral locations a target signal would appear, or it gave no information about the target location. As observed previously, PSZ displayed a larger reaction time difference between predictive and non-predictive cue trials than HCS. Activity in frontoparietal and occipital regions was greater for predictive than non-predictive cues. This effect was almost identical between PSZ and HCS. There was no sign of over-recruitment when the cue was predictive, or of inappropriate recruitment when the cue was non-predictive. However, PSZ differed from HCS in their cue-dependent deactivation of the default mode network. Unexpectedly, PSZ displayed significantly greater deactivation than HCS in predictive cue trials, which may reflect a tendency to expend more processing resources when focusing attention in space.

Adjunctive Minocycline in Clozapine-Treated Schizophrenia Patients With Persistent Symptoms.

OBJECTIVE: Clozapine is the most effective antipsychotic for treatment refractory people with schizophrenia, yet many patients only partially respond. Accumulating preclinical and clinical data suggest benefits with minocycline. We tested adjunct minocycline to clozapine in a 10-week, double-blind, placebo-controlled trial. Primary outcomes tested were positive, and cognitive symptoms, while avolition, anxiety/depression, and negative symptoms were secondary outcomes. METHODS: Schizophrenia and schizoaffective participants (n = 52) with persistent positive symptoms were randomized to receive adjunct minocycline (100 mg oral capsule twice daily; n = 29) or placebo (n = 23). RESULTS: Brief Psychiatric Rating Scale (BPRS) psychosis factor (P = 0.098; effect size [ES], 0.39) and BPRS total score (P = 0.075; ES, 0.55) were not significant. A change in total BPRS symptoms of more than or equal to 30% was observed in 7 (25%) of 28 among minocycline and 1 (4%) of 23 among placebo participants, respectively (P = 0.044). Global cognitive function (MATRICS Consensus Cognitive Battery) did not differ, although there was a significant variation in size of treatment effects among cognitive domains (P = 0.03), with significant improvement in working memory favoring minocycline (P = 0.023; ES, 0.41). The Scale for the Assessment of Negative Symptoms total score did not differ, but significant improvement in avolition with minocycline was noted (P = 0.012; ES, 0.34). Significant improvement in the BPRS anxiety/depression factor was observed with minocycline (P = 0.028; ES, 0.49). Minocycline was well tolerated with significantly fewer headaches and constipation compared with placebo. CONCLUSIONS: Minocycline's effect on the MATRICS Consensus Cognitive Battery composite score and positive symptoms were not statistically significant. Significant improvements with minocycline were seen in working memory, avolition, and anxiety/depressive symptoms in a chronic population with persistent symptoms. Larger studies are needed to validate these findings.

Integrating frequency and magnitude information in decision-making in schizophrenia: An account of patient performance on the Iowa Gambling Task.

BACKGROUND: The Iowa Gambling Task (IGT; Bechara et al., 1994) has frequently been used to assess risky decision making in clinical populations, including patients with schizophrenia (SZ). Poor performance on the IGT is often attributed to reduced sensitivity to punishment, which contrasts with recent findings from reinforcement learning studies in schizophrenia. METHODS: In order to investigate possible sources of IGT performance deficits in SZ patients, we combined data from the IGT from 59 SZ patients and 43 demographically-matched controls with data from the Balloon Analog Risk Task (BART) in the same participants. Our analyses sought to specifically uncover the role of punishment sensitivity and delineate the capacity to integrate frequency and magnitude information in decision-making under risk. RESULTS: Although SZ patients, on average, made more choices from disadvantageous decks than controls did on the IGT, they avoided decks with frequent punishments at a rate similar to controls. Patients also exhibited excessive loss-avoidance behavior on the BART. CONCLUSIONS: We argue that, rather than stemming from reduced sensitivity to negative consequences, performance deficits on the IGT in SZ patients are more likely the result of a reinforcement learning deficit, specifically involving the integration of frequencies and magnitudes of rewards and punishments in the trial-by-trial estimation of expected value.

In vivo assessment of neurotransmitters and modulators with magnetic resonance spectroscopy: application to schizophrenia.

