José Manuel Olivares

Definitions and drivers of relapse in patients with schizophrenia: a systematic literature review

Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple scales often appeared within the same definition. There were 95 references to factors that may drive relapse, including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95). Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates—continuous antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse. Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid the identification of at-risk patients.

Serotonin transporter clustering in blood lymphocytes as a putative biomarker of therapeutic efficacy in major depressive disorder

BACKGROUNDnSerotonin transporter (SERT) binding is decreased in lymphocytes of depression patients and this decrease is partially reversed by antidepressant medication. However, recent evidence has shown that clustering of SERT on cell membranes is very important for receptor functionality. Alteration in SERT clustering on peripheral lymphocytes does not affect symptoms severity. At the most it is associated or predicts responsivity to treatment.nnnMETHODSnWe collected blood samples from 38 untreated and newly diagnosed depression patients at the time of diagnosis and after 8weeks of pharmacological treatment and of 38 control subjects. We used the Hamilton Scale to quantify the level of depression in patients both before and after pharmacological treatment. We then used immunocytochemistry to assess SERT protein clusters in lymphocyte blood samples.nnnRESULTSnWe found an increase in SERT cluster size, but not the number of SERT clusters, in naïve depression patients compared to control subjects. Based on the distribution of SERT cluster size we differentiated the naïve depression patients into two groups (D-I and D-II). Naïve D-I and D-II patients initially showed similar Hamilton scores. However, after pharmacological treatment the D-II patients showed a greater decrease in Hamilton scores than did the D-I patients, and they had an increase in the number of SERT clusters.nnnLIMITATIONSnThe data should be replicated in a larger cohort of patients and with a proper clinical trial.nnnCONCLUSIONSnWe propose that SERT clustering in blood lymphocytes may be a putative biomarker for antidepressant efficacy in major depressive disorder.

Serotonin 2A receptor clustering in peripheral lymphocytes is altered in major depression and may be a biomarker of therapeutic efficacy

BACKGROUNDnIn a previous report, we showed that the clustering of serotonin (5HT) transporter (SERT) protein on cell membranes of peripheral lymphocytes predicts responsivity to antidepressant medication in two subpopulations of naïve depression patients (Rivera-Baltanas et al., J Affect Disord, 2012, 137, 46-55). In this study, we extended this idea to 5-HT2A receptor clusters in a similar patient population.nnnMETHODSnWe collected blood samples from a subset of patients from our previous study on SERT clustering (20 untreated and newly diagnosed depression patients, and 20 matched control subjects). Blood samples were collected at the time of diagnosis and after 8 weeks of pharmacological treatment and at analogous times in control subjects. We used the Hamilton scale to quantify the level of depression in patients both before and after treatment. We then used immunocytochemistry to assess 5-HT2A receptor clusters in lymphocytes at the same time points.nnnRESULTSnWe found that both the size and number of 5-HT2A receptor clusters were increased in naïve depression patients compared to control subjects. Interestingly, there were individual differences in the distribution of 5-HT2A receptor cluster size that allowed us to differentiate the depression patients into two subgroups: a D-I group and a D-II group. After 8 weeks of pharmacological treatment, patients in both groups showed an improvement of symptoms, but patients in the D-II group had a much better outcome with many of them showing remission of symptoms. Furthermore, although treatment decreased cluster number and size in both D-I and D-II groups, only the D-II patients showed an increase in the number of clusters within the modal peak. Importantly, the same patients that belonged in the D-I or D-II groups in the present report were also assigned to the same groups in our previous study on SERT clustering.nnnLIMITATIONSnThe data should be replicated within a proper clinical trial.nnnCONCLUSIONSn5-HT2A receptor clusters in peripheral lymphocytes are altered in major depression, partially reversed by antidepressant treatment, and may be considered a putative biomarker of therapeutic efficacy in major depression.

Psychiatrists’ awareness of adherence to antipsychotic medication in patients with schizophrenia: results from a survey conducted across Europe, the Middle East, and Africa

Background Nonadherence is common among patients with schizophrenia, although the rates vary according to means of assessment and patient population. Failure to adhere to medication can have a major impact on the course of illness and treatment outcomes, including increasing the risk of relapse and rehospitalization. Understanding psychiatrists’ perception of the causes and consequences of nonadherence is crucial to addressing adherence problems effectively. Methods The Europe, the Middle East, and Africa (EMEA) Spanish Adherencia Terapéutica en la Esquizofrenia (ADHES) survey was conducted by questionnaire during January–March 2010 among psychiatrists treating patients with schizophrenia in 36 countries. The survey comprised 20 questions. In addition to recording the demographic details of the 4722 respondents (~12% response rate), it canvassed their preferred methods of assessing adherence, their perceptions of adherence rates, reasons for nonadherence, and strategies to improve adherence. Results Psychiatrists estimated that 53% of their patients with schizophrenia were partially/nonadherent during the previous month. They estimated only one-third of patients who deteriorated after stopping medication were able to attribute this to nonadherence. Psychiatrists assessed adherence most often by patient interview. Lack of insight was viewed as the most important cause of medication discontinuation, followed by patients feeling better and thinking their medication unnecessary, and experiencing undesirable side effects. Considerably fewer psychiatrists viewed insufficient efficacy, cognitive impairment, or drug/alcohol abuse as the most important reasons for their patients stopping medication. Conclusion Psychiatrists throughout EMEA recognize the impact of partial/nonadherence to medication, with patient enquiry being the most commonly used means of assessment. There remains a need for more proactive management of patients with schizophrenia, particularly in increasing patient insight of their illness in order to improve adherence and minimize the consequences of relapse. Strategies focused on raising awareness of the importance of adherence are also warranted, with the aim of improving patient outcomes in schizophrenia.

