The Group of Treatment Resistant Schizophrenias. Heterogeneity in Treatment Resistant Schizophrenia (TRS)

Schizophrenia is composed of a heterogeneous group of patient segments. Our current notion of the heterogeneity in schizophrenia is based on patients presenting with diverse disease symptom phenotypes, risk factors, structural and functional neuropathology, and a mixed range of expressed response to treatment. It is important for clinicians to recognize the various clinical presentations of resistance to treatment in schizophrenia and to understand how heterogeneity across treatment resistant patient segments may potentially inform new strategies for the development of effective treatments for Treatment Resistant Schizophrenia (TRS). The heterogeneity of schizophrenia may be reduced by parsing patient segments based on whether patients demonstrate an adequate or inadequate response to treatment. In our current concept of TRS, TRS is defined as non-response to at least two adequate trials of antipsychotic medication and is estimated to affect about 30% of all patients with schizophrenia. In this narrative review, the author discusses that the demonstration of inadequate response to antipsychotic drugs (APDs) may infer that some TRS patients may be suffering from a non-dopamine pathophysiology since D2 receptor antagonist-based treatment is ineffective. Preliminary neurobiological findings may further support the pathophysiologic distinction of TRS from that of general schizophrenia. Investigation of the basis for heterogeneity in TRS through the systematic investigation of relevant “clusters” of similarly at risk individuals may hopefully bring us closer to realize a precision medicine approach for developing effective therapies for TRS patient segments

Discontinuation of treatment of schizophrenic patients is driven by poor symptom response: a pooled post-hoc analysis of four atypical antipsychotic drugs

BACKGROUND: Stopping antipsychotic treatment can interrupt improvement and exacerbate the illness. The reasons for discontinuing treatment during controlled clinical trials were analyzed to explore this phenomenon. METHODS: A post-hoc, pooled analysis was made of 4 randomized, double-blind clinical trials, 24–28 weeks in duration, involving 1627 patients with schizophrenia or a related disorder. Analyses combined all the atypical antipsychotic treatment groups in the studies. RESULTS: The majority of patients (53%) stopped their treatment at an early stage. Poor psychiatric response along with worsening symptoms was the most frequently given reason for discontinuing the course (36%), which was substantially more common than discontinuation due to poor tolerability of the medication (12%). This phenomenon was corroborated by less improvement in patients who discontinued treatment compared with those who completed, based on the PANSS total scores. Discontinuation due to poor response was, apparently, more predominantly linked to patient perception than to physicians' conclusions alone (80% vs. 20%). Discontinuation due to patient perception of poor response appeared to occur particularly early in the course of treatment. Patients who discontinued due to poor toleration of the medication responded in a more comparable manner with completers. CONCLUSION: Discontinuing treatment may lead to exacerbation of symptoms, undermining therapeutic progress. In these studies, poor response to treatment and worsening of underlying psychiatric symptoms, and to a lesser extent, intolerability to medication were the primary contributors to treatment being discontinued. Our findings suggest that adherence may be enhanced by effective symptom control, as objectively measured and as subjectively perceived. Such strategies may improve patients' willingness to undertake long-term therapy and increase the likelihood of a better prognosis

Sexual dysfunction in patients with schizophrenia treated with conventional antipsychotics or risperidone

Hong Liu-Seifert1, Bruce J Kinon1, Christopher J Tennant2, Jennifer Sniadecki1, Jan Volavka31Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA; 2CJT Biomedical Consulting, South Lake Tahoe, CA, USA; 3New York University, New York, NY, USAObjective: To better understand sexual dysfunction in patients with schizophrenia and its associations with prolactin and reproductive hormones.Methods: This was a secondary analysis of an open-label, one-day study (N = 402). The primary objective of the study was to assess the prevalence of hyperprolactinemia in patients with schizophrenia who had been treated with conventional antipsychotics or risperidone. Other atypical antipsychotics available at the time of the study were not included due to a more favorable prolactin profile.Results: The majority of patients (59% of females and 60% of males) reported impairment of sexual function. In postmenopausal females, risk of impaired sexual interest was increased by 31% for every 10 ng/ml increase in prolactin (p = 0.035). In males, lower testosterone was associated with higher prolactin (p < 0.001) and with orgasmic (p = 0.004) and ejaculatory dysfunction (p = 0.028).Conclusion: These findings suggest that hyperprolactinemia may be associated with sexual dysfunction. They also provide more information on the relationships between prolactin, reproductive hormones, and sexual dysfunction. Sexual dysfunction is an understudied yet important consideration in the treatment of schizophrenia. More attention is warranted in this area as it may provide opportunities for improved quality of life and adherence to treatment for patients.Keywords: sexual dysfunction, schizophrenia, hyperprolactinemia, antipsychotics, risperidon

