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Most individuals with psychotic disorders relapse over their course of illness, yet the neural processes that may lead to symptom worsening are poorly understood. Importantly, such processes could be potentially affected by antipsychotic adherence status upon relapse (i.e., relapse despite ongoing antipsychotic maintenance vs following antipsychotic discontinuation), reflecting distinct mechanisms. As a first foray into this question, we aim to compare the striatal connectivity index (SCI), a biomarker derived from striatal resting state functional connectivity predictive of treatment response, by adherence status upon relapse. In order to confirm adherence status upon relapse, we compared individuals treated with long-acting injectable antipsychotics upon relapse (i.e., breakthrough psychosis) (n = 23), with individuals who had decided to interrupt antipsychotic treatment and then relapsed (n = 27), as well as healthy controls (n = 26). We acquired for each individual >10 min of resting state fMRI, to generate functional connectivity maps. Region of interest (ROI) analyses were conducted to calculate SCI values for each participant. These values were entered as dependent variable in a linear regression adjusted for sex and age for which adherence status was the independent variable. Individuals in the breakthrough psychosis group had significantly lower SCI values than healthy controls (Cohen's d = 0.99, p < 0.001), and non-adherent individuals upon relapse (Cohen's d = 0.58, p = 0.032), whereas non-adherent individuals had also trend level lower SCI values than healthy controls (Cohen's d = 0.44, p = 0.09). These results suggest the hypothesis that striatal functional connectivity may be aberrant in psychosis relapse, and that this dysfunction may be greater among individuals who developed relapse despite ongoing antipsychotic treatment. [ABSTRACT FROM AUTHOR]

Objective To quantify the risk and predictors of relapse among individuals with schizophrenia randomly withdrawn from antipsychotic maintenance treatment. Methods We re-analyzed time-to-event and baseline predictors from placebo arms in five placebo-controlled randomized trials of antipsychotics (n = 688 individuals; 173 stabilized on oral antipsychotic [OAP] and 515 on long-acting injectables [LAI]) for relapse-prevention available in the Yale Open Data Access repository. Using a survival and Cox-proportional hazards regression analyses, we estimated survival rates of "relapse-free" individuals by the end of follow-up (median = 118 days, IQR = 52.0–208.0), the rate of study-confirmed relapse, and adjusted hazard ratios (aHR, 95% confidence intervals [CI]) associated with baseline predictors. We also estimated these parameters for individuals followed for >5 half-lives of the stabilizing antipsychotic, and studied predictors of "rebound psychosis" in OAP-stabilized participants, defined as occurring within 30 days of antipsychotic withdrawal. Results 29.9% (95%CI = 23.2–38.5) remained relapse-free by the end of follow-up, 11.1% (95%CI = 5.65–21.9) among those OAP-stabilized, 36.4% (95%CI = 28.4–46.7) among those LAI-stabilized. The study-confirmed relapse rate was 45.2%, 62.4% among those OAP-stabilized and 39.4% among those LAI-stabilized. Predictors of relapse included smoking (aHR = 1.54, 95%CI = 1.19–2.00), female sex (aHR = 1.37, 95%CI = 1.08–1.79), and having been stabilized on OAPs vs LAIs (aHR = 3.56, 95%CI = 2.68–4.72). Greater risk of relapse on OAP persisted even after sufficient time had elapsed to clear antipsychotic plasma level among LAI-stabilized (aHR = 5.0, 95%CI = 3.5–7.1). "Rebound psychosis" did not show predictors. Conclusions and relevance Our results corroborate the high relapse risk following antipsychotic withdrawal after symptom stabilization with limited patient-related predictors of safe treatment discontinuation. Stabilization with LAIs reduces the short-/medium-term relapse risk. [ABSTRACT FROM AUTHOR]

There is an ongoing debate about the potential risks and benefits of long-term antipsychotic treatment in schizophrenia. The data for and against the chronic use of these medicines is mostly indirect, either from observational studies potentially exposed to reverse causation bias or randomized controlled studies that do not cover beyond 2–3 years. We propose that perseverating on the question of what positive or negative outcomes are causally associated with chronic antipsychotic treatment may not lead to better answers than the limited ones that we have, given the limited feasibility of more conclusive studies. Rather, we argue that addressing the research question of the risks and benefits of antipsychotic discontinuation from a perspective of personalized medicine, can be more productive and meaningful to people living with schizophrenia. To this end, research that can quantify the risk of relapse after treatment continuation for a given individual should be prioritized. We make the case that clinically feasible neuroimaging biomarkers have demonstrated promise in related paradigms, and that could be offering a way past this long debate on the risks and benefits of chronic antipsychotic use. [ABSTRACT FROM AUTHOR]

