George Foussias

Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention

Importance of the field: Antipsychotic medications are the cornerstone of treatment in schizophrenia, and a large body of data confirms the value of ongoing and continuous antipsychotic pharmacotherapy in controlling symptoms and preventing relapse. However, nonadherence with antipsychotic treatment is a significant issue, with estimates as high as 90%. Areas covered in this review: This review focuses on long-acting injectable (LAI) antipsychotics and their role in the treatment of schizophrenia. The existing literature, with an emphasis on clinical evidence, is assessed. This includes both reviews and specific trials that examine LAIs and compare them with oral agents, with measures ranging from relapse and rehospitalization to adherence. Both advantages and limitations (e.g., challenges in terms of dose titration and time to steady state) are examined. What the reader will gain: This overview serves as an update for clinicians wishing to understand LAIs better, including the newer second-generation antipsychotics (SGAs) with this formulation available, and their potential role in the long-term treatment of individuals with schizophrenia. Take home message: Despite identified advantages, LAIs are not used as widely as might be expected. It would seem that clinicians are at least partly responsible for this, influenced by our own misperceptions (e.g., that LAIs are not acceptable to patients) and, perhaps, misinformation (e.g., increased side effect risk). As clinicians, we may well be shortchanging LAIs if we position them as a treatment of last resort for the multi-episode, nonadherent, ‘revolving door’ patient, especially given recent evidence underscoring their potential benefits in first-episode patients. The search for new and more effective antipsychotics will continue, but we are reminded that suboptimal outcomes may have as much to do with nonadherence as inadequate treatments. Evidence has established that LAI antipsychotics demonstrate distinct benefits in this regard, and we would be remiss if we did not exploit this already available strategy. As well as additional research, we need to rethink how we position these agents in our treatment algorithms if we are to maximize their potential.

Antipsychotics and Schizophrenia: From Efficacy and Effectiveness to Clinical Decision-Making

Objective: To comprehensively review the 2 recent and large antipsychotic effectiveness trials for treatment of schizophrenia: the United Kingdoms Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), and the National Institute of Mental Health-initiated Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial. Method: We present a review of the rationale, methodology, and findings to date from the CUtLASS and CATIE schizophrenia trials, including all primary and secondary outcomes. Results: The primary findings from both trials, CUtLASS and CATIE, suggest that first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) are equally effective in the treatment of schizophrenia. The exception is in treatment-resistant populations where clozapine exhibits superiority, compared with other SGAs. In the CATIE trial, there is a suggestion that olanzapine is superior in effectiveness, compared with other nonclozapine SGAs, although this seems to be mediated by past history of olanzapine use, and carries with it increased weight gain and metabolic adverse events. From a cost-effectiveness perspective, there is no evidence that SGAs are superior to FGAs, with findings suggesting the possibility that FGAs may be superior. Conclusion: Past efficacy trials have strongly supported the position that SGAs are superior to FGAs in the treatment of schizophrenia and in side effect profile. Two large independent effectiveness trials, CUtLASS and CATIE, have offered a strong challenge to these claims. Both suggest that SGAs, except clozapine in the treatment-resistant population, offer little, if any, clinical benefits, and, moreover, harbour their own significant side effects.

Where to Position Clozapine: Re-Examining the Evidence

Objective: To review clozapines position in treatment algorithms for schizophrenia. Method: Clozapines status is reviewed in the context of its initial discovery and unique clinical and (or) pharmacological profile, withdrawal and link with hematologic concerns, reintroduction with monitoring guidelines, prototype for atypicality, positioning in treatment algorithms, and current evidence regarding efficacy, effectiveness, and side effects. Results: The hematologic monitoring implemented with clozapines reintroduction here in North America has proven successful in preventing clozapine-related deaths secondary to agranulocytosis. While its other side effects are not without concern, present evidence does not link clozapine to increased mortality rates; indeed, it appears better than other antipsychotics in this regard. Moreover, its clinical superiority compared with all other antipsychotics has been confirmed both in efficacy and in effectiveness trials. Conclusions: Schizophrenia continues to represent a treatment challenge, with many people demonstrating suboptimal response and poor functional outcome. Clozapine is routinely positioned as a third-line treatment in schizophrenia, but in light of existing evidence this warrants re-examination.

Schizophrenia as a disorder of too little dopamine: implications for symptoms and treatment.

