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Objective: Clozapine has strong recommendations for therapeutic drug monitoring. While factors that influence interindividual variation in plasma clozapine levels have been extensively reported, intraindividual variation remains poorly studied. We employed a population pharmacokinetic approach to assess intraindividual variations in plasma levels of both clozapine and N-desmethylclozapine, as well as the impact of smoking on this variability., Methods: Patients who were initiated on clozapine from January 2009 to December 2010 and who provided at least 2 plasma samples were included in this study. The observed concentrations of clozapine and N-desmethylclozapine were applied in a Bayesian pharmacokinetic modeling approach by using a previously published pharmacokinetic model from an independent sample to compute a predicted concentration. The predicted concentrations of clozapine and N-desmethylclozapine were then compared with the observed concentrations in the form of a ratio: predicted-to-observed concentration ratio (Cpred/Cobs). The coefficient of variation of the Cpred/Cobs ratios was taken as a measure of intraindividual variation., Results: A total of 723 plasma levels from 61 patients were included in this analysis. The coefficient of variation of Cpred/Cobs ratios for clozapine and N-desmethylclozapine were 29.8% (SD = 17.2%) and 27.4% (SD = 16.4%), respectively. Though values were higher, smoking did not have a significant effect on coefficients of variation of clozapine (33.5% vs 26.3%, P = .184) or N-desmethylclozapine (30.7% vs 24.2%, P = .100)., Conclusions: Clinicians need to be aware of intraindividual variability and not assume that plasma levels are static. If plasma levels are used to guide dosing of clozapine, serial measurements rather than a single level might be necessary to make an informed clinical decision. The clinical implications of intraindividual variability in plasma clozapine levels need further study., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

While several studies have examined how particular personality traits are related to dopamine D2/3 receptor (D2/3R) availability in the striatum of humans, few studies have reported how multiple traits measured in the same persons are differentially related to D2/3R availability in different striatal sub-regions. We examined how personality traits measured with the Karolinska Scales of Personality are related to striatal D2/3R availability measured with [(11)C]-raclopride in 30 healthy humans. Based on previous the literature, five personality traits were hypothesized to be most likely related to D2/3R availability: impulsiveness, monotony avoidance, detachment, social desirability, and socialization. We found self-reported impulsiveness was negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. After controlling for age and gender, monotony avoidance was also negatively correlated with D2/3R availability in the ventral striatum and globus pallidus. Socialization was positively correlated with D2/3R availability in the ventral striatum and putamen. After controlling for age and gender, the relationship between socialization and D2/3R availability in these regions survived correction for multiple comparisons (p-threshold=.003). Thus, within the same persons, different personality traits are differentially related to in vivo D2/3R availability in different striatal sub-regions., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Background: Many individuals with major depressive disorder present with prominent motivational deficits; however, the effect of these symptoms on functional outcomes in the illness remains unclear., Method: Individuals with major depression who participated in the Sequenced Treatment Alternatives to Relieve Depression study were included in the present investigation (N=1563). Motivational deficits were evaluated using a derived measure from the Hamilton Depression Rating Scale, while functioning was assessed using the Work and Social Adjustment Scale. Subjective outcomes were also evaluated using the Quality of Life Enjoyment and Satisfaction Questionnaire., Results: After treatment with citalopram, over 70% of participants continued to experience some degree of motivational deficits. These deficits were significantly associated with greater functional impairments both globally and in each domain of functioning evaluated. These symptoms were also linked to worse subjective outcomes such as overall life satisfaction and quality of life. Change in the severity of motivational deficits over time was significantly linked with changes in outcome. Motivational deficits continued to demonstrate a significant association with outcomes, even after controlling for potentially confounding variables such as duration of depressive episode and severity of other depressive symptoms., Conclusions: Motivational deficits are significantly linked to the functional impairment present in many people with major depression, just as they are in other psychiatric illnesses such as schizophrenia. A greater understanding of the underlying mechanisms of these motivational deficits in particular, beyond other depressive symptoms, is critical to the development of strategies aimed at enhancing functional recovery and improved subjective well-being., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Interest in the negative symptoms of schizophrenia has increased rapidly over the last several decades, paralleling a growing interest in functional, in addition to clinical, recovery, and evidence underscoring the importance negative symptoms play in the former. Efforts continue to better define and measure negative symptoms, distinguish their impact from that of other symptom domains, and establish effective treatments as well as trials to assess these. Multiple interventions have been the subject of investigation, to date, including numerous pharmacological strategies, brain stimulation, and non-somatic approaches. Level and quality of evidence vary considerably, but to this point, no specific treatment can be recommended. This is particularly problematic for individuals burdened with negative symptoms in the face of mild or absent positive symptoms. Presently, clinicians will sometimes turn to interventions that are seen as more "benign" and in line with routine clinical practice. Strategies include use of atypical antipsychotics, ensuring the lowest possible antipsychotic dose that maintains control of positive symptoms (this can involve a shift from antipsychotic polypharmacy to monotherapy), possibly an antidepressant trial (given diagnostic uncertainty and the frequent use of these drugs in schizophrenia), and non-somatic interventions (e.g., cognitive behavioral therapy, CBT). The array and diversity of strategies currently under investigation highlight the lack of evidence-based treatments and our limited understanding regarding negative symptoms underlying etiology and pathophysiology. Their onset, which can precede the first psychotic break, also means that treatments are delayed. From this perspective, identification of biomarkers and/or endophenotypes permitting earlier diagnosis and intervention may serve to improve treatment efficacy as well as outcomes.

