Abstract Negative symptoms, in particular motivational deficits, are reported as impediments to functional recovery in patients with schizophrenia. This study examined the prevalence of motivational ...deficits in patients early in the illness, and the impact these deficits have on community functioning. Patients with schizophrenia between the ages of 18 and 35 years, and within 5 years of initiating antipsychotic treatment were included in the present investigation (N = 166). The impact of motivation and cognition on concurrent and longitudinal functioning was evaluated. Motivational impairments were found in more than 75% of participants, and were not associated with receipt of social support. These deficits served as the most robust and reliable predictor of functional outcome, while neurocognition demonstrated significantly weaker associations with outcome. When considered together, motivational deficits demonstrated a reliable link with concurrent and longitudinal functioning, with cognition not offering any independent predictive value. Moreover, motivation was found to mediate the relationship between cognition and outcome. Changes in motivation were linked to changes in functioning; however, this was not the case for changes in cognitive performance. Motivation emerged as a significant predictor of functioning even after selected demographic and clinical characteristics (e.g., positive symptoms) were accounted for. These data indicate that motivational deficits are prevalent in patients with schizophrenia, even in the early stages of the illness, and these deficits stand as one of the most robust barriers to people with schizophrenia achieving functional recovery. Greater understanding of the mechanisms underlying these deficits is critical to effective treatment innovation.
Abstract Negative symptoms have long been recognized as a central feature of the phenomenology of schizophrenia, dating back to the early descriptions by Kraepelin and Bleuler. Over the ensuing ...century, there have been important clarifications and reconceptualizations regarding the phenomenology of negative symptoms in schizophrenia. This review explores these developments, including the delineation of two underlying subdomains of negative symptoms – amotivation (i.e., avolition/apathy and asociality) and diminished expression (i.e., poverty of speech and affective flattening). Further, advances in our understanding of specific motivational and hedonic deficits seen in schizophrenia are explored. The findings that negative symptoms stand apart from depressive and cognitive symptoms in schizophrenia are also discussed. In terms of the predictors of functional outcomes in schizophrenia, we explore both the direct role of negative symptoms in this regard, as well as their indirect role through cognition. We then broaden our examination of negative symptoms to related disorders across the schizophrenia spectrum, as well as to other neuropsychiatric illnesses, where negative symptoms have been increasingly recognized. We explore the differential characteristics of negative symptoms across these illnesses, and their relevance to functional outcomes. This transdiagnostic presence and relevance of negative symptoms highlights the need for continued exploration of their phenomenology and neurobiology as we move to develop effective interventions to address these debilitating symptoms and improve functional outcomes.
Although some studies have suggested that relapse may be associated with antipsychotic treatment resistance in schizophrenia, the number and quality of studies is limited. The current analysis ...included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse (i.e., second episode) in association with non-adherence; and (5) reintroduction of antipsychotic treatment with the same agent used to achieve response in the first episode. The following outcomes were used as an index of antipsychotic treatment response: changes in the brief psychiatric rating scale (BPRS) total and positive symptom scores and number of patients who achieved positive symptom remission and 20 and 50% response. A total of 130 patients were included in the analyses. Although all patients took the same antipsychotic in both episodes, there were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode (50% response rate: 48.7 vs. 10.4% at week 7; 88.2 vs. 27.8% at week 27, respectively). Although antipsychotic doses in the second episode were significantly higher than those in the first episode, results remained unchanged after adjusting for antipsychotic dose. The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia.