Involvement in the US criminal justice system and cost implications for persons treated for schizophrenia

<p>Abstract</p> <p>Background</p> <p>Individuals with schizophrenia may have a higher risk of encounters with the criminal justice system than the general population, but there are limited data on such encounters and their attendant costs. This study assessed the prevalence of encounters with the criminal justice system, encounter types, and the estimated cost attributable to these encounters in the one-year treatment of persons with schizophrenia.</p> <p>Methods</p> <p>This post-hoc analysis used data from a prospective one-year cost-effectiveness study of persons treated with antipsychotics for schizophrenia and related disorders in the United States. Criminal justice system involvement was assessed using the Schizophrenia Patients Outcome Research Team (PORT) client survey and the victimization subscale of the Lehman Quality of Life Interview (QOLI). Direct cost of criminal justice system involvement was estimated using previously reported costs per type of encounter. Patients with and without involvement were compared on baseline characteristics and direct annual health care and criminal justice system-related costs.</p> <p>Results</p> <p>Overall, 278 (46%) of 609 participants reported at least 1 criminal justice system encounter. They were more likely to be substance users and less adherent to antipsychotics compared to participants without involvement. The 2 most prevalent types of encounters were being a victim of a crime (67%) and being on parole or probation (26%). The mean annual per-patient cost of involvement was $1,429, translating to 6% of total annual direct health care costs for those with involvement (11% when excluding crime victims).</p> <p>Conclusions</p> <p>Criminal justice system involvement appears to be prevalent and costly for persons treated for schizophrenia in the United States. Findings highlight the need to better understand the interface between the mental health and the criminal justice systems and the related costs, in personal, societal, and economic terms.</p

Identification of early changes in specific symptoms that predict longer-term response to atypical antipsychotics in the treatment of patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>To identify a simple decision tree using early symptom change to predict response to atypical antipsychotic therapy in patients with (Diagnostic and Statistical Manual, Fourth Edition, Text Revised) chronic schizophrenia.</p> <p>Methods</p> <p>Data were pooled from moderately to severely ill patients (n = 1494) from 6 randomized, double-blind trials (N = 2543). Response was defined as a ≥30% reduction in Positive and Negative Syndrome Scale (PANSS) Total score by Week 8 of treatment. Analyzed predictors were change in individual PANSS items at Weeks 1 and 2. A decision tree was constructed using classification and regression tree (CART) analysis to identify predictors that most effectively differentiated responders from non-responders.</p> <p>Results</p> <p>A 2-branch, 6-item decision tree was created, producing 3 distinct groups. First branch criterion was a 2-point score decrease in at least 2 of 5 PANSS positive items (Week 2). Second branch criterion was a 2-point score decrease in the PANSS excitement item (Week 2). "Likely responders" met the first branch criteria; "likely non-responders" did not meet first or second criterion; "not predictable" patients did not meet the first but did meet the second criterion. Using this approach, response to treatment could be predicted in most patients (92%) with high positive predictive value (79%) and high negative predictive value (75%). Predictive findings were confirmed through analysis of data from 2 independent trials.</p> <p>Conclusions</p> <p>Using a data-driven approach, we identified decision rules using early change in the scores of selected PANSS items to accurately predict longer-term treatment response or non-response to atypical antipsychotic therapy. This could lead to development of a simple quantitative evaluation tool to help guide early treatment decisions.</p> <p>Trial Registration</p> <p>This is a retrospective, non-intervention study in which pooled results from 6 previously published reports were analyzed; thus, clinical trial registration is not required.</p