Reelin-Related Disturbances in Depression: Implications for Translational Studies

The finding that reelin expression is significantly decreased in mood and psychotic disorders, together with evidence that reelin can regulate key aspects of hippocampal plasticity in the adult brain, brought our research group and others to study the possible role of reelin in the pathogenesis of depression. This review describes recent progress on this topic using an animal model of depression that makes use of repeated corticosterone (CORT) injections. This methodology produces depression-like symptoms in both rats and mice that are reversed by antidepressant treatment. We have reported that CORT causes a decrease in the number of reelin-immunopositive cells in the dentate gyrus subgranular zone (SGZ), where adult hippocampal neurogenesis takes place; that down-regulation of the number of reelin-positive cells closely parallels the development of a depression-like phenotype during repeated CORT treatment; that reelin downregulation alters the co-expression of reelin with neuronal nitric oxide synthase (nNOS); that deficits in reelin might also create imbalances in glutamatergic and GABAergic circuits within the hippocampus and other limbic structures; and that co-treatment with antidepressant drugs prevents both reelin deficits and the development of a depression-like phenotype. We also observed alterations in the pattern of membrane protein clustering in peripheral lymphocytes in animals with low levels of reelin. Importantly, we found parallel changes in membrane protein clustering in depression patients, which differentiated two subpopulations of naïve depression patients that showed a different therapeutic response to antidepressant treatment. Here, we review these findings and develop the hypothesis that restoring reelin-related function could represent a novel approach for antidepressant therapies.

Serotonin transporter clustering in blood lymphocytes predicts the outcome on anhedonia scores in naïve depressive patients treated with antidepressant medication

BackgroundWe have shown that serotonin transporter (SERT) clustering in blood lymphocytes is altered in major depression and correlates with pharmacological therapeutic responses measured with the Hamilton scale. In the present report, we extend these results to the self-assessment anhedonia scale, as anhedonia is a cardinal symptom of major depression that is difficult to treat with first-line antidepressants.MethodsWe collected blood samples from 38 untreated depression patients at the time of enrolment and 8xa0weeks after pharmacological treatment. We used the self-assessment anhedonia scale to evaluate anhedonia symptoms before and after treatment. We also used quantitative immunocytochemistry to measure SERT clusters in blood lymphocytes.ResultsEvaluation of the distribution of SERT clusters size in the plasma membrane of lymphocytes identified two subpopulations of naive depression patients: Depression I (D-I) and Depression II (D-II). While naïve D-I and D-II patients initially showed similar anhedonia scores, D-II patients showed a good response in anhedonia symptoms after 8 weeks of psychopharmacological treatment, whereas D-I patients failed to show any improvement. Psychopharmacological treatment also induced an increase in the number of SERT clusters in lymphocytes in the D-II group, and this increase correlated with the improvement in anhedonia symptoms.ConclusionsSERT clustering in peripheral lymphocytes can be used to identify patient response to antidepressant therapy as ascertained by anhedonia scores.

Relapse and therapeutic interventions in a 1-year observational cohort study of nonadherent outpatients with schizophrenia.

OBJECTIVESnTo evaluate the incidence rate of relapse, the clinical profiles, and the therapeutic interventions employed for patients with schizophrenia deemed as likely nonadherers to oral antipsychotic drugs.nnnMETHODSnA cohort of 597 outpatients whose therapy was modified because of a psychiatrist-perceived risk of nonadherence was followed for 12 months in an observational study. Baseline correlates of subsequent relapse were analyzed with Cox regression.nnnRESULTSnAt baseline, patients mean (SD) age and time since diagnosis were 40.1 (11.1) and 15.2 (10.0) years, respectively; 63.7% were males. The Clinical Global Impression scale-Severity (CGI-S) score was ≥ 4 in 87.3% of the patients. Antipsychotic drugs were modified in 506 patients (84.8%); nonpharmacologic therapies were modified in 190 patients (31.8%). In both cases, the primary reason for the modifications was insufficient efficacy of current therapeutic regimen. The proportion of patients in oral antipsychotic monopharmacy decreased from 83.8% to 57.6%; 15.4% started long-acting (depot) formulations. Over the 12-month observation period, 90 patients (15.1%) relapsed. The hazard rate of relapse was higher in patients with substance use disorder or familial psychiatric antecedents and lower in patients who underwent modifications of nonpharmacological therapies or with negative attitude toward antipsychotic medication at baseline.nnnCONCLUSIONSnEffective interventions to prevent relapse in patients with long-standing schizophrenia involving therapeutic challenges related to nonadherence are feasible. Rationale for the baseline correlates, and cues for clinical prevention of relapse in these patients are provided.

