Ofer Agid

Incentive motivation deficits in schizophrenia reflect effort computation impairments during cost-benefit decision-making

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.

Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response-a double-blind PET study in schizophrenia

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

An Algorithm-Based Approach to First-Episode Schizophrenia: Response Rates Over 3 Prospective Antipsychotic Trials With a Retrospective Data Analysis

OBJECTIVE Early, effective treatment in first-episode schizophrenia is advocated, although evidence based on a systematic approach over multiple antipsychotic trials is lacking. Employing a naturalistic design, we examined response rates over 3 circumscribed antipsychotic trials. METHOD Between June 2003 and December 2008, 244 individuals with first-episode schizophrenia or schizoaffective disorder according to DSM-IV criteria were treated at the Centre for Addiction and Mental Health, Toronto, Ontario, Canada, following an algorithm that moved them through 2 antipsychotic trials, followed by a trial with clozapine. For the first 2 trials, treatment consisted of risperidone followed by olanzapine, or vice versa; each trial consisted of 3 stages (low-, full-, or high-dose) lasting up to 4 weeks at each level and adjusted according to response/tolerability. Clinical response was defined as a Clinical Global Impressions-Improvement score of 2 (much improved) or 1 (very much improved) and/or a Brief Psychiatric Rating Scale Thought Disorder subscale score ≤ 6. Data were analyzed retrospectively, and publication of anonymized clinical data was approved by the Research Ethics Board of the Centre for Addiction and Mental Health in May 2003. RESULTS In trial 1, 74.5% of individuals responded, with rates significantly higher for olanzapine (82.1%, 115/140) versus risperidone (66.3%, 69/104; P = .005). With trial 2, response rate dropped dramatically to 16.6% but again was significantly higher for olanzapine (25.7%, 9/35) compared to risperidone (4.0%, 1/25; P = .04). Response rate climbed above 70% once more, specifically 75.0% (21/28), in those individuals who agreed to a third trial with clozapine. CONCLUSIONS Results confirm a high response rate (75%) to initial antipsychotic treatment in first-episode schizophrenia. A considerably lower response rate (< 20%) occurs with a second antipsychotic trial. Results here were specific to olanzapine and risperidone, suggesting clinical differences (ie, olanzapine more effective than risperidone). A subsequent trial with clozapine is clearly warranted, although it remains unclear whether outcome would be further enhanced if it were used earlier in the treatment algorithm.

The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: a clinical [11C]-(+)-PHNO PET study.

The dopamine D2 receptors exist in two states: a high-affinity state (D2high) that is linked to second messenger systems, is responsible for functional effects, and exhibits high affinity for agonists; and a low-affinity state that is functionally inert and exhibits lower affinity for agonists. The dopamine D3 receptors have high-affinity for agonist (eg dopamine) and the existence of the two affinity states is controversial. Although preclinical studies in animal models of psychosis have shown a selective increase of D2high as the common pathway to psychosis, the D3 has been suggested to be involved in the pathophysiology of psychosis. We report the first study of the D2high and D3 in schizophrenia using the novel PET radiotracer, [11C]-(+)-PHNO. We recruited 13 patients with schizophrenia-spectrum disorder amidst an acute psychotic episode, drug free for at least 2 weeks, and 13 age–sex-matched healthy controls. The binding potential no-displaceable (BPND) was examine in the main regions of interest (caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and anterior thalamus) and in a voxel-wise analysis. The BPND between patients and controls was not different in any of the regions. The voxel-wise analysis did not reveal any difference and no correlations were found between the BPND and positive and negative syndrome scale subscales. Our results do not find support for the hypothesis linking psychosis to a selective increase in D2high and/or D3 in schizophrenia. It is possible that receptors with high affinity are not accessible by [11C]-(+)-PHNO because they are occupied by endogenous dopamine, a possibility that can be ruled out in future experiments.

Motivational and neurocognitive deficits are central to the prediction of longitudinal functional outcome in schizophrenia

Functional impairment is characteristic of most individuals with schizophrenia; however, the key variables that undermine community functioning are not well understood. This study evaluated the association between selected clinical variables and one‐year longitudinal functional outcomes in patients with schizophrenia.

