Maintenance Antipsychotic Treatment Research Articles

A Narrative Review Exploring Attention Deficit/Hyperactivity Disorder in Patients with Early Psychosis.

While both Attention deficit hyperactivity disorder (ADHD) and schizophrenia are considered to have neurodevelopmental origins with associated impairments in executive functioning, there is a paucity of clinical guidelines pertaining specifically to this comorbidity. We sought to summarize the existing literature on ADHD in early psychosis patients, focusing on issues that would be most relevant to clinical practice. For this narrative review, we completed a search on PubMed and PsycINFO with 22 papers meeting criteria for review. Overall, it appears that a diagnosis of ADHD in childhood increases the risk of the subsequent development of a primary psychotic disorder. This risk may be modified by higher rates of substance use and could be related to shared premorbid risk factors for both conditions, such as obstetrical complications. Stimulant use has been associated with the onset of psychotic symptoms in some individuals, but it is unclear whether certain subgroups are more susceptible. Despite the fact that these two conditions co-occur relatively frequently, there is currently a lack of objective diagnostic tests for ADHD specific to populations with primary psychotic disorders, and a paucity of evidence on whether stimulants are effective for ADHD symptoms in this sub-group. Future research is warranted to investigate whether stimulant treatment confers any additional risks for symptom exacerbation in individuals with primary psychotic disorders taking antipsychotic maintenance treatment.

Time-dependent effect of antipsychotic discontinuation and dose reduction on social functioning and subjective quality of life–a multilevel meta-analysis

Meta-analyses indicate superiority of antipsychotic maintenance treatment over discontinuation within up to 24 months after treatment initiation for patients with schizophrenia-spectrum disorders. In terms of functional recovery, long-term trials show improved functioning after discontinuation, suggesting a time-dependent effect of antipsychotic maintenance. However, these trials were not included in previous meta-analyses. We therefore investigated whether the effect of antipsychotic maintenance treatment vs. discontinuation on social functioning and quality of life varies by trial length. The study was preregistered with PROSPERO (CRD42021248933). PubMed, PsycINFO, Web of Science, Embase and trial registers were systematically searched on 8th November 2021 and updated on 25th June, 2023 and 10th August, 2023 for studies that compared antipsychotic maintenance to discontinuation and reported data on social functioning or subjective quality of life in patients with schizophrenia-spectrum disorders. Risk of bias was assessed with the RoB 2, the ROBINS-I and the RoB-ME tools. Quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation approach. We included k=35 studies (N=5924) with follow-ups between one month and 15 years. Overall, maintenance and discontinuation did not differ on social functioning (k=32; n=5330; SMD=0.204; p=0.65; 95% CI [-0.69, 1.10]) or quality of life (k=10; n=943; SMD=-0.004; p=0.97; 95% CI [-0.22, 0.21]), whilst subgroup analyses of middle- (2-5 years; k=7; n=1032; SMD=0.68; 95% CI [0.06, 1.28]) and long-term follow-ups (>5 years; k=2; n=356; SMD=1.04; 95% CI [0.82, 1.27]) significantly favoured discontinuation. However, the quality of evidence was rated as very low. Although our findings suggest a time-dependent decrease in the effect of maintenance treatment on social functioning, interpretation of these findings is limited by the serious risk of bias in middle- and long-term trials. Therefore, any conclusions regarding the long-term benefits of antipsychotic treatment or discontinuation for functional recovery are premature and more high-quality trials tailored to comparing state of the art maintenance treatment vs. discontinuation are needed. None.

Targeted Treatment of Schizophrenia Symptoms as They Manifest, or Continuous Treatment to Reduce the Risk of Psychosis Recurrence.

Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate's questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient's quality of life. Patients' profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered.

Mental Health Staff's Perspectives on Tapering of Antipsychotic Medication: A Focus Group Study.