Negative symptoms are a prominent feature of schizophrenia that are intimately linked to poor outcomes characterizing the illness. One mechanistic model suggests that these symptoms are produced and maintained, at least in part, through maladaptive attitudes. Beyond mechanisms, it remains phenomenologically unclear if these symptoms are particularly distressing. In the present study we examined whether subclinical negative symptoms evaluated in a non-clinical sample of young adults (N=370) were distressful or bothersome to participants and, further, whether these symptoms were associated with dysfunctional attitudes. We found that greater severity of subclinical negative symptoms such as amotivation and anhedonia were associated with higher ratings of distress specifically attributable to these symptoms. This relationship held even after controlling for severity of depressive symptoms. Moreover, greater negative symptom burden was associated with greater endorsement of defeatist performance beliefs. Negative symptoms expressed in the general population were found to be particularly distressing. Maladaptive cognitive schemas are implicated in the expression of these symptoms, as well as the amount of distress these symptoms instil. A greater understanding of the mechanisms underlying negative symptoms, including both neurobiological and cognitive, is needed in order to effectively develop treatment strategies for these disabling symptoms., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Motivational deficits are a key determinant of poor functional outcomes in schizophrenia. These impairments are typically evaluated using various clinical rating scales; however, the degree of convergence between motivation scores derived from different instruments is not clear. In the present study, we measured motivational deficits in 62 patients with schizophrenia using 5 scores derived from 3 different instruments. We found that the scores from these different instruments were highly inter-correlated, and largely independent of severity of other symptom domains (e.g., depression). Our findings suggest that clinical ratings scales evaluating motivational deficits are tapping into a similar underlying construct., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Social amotivation and diminished expression have been reported to underlie negative symptomatology in schizophrenia. In the current study we sought to establish and validate these negative symptom domains in a large cohort of schizophrenia subjects (n=887) and individuals who are deemed to be Ultra-High Risk (UHR) for psychosis. Confirmatory factor analysis conducted on PANSS item domains demonstrate that the dual negative symptom domains exist in schizophrenia and UHR subjects. We further sought to examine if these negative symptom domains were associated with functioning in UHR subjects. Linear regression analyses confirmed that social amotivation predicted functioning in UHR subjects prospectively at 1 year follow up. Results suggest that the association between social amotivation and functioning is generalisable beyond schizophrenia populations to those who are at-risk of developing psychosis. Social amotivation may be an important dimensional clinical construct to be studied across a range of psychiatric conditions., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

We have recently proposed a model for subtyping schizophrenia based on antipsychotic (AP) treatment response. Evidence suggests that APs, both old and new, are comparable in terms of efficacy; however, one AP, clozapine, is uniquely effective in one subgroup of patients (that is, those with treatment-resistant schizophrenia [TRS]). This permits us to subdivide schizophrenia into 3 specific groups: AP responsive, clozapine responsive, and clozapine resistant. Here, we integrate this model with current criteria related to TRS and ultraresistant schizophrenia, the latter referred to in our model as clozapine resistant. We suggest several modifications to existing criteria, in line with current evidence and practice patterns, particularly emphasizing the need to focus on positive symptoms. While APs can favourably impact numerous dimensions related to schizophrenia, it is their effect on positive symptoms that distinguishes them from other psychotropics. Further, it is positive symptoms that are central to AP and clozapine resistance, and it is these people that place the greatest demands on acute and long-term inpatient resources. In moving AP development forward, we advocate specifically focusing on positive symptoms and capitalizing on the evidence we have of 3 subtypes of psychosis (that is, positive symptoms) based on treatment response, implicating 3 distinguishable forms of underlying pathophysiology. Conversely, pooling these groups risks obfuscating potentially identifiable differences. Such a position does not challenge the importance of dopamine D2 receptor blockade, but rather highlights the need to better isolate those other subgroups that require something more or entirely different.

Objective: Functional impairment continues to represent a major challenge in schizophrenia. Surprisingly, patients with schizophrenia report a level of happiness comparable with control subjects, even in the face of the prominent functional deficits, a finding at odds with evidence indicating a positive relation between happiness and level of functioning. In attempting to reconcile these findings, we chose to examine the issue of values, defined as affectively infused criteria or motivational goals used to select and justify actions, people, and the self, as values are related to both happiness and functioning., Methods: Fifty-six first-episode patients in remission and 56 healthy control subjects completed happiness and values measures. Statistical analyses included correlations, analysis of variance, structural equation modelling, and smallest space analysis., Results: Results indicated that patients with schizophrenia placed significantly greater priority on the value dimensions of Tradition (P = 0.02) and Power (P = 0.03), and significantly less priority on Self-direction (P = 0.007) and Stimulation, (P = 0.008)., Conclusions: Essentially, people with schizophrenia place more emphasis on the customs and ideas that traditional culture or religion provide in conjunction with a decreased interest in change, which is at odds with the expectations of early adulthood. This value difference could be related to functional deficits. To this point, we have assumed that people hold to the same values that guided them before the illness' onset, but this may not be the case. Our study indicates that values differ in people with schizophrenia, compared with control subjects, even early in the illness and in the face of symptomatic remission.

Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and is linked to a need for mandatory hematological monitoring. Besides agranulocytosis, other hematological aberrations have resulted in premature termination in some cases. Considering clozapine's role in immunomodulation, we proceeded to investigate the impact of clozapine on the following 3 main hematological cell lines: red blood cells, platelets, white blood cells (WBCs), and its differential counts. Data were extracted from patients initiated on clozapine between January 2009 and December 2010 at a single hospital. Patients with a preclozapine complete blood count, who were receiving clozapine during the 1-year follow-up period, were included in the present investigation. Counts of red blood cells, platelets, WBC, and its differential including neutrophils, lymphocytes, monocytes, eosinophils, and basophils were extracted and trajectories plotted. One hundred one patients were included in this study and 66 remained on clozapine at the end of 1 year. There was a synchronized but transient increase in WBC, neutrophils, monocytes, eosinophils, basophils, and platelets beginning as early as the first week of clozapine treatment. There were no cases of agranulocytosis reported in this sample, and five developed neutropenia. A spike in neutrophils immediately preceded the onset of neutropenia in three of the five. The cumulative incidence rates were 48.9% for neutrophilia, 5.9% for eosinophilia, and 3% each for thrombocytosis and thrombocytopenia. Early hematological aberrations are visible across a range of cell lines, primarily of the myeloid lineage. These disturbances are transient and are probably related to clozapine's immunomodulatory properties. We do not suggest discontinuing clozapine as a consequence of the observed aberrations.