Treatment-resistant schizophrenia (TRS) occurs in approximately 30% of individuals diagnosed with schizophrenia. The identification and management of TRS in clinical practice are inconsistent and not ...evidence based. No established clinically relevant criteria for defining and treating TRS exist, although guidelines have been promulgated for clozapine use among TRS patients. This report summarizes the consensus from a roundtable that focused on defining and identifying TRS, pathways to treatment resistance, current treatments, unmet needs, and disease burden. Nine clinical experts in schizophrenia and TRS participated in a closed meeting on June 23, 2017, sponsored by Lundbeck, at which published literature in key areas of TRS research was reviewed. The findings from published studies were synthesized by experts in each area and presented to the group for review and discussion. It was agreed that inadequate response to 2 different antipsychotics, each taken with adequate dose and duration, is required to establish TRS. This recommendation is consistent with guidelines for clozapine use. For each trial, objective symptom measures should be used to assess treatment response, with medication adherence ensured. Once nonresponse is established (after ≥ 12 weeks for positive symptoms 2 trials of ≥ 6 weeks), the treatment plan should be reevaluated and alternative pharmacologic or nonpharmacologic treatments considered. With increased awareness, those involved in the care of patients with schizophrenia will be able to identify TRS earlier in its course, thus supporting more informed treatment decisions by clinicians, patients, and caregivers to reduce the overall disease burden.
Background:
It is commonly recommended that a switch to clozapine be implemented in the face of tardive dyskinesia, even if current treatment involves another “atypical” agent. However, reports do ...indicate clozapine carries a liability for tardive dyskinesia.
Aims:
This review sought to evaluate clozapine in relation to tardive dyskinesia in the context of available evidence.
Methods:
Medline, Embase, and PsycINFO databases were searched for studies published in English, using the keywords: clozapine AND tardive dyskinesia OR TD. References from major review articles were searched for additional relevant publications. Studies were included if they investigated: tardive dyskinesia in clozapine-treated patients diagnosed with schizophrenia spectrum disorders, and reported on two or more assessments of tardive dyskinesia severity measured by the Abnormal Involuntary Movement Scale; or clozapine’s tardive dyskinesia liability.
Results:
In total, 513 unique citations were identified and 29 reports met the inclusion criteria. Thirteen studies suggest clozapine reduces dyskinetic symptoms over time (n=905 clozapine-treated participants); however, the minimum required dose and effect of withdrawal requires further investigation. The majority of reports which address clozapine’s liability for tardive dyskinesia are case studies (11 of 14 reports, 79%), and clozapine was only the first-line treatment in one of the remaining three studies reporting treatment-emergent dyskinetic symptoms with clozapine in 12% of patients. No significant between-drug differences were identified comparing clozapine’s risk to other atypical antipsychotics.
Conclusions:
Research to date supports switching to clozapine for the purpose of reducing tardive dyskinesia risk and/or treating existing tardive dyskinesia, but prospective randomized controlled trials are necessary if we are to substantiate existing recommendations.
Abstract Background Motivational impairments are a core feature of schizophrenia and although there are numerous reports studying this feature using clinical rating scales, objective behavioural ...assessments are lacking. Here, we use a translational paradigm to measure incentive motivation in individuals with schizophrenia. Methods Sixteen stable outpatients with schizophrenia and sixteen matched healthy controls completed a modified version of the Effort Expenditure for Rewards Task that accounts for differences in motoric ability. Briefly, subjects were presented with a series of trials where they may choose to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Additionally, the probability of receiving money for a given trial was varied at 12%, 50% and 88%. Clinical and other reward-related variables were also evaluated. Results Patients opted to expend greater effort significantly less than controls for trials of high, but uncertain (i.e. 50% and 88% probability) incentive value, which was related to amotivation and neurocognitive deficits. Other abnormalities were also noted but were related to different clinical variables such as impulsivity (low reward and 12% probability). These motivational deficits were not due to group differences in reward learning, reward valuation or hedonic capacity. Conclusions Our findings offer novel support for incentive motivation deficits in schizophrenia. Clinical amotivation is associated with impairments in the computation of effort during cost-benefit decision-making. This objective translational paradigm may guide future investigations of the neural circuitry underlying these motivational impairments.
Abstract Negative symptoms, particularly amotivation/apathy, are intimately tied to functional outcomes. In the present study, apathy strongly predicted psychosocial functioning in a sample of early ...course schizophrenia patients. This relationship remained robust even after controlling for other clinical variables. These data suggest amotivation is core to functioning across the disease course.