Contemporary practices of long-term antipsychotic maintenance treatment for schizophrenia are being challenged, and clinicians must consider the possibilities of reducing long-term maintenance use. However, research indicates that people with schizophrenia receive little support from mental health staff to reduce antipsychotic medication. This article reports a study which aimed to investigate interdisciplinary mental health staff's accounts of tapering of antipsychotic medication and to explore different positions that mental health staff assign to themselves and others. Six focus groups were conducted with 39 mental health staff from outpatient clinics, inpatient units, forensic mental health units, and community mental health services. The data analysis combined analyses of the interactions during focus groups and the thematic content. Results were considered from a discourse analytic perspective considering the function and consequence of accounts applied by the mental health staff. The mental health staff accounted for their perspectives on tapering from the following three distinctive positions: 1) No, patients will eventually realize that they need the medication, 2) Yes, but tapering means running a big risk of relapse in symptoms, and 3) Yes, we need to welcome risks to support personal recovery. Our findings indicated that there was reluctance among interdisciplinary mental health staff to let service users make decisions and limited possibilities for people with schizophrenia to have their request for tapering of their antipsychotic medication met by mental health staff.

Therapeutic Drug Monitoring of Long-Acting Injectable Antipsychotics as a Predictor of Relapse in Schizophrenia Spectrum Disorders: A 1-Year Pilot Study.

Long-acting injectable antipsychotics (LAIs) have been shown to reduce acute episodes of schizophrenia spectrum disorders (SSDs). However, breakthrough relapses are frequent, possibly because of underdosing in clinical practice. In this framework, the advantages of therapeutic drug monitoring (TDM) may be overlooked. This study explored the association of low steady-state LAI levels with a higher risk of relapse in SSDs, despite the use of a licensed posology. Forty-eight clinically stable outpatients with SSD underwent LAI-TDM using liquid chromatography-mass spectrometry for routine observational purposes. Baseline anamnestic, pharmacological, and psychometric evaluations compared subjects with "under-range" versus "in-range" LAI serum levels; between-group comparisons for different LAI treatments were also performed. A binary logistic regression explored which baseline factors (age, sex, previous hospitalizations, psychopathology, specific LAI treatment, and underrange serum levels) predicted relapse during the next 12 months. Baseline comparisons did not show significant between-group differences, except for a higher percentage of underrange values in individuals receiving olanzapine pamoate. A total of 10 patients (20.8%) relapsed during the follow-up; only underrange LAI levels predicted the event (odds ratio 0.03, 95% confidence interval 0.01-0.36; P = 0.005). Even if relapse remains as a multifactorial event, LAI-TDM may identify subjects at risk for this negative outcome, thus optimizing antipsychotic maintenance treatment in the context of precision medicine. The finding of underrange LAI plasma levels in real-world practice should prompt adequate monitoring of clinically stable outpatients to identify the early signs of psychopathological deterioration.

Review finds antipsychotic switching comparably effective to continuation

A systematic review and network meta‐analysis comparing antipsychotic maintenance treatment strategies for patients with schizophrenia has concluded that antipsychotic continuation and medication switching are comparably effective approaches. This finding was contrary to researchers’ hypothesis that antipsychotic switching would be associated with a higher risk of relapse than continuation at standard doses. Results were published online June 23, 2022, in Lancet Psychiatry.

Continuing, reducing, switching, or stopping antipsychotics in individuals with schizophrenia-spectrum disorders who are clinically stable: a systematic review and network meta-analysis