Background: Negative symptoms and motivational deficits are prevalent features of schizophrenia, and represent robust predictors of real-world functional outcomes. The standard for assessment of these symptoms is clinical interview and severity ratings on standardized rating scales. In the present study we examined the psychometric properties of a performance-based measure of motivational deficits in patients with schizophrenia., Methods: Ninety-seven patients with schizophrenia were included in this investigation. Patients' willingness to expend effort for reward (i.e., motivation) was evaluated using an effort-based decision making paradigm where participants chose over a series of trials whether to expend a greater amount of effort for a larger monetary reward versus less effort for a smaller reward. Effort performance was evaluated twice, separated by a two-week interval., Results: Patients with schizophrenia opted to expend greater effort for trials with higher reward value and greater likelihood of reward receipt. Patients did not find the task overly difficult and reported being motivated to perform well, underscoring the tolerability of the task for patients. Test-retest consistency was good and there was only minimal change in scores over time. Effort performance was not related to sociodemographic or clinical variables (e.g., positive symptoms); however, deficit syndrome patients exerted effort for reward at a significantly lower rate than nondeficit patients., Conclusions: The effort-based decision making task used in the present study represents an objective paradigm that can be used to evaluate motivational impairments in patients with schizophrenia. Such performance-based measures of motivation may also serve as viable endpoints in clinical trials., (Copyright © 2015 Elsevier B.V. All rights reserved.)

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 35years, and within 5years 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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Although many comprehensive batteries exist to evaluate the nature and degree of cognitive impairments in patients with schizophrenia, short batteries hold promise for rapidly screening and estimating deficits in global cognition. Recently, the Brief Neurocognitive Assessment (BNA) was established and has been shown to have similar validity and utility to a more comprehensive battery of cognitive tests in evaluating global cognitive impairments in patients with schizophrenia. The present study sought to further establish the validity of the BNA by comparing it with the MATRICS Consensus Cognitive Battery (MCCB)., Methods: One-hundred seventy-six patients with schizophrenia and 300 healthy volunteers participated in the present study. Global cognition was evaluated using the MCCB composite score and estimated using the BNA. To examine practice effects and test-retest reliability, patients were re-assessed after 4weeks., Results: The BNA was highly correlated with global cognition as evaluated by the MCCB in both the schizophrenia (r=0.82) and healthy control samples (r=0.75). Both instruments were similarly sensitive to deficits in global cognition in patients with schizophrenia relative to healthy controls. The BNA also demonstrated high test-retest reliability in patients with schizophrenia (r=0.87), comparable to the level observed with the MCCB (r=0.91). In addition, both the BNA and MCCB showed a similar level of practice effects (both Cohen's d=0.11), and both instruments demonstrated equivalent sensitivities to longitudinal change. Furthermore, scores from the BNA and MCCB were related to symptom severity and functional capacity to a similar degree., Conclusions: The BNA provides clinicians and researchers with an efficient and reliable means by which to evaluate global neurocognitive impairments in patients with schizophrenia by allowing estimation of performance on a more comprehensive standardized battery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Social cognition, referring to one's ability to perceive and process social cues, is an important domain in schizophrenia. Numerous studies have demonstrated that patients with schizophrenia have poorer performance on tests assessing social cognition relative to healthy comparison participants. However, whether variables such as motivation are related to performance on these tests in patients with schizophrenia is unclear. One thousand three-hundred and seventy-eight patients with schizophrenia completed the Facial Emotion Discrimination Task as a measure of emotional processing, a key facet of social cognition. Level of motivation was also evaluated in these patients using a derived measure from the Quality of Life Scale. The relationship between motivation and task performance was examined using bivariate correlations and logistic regression modeling, controlling for the impact of age and overall severity of psychopathology, the latter evaluated using the Positive and Negative Syndrome Scale. Motivation was positively related to performance on the social cognition test, and this relationship remained significant after controlling for potential confounding variables such as age and illness severity. Social cognition was also related to functioning, and the relationship was mediated by level of motivation. The present study found a significant relationship between motivation and performance on a test of social cognition in a large sample of patients with schizophrenia. These findings suggest that amotivation undermines task performance, or alternatively that poor social cognitive ability impedes motivation. Future studies evaluating social cognition in patients with schizophrenia should concurrently assess for variables such as effort and motivation.

Objective: The contribution of specific symptoms on ratings of global illness severity in patients with schizophrenia is not well understood. The present study examined the clinical determinants of clinician and patient ratings of overall illness severity., Method: This study included 1,010 patients with a DSM-IV diagnosis of schizophrenia who participated in the baseline visit of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study conducted between January 2001 and December 2004 and who had available symptom severity, side effect burden, cognition, and community functioning data. Both clinicians and patients completed the 7-point Clinical Global Impressions-Severity of Illness scale (CGI-S), the primary measure of interest in the present study. Symptoms were rated using the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia, and functional status with the Quality of Life Scale. Neurocognition, insight, and medication-related side effects were also evaluated., Results: Clinicians rated illness severity significantly higher than patients (P < .001). There was moderate overlap between CGI-S ratings made by clinicians and patients, with almost one third of patients showing substantial (ie, greater than 1 point) discrepancies with clinician ratings. Clinician-rated CGI-S scores were most strongly associated with positive symptoms, with additional independent contributions made by negative, disorganized, and depressive symptoms, as well as functional outcome (all P values < .01). Patient-rated CGI-S scores, on the other hand, were most closely related to depressive symptoms, with additional independent contributions made by positive and anxiety symptoms, clinical insight, and neurocognition (all P values < .01). Depressive symptoms were the strongest predictor of patient-rated CGI-S scores even in patients with good clinical insight (P < .001)., Conclusions: Patient and clinician views of overall illness severity are not necessarily interchangeable and differ in their clinical correlates. Taking these differences into account may enhance patient engagement in care and improve outcomes., Trial Registration: ClinicalTrials.gov identifier: NCT00014001., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Previous investigations on the relationship between global rating measures and symptoms have not considered the additional role of functioning. In this naturalistic study, we examined the relationship between symptom domains and functioning on Clinical Global Impression scales for severity (CGI-S) and improvement (CGI-I) in a sample of patients with schizophrenia assessed to be treatment resistant. Participants were patients with a diagnosis of schizophrenia or schizoaffective disorder who failed 2 prior antipsychotic trials and were considered candidates for clozapine. They were assessed on the 18-item Brief Psychiatric rating Scale (BPRS), Social Occupational Functioning Assessment Scale (SOFAS), and CGI-S at baseline. A subset of patients was followed up at 6 weeks after initiation of clozapine and assessed on the CGI-I. The independent effects of symptom domains and functioning on the CGI scales were examined via multivariate regression models. Brief Psychiatric rating Scale positive factor (P < 0.001) and SOFAS (P < 0.001) scores were significant determinants of CGI-S at baseline. Multivariate models suggested that relative change measures had a better fit for the CGI-I compared to absolute change measures (R = 0.72 vs R = 0.61, respectively). Improvements in BPRS positive (P < 0.001) and affect (P = 0.002) factors and SOFAS (P = 0.030) scores were significant determinants of CGI-I. Ratings of 1 and 2 on the CGI-I corresponded to a mean relative change in the BPRS total of 65% and 41%, respectively. Positive symptoms were a key determinant of clinicians' impression of severity and improvement in this study. Although psychosocial functioning played a large part in determining severity, it was not as significant in the assessment of improvement.

