Negative symptoms have long been conceptualized as a core aspect of schizophrenia. They play a key role in the functional outcome of the disorder, and their management represents a significant unmet ...need. Improvements in definition, characterization, assessment instruments and experimental models are needed in order to foster research aimed at developing effective interventions. A consensus has recently been reached on the following aspects: a) five constructs should be considered as negative symptoms, i.e. blunted affect, alogia, anhedonia, asociality and avolition; b) for each construct, symptoms due to identifiable factors, such as medication effects, psychotic symptoms or depression, should be distinguished from those regarded as primary; c) the five constructs cluster in two factors, one including blunted affect and alogia and the other consisting of anhedonia, avolition and asociality. In this paper, for each construct, we report the current definition; highlight differences among the main assessment instruments; illustrate quantitative measures, if available, and their relationship with the evaluations based on rating scales; and describe correlates as well as experimental models. We conclude that: a) the assessment of the negative symptom dimension has recently improved, but even current expert consensus‐based instruments diverge on several aspects; b) the use of objective measures might contribute to overcome uncertainties about the reliability of rating scales, but these measures require further investigation and validation; c) the boundaries with other illness components, in particular neurocognition and social cognition, are not well defined; and d) without further reducing the heterogeneity within the negative symptom dimension, attempts to develop successful interventions are likely to lead to great efforts paid back by small rewards.
The negative symptoms of schizophrenia, which often appear earlier than any other symptom, are prominent and clinically relevant in the majority of patients. As a result, interest in their treatment ...has increased. Patients who exhibit significant negative symptoms have worse functional outcomes than those without, resulting in impairments in occupational, household, and recreational functioning, as well as difficulties in relationships. Yet treatment with currently available medications does not lead to any significant improvements in this core component of schizophrenia. An increased understanding of the pathophysiology underlying negative symptoms and the discovery of novel treatments that do not directly target dopamine offer the potential to develop therapies that may reduce negative symptoms and increase quality of life for patients. The current article will discuss the impact of negative symptoms, outline current measurement tools for the assessment of negative symptoms, and examine how these measures may be improved. Insights into the neural circuitry underlying negative symptoms will be discussed, and promising targets for the development of effective treatments for these symptoms will be identified. As more prospective, large-scale, randomized studies focus on the effects of treatments on negative symptoms, progress in this area is foreseeable. However, improvements in clinical assessment instruments, a better understanding of the underlying neural mechanisms, development of novel treatments with varied targets, and a greater focus on personalized treatment are all important to produce significant benefits for patients with negative symptoms of schizophrenia.
Abstract Background There is currently no standard of care for the treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. ...Methods Three (SunLyte WN25308, DayLyte WN25309 and FlashLyte NN25310) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the pre-specified criteria for the lack of efficacy and was declared futile. Key inclusion criteria were: age ≥18 years; DSM-IV-TR diagnosis of schizophrenia; score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale (PANSS) negative symptoms and disorganized thought factors; unaltered antipsychotic treatment and clinical stability. Following a 4-week prospective stabilization period, patients were randomized 1:1:1 to bitopertin or placebo once daily for 24 weeks (doses: bitopertin 5 and 10 mg DayLyte and bitopertin 10 and 20 mg FlashLyte). The primary efficacy endpoint was mean change from baseline in the PANSS Negative Symptom Factor Score (NSFS) at week 24. Results 605 and 594 patients were included in the intent-to-treat population in DayLyte and FlashLyte, respectively. At week 24, the mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in the PANSS NSFS and all other endpoints. Bitopertin was well tolerated. Conclusions These studies provide no evidence for superior efficacy of adjunctive bitopertin over placebo in patients with persistent predominant negative symptoms of schizophrenia, in any of the doses tested. SunLyte (WN25308; NCT01192880): https://clinicaltrials.gov/ct2/results?term=NCT01192880&Search=Search DayLyte (WN25309; NCT01192906): https://clinicaltrials.gov/ct2/results?term=NCT01192906&Search=Search FlashLyte (NN25310; NCT01192867): https://clinicaltrials.gov/ct2/results?term=NCT01192867&Search=Search
The impairments in social and vocational outcome that are common in schizophrenia are strongly related to the severity of impaired neurocognition. This observation led to the initiation of The NIMH's ...Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, which supports the development of pharmacological agents to improve cognition in schizophrenia. MATRICS addresses barriers to drug development through a number of activities, including the development of a consensus battery for measuring cognition in schizophrenia; the development of a consensus regarding the most promising molecular targets that should be the focus of drug development; the use of a joint meeting with representatives from the industry, academia, NIMH, and the U.S. Food and Drug Administration (FDA) to clarify guidelines for the design of clinical trials for cognition enhancing agents; and finally, to assist NIMH in developing its research agenda in this area.