Although antipsychotic maintenance treatment is widely recommended to prevent relapse in chronic psychoses, evidence-based guidelines do not provide clear indications on different maintenance treatment strategies, including continuing the antipsychotic at standard doses, reducing the dose, switching to another antipsychotic, or even stopping the antipsychotic. We aimed to compare the effectiveness of these maintenance treatment strategies, hypothesising the superiority of all strategies over stopping, and of continuing at standard doses over both switching and reducing the dose. We did a systematic review and network meta-analysis of randomized controlled trials (RCTs) that investigated antipsychotics for relapse prevention in adults with schizophrenia-spectrum disorders who were clinically stable, and which compared four treatment strategies: continuing the current antipsychotic at standard doses recommended for acute treatment; reducing the current antipsychotic dose; switching to a different antipsychotic; and stopping the antipsychotic and replacing it with placebo. We excluded RCTs with fewer than 25 individuals, a prerandomisation washout period greater than 4 weeks, a follow-up shorter than 6 weeks, and those recruiting treatment-resistant individuals. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term treatment for schizophrenia-spectrum disorders. Relative risks (RRs) and standardised mean differences were pooled using random-effects pairwise and network meta-analyses. We assessed risk of bias of each RCT with the Cochrane Risk-of-Bias 2 tool, and confidence of pooled estimates with CINeMA. The primary outcome was relapse prevention. The study protocol was registered in advance in the Open Science Forum registry. Of 3936 records identified, 119 records, reporting on 101 RCTs, were eligible, 98 of which (including 13 988 individuals) provided data that could be meta-analysed for at least one outcome. The mean proportion of female participants per study was 38% (range 0-100; median 39%, IQR 29-50), whereas for male participants it was 62% (range 0-100; median 61%, IQR 50-71), and the overall mean age was 38·8 years (range 23·2-63·9; median 39·3, IQR 35·0-43·9). Of the 98 RCTs meta-analysed, 89·8% were done in high-income and upper-middle-income countries. The ethnic group White or so-called Caucasian was the most represented (mean 56% participants per study), although this information was relatively scarce. All continuation strategies were significantly more effective in preventing relapse than stopping antipsychotic treatment, with a large risk reduction for continuing at standard doses (RR 0·37, 95% CI 0·32-0·43; number-needed-to-treat [NNT] 3·17, 95% CI 2·94-3·51) and antipsychotic switching (RR 0·44, 0·37-0·53; NNT 3·57, 3·17-4·25), and moderate risk reduction for dose reduction (RR 0·68, 0·51-0·90; NNT 6·25, 4·08-20·00). Continuing and switching antipsychotics did not differ significantly (RR 0·84, 0·69-1·02; with lower values favouring continuing), whereas reducing antipsychotic dose was outperformed by both continuing (RR 0·55, 0·42-0·71; NNT 4·44, 3·45-6·90) and switching (RR 0·65, 0·47-0·89; NNT 5·17, 3·77-18·18). Results were supported by moderate confidence of evidence and confirmed by secondary analyses and by several sensitivity and subgroup analyses, including removing studies with abrupt antipsychotic discontinuation or fast tapering (≤4 weeks). No tolerability differences emerged between treatment strategies. According to the Cochrane Risk-of-Bias tool, version 2, 16·8% of included RCTs had an overall high risk of bias for the primary outcome. We found moderate heterogeneity (τ2=0·13; I2=61%) and no overall incoherence for the primary analysis. Results were supported by moderate confidence of evidence and confirmed by secondary analyses. Contrary to our original hypothesis, we found that continuing antipsychotic treatment at standard doses or switching to a different antipsychotic are similarly effective treatment strategies, whereas reducing antipsychotic doses below standard doses is associated with higher risk of relapse than the other two maintenance treatment strategies and should therefore be limited to selected cases. Despite limitations, including moderate heterogeneity and moderate certainty of evidence, these results are of pragmatic relevance for clinicians, and should support the update of evidence-based guidelines. None.

Antipsychotic maintenance treatment versus dose reduction: how the story continues

In this issue of The Lancet Psychiatry, Giovanni Ostuzzi and colleagues1 evaluated the effect of different antipsychotic treatment strategies on risk of relapse by combining 98 randomised controlled trials (RCTs) in meta-analysis (n=13 988 individuals). Compared with discontinuation, the risk for relapse was largely reduced when continuing at standard doses (relative risk [RR] 0·37, 95% CI 0·32–0·43) or when switching antipsychotics (RR 0·44, 0·37–0·53) and moderately reduced when lowering dose (RR 0·68, 0·51–0·90).

Do Clinicians Need to Rethink Antipsychotic Maintenance Treatment?

Schizophrenia remains a challenging illness to treat despite considerable progress. The heterogeneity of symptoms and variability in course, outcome, and treatment response lead to considerable uncertainties in treatment guidelines. One of the most challenging issues is how to determine the need for and duration of the maintenance treatment that is intended to reduce the risk of exacerbation, relapse, and hospitalization. It is clear that in large populations, antipsychotic medication is very effective in reducing those risks, however, there is likely a subpopulation of patients with diminished risk for such outcomes even when medication is discontinued. Although attempts have been made to utilize “intermittent” or “targeted” treatment, those randomized controlled trials that have been conducted show a statistically significant advantage for continuous treatment. At the same time, many patients continue to receive higher than necessary doses of antipsychotic medication and practice needs to be reevaluated in terms of dosage requirements. The challenge remains that there are no good biomarkers or predictors of who is at risk and, therefore, dosage reduction is only titrated against exacerbation or relapse. We need to proactively reconsider who requires maintenance treatment by establishing predictive biomarkers (clinical or biological) that can help us to have a more personalized approach.DisclosureConsultant to or receives honoraria: Alkermes, Allergan, Dainippon Sumitomo, H. Lundbeck, Indivior, Intracellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Novartis Pharmaceuticals,

Mortality in people with schizophrenia: a systematic review and meta-analysis of relative risk and aggravating or attenuating factors.