Cytokines dysregulation in schizophrenia: A systematic review of psychoneuroimmune relationship

INTRODUCTIONnSchizophrenia is a multifactorial psychiatric disease with complex interactions among the brain and the immune system. A psycho-immune relationship underling schizophrenia is supported by several studies and integrates a specific area of knowledge - psychoneuroimmunology.nnnMETHODSnA systematic review was performed by 2009 Preferred Reporting Items (PRISMA) recommendations. Based on the inclusion/exclusion criteria, publications with relevant information (evaluated by the Joanna Briggs Institute Critical Appraisals tools to quality assessment) were included.nnnRESULTSnIn this review, we considered the inflammatory activity promoted by cytokine alterations in schizophrenia aetiology, which reflects the systemic comprehension of this disease in opposition to the traditional approach focused solely on the brain. We focus on the analysis of several specific outcomes, such as proinflammatory cytokines, sample sort, laboratory techniques, diagnosis scales and results of each publication.nnnCONCLUSIONnThis systematic review confirms the existence of cytokines abnormalities in schizophrenia disease. Immune imbalances such as increased levels of some cytokines (either at protein level or at mRNA expression), cytokine mRNAs, as well as cytokine gene polymorphisms have been reported with a large support in schizophrenia. These findings provide a strong evidence of a concomitant process of inflammatory activity in schizophrenia illness course.

Treatment patterns and health care resource utilization in a 1‑year observational cohort study of outpatients with schizophrenia at risk of nonadherence treated with long‑acting injectable antipsychotics

Purpose To describe (1) the clinical profiles and the patterns of use of long-acting injectable (LAI) antipsychotics in patients with schizophrenia at risk of nonadherence with oral antipsychotics, and in those who started treatment with LAI antipsychotics, (2) health care resource utilization and associated costs. Patients and methods A total of 597 outpatients with schizophrenia at risk of nonadherence, according to the psychiatrist’s clinical judgment, were recruited at 59 centers in a noninterventional prospective observational study of 1-year follow-up when their treatment was modified. In a post hoc analysis, the profiles of patients starting LAI or continuing with oral antipsychotics were described, and descriptive analyses of treatments, health resource utilization, and direct costs were performed in those who started an LAI antipsychotic. Results Therapy modifications involved the antipsychotic medications in 84.8% of patients, mostly because of insufficient efficacy of prior regimen. Ninety-two (15.4%) patients started an LAI antipsychotic at recruitment. Of these, only 13 (14.1%) were prescribed with first-generation antipsychotics. During 1 year, 16.3% of patients who started and 14.9% of patients who did not start an LAI antipsychotic at recruitment relapsed, contrasting with the 20.9% who had been hospitalized only within the prior 6 months. After 1 year, 74.3% of patients who started an LAI antipsychotic continued concomitant treatment with oral antipsychotics. The mean (median) total direct health care cost per patient per month during the study year among the patients starting any LAI antipsychotic at baseline was €1,407 (€897.7). Medication costs (including oral and LAI antipsychotics and concomitant medication) represented almost 44%, whereas nonmedication costs accounted for more than 55% of the mean total direct health care costs. Conclusion LAI antipsychotics were infrequently prescribed in spite of a psychiatrist-perceived risk of nonadherence to oral antipsychotics. Mean medication costs were lower than nonmedication costs.

Schizophrenia: A review of potential biomarkers

OBJECTIVESnUnderstanding the biological process and progression of schizophrenia is the first step to developing novel approaches and new interventions. Research on new biomarkers is extremely important when the goal is an early diagnosis (prediction) and precise theranostics. The objective of this review is to understand the research on biomarkers and their effects in schizophrenia to synthesize the role of these new advances.nnnMETHODSnIn this review, we search and review publications in databases in accordance with established limits and specific objectives. We look at particular endpoints such as the category of biomarkers, laboratory techniques and the results/conclusions of the selected publications.nnnRESULTSnThe investigation of biomarkers and their potential as a predictor, diagnosis instrument and therapeutic orientation, requires an appropriate methodological strategy. In this review, we found different laboratory techniques to identify biomarkers and their function in schizophrenia.nnnCONCLUSIONnThe consolidation of this information will provide a large-scale application network of schizophrenia biomarkers.