Bernard A. Fischer

The Brief Negative Symptom Scale: Psychometric Properties

The participants in the NIMH-MATRICS Consensus Development Conference on Negative Symptoms recommended that an instrument be developed that measured blunted affect, alogia, asociality, anhedonia, and avolition. The Brief Negative Symptom Scale (BNSS) is a 13-item instrument designed for clinical trials and other studies that measures these 5 domains. The interrater, test-retest, and internal consistency of the instrument were strong, with respective intraclass correlation coefficients of 0.93 for the BNSS total score and values of 0.89-0.95 for individual subscales. Comparisons with positive symptoms and other negative symptom instruments supported the discriminant and concurrent validity of the instrument.

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.

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.

Factor structure of the Brief Negative Symptom Scale.

The current study examined the factor structure of the Brief Negative Symptom Scale (BNSS), a next-generation negative symptom rating instrument developed in response to the NIMH-sponsored Consensus Development Conference on Negative Symptoms. Participants included 146 individuals with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder. Principal axis factoring indicated two distinct factors explaining 68.7% of the variance. Similar to previous findings, the factors reflected motivation and pleasure and emotional expressivity. These findings provide further support for the construct validity of the BNSS, and for the existence of these two negative symptom factors.

Will the Kraepelinian Dichotomy Survive DSM-V?

Kraepelin proposed dementia praecox and manic-depressive illness as the two major psychotic disorders. This paradigm is still prevalent, but observations of overlapping boundaries between bipolar disorder and schizophrenia challenge this dichotomy. However, the concept of schizophrenia has been radically altered from the original Kraepelinian proposal. We defend the two psychoses positions, but suggest two flaws in the heuristic application: (1) overlapping features, such as psychotic symptoms, are not decisive in differential diagnosis; and (2) each disorder is a syndrome, not a disease entity. An alternative paradigm based on domains of pathology is more powerful for studies of etiology, pathophysiology, and therapeutic discovery.

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.

Cortical structural abnormalities in deficit versus nondeficit schizophrenia

OBJECTIVE To examine the structural integrity of the dorsolateral prefrontal-basal ganglia-thalamocortical circuit in people with the deficit form of schizophrenia. METHOD A three-dimensional structural MRI sequence was used to conduct morphometric assessments of cortical and subcortical regions in deficit and nondeficit outpatients with schizophrenia and healthy controls. RESULTS The superior prefrontal and superior and middle temporal gyral gray matter volumes were significantly smaller in the deficit versus the nondeficit group and normal control groups. There were no significant group differences in examined subcortical structures. CONCLUSION People with deficit schizophrenia are characterized by selective reductions in the prefrontal and temporal cortex.

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 Minocyclines 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.

Revisiting the Diagnosis of Schizophrenia: Where have we been and Where are We Going?

Appropriate and reliable classification of mental illness is crucial for advancing the field of psychiatry as agreement on diagnosis has broad implications for treatment of mental disorders and research into the etiopathophysiology of mental disorders. Since schizophrenia was first recognized by Kraepelin (as dementia praecox), there has been much discussion about what does and does not diagnostically constitute the disorder. The importance placed upon different symptoms and course types associated with schizophrenia has been as heterogeneous as the disorder itself. This article focuses upon the classification of schizophrenia over the last 100 years, the current diagnosis of schizophrenia, changes for schizophrenia planned in the upcoming DSM 5, future directions for improving the diagnosis of schizophrenia, and the implications of a new diagnostic paradigm for the illness.

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.