Antipsychotic drugs are thought to produce secondary negative symptoms, which can also exacerbate primary negative symptoms. In the present study, we examined whether motivational deficits in particular were related to antipsychotic treatment in patients with schizophrenia in a dose-dependent manner. Five hundred and twenty individuals with schizophrenia who were receiving antipsychotic monotherapy for at least 6 months and followed prospectively were included in the present study. Participants were receiving one of five antipsychotic medications (olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone), and analyses were conducted for patients receiving each drug separately. Analysis of covariance models were constructed to examine the effect of antipsychotic dose on level of motivational impairment, controlling for selected demographic and clinical variables (eg, positive symptoms). Level of motivation, or deficits therein, were evaluated using a derived measure from the Quality of Life Scale, and in addition with scores derived from the Positive and Negative Syndrome Scale. Antipsychotic dose was not related to the level of amotivation for any of the medications examined. Moreover, severity of sedation was not significantly related to the degree of amotivation. One hundred and twenty-one individuals were identified as antipsychotic-free at baseline, and after 6 months of antipsychotic treatment, no change in motivation was found. Chronic treatment with antipsychotics does not necessarily impede or enhance goal-directed motivation in patients with schizophrenia. It is possible that the negative impact of antipsychotics in this regard is overstated; conversely, the present results also indicate that we must look beyond antipsychotics in our efforts to improve motivation.

Background: Recent developments in neuroimaging have advanced the understanding of biological mechanisms underlying schizophrenia. However, neuroimaging correlates of treatment-resistant schizophrenia (TRS) and superior effects of clozapine on TRS remain unclear., Methods: Systematic search was performed to identify neuroimaging characteristics unique to TRS and ultra-resistant schizophrenia (i.e. clozapine-resistant [URS]), and clozapine's efficacy in TRS using Embase, Medline, and PsychInfo. Search terms included (schizophreni*) and (resistan* OR refractory OR clozapine) and (ASL OR CT OR DTI OR FMRI OR MRI OR MRS OR NIRS OR PET OR SPECT)., Results: 25 neuroimaging studies have investigated TRS and effects of clozapine. Only 5 studies have compared TRS and non-TRS, collectively providing no replicated neuroimaging finding specific to TRS. Studies comparing TRS and healthy controls suggest that hypometabolism in the prefrontal cortex, hypermetabolism in the basal ganglia, and structural anomalies in the corpus callosum contribute to TRS. Clozapine may increase prefrontal hypoactivation in TRS although this was not related to clinical improvement; in contrast, evidence has suggested a link between clozapine efficacy and decreased metabolism in the basal ganglia and thalamus., Conclusion: Existing literature does not elucidate neuroimaging correlates specific to TRS or URS, which, if present, might also shed light on clozapine's efficacy in TRS. This said, leads from other lines of investigation, including the glutamatergic system can prove useful in guiding future neuroimaging studies focused on, in particular, the frontocortical-basal ganglia-thalamic circuits. Critical to the success of this work will be precise subtyping of study subjects based on treatment response/nonresponse and the use of multimodal neuroimaging., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Whether improvement on ratings of global illness severity is differentially associated with improvement in specific symptom domains in patients with schizophrenia is not well understood. The present study examined the independent relationships between improvement in specific symptom clusters and change in global impressions of illness severity., Methods: This study included 589 patients with chronic schizophrenia who were assessed at baseline and after 6 months of antipsychotic treatment. Both clinicians and patients completed the Clinical Global Impressions-Severity of Illness Scale (CGI-S). Symptom severity was assessed using factor scores derived from the Positive and Negative Syndrome Scale., Results: Change in illness severity ratings made by the clinician and those made by the patient demonstrated moderate overlap. Nearly half of the patients were evaluated as clinically improved during the 6-month period, as rated by the clinician, with less than a third of patients experiencing a reduction in illness severity as determined by both the clinician and themselves. Improvements in clinician-rated CGI-S scores were most strongly associated with reduction in positive symptom severity. In contrast, change in patient-rated CGI-S scores was not linked to reduction in positive symptoms but rather to improvement in depressive and anxiety symptoms. This latter finding remained in a subsample of patients with relatively preserved insight into illness, suggesting that lack of insight cannot account for these findings. Finally, reduction in positive symptoms beyond 2 to 3 points was found to be clinically meaningful., Conclusions: In conclusion, change in overall illness severity, as determined by clinicians, is not necessarily interchangeable with patients' view of improvement of their own clinical status. Moreover, changes in the 2 evaluations of illness severity are associated with changes in different symptom domains.

Objective: To examine how advances in our understanding of schizophrenia have shaped thinking about antipsychotics (APs) and their role in treatment., Method: Three specific developments in the field of schizophrenia are highlighted: advances in knowledge related to the earliest stages of schizophrenia, specifically the prodrome; reconceptualization of schizophrenia as an illness of multiple symptom domains; and greater clarification regarding the efficacy of clozapine and a new generation of APs., Results: Evidence indicating that negative and cognitive symptoms are present during the prodrome suggests that intervention at the time of first-episode psychosis constitutes late intervention. The limited efficacy of APs beyond psychosis argues against a magic bullet approach to schizophrenia and for polypharmacy that is symptom domain-specific. Clozapine's unique, but limited, efficacy in treatment resistance supports subtyping schizophrenia based on treatment response., Conclusions: Advances in our understanding of schizophrenia have important implications regarding the current use of APs, expectations regarding response, and future drug development.