Antipsychotics represent the first effective therapy for schizophrenia, with their benefits linked to dopamine D2 blockade. Schizophrenia was soon identified as a hyperdopaminergic disorder, and antipsychotics proved to be reasonably effective in controlling positive symptoms. However, over the years, schizophrenia has been reconceptualized more broadly, now defined as a heterogeneous disorder with multiple symptom domains. Negative and cognitive features, not particularly responsive to antipsychotic therapy, have taken on increased importance – current thinking suggests that these domains predate the onset of positive symptoms and are more closely tied to functional outcome. That they are better understood in the context of decreased dopamine activity suggests that schizophrenia may fundamentally represent a hypodopaminergic disorder. This shift in thinking has important theoretical implications from the standpoint of etiology and pathophysiology, but also clinically in terms of treatment and drug development.

Clozapine’s critical role in treatment resistant schizophrenia: ensuring both safety and use

ABSTRACT Introduction: Clozapine was first introduced as an antipsychotic in the 1970‘s but a cluster of deaths, later linked to the drug’s risk of agranulocytosis, led to its withdrawal in most countries. However, work in the 1980’s established its unique efficacy in treatment resistant schizophrenia (TRS), which constitutes as many as 30% of those with the illness. Clozapine was reintroduced with this indication shortly thereafter, but because of this risk its use requires routine hematologic monitoring. Areas covered: An update is provided regarding clozapine’s risk of neutropenia, agranulocytosis, and associated mortality. In addition, updates are provided on other side effects, specifically myocarditis and bowel obstruction, as evidence suggests these are more common than agranulocytosis and associated with higher mortality rates. Expert opinion: Clozapine remains the only treatment indicated in TRS, but it is dramatically underutilized. Clearly there are serious side effects associated with its use, and while the focus has historically been on hematologic concerns, we highlight other side effects that also demand systematic monitoring. Because it is the only effective treatment option we have for TRS, though, efforts must be implemented that ensure its use in this population while maximizing safety.

Subtyping schizophrenia by treatment response: Antipsychotic development and the central role of positive symptoms

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.

Motivation and Social Cognition in Patients with Schizophrenia.

Social cognition, referring to ones 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.

Values in First-Episode Schizophrenia

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.

F225. LEVODOPA AUGMENTATION OF ANTIPSYCHOTICS FOR THE TREATMENT OF NEGATIVE SYMPTOMS IN SCHIZOPHRENIA

Abstract Background Negative symptoms (i.e., motivation deficits and diminished emotional expression) are prevalent in schizophrenia and consistently linked with functional impairment for affected individuals. Despite advances in psychopharmacology for schizophrenia, there remain no effective treatments for these negative symptoms. Older literature, however, suggests that levodopa in conjunction with antipsychotic treatment can have beneficial effects for patients with schizophrenia. While supporting the safety and potential efficacy of dopamine augmentation, these studies did not evaluate effects within specific symptom domains, particularly negative symptoms. This open-label pilot study was conducted to evaluate the preliminary efficacy and safety of levodopa augmentation of antipsychotics for the treatment of negative symptoms. Methods Ten stable outpatients with schizophrenia between the ages of 18 and 60 were enrolled. All were treated with stable atypical antipsychotic monotherapy for at least eight weeks, and had a minimum total score of 30 on the Scale for the Assessment of Negative Symptoms (SANS). Participants were treated with adjunctive open-label levodopa/carbidopa, with dose titration to levodopa 300mg TID over 38 days as tolerated, and dose maintenance for the remainder of the eight-week trial. Baseline assessments consisted of the SANS, Scale for the Assessment of Positive Symptoms (SAPS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Calgary Depression Scale for Schizophrenia (CDSS), MATRICS Consensus Cognitive Battery (MCCB), and Quality of Life Scale (QLS) for community functioning. Treatment side effects were evaluated with the Simpson Angus Scale (SAS), Barnes Akathisia Rating Scale (BARS), Abnormal Involuntary Movement Scale (AIMS), UKU side effect rating scale (UKU), Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and Barratt Impulsiveness Scale (BIS). Participants were reassessed on measures of psychosis and side effects weekly for the first four weeks, and every two weeks thereafter. The SANS and CGI were repeated at weeks 4 and 8, with the MCCB and QLS re-administered at week 8. Statistical analyses included the intent-to-treat sample (i.e., participants who received at least one dose of study medication) and consisted of linear mixed models for change in SANS total score (our primary outcome), and change in other clinical and side effects measures as a result of treatment. Results Enrolled participants (eight male and two female) had a mean age of 37.2 years. Seven participants completed the study, with three participants dropping out. The mean final dose of levodopa for study completers was 835.7 mg (SD 170.1). Levodopa augmentation resulted in a significant improvement in negative symptoms, with a mean SANS reduction for study completers of 15.3 (SD 5.7). This equated to a mean SANS improvement of 25.5% (range 17% to 57%), with 43% of study completers experiencing > 20% improvement in SANS score. Notably, significant improvement in negative symptoms emerged after the first four weeks of treatment. There was no significant change in positive symptoms, nor other clinical outcomes or side effect measures. Discussion Our findings suggest that levodopa augmentation of antipsychotics may be an effective and well-tolerated treatment for negative symptoms in schizophrenia. These findings, however, need replication in larger randomized controlled trials. With the dearth of available treatments for negative symptoms, levodopa augmentation may represent a novel pharmacologic strategy to address this critical unmet therapeutic need for schizophrenia.