In vivo measurement of neurotransmitters and modulators is now feasible with advanced proton magnetic resonance spectroscopy ((1)H MRS) techniques. This review provides a basic tutorial of MRS, describes the methods available to measure brain glutamate, glutamine, γ-aminobutyric acid, glutathione, N-acetylaspartylglutamate, glycine, and serine at magnetic field strengths of 3T or higher, and summarizes the neurochemical findings in schizophrenia. Overall, (1)H MRS holds great promise for producing biomarkers that can serve as treatment targets, prediction of disease onset, or illness exacerbation in schizophrenia and other brain diseases.

Risk-taking in schizophrenia and controls with and without cannabis dependence.

BACKGROUND: Risk-based decision making is altered in people with schizophrenia and in people with cannabis use compared to healthy controls; the pattern of risk-assessment in people with co-occurring schizophrenia and cannabis dependence is poorly understood. This study examined measures of risk-taking and decision-making in people with and without schizophrenia and/or cannabis dependence. METHODS: Participants with schizophrenia (n=24), cannabis dependence (n=23), schizophrenia and co-occurring cannabis dependence (n=18), and healthy controls (n=24) were recruited from the community via advertisements and completed a one-visit battery of symptom, risk-based decision making, gambling behavior, cognitive, and addiction assessments. This report presents self-assessments of self-mastery, optimism, impulsivity, and sensation seeking and a behavioral assessment of risk (Balloon Analog Risk Task [BART]). RESULTS: On self-report measures, participants with schizophrenia and co-occurring cannabis dependence were intermediate between those with only cannabis dependence or only schizophrenia on ratings of self-mastery, sensation-seeking, and impulsivity. There were no group differences on ratings of optimism. Their behavior on the BART was most similar to participants with only cannabis dependence or healthy controls, rather than to participants with only schizophrenia. CONCLUSIONS: People with schizophrenia and co-occurring cannabis dependence may represent a unique group in terms of risk-perception and risk-taking. This has implications for interventions designed to influence health behaviors such as motivational interviewing.

Meta-Analysis of Efficacy of Mirtazapine as an Adjunctive Treatment of Negative Symptoms in Schizophrenia.

CONTEXT: Despite advances made in treating the positive symptoms of schizophrenia, treatment of negative symptoms remains an unmet therapeutic need. Adjunctive mirtazapine has shown promise for treatment of negative symptoms in several small clinical trials. OBJECTIVE: To assess the efficacy of mirtazapine as an adjunctive treatment of negative symptoms in patients with chronic schizophrenia via meta-analysis. DATA SOURCES: A systematic literature review of articles in English and Spanish was conducted in November 2011 by searching PubMed, the Cochrane Library, the Clinical Trial Registry of the NIH, and SIGLE (System for Grey Literature in Europe). Free text search terms for PubMed were "schizophrenia," "negative symptoms" and "mirtazapine." Publication date was not a limitation. STUDY SELECTION: Studies of people with schizophrenia/schizoaffective disorder were included in the meta-analysis if they were randomized, double-blind, and used the Positive and Negative Syndrome Scale (PANSS) as an outcome measure. Nine studies were initially identified. Five studies were included in the meta-analysis; 1 study was excluded for not using the PANSS, 3 were excluded as representing duplicate publications and open-label phases of one of the selected randomized control trials. Studies varied in the quality of their selection for participants with primary negative symptoms. RESULTS: Three of the 5 studies showed significant improvement in negative symptoms individually. The overall analysis showed improvement in negative symptoms with an effect size of 1.00 (0.084-1.918), which was statistically significant (p=0.032). Data from the negative symptoms subscale of the PANSS from 169 subjects was used in a forest plot to illustrate the relative strength of treatment effects. The variation in standard median deviation (SMD) attributable to heterogeneity was 27.35 %, indicating a high degree of heterogeneity. CONCLUSIONS: This meta-analysis supports the hypothesis that adding mirtazapine to treatment with antipsychotics can improve negative symptoms in schizophrenia. However, additional studies with more stringent negative symptom selection criteria and homogeneous use of antipsychotics are needed.

Community adherence to schizophrenia treatment and safety monitoring guidelines.