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology

OBJECTIVE Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines. METHOD A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus. RESULTS Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients. CONCLUSIONS There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.

Negative symptoms of schizophrenia: Clinical features, relevance to real world functioning and specificity versus other CNS disorders

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.

Prediction of longitudinal functional outcomes in schizophrenia: The impact of baseline motivational deficits

Emerging evidence suggests that motivational deficits are a central component of negative symptoms in schizophrenia, and linked to functional impairment characterizing this illness. This study extends previous cross-sectional findings by examining the concurrent contributions of baseline motivational deficits, other negative symptoms, and other symptom domains on longitudinal functional outcomes in schizophrenia. Results of this longitudinal examination of 18 patients from our previous pilot study reveal that amotivation accounts for 74% and 72% of the variance in functional outcomes at baseline and 6-month follow-up, respectively. These findings further suggest a fundamental role for motivational deficits in predicting functional outcomes in schizophrenia.

How antipsychotics work-from receptors to reality.

How does a small molecule blocking a few receptors change a patients’ passionately held paranoid belief that the FBI is out to get him? To address this central puzzle of anti-psychotic action, we review a framework linking dopamine neurochemistry to psychosis, and then link this framework to the mechanism of action of antipsychotics. Normal dopamine transmission has a role in predicting novel rewards and in marking and responding to motivationally salient stimuli. Abnormal dopamine transmission alters these processes and results in an aberrant sense of novelty and inappropriate assignment of salience leading to the experience of psychosis. Antipsychotics improve psychosis by diminishing this abnormal transmission by blocking the dopamine D2/3 receptor (not D1 or D4), and although several brain regions may be involved, it is suggested that the ventral striatal regions (analog of the nucleus accumbens in animals) may have a particularly critical role. Contrary to popular belief, the antipsychotic effect is not delayed in its onset, but starts within the first few days. There is more improvement in the first 2 weeks, than in any subsequent 2-week period thereafter. However, a simple organic molecule cannot target the complex phenomenology of the individual psychotic experience. Antipsychotics diminish dopamine transmission and thereby dampen the salience of the preoccupying symptoms. Therefore, in the initial stage of an antipsychotic response, the patients experience a detachment from symptoms, a relegation of the delusions and hallucinations to the back of their minds, rather than a complete erasure of the symptoms. Only with time, and only in some, via the mediation of new learning and plasticity, is there a complete resolution of symptoms. The implications of these findings for clinical care, animal models, future target discovery and drug development are discussed.

Meta-Regression Analysis of Placebo Response in Antipsychotic Trials, 1970-2010

OBJECTIVE Large placebo response presents a major challenge for psychopharmacologic drug development and contributes to the increasing failure of psychiatric trials. The objective of this meta-regression analysis was to identify potential contributors to placebo response in randomized controlled trials of antipsychotic treatment in schizophrenia. METHOD The authors extracted trial design and clinical variables from eligible randomized controlled trials (N=50) identified through searches of MEDLINE (1960-2010) and other sources. Standardized mean change (SMC) was used as the effect size measure for placebo response, based on change scores on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale from baseline to endpoint (2 to 12 weeks). RESULTS The results suggest significant heterogeneities (Q=387.83, df=49) in the magnitude of placebo response (mean SMC, -0.33, range -1.4 to 0.9) and in study quality. Both placebo SMC and study quality increased over time. Younger age, shorter duration of illness, greater baseline symptom severity, and shorter trial duration were significantly associated with greater placebo response, while country (United States compared with other countries) was not. More study sites, fewer university or Veterans Affairs treatment settings, and a lower percentage of patients assigned to receive placebo were associated with a greater placebo response, but these were not independent of publication year. Study quality affected the variability but not mean levels of placebo response. CONCLUSIONS This study identified important patient characteristics and trial design factors affecting the level of placebo response and hence the likelihood of detecting efficacy signals in randomized controlled trials. Future studies should test whether controlling these factors improves the detection of an antipsychotic effect.