Optimal outcome in schizophrenia is thought to include remission of symptoms, functional recovery, and improved subjective well-being. The present study examined the characteristics of individuals with schizophrenia who report being satisfied with their life in general. Individuals with schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness study were included in the present analysis. Approximately half of the individuals evaluated reported a high level of life satisfaction, even while many concurrently described themselves as at least moderately ill and experiencing moderate-severe symptoms and manifested severe functional deficits. Of all individuals evaluated, only about 1% experienced what was considered to be optimal outcome. Individuals with schizophrenia are able to experience a high level of life satisfaction, despite experiencing severe illness and functional deficits. Those involved in care should be aware that life satisfaction as an outcome is not necessarily associated with symptom remission and superior functioning.

The objective of this study was to evaluate the effectiveness and impact of once- versus twice-daily dosing of risperidone and olanzapine on clinical outcomes in patients with schizophrenia. Data from phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were used. Patients with schizophrenia were randomly allocated to treatment with risperidone and olanzapine, and were also randomly assigned to once-daily (N=173 and 169, respectively) or twice-daily (N=168 and 167, respectively) dosing and followed for up to 18 months. Discontinuation rate and time to discontinuation were used as primary outcome measures to compare the two groups. The following outcome measures were also analyzed: efficacy, safety, medication adherence, adverse events, and concomitant psychotropic medications. No significant differences in discontinuation rates and time to discontinuation were observed between the once- and twice-daily dosing groups (P>0.05) in patients receiving risperidone or olanzapine. The once-daily dosing group demonstrated significantly lower mean daily doses of risperidone and olanzapine across phase 1, and lower rates of hospitalization for exacerbation of schizophrenia, sleepiness, and orthostatic faintness in patients receiving olanzapine (P<0.05) compared to the twice-daily dosing group. No significant differences were found in any other outcome measures between the two dosing groups. In conclusion, effectiveness and efficacy outcomes between once- and twice-daily dosing for risperidone and olanzapine were not significantly different. However, in view of the lower mean dose and better side effect profile, it is advisable to adhere to a once-daily dosing regimen, especially in the case of olanzapine., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Background: The comparative antidepressant effects of clozapine and other atypical antipsychotics for schizophrenia remain elusive, leading us to examine this question using the data from the Clinical Antipsychotic Trials of Intervention Effectiveness phase 2E., Methods: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone because of inadequate efficacy were randomly assigned to open-label treatment with clozapine (n=49) or double-blind treatment with another atypical antipsychotic not previously received in the trial (olanzapine [n=19], quetiapine [n=15], or risperidone [n=16]). The primary outcome was the Calgary Depression Scale for Schizophrenia (CDSS) total score. Antidepressant effects of clozapine and the other atypical antipsychotics were compared in patients with chronic schizophrenia and those with a major depressive episode (MDE) at baseline (i.e. ≥6 on the CDSS), using mixed models., Results: No differences in the baseline CDSS total scores were found between the treatment groups regardless of presence of an MDE. Clozapine was more effective than quetiapine in antidepressant effects for chronic schizophrenia (p<.01 for the whole sample and p=.01 for those with an MDE), and comparable to olanzapine and risperidone., Conclusion: The present findings suggest that clozapine demonstrates superior antidepressant effects to quetiapine and comparable effects to olanzapine and risperidone in chronic schizophrenia regardless of presence of MDE. Given the indication of clozapine for treatment-resistant schizophrenia (TRS) and the negative impacts of depressive symptoms on clinical outcomes in schizophrenia, further research is warranted to investigate antidepressant effects of clozapine in TRS with an MDE., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Among the constellation of symptoms that characterize schizophrenia, negative symptoms have emerged as a critical feature linked to the functional impairment experienced by affected individuals. Despite advances in our understanding of the role of negative symptoms in the illness, effective treatments for these debilitating symptoms have remained elusive. In this review we explore the contemporary conceptualization of negative symptoms in schizophrenia, including the identification of two key subdomains of diminished expression and amotivation, and clarifications around hedonic capacity. We then explore strategies for clinical assessments of negative symptoms, followed by findings using objective paradigms for evaluating discrete aspects of these negative symptoms in clinical populations and animal models, both for symptoms of diminished expression and within the multifaceted motivation system. We conclude with a consideration of current strategies for drug development for these negative symptoms, the role of heterogeneity in the clinical presentation of symptoms in schizophrenia and opportunities for personalized assessment and treatment approaches, as well as a commentary on current clinical drug trial design and the role of environmental opportunities for novel treatments to effect change and improve outcomes for affected individuals., (© The Author(s) 2014.)