Motivational and cognitive deficits are core features of schizophrenia, both closely linked with functional outcomes. Although poor effort and decreased motivation are known to affect performance on ...cognitive tests, the extent of this relationship is unclear in patients with schizophrenia.
To evaluate the association between intrinsic motivation and cognitive test performance in patients with schizophrenia.
Cross-sectional and 6-month prospective follow-up study performed at 57 sites in the United States, including academic and community medical treatment centers, participating in the Clinical Antipsychotic Trials of Intervention Effectiveness study. The primary sample included 431 stable patients with a DSM-IV diagnosis of schizophrenia currently receiving a stable medication regimen.
Cognitive performance and intrinsic motivation were evaluated using a comprehensive neuropsychological test battery and a derived measure from the Heinrichs-Carpenter Quality of Life Scale, respectively. Symptom severity and functional status were also assessed.
The primary outcome variable was global neurocognition. Individual domains of cognition were also evaluated for their association with motivation.
Level of intrinsic motivation was significantly and positively correlated with global cognitive test performance, a relationship that held for each domain of cognition evaluated (correlation range, 0.20-0.34; P < .001). This association was found to be reliable after statistically accounting for positive, negative, depressive, and overall symptom severity (P < .05) and after accounting for community functioning (P < .001). The relationship between motivation and cognitive performance also remained significant after controlling for antipsychotic dose (P < .05). Prospective increase in motivation during the 6-month follow-up was also found to be significantly related to improvement in global cognitive performance (P < .05).
The present findings provide strong support for a robust and reliable relationship between motivation and cognitive performance and suggest that test performance is not purely a measure of ability. Future studies assessing cognition in patients with schizophrenia should consider potential moderating variables such as effort and motivation. Implications for the assessment and interpretation of cognitive impairment based on neuropsychological test measures in schizophrenia are discussed, especially in the case of clinical trials for cognition-enhancing treatments.
clinicaltrials.gov Identifier: NCT00014001.
The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and ...their shift from ‘typical’ to ‘atypical’. Atypicality is reviewed in reference to its original definition, clozapine’s role, and developments that now leave the concept’s utility in question. In a similar fashion, drug development is reviewed in the context of the illness’ multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness’ heterogeneity and complexity. Just as ‘atypical’ as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat ‘schizophrenia’.
How antipsychotics should be initiated/titrated in patients with acute schizophrenia as well as patients undergoing an antipsychotic switch remains a question.
MEDLINE, Embase, and Cochrane Central ...Register of Controlled Trials were systematically searched. Randomized controlled trials examining rapid vs. slow antipsychotic initiation in patients with schizophrenia were selected. Data on study discontinuation, psychopathology, extrapyramidal symptoms (EPS), and treatment-emergent adverse events (TEAEs) were extracted and synthesized in studies including clinically different populations of acute patients and stable patients undergoing an antipsychotic switch.
Among 11 studies that met eligibility criteria, 8 and 3 studies involving 809 and 777 patients were identified as acute patient studies and stable patient switching studies, respectively. Rapid antipsychotic initiation was not significantly different from slow antipsychotic initiation in acute patient studies for all-cause study discontinuation, while the former was significantly inferior to the latter in stable patient switching studies (N=3, n=777, RR=1.45, 95% CI=1.05–2.00, P=0.02). In contrast, rapid initiation was significantly superior to slow initiation for all psychopathology outcomes including the PANSS/BPRS total score (N=3, n=336, SMD=−0.28, 95% CI=−0.51–−0.05, P=0.02) in acute patient studies, but not different in stable patient switching studies. Any other outcomes except for nausea did not significantly differ between the 2 groups.
Rapid initiation of antipsychotics may represent a reasonable option for the treatment of acute schizophrenia, while slower initiation may be a safer strategy when switching antipsychotics in stable schizophrenia. Because of the low to very low quality of evidence, findings should be considered preliminary.
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