Comparison of patients undergoing switching versus augmentation of antipsychotic medications during treatment for schizophrenia

It is often difficult to determine whether a patient may best benefit by augmenting their current medication or switching them to another. This post-hoc analysis compares patients’ clinical and functional profiles at the time their antipsychotic medications were either switched or augmented. Adult outpatients receiving oral antipsychotic treatment for schizophrenia were assessed during a 12-month international observational study. Clinical and functional measures were assessed at the time of first treatment switch/augmentation (0–14 days prior) and compared between Switched and Augmented patient groups. Due to low numbers of patients providing such data, interpretations are based on effect sizes. Data at the time of change were available for 87 patients: 53 Switched and 34 Augmented. Inadequate response was the primary reason for treatment change in both groups, whereas lack of adherence was more prevalent in the Switched group (26.4% vs 8.8%). Changes in clinical severity from study initiation to medication change were similar, as indicated by Clinical Global Impressions–Severity scores. However, physical and mental component scores of the 12-item Short-Form Health Survey improved in the Augmented group, but worsened in the Switched group. These findings suggest that the patient’s worsening or lack of meaningful improvement prompts clinicians to switch antipsychotic medications, whereas when patients show some improvement, clinicians may be more likely to try bolstering the improvements through augmentation. Current findings are consistent with physicians’ stated reasons for switching versus augmenting antipsychotics in the treatment of schizophrenia. Confirmation of these findings requires further research

The relationship, structure and profiles of schizophrenia measurements: a post-hoc analysis of the baseline measures from a randomized clinical trial

<p>Background</p> <p>To fully assess the various dimensions affected by schizophrenia, clinical trials often include multiple scales measuring various symptom profiles, cognition, quality of life, subjective well-being, and functional impairment. In this exploratory study, we characterized the relationships among six clinical, functional, cognitive, and quality-of-life measures, identifying a parsimonious set of measurements.</p> <p>Methods</p> <p>We used baseline data from a randomized, multicenter study of patients diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder who were experiencing an acute symptom exacerbation (n = 628) to examine the relationship among several outcome measures. These measures included the Positive and Negative Syndrome Scale (PANSS), Montgomery-Asberg Depression Rating Scale (MADRS), Brief Assessment of Cognition in Schizophrenia Symbol Coding Test, Subjective Well-being Under Neuroleptics Scale Short Form (SWN-K), Schizophrenia Objective Functioning Instrument (SOFI), and Quality of Life Scale (QLS). Three analytic approaches were used: 1) path analysis; 2) factor analysis; and 3) categorical latent variable analysis. In the optimal path model, the SWN-K was selected as the final outcome, while the SOFI mediated the effect of the exogenous variables (PANSS, MADRS) on the QLS.</p> <p>Results</p> <p>The overall model explained 47% of variance in QLS and 17% of the variance in SOFI, but only 15% in SWN-K. Factor analysis suggested four factors: "Functioning," "Daily Living," "Depression," and "Psychopathology." A strong positive correlation was observed between the SOFI and QLS (r = 0.669), and both the QLS and SOFI loaded on the "Functioning" factor, suggesting redundancy between these scales. The measurement profiles from the categorical latent variable analysis showed significant variation in functioning and quality of life despite similar levels of psychopathology.</p> <p>Conclusions</p> <p>Researchers should consider collecting PANSS, SOFI, and SWN-K in their trials. This would allow a broad spectrum of assessments that would have the ability to capture a wide range of treatment outcomes and allow for a rich characterization of the subgroups involved. Additional research is needed to identify the critical cognitive measures.</p> <p>Trials registration</p> <p>Clinical trials registration: Predicting Response to Risperidone Treatment Through Identification of Early-onset of Antipsychotic Drug Action in Schizophrenia</p> <p>ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00337662">NCT00337662</a>; <url>http://www.clinicaltrials.gov/</url></p