Background: Movement disorders are common in individuals with schizophrenia, even in those who are not exposed to antipsychotic medications. Extrapyramidal symptoms (EPS) are among the most common abnormal movements in schizophrenia, but their relationship with other features of the illness such as cognition is not well characterized., Methods: Three hundred and twenty-five individuals with schizophrenia who were not receiving any antipsychotic or anticholinergic medication and participated in the baseline visit of the Clinical Antipsychotic Treatment of Intervention Effectiveness study were included in the present study. EPSs were assessed using the Simpson-Angus Scale, while cognition was measured with a comprehensive neuropsychological test battery. The relationship between EPS and cognitive test performance was evaluated both dimensionally and categorically., Results: Greater severity of EPS was significantly associated with worse cognitive test performance evaluated using a composite score. Eighty-six patients were identified as having parkinsonism and these patients performed worse on cognitive tests than non-parkinsonian patients. These findings remained significant even after accounting for other variables such as severity of psychopathology, sedation, akathisia and dyskinesia., Conclusions: The present results demonstrate that severity of EPS is reliably linked with poorer scores on tests of cognition. While this may reflect a common pathophysiology underlying neuromotor and neurocognitive deficits, it may also be the case that parkinsonian symptoms such as rigidity and bradykinesia impede test taking ability. Regardless of mechanism, inferences regarding cognitive impairment should take into account the presence of EPS, as well as other variables that may mediate cognitive test findings., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Impaired insight into illness (clinical insight) in schizophrenia has negative effects on treatment adherence and clinical outcomes. Schizophrenia is described as a disorder of disrupted brain connectivity. In line with this concept, resting state networks (RSNs) appear differentially affected in persons with schizophrenia. Therefore, impaired clinical, or the related construct of cognitive insight (which posits that impaired clinical insight is a function of metacognitive deficits), may reflect alterations in RSN functional connectivity (fc). Based on our previous research, which showed that impaired insight into illness was associated with increased left hemisphere volume relative to right, we hypothesized that impaired clinical insight would be associated with increased connectivity in the DMN with specific left hemisphere brain regions., Methods: Resting state MRI scans were acquired for participants with schizophrenia or schizoaffective disorder (n=20). Seed-to-voxel and ROI-to-ROI fc analyses were performed using the CONN-fMRI fc toolbox v13 for established RSNs. Clinical and cognitive insight were measured with the Schedule for the Assessment of Insight-Expanded Version and Beck Cognitive Insight Scale, respectively, and included as the regressors in fc analyses., Results: As hypothesized, impaired clinical insight was associated with increased connectivity in the default mode network (DMN) with the left angular gyrus, and also in the self-referential network (SRN) with the left insula. Cognitive insight was associated with increased connectivity in the dorsal attention network (DAN) with the right inferior frontal cortex (IFC) and left anterior cingulate cortex (ACC)., Conclusion: Increased connectivity in DMN and SRN with the left angular gyrus and insula, respectively, may represent neural correlates of impaired clinical insight in schizophrenia spectrum disorders, and is consistent with the literature attributing impaired insight to left hemisphere dominance. Increased connectivity in the DAN with the IFC and ACC in relation to cognitive insight may facilitate enhanced mental flexibility in this sample., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Impairment in psychosocial functioning is a key feature in schizophrenia, but few studies have examined the relationship between improvements in symptoms and functioning. We examined the relationship between change in symptoms and change in functioning in a group of patients with treatment-resistant schizophrenia after 6 and 12 weeks of clozapine treatment. Participants were assessed prior to clozapine and again at 6 and 12-week on the 18-item Brief Psychiatric Rating Scale (BPRS) and the Social and Occupational Functioning Scale (SOFAS). Change scores in BPRS and SOFAS at 6 and 12-week post-clozapine were calculated and the direct relationship was assessed via regression models. Forty-three participants were included in this study; age of sample was 42.1 ± 12.7 years, with 31 (72.1%) male participants. At baseline, the mean BPRS total and SOFAS scores were 46.98 ± 12.86 and 33.07 ± 10.79, respectively. There were significant improvements in BPRS total and SOFAS scores at 6 weeks, but no significant differences between 6 and 12-week assessments. There was no significant change in negative symptoms at both follow-up assessments. At 6-week, change in symptoms was not correlated with change in functioning and while the relationship between change in symptoms and functioning was stronger at 12 weeks, none of the BPRS factors emerged as a significant predictor. The present study found that lower baseline SOFAS score was the most robust predictor for improvements in SOFAS at 6 and 12-weeks. There appears to be a "ceiling" for functional improvements on clozapine, but follow-up studies are needed to examine functional gains beyond 12 weeks., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Importance: 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., Objective: To evaluate the association between intrinsic motivation and cognitive test performance in patients with schizophrenia., Design, Setting, and Participants: 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., Interventions: 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., Main Outcomes and Measures: The primary outcome variable was global neurocognition. Individual domains of cognition were also evaluated for their association with motivation., Results: 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)., Conclusions and Relevance: 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., Trial Registration: clinicaltrials.gov Identifier: NCT00014001.

In the field of schizophrenia research, as in other areas of psychiatry, there is a sense of frustration that greater advances have not been made over the years, calling into question existing research strategies. Arguably, many purported gains claimed by research have been "lost in translation," resulting in limited impact on diagnosis and treatment in the clinical setting. There are exceptions; for example, we would argue that different lines of preclinical and clinical research have substantially altered how we look at antipsychotic dosing. While this story remains a work in progress, advances "found in translation" have played an important role. Detailing these changes, the present paper speaks to a body of evidence that has already shifted clinical practice and raises questions that may further alter the manner in which antipsychotics have been administered over the last 6 decades.

The field of schizophrenia is redefining optimal outcome, moving beyond clinical remission to a more comprehensive model including functional recovery and improved subjective well-being. Although numerous studies have evaluated subjective outcomes within the domain of subjective quality of life in patients with schizophrenia, less is known about global evaluations of subjective well-being. This study examined the effects of antipsychotic medication on overall life satisfaction in patients with chronic schizophrenia. Data were drawn from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study, where participants with a DSM-IV diagnosis of schizophrenia were randomized to receive olanzapine, perphenazine, quetiapine, risperidone or ziprasidone under double-blind conditions (N=753). The primary outcome measure was prospective change in subjectively evaluated overall life satisfaction scores following 12 months of antipsychotic treatment. Psychopathology, medication side effects and functional status were also evaluated, among other variables. Patients experienced modest improvements in overall life satisfaction (d=0.22, p<0.001), with no differences between antipsychotic medications (all tests, p>0.05). Change in severity of positive, negative, and depressive symptoms as well as functional status each demonstrated a small, albeit statistically significant, association with change in life satisfaction (r=0.10-0.21, p׳s<0.01). In a multivariate regression model, change in clinical symptoms and functional status had limited independent predictive value for change in life satisfaction scores (explained variance <3%). These data suggest that despite antipsychotic medications being effective for symptom-based psychopathology, such clinical effectiveness does not necessarily translate to improved general satisfaction with life. Clinicians should be aware that these two domains are not inextricably linked., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Background: Impairment in community functioning is characteristic of many individuals with schizophrenia. Despite a wealth of literature documenting such functional impairments, how patients spend their time on a daily basis and the types of activities they engage in remains less clear. The present investigation set out to examine the daily activity patterns of remitted first-episode patients with schizophrenia., Methods: Twenty-eight first-episode schizophrenia patients in symptomatic remission and twenty-eight age-, gender-, and education-matched healthy comparison subjects participated in the present study. The Day Reconstruction Method (DRM) was employed to evaluate daily life activities, while the Social and Occupational Functional Assessment Scale was used to for assessment of community functioning. Psychopathology was assessed using the Positive and Negative Syndrome Scale, depressed mood using the Calgary Depression Scale for Schizophrenia, and clinical insight using the Schedule for the Assessment of Insight. Neurocognition was also evaluated with the Brief Assessment of Cognition in Schizophrenia., Results: First-episode schizophrenia patients experienced marked impairment in functioning, despite being in symptomatic remission. Patients and controls did not differ in the number of activities reported throughout their day. However, first-episode schizophrenia patients had significantly shorter days than comparison subjects and spent significantly less time engaged in non-passive (i.e., effortful) activities, which was related to poorer functional status., Conclusions: Individuals with first-episode schizophrenia and in symptomatic remission demonstrate decreased levels of non-passive activities and poorer functional outcomes. A better understanding of the underlying factors is very likely critical to the development of strategies aimed at enhancing functional recovery in schizophrenia., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (© 2013 Published by Elsevier B.V. and ECNP.)