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.
New advances in the understanding of schizophrenia etiology, course, and treatment have increased interest on the part of patients, families, advocates, and professionals in the development of ...consensus-defined standards for clinical status and improvement, including illness remission and recovery. As demonstrated in the area of mood disorders, such standards provide greater clarity around treatment goals, as well as an improved framework for the design and comparison of investigational trials and the subsequent evaluation of the effectiveness of interventions. Unlike the approach to mood disorders, however, the novel application of the concept of standard outcome criteria to schizophrenia must reflect the wide heterogeneity of its long-term course and outcome, as well as the variable effects of different treatments on schizophrenia symptoms. As an initial step in developing operational criteria, an expert working group reviewed available definitions and assessment instruments to provide a conceptual framework for symptomatic, functional, and cognitive domains in schizophrenia as they relate to remission of illness. The first consensus-based operational criteria for symptomatic remission in schizophrenia are based on distinct thresholds for reaching and maintaining improvement, as opposed to change criteria, allowing for alignment with traditional concepts of remission in both psychiatric and nonpsychiatric illness. This innovative approach for standardizing the definition for outcome in schizophrenia will require further examination of its validity and utility, as well as future refinement, particularly in relation to psychosocial and cognitive function and dysfunction. These criteria should facilitate research and support a positive, longer-term approach to studying outcome in patients with schizophrenia.
Abstract Recent attention has focused on negative symptoms as a target for new therapeutic approaches including pharmacological agents, medical devices, and psychosocial treatments. Each of these ...approaches requires an instrument for measuring the severity of negative symptoms as well as changes in severity over time. The instrument selected should provide coverage for the domains of negative symptoms; it should be sensitive to change; it should be reliable and relatively brief; and it should be useful for large international trials. These criteria were used to evaluate a number of older instruments including the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptoms Scale (PANSS), and the Negative Symptom Assessment Scale (NSA). Two newer scales, the Brief Negative Symptom Scale (BNSS) and the Clinical Assessment Interview for Negative Symptoms (CAINS) were developed following a National Institute of Mental Health consensus meeting and addressed some of the shortcomings of earlier instruments.
Abstract Clinical trials of pharmacological agents targeting negative symptoms in schizophrenia are reviewed. The focus is on trials that occurred in patients who were stable on an antipsychotic ...medication at entry to the trial. A small number of trials compared antipsychotics as monotherapy for negative symptoms. Although the data supporting amisulpride for negative symptoms is promising the trials have limitations and it is plausible that the advantages of amisulpride over placebo may result from effects on secondary negative symptoms. Among available agents, antidepressant medications may have effects in negative symptoms. Other promising agents include minocycline, glutamatergic agents, and alpha-7 nicotinic agents. More than 15 active trials are currently underway to evaluate new treatments for negative symptoms.
History of Psychopharmacology Braslow, Joel T; Marder, Stephen R
Annual review of clinical psychology,
05/2019, Volume:
15, Issue:
1
Journal Article
Peer reviewed
Open access
We live in an age of psychopharmacology. One in six persons currently takes a psychotropic drug. These drugs have profoundly shaped our scientific and cultural understanding of psychiatric disease. ...By way of a historical review, we try to make sense of psychiatry's dependency on psychiatric drugs in the care of patients. Modern psychopharmacology began in 1950 with the synthesis of chlorpromazine. Over the course of the next 50 years, the psychiatric understanding and treatment of mental illness radically changed. Psychotropic drugs played a major part in these changes as state hospitals closed and psychotherapy gave way to drug prescriptions. Our review suggests that the success of psychopharmacology was not the consequence of increasingly more effective drugs for discrete psychiatric diseases. Instead, a complex mix of political economic realities, pharmaceutical marketing, basic science advances, and changes in the mental health-care system have led to our current infatuation with psychopharmacology.
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