The 2003 Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations and the Mount Sinai Conference Safety Monitoring recommendations generated guidelines for pharmacological treatment of schizophrenia and monitoring of antipsychotic side effects. This study examined rate of recommendation adherence and impact of adherence on outcomes of outpatients with schizophrenia or schizoaffective disorder in community mental health centers. Clinical practice was assessed as conformant, nonconformant, or not applicable. Treatment practices were conformant for antipsychotic dose (83%); use of antiparkinsonian (97%), antidepressant (100%), and antianxiety agents (90%) but not clozapine for residual positive symptoms (31%); and monitoring weight gain (48%), glucose dysregulation (53%), hyperlipidemia (34%), or extrapyramidal symptoms (11%). Community mental health center treatment practices were largely conformant with the 2003 Schizophrenia PORT treatment recommendations. There is less evidence that patients who receive treatment in the community are adequately monitored for antipsychotic side effects per the Mount Sinai recommendations.

Treating symptomatic hyperprolactinemia in women with schizophrenia: presentation of the ongoing DAAMSEL clinical trial (Dopamine partial Agonist, Aripiprazole, for the Management of Symptomatic ELevated prolactin).

Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.

Participants with schizophrenia retain the information necessary for informed consent during clinical trials.

OBJECTIVE: Cognitive impairment is a characteristic of schizophrenia. This impairment may affect the retention of information required for ongoing knowledgeable participation in clinical trials. This study monitored retention of study-related knowledge-including assessment of therapeutic misconception-in people with stable, DSM-IV schizophrenia during participation in placebo-controlled clinical trials of adjunctive agents. Stability was defined as being on an antipsychotic with no change in medication or dose over the previous 4 weeks. METHOD: This longitudinal study assessed retention of clinical trial-related consent information. Individuals enrolling in 1 of 8 clinical trials were approached for participation. Participants came from research clinics and community mental health centers. At baseline, clinical trial consent forms were reviewed and study knowledge assessed. Participants were randomized to follow-up assessments at weeks 1, 4, and 8; weeks 4 and 8; or at week 8 only. Clinical trial consent forms were not rereviewed at any follow-up visit. RESULTS: Fifty-nine participants were enrolled; analysis included 52 participants with at least 1 follow-up visit. Study knowledge did not decrease meaningfully in any group. Therapeutic misconception was not observed in participants during the study. The group assessed most frequently demonstrated significant improvement over baseline (t44 = 3.43, P = .001). Retention of study knowledge was not related to symptoms but had a weak correlation with cognitive capacity (R = 0.28, P = .07). Performance did not differ between participants from research clinics and those from community mental health centers. CONCLUSIONS: Clinically stable people with schizophrenia enrolling in a placebo-controlled adjunctive medication study, once determined to have capacity to consent to a clinical trial, retained appropriate study knowledge for at least 8 weeks. In the absence of a specific reason to suspect a loss of decisional capacity, there appears to be no need to routinely reevaluate participants during this type of clinical trial.

Deconstructing negative symptoms of schizophrenia: avolition-apathy and diminished expression clusters predict clinical presentation and functional outcome.

BACKGROUND: Previous studies indicate that negative symptoms reflect a separable domain of pathology from other symptoms of schizophrenia. However, it is currently unclear whether negative symptoms themselves are multi-faceted, and whether sub-groups of patients who display unique negative symptom profiles can be identified. METHODS: A data-driven approach was used to examine the heterogeneity of negative symptom presentations in two samples: Study 1 included 199 individuals with schizophrenia assessed with a standard measure of negative symptoms and Study 2 included 169 individuals meeting criteria for deficit schizophrenia (i.e., primary and enduring negative symptoms) assessed with a specialized measure of deficit symptoms. Cluster analysis was used to determine whether different groups of patients with distinct negative symptoms profiles could be identified. RESULTS: Across both studies, we found evidence for two distinctive negative symptom sub-groups: one group with predominantly Avolition-Apathy (AA) symptoms and another with a predominantly Diminished Expression (DE) profile. Follow-up discriminant function analyses confirmed the validity of these groups. AA and DE negative symptom sub-groups significantly differed on clinically relevant external validators, including measures of functional outcome, premorbid adjustment, clinical course, disorganized symptoms, social cognition, sex, and ethnicity. CONCLUSIONS: These results suggest that distinct subgroups of patients with elevated AA or DE can be identified within the broader diagnosis of schizophrenia and that these subgroups show clinically meaningful differences in presentation. Additionally, AA tends to be associated with poorer outcomes than DE, suggesting that it may be a more severe aspect of psychopathology.