Objective: The objective of this study was to evaluate the impact of once- versus twice-daily dosing of perphenazine, which has a plasma half-life of 8-12 hours, on clinical outcomes in patients with schizophrenia., Method: Data from phase 1 of the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) conducted between January 2001 and December 2004 were used in this post hoc analysis. Patients with schizophrenia (DSM-IV) randomly allocated to treatment with perphenazine were also randomly assigned to once-daily (N = 133) or twice-daily (N = 124) dosing and followed over 18 months. Discontinuation rate and time to discontinuation were used as primary outcomes to compare the 2 groups. The following clinical outcomes were analyzed as secondary measures: efficacy-Positive and Negative Syndrome Scale, Clinical Global Impressions-Severity scale, Calgary Depression Scale for Schizophrenia, and Drug Attitude Inventory and safety/tolerability-Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale, and body weight. Data on treatment-emergent adverse events, concomitant psychotropic medications, and medication adherence (pill count and clinician rating scale) were also analyzed for each group., Results: No significant differences were found in any outcome measures between the once-daily and twice-daily dosing groups, which remained the same when using the mean dose of perphenazine as a covariate., Conclusions: Perphenazine is routinely administered in a divided dosage regimen because of its relatively short plasma half-life. However, the present findings challenge such a strategy, suggesting that once-daily represents a viable treatment option. Results are discussed in the context of more recent evidence that challenges the need for high and continuous dopamine D2 receptor blockade to sustain antipsychotic response., Trial Registration: ClinicalTrials.gov identifier: NCT00014001., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Background: Many individuals with schizophrenia experience a profound deficit in global cognitive ability, which is related to poor functional outcomes. Historically, the standard of assessing neurocognitive impairments is one of extensive neuropsychological batteries that are labour-intensive. The present study examined whether a brief neurocognitive assessment (BNA) instrument could effectively estimate global neurocognition and further examined its clinical utility., Methods: The validity and clinical utility of a BNA that takes approximately 10 min to administer was examined against a full neuropsychological battery that takes approximately 90 min to administer in a large and heterogeneous sample of 1303 patients with schizophrenia., Results: The BNA explained 76% of the variance in global neurocognition in the total sample and remained consistent in subsamples stratified by clinical characteristics (e.g., severity of psychopathology) and in randomized re-sampling simulations. The two items that comprised the BNA were the letter-number sequencing test, a measure of working memory, and the digit-symbol test, a measure of processing speed. Next, perhaps more importantly, the BNA and full neuropsychological battery were related to symptoms and functional status to a similar degree in both univariate and multivariate regression models; moreover, both instruments were sensitive to longitudinal treatment related change to a similar degree., Conclusions: The BNA is able to rapidly, easily, and validly assess global neurocognition in schizophrenia. The BNA was associated with important clinical outcomes to a similar degree as a full cognitive battery. This tool provides clinicians and researchers a means to assess global neurocognitive impairments without requiring extensive neuropsychological testing., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The Heinrichs-Carpenter Quality of Life Scale (QLS) is the most extensively used real-world community functioning scale in schizophrenia research. However, the extensive time required to administer it and the inclusion of items that overlap conceptually with negative symptoms limit its use across studies. The present study examined the validity and utility of two abbreviated QLS measures against the full QLS excluding negative symptom items., Method: The sample included 1427 patients with schizophrenia who completed the baseline visit in the CATIE study. The validity of two abbreviated QLS measures (7-item and 4-item) were examined with the full QLS, excluding the intrapsychic foundations subscale, using correlation analysis. The utility of the abbreviated measures was explored by examining associations between the functioning scales and clinical variables and longitudinal change., Results: Both abbreviated QLS measures were highly predictive of the full QLS (both r=0.91, p<0.001), with no difference in predictive value between the abridged measures. Functional status was significantly associated with symptoms and cognition. Importantly, the strength of these associations was similar between the abbreviated and full QLS. Finally, multiple regression models examining the explanatory power of amotivation/apathy in predicting functioning scores after other symptoms and neurocognition had been accounted for were essentially identical irrespective of the QLS instrument used as the dependent measure. Longitudinal change was also similar across the three scales., Conclusions: The 7-item abbreviated QLS is recommended as a brief measure of community functioning for individuals with schizophrenia, especially when assessment of functional outcome is not the focus., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Dopamine's proposed role in psychosis proved a starting point in our understanding of the neurobiology of relapse, fitting given the central role positive symptoms play. This link is reflected in early work examining neurotransmitter metabolite and drug (e.g. amphetamine, methylphenidate) challenge studies as a means of better understanding relapse and predictors. Since, lines of investigation have expanded (e.g. electrophysiological, immunological, hormonal, stress), an important step forward if relapse per se is the question. Arguably, perturbations in dopamine represent the final common pathway in psychosis but it is evident that, like schizophrenia, relapse is heterogeneous and multidimensional. In understanding the neurobiology of relapse, greater gains are likely to be made if these distinctions are acknowledged; for example, efforts to identify trait markers might better be served by distinguishing primary (i.e. idiopathic) and secondary (e.g. substance abuse, medication nonadherence) forms of relapse. Similarly, it has been suggested that relapse is 'neurotoxic', yet individuals do very well on clozapine after multiple relapses and the designation of treatment resistance. An alternative explanation holds that schizophrenia is characterized by different trajectories, at least to some extent biologically and/or structurally distinguishable from the outset, with differential patterns of response and relapse. Just as with schizophrenia, it seems naïve to conceptualize the neurobiology of relapse as a singular process. We propose that it is shaped by the form of illness and in place from the outset, modified by constitutional factors like resilience, as well as treatment, and confounded by secondary forms of relapse., (© 2013 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The lack of initiative, drive or effort in patients with schizophrenia is linked to marked functional impairments. However, our assessment of effort and motivation is crude, relying on clinical rating scales based largely on patient recall. In order to better understand the neurobiology of effort in schizophrenia, we need more rigorous measurements of this construct. In the behavioural neuroscience literature, decades of work has been carried out developing various paradigms to examine the neural underpinnings of an animal's willingness to expend effort for a reward. Here, we shall review this literature on the nature of paradigms used in rodents to assess effort, as well as those used in humans. Next, the neurobiology of these effort-based decisions will be discussed. We shall then review what is known about effort in schizophrenia, and what might be inferred from experiments done in other human populations. Lastly, we shall discuss future directions of research that may assist in shedding light on the neurobiology of effort cost computations in schizophrenia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Data collected through self-report questionnaires are particularly susceptible to inappropriate or random responding, and such invalid data increase noise and attenuate true statistical relationships. While many researchers studying schizotypy have employed infrequency measures to exclude participants, such measures are not universally employed. Moreover, some researchers have even outright questioned whether validity scales are warranted. Here, we show the effect of invalid responses on the relationship between schizotypy and hedonic reaction. For valid responders, negative schizotypal traits were inversely related to both anticipatory and consummatory pleasure (p < .01). Invalid responses were found for 23% of respondents, and within these subjects, no relationship was found between any of the measures. When the valid and invalid respondents were pooled, the relationship was dampened. Furthermore, linear multiple regression modeling showed that validity trended toward moderating the relationship between the variables of interest. These data highlight the importance of screening for, and excluding, invalid responses in schizotypy research. Our results also affirm that screening for random responding is effective and warranted. Implications for future studies employing questionnaire-based methods are discussed., ((c) 2013 APA, all rights reserved.)