S245. LOWER- AND HIGHER-LEVEL SOCIAL COGNITIVE FACTORS ACROSS INDIVIDUALS WITH SCHIZOPHRENIA SPECTRUM DISORDERS AND HEALTHY CONTROLS: RELATIONSHIP WITH NEUROCOGNITION AND FUNCTIONAL OUTCOME

Abstract Background Individuals with schizophrenia spectrum disorders (SSDs) often suffer social cognitive deficits, which are associated with functional outcome. These include lower-level “simulation” processes (emotion recognition), thought to be subserved by a frontoparietal circuit, and higher-level “mentalizing” processes (theory of mind), involving cortical midline and lateral temporal regions. Despite evidence supporting the distinction of these constructs, little work has focused on the factor structure of social cognition. In schizophrenia, factor analytic results have been inconsistent, likely due to task and analytic approach variability, and inadequate sample sizes. Further, confirmatory factor analysis (CFA) has not been used to compare multiple models across people with SSDs and healthy controls. Thus, our objective was to elucidate the factor structure of social cognition across a large group of people with SSDs and healthy controls. We hypothesized that a two-factor model, including simulation and mentalizing factors, would demonstrate the best fit across participants. We also expected social cognitive and neurocognitive factors to load on separate respective higher-order factors, and social cognition to mediate the relationship between neurocognition and clinical and functional outcome measures. Methods Behavioural data was collected from 164 participants with SSDs and 102 healthy controls across three sites. Participants completed four tasks including measures of social cognition, ranging from basic emotion recognition to complex mental state inference. Participants also completed measures of functional outcome, symptom ratings, and the MATRICS Consensus Cognitive Battery. CFAs were conducted to test social cognitive models, as well as models of social cognition and neurocognition, and multi-group CFA was used to test measurement invariance between patients and controls. Results As predicted, a two-factor (simulation, mentalizing) model fit the social cognitive data well across participants with SSDs and healthy controls (RMSEA = .010, CFI = 1.00). This model also fit significantly better than a one-factor model (p < .001). Further, measurement invariance testing revealed factor structure invariance, loading invariance, and partial intercept invariance between groups, allowing for between-group comparisons. Participants with SSDs showed lower scores than controls for both simulation and mentalizing factors (p < .001), and scores on both factors correlated significantly with symptom ratings and functional outcome measures. Including neurocognitive data, a higher-order two-factor (social cognition, neurocognition) model fit the data well (RMSEA = .047, CFI = .971), and showed significantly better fit than a one- or two-factor model (p < .001). Lastly, social cognition was found to mediate the relationship between neurocognition and negative symptoms, as well as social functioning and quality of life measures (p < .05). Discussion Our results provide evidence that social cognition includes lower- and higher-level dimensions across both individuals with SSDs and healthy controls. They also suggest that both aspects are associated with clinical and functional outcome indices, and act as a mediator between neurocognition and these measures. This provides support for distinguishing lower- and higher-level social cognition between and across people with SSDs and healthy controls, and suggests that they may indeed have partially distinct underlying mechanisms. Further, results confirm the importance of social cognition as it relates to clinical and functional outcomes, and thereby as a potential treatment target for patients with SSDs.