Tacrolimus-induced paranoid delusions and fugue-like state.

We report the case of a 43 year old male with no prior psychiatric history with apparent tacrolimus-induced psychosis. Previous reports have identified other neurotoxic adverse effects due to tacrolimus, however, to our knowledge, there are few reports that describe psychosis induced by the immunosuppressant drug. Although psychosis may be a rare adverse effect, it can have significant impact on the long-term prognosis and treatment in transplant recipients. It is imperative to quickly identify patients who develop a mental status change while on tacrolimus and to work with the appropriate transplant team in managing these patients. Treatment usually calls for prompt discontinuation of tacrolimus, substituting with another immunosuppressant, and possible use of antipsychotics.

The role of social media networks in psychotic disorders: a case report.

We report the case of a young man diagnosed with schizophrenia who presented with stalking behaviors that may have been caused by problematic use or participation in social media networks (SMN). We review the possible role of SMN in the formation of his romantic delusion and offer suggestions for clinicians around incorporation of SMN questions into assessments. It is imperative to identify populations at risk of SMN-related stalking behaviors to stratify mental health resources and interventions. Additional studies are needed to further clarify the role of SMN in psychotic disorders.

A review of American psychiatry through its diagnoses: the history and development of the Diagnostic and Statistical Manual of Mental Disorders.

The history of the Diagnostic and Statistical Manual of Mental Disorders (DSM) reflects the larger history of American psychiatry. As the field anticipates DSM-5, it is useful to take stock of this history and consider not only how diagnosis impacts our understanding of mental illness but also how contemporary thought influences diagnosis. Before the DSM, the field was disjointed. The publication of the first American diagnostic manual, the precursor of the DSM, mirrored society's interest in organized record keeping and prevention rather than treatment of mental illness. The first and second editions of DSM brought a common language to diagnosis and were largely the work of outpatient and academic psychiatrists rather than those based in large state hospitals. The third edition of the DSM saw the shift in American psychiatry's leadership from the eminent clinician to the researcher, whereas the fourth edition reflected the rise of "evidence-based medicine." DSM-5 will likewise represent the current status of the field-not only with regard to science but also reflecting the place of American psychiatry in medicine today.

Maltreatment of people with serious mental illness in the early 20th century: a focus on Nazi Germany and eugenics in America.

Prejudice and stigma against people with mental illness can be seen throughout history. The worst instance of this prejudice was connected to the rise of the eugenics movement in the early 20th century. Although the Nazi German T-4 program of killing people with mental illness was the most egregious culmination of this philosophy, the United States has its own dark eugenics history-nearing a slippery slope all too similar to that of the Nazis. Mental health care clinicians need to examine this period to honor the memory of the victims of eugenics and to guarantee that nothing like this will ever happen again.

Next-generation negative symptom assessment for clinical trials: validation of the Brief Negative Symptom Scale.

The current study examined the psychometric properties of the Brief Negative Symptom Scale (BNSS), a next-generation rating instrument developed in response to the NIMH sponsored consensus development conference on negative symptoms. Participants included 100 individuals with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder who completed a clinical interview designed to assess negative, positive, disorganized, and general psychiatric symptoms, as well as functional outcome. A battery of anhedonia questionnaires and neuropsychological tests were also administered. Results indicated that the BNSS has excellent internal consistency and temporal stability, as well as good convergent and discriminant validity in its relationships with other symptom rating scales, functional outcome, self-reported anhedonia, and neuropsychological test scores. Given its brevity (13-items, 15-minute interview) and good psychometric characteristics, the BNSS can be considered a promising new instrument for use in clinical trials.