Objective: Quality of life is seen as an important outcome variable for patients with schizophrenia. However, the precise definition of this construct varies and has often been used to define health-related domains. The present study sought to focus on global life satisfaction as a key subjective domain and determine its relationship with clinical variables., Method: The study sample included 1437 patients with chronic schizophrenia who participated in the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study. Patients were evaluated with a comprehensive battery of assessments capturing symptoms, cognition and medication side effects, among other variables. Life satisfaction was evaluated with a global self-report item., Results: Greater depressive symptoms were the most robust indicator of worse life satisfaction. Lower life satisfaction was also associated with poorer psychosocial functioning, greater symptoms of anxiety, apathy and more negative attitudes toward medication. Taken together, these variables explained 20% of the variance in life satisfaction scores. Positive symptoms and other medication side effects also negatively influenced life satisfaction scores., Conclusions: These results affirm that clinical variables have an adverse effect on the overall subjective well-being of patients with schizophrenia. The relatively small amount of variance explained, though, argues for a better understanding of those other variables that contribute to life satisfaction., (© 2013 Elsevier B.V. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The field of therapeutics in schizophrenia is redefining optimal outcome, moving beyond clinical remission to a more comprehensive model that also includes functional recovery. The Quality of Life Scale (QLS) has been adopted by many large clinical trials, including CATIE and CUtLASS, as a measure of functioning. The QLS is a 21-item semi-structured interview that takes approximately 45min to administer. Although the QLS is considered comprehensive, its length limits its applicability across studies. To circumvent this issue, short scales of the QLS have been created that estimate total scores with high accuracy. However, these abbreviated measures have not been adequately cross-validated in a large enough sample to allow for subsample estimations nor has its predictive ability been compared to the full scale. Here, we used data from the CATIE trial (n=1460) to demonstrate the validity and utility of an abbreviated 7-item QLS. The shortened QLS was robust in estimating total scores (r=0.953, p<0.001) across subsamples and demonstrated predictive ability similar to the full QLS in multiple regression models. The abridged QLS is recommended as a surrogate measure of psychosocial functioning, especially in cases where functioning is not the primary outcome., (Copyright © 2012 Elsevier B.V. and ECNP. All rights reserved.)

Clinicians treating schizophrenia routinely employ high doses and/or antipsychotic switching to achieve response. However, little is actually known regarding the value of these interventions in early schizophrenia. Data were gathered from a treatment algorithm implemented in patients with first-episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine. Patients were initially treated with either olanzapine or risperidone across three dose ranges, (low, full, high), and in the case of suboptimal response were switched to the alternate antipsychotic. We were interested in the value of (a) high dose treatment and (b) antipsychotic switching. A total of 244 patients were evaluated, with 74.5% (184/244) responsive to Trial 1, and only 16.7% (10/60) responsive to Trial 2. Percentage of response for subjects switched from olanzapine to risperidone was 4.0% (1/25) vs. 25.7% (9/35) for those switched from risperidone to olanzapine. High doses yielded a 15.5% response (14.6% for risperidone vs. 16.7% for olanzapine).The present findings concur with other research indicating that response rate to the initial antipsychotic trial in first-episode schizophrenia is robust; thereafter it declines notably. In general, the proportion of responders to antipsychotic switching and high dose interventions was low. For both strategies olanzapine proved superior to risperidone, particularly in the case of antipsychotic switching (i.e. risperidone to olanzapine vs. vice versa). It remains to be established whether further antipsychotic trials are associated with even greater decrements in rate of response. Findings underscore the importance of moving to clozapine when treatment resistance has been established., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

Background: Schizotypal personality disorder is the prototypical schizophrenia-spectrum condition, sharing similar phenomenological, cognitive, genetic, physiological, neurochemical, neuroanatomical and neurofunctional abnormalities with schizophrenia. Investigations into SPD circumvent many confounds inherent to schizophrenia such as medication and institutionalization. Hence, SPD offers a unique vantage point from which to study schizophrenia-spectrum conditions., Methods: We systematically reviewed the neuroimaging literature in SPD to establish: (1) whether there are concordant findings in SPD and schizophrenia, possibly reflective of core pathology between the two conditions and (2) whether there are discordant findings in SPD and schizophrenia, possibly reflecting protective factors in the former. The findings are synthesized across structural and functional neuroimaging domains., Results: A total of 54 studies were identified. Medial temporal lobe structures seem to be compromised in both SPD and schizophrenia. In schizophrenia prefrontal structures are further compromised, whereas in SPD these seem to be larger-than-normal, possibly reflecting a compensatory mechanism. Additional pathology is discussed, including evidence of aberrant subcortical dopaminergic functioning., Conclusions: SPD is a schizophrenia-spectrum condition that shares pathology with schizophrenia, but is distinct in showing unique neural findings. Future studies are needed to confirm and localize regions of common and disparate pathology between SPD and schizophrenia., (Copyright © 2012 Elsevier Inc. All rights reserved.)