Background: There is uncertainty about the incidence of breakthrough psychosis in treatment adherent patients, and the role that factors, such as cumulative antipsychotic exposure, play in this phenomenon. Methods: In a nationwide cohort of individuals treated for schizophrenia-spectrum disorders in Finland between 1 January 1996 and 31 December 2015, 'Breakthrough Psychosis on Antipsychotic Maintenance Medication' (BAMM) was defined as hospitalization for psychosis despite ongoing continuous treatment with long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs) for ⩾8 weeks. Incidence rates, survival curves, and risk factors were presented. Results: In a cohort of 16 031 continuous LAI treatment episodes with virtually assured adherence [median duration = 441 days, interquartile range (IQR) = 155–1277], BAMM incidence was 31.5%. For 42 867 OAPs treatment episodes (median duration = 483 days, IQR = 167–1491), for whom adherence was modeled by the PRE2DUP method, BAMM incidence was 31.1%. Factors related to illness instability at treatment onset were associated with BAMM, although median time to BAMM was 291 days (IQR = 121–876) for LAIs and 344 days (IQR = 142–989) for OAPs, and 27.4% (N = 1386) of the BAMM events in the LAI, and 32.9% (N = 4378) in the OAP group occurred despite >1 year since last hospitalization at treatment onset. Cumulative antipsychotic exposure was not a consistent risk factor. Conclusion: BAMM was relatively common even when adherence was confirmed with LAIs. Illness instability at treatment onset accounted for most cases, but relapse after years of continuous treatment was still prevalent. There was insufficient evidence to support causality between cumulative antipsychotic exposure and BAMM. Future research needs to address the role of symptom severity and neurobiology in BAMM. [ABSTRACT FROM AUTHOR]

Schizophrenia is a chronic disorder that often requires long-term relapse-prevention treatment. This treatment is effective for most individuals, yet approximately 20–30 % of them may still relapse despite confirmed adherence. Alternatively, for about 15 % it may be safe to discontinue medications over the long term, but since there are no means to identify who those individuals will be, the recommendation is that all individuals receive long-term relapse-prevention treatment with antipsychotic maintenance. Thus, the current approach to prevent relapse in schizophrenia may be suboptimal for over one third of individuals, either by being insufficient to protect against relapse, or by unnecessarily exposing them to medication side effects. There is great need to identify biomarkers of relapse in schizophrenia to stratify treatment according to the risk and develop therapeutics targeting its pathophysiology. In order to develop a line of research that meets those needs, it is necessary to create a framework by identifying the challenges to this type of study as well as potential areas for biomarker identification and development. In this manuscript we review the literature to create such a framework. [ABSTRACT FROM AUTHOR]

Background: Some patients develop breakthrough psychotic symptoms on antipsychotic maintenance medication (BAMM), despite receiving therapeutic antipsychotic doses to which they previously responded.Methods: We examined the occurrence of BAMM in previously minimally treated first-episode patients with schizophrenia-spectrum disorders who were treated according to a standard protocol with a long-acting injectable antipsychotic and regularly assessed over 24 months.Results: Of 99 patients (age = 24.1 ± 6.5 years, male = 73.7%) who received treatment for ≥6 months (mean follow-up = 20.0 ± 6.5 months) and had responded well to treatment, 21 (21.2%) developed BAMM using operationally defined criteria, after a mean of 17.4 ± 6.1 months. Baseline risk factors for BAMM included lower baseline Positive and Negative Syndrome Scale positive symptoms, poorer quality of life in social relationships and higher blood - high-density lipoprotein-cholesterol. Regarding intra-treatment-factors, BAMM was independently predicted by an increase in low-density lipoprotein-cholesterol and current cannabis use. We did not find a relationship between BAMM and cumulative antipsychotic exposure or dose escalation. While symptoms of the BAMM episode were less severe than during the first episode, the post-BAMM treatment response was poorer than that for the first psychotic episode, suggesting a relationship between BAMM and emergent treatment refractoriness.Conclusions: About one in five patients with first-episode schizophrenia developed BAMM during the first two years of treatment, despite assured antipsychotic LAI treatment, indicating that this phenomenon is not restricted to the chronic stages of illness. The role of cannabis use and a possible link between BAMM and blood lipids should be further explored. [ABSTRACT FROM AUTHOR]