People with schizophrenia die 15-20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random-effects meta-analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all-cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific-cause mortality. Publication bias, subgroup and meta-regression analyses, and quality assessment (Newcastle-Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all-cause mortality was increased in people with schizophrenia versus any non-schizophrenia control group (RR=2.52, 95% CI: 2.38-2.68, n=79), with the largest risk in first-episode (RR=7.43, 95% CI: 4.02-13.75, n=2) and incident (i.e., earlier-phase) schizophrenia (RR=3.52, 95% CI: 3.09-4.00, n=7) versus the general population. Specific-cause mortality was highest for suicide or injury-poisoning or undetermined non-natural cause (RR=9.76-8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79-7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio-cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All-cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001-0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all-cause and suicide-related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide-related mortality risk in incident schizophrenia samples. All-cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all-cause mortality (RR=1.62, 95% CI: 1.47-1.80, n=3). Antipsychotics were protective against all-cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59-0.84, n=11), with largest effects for second-generation long-acting injectable anti-psychotics (SGA-LAIs) (RR=0.39, 95% CI: 0.27-0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34-0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39-0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44-0.63, n=4). Antipsychotics were also protective against natural cause-related mortality, yet first-generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural-cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long-term maintenance antipsychotic treatment and appropriate/earlier use of SGA-LAIs and clozapine could reduce this mortality gap.

Antipsychotic Maintenance Treatment for Patients With Schizophrenia: The Need for Placebo-Controlled Trials and The Risk of Paradigm Shifts

Abstract Background and Hypothesis There is limited evidence guiding clinicians and patients on how long to continue antipsychotic medication beyond the first 1–2 years of treatment. Data from long-term (beyond 2 years) placebo-controlled trials would be informative but would be resource-intensive and technically difficult to obtain. Philosophy and history offer perspective on whether schizophrenia researchers should invest in such trials. Study Design Essay. Results In Descartes’ model of science, knowledge grows by accumulation and evolves from simpler toward more complex areas. From this perspective, the most important questions are when and how to build this evidence base. In Kuhn’s model of science, paradigm shifts can occur that reframe which questions and answers are meaningful. From this perspective, the question of whether to invest in long-term placebo-controlled trials is especially important. An historical review of schizophrenia over the past century indicates that major paradigm shifts have occurred regarding schizophrenia treatments, what counts as evidence, and the definition of schizophrenia. Conclusions While long-term placebo-controlled trials would add value within the current paradigm, if a paradigm shift occurs there is a risk that this value would not be maintained in the new paradigm.

Antipsychotic nonadherence measured by electronic adherence monitoring in stabilized chronic schizophrenia: Clinical implications

BackgroundThere have been a number of studies investigating antipsychotic adherence measured by electronic adherence monitoring (EAM) in patients with schizophrenia. However, no study has looked at overall adherence and both baseline and endpoint illness/symptom severity. MethodsWe performed a secondary analysis of our previous study to examine antipsychotic adherence, as measured by EAM, and illness/symptom severity at baseline and endpoint in patients with schizophrenia. Adherence rates were defined as the proportion of adherent days over 3 months. Adherent days were defined as the subject having taken the medication at the prescribed time, with 2 tolerance margins operationally defined i.e., ±3 h and ±12 h. In addition, a dichotomous version of adherence was defined i.e., if he/she was adherent greater than 80% of the days. Illness severity and symptom severity were assessed using the Brief Psychiatric Rating Scale (BPRS) total score and the Clinical Global Impression – Severity of illness (CGI-S) scale score, respectively. ResultsA total of 111 patients were enrolled in the study. Neither continuous or dichotomous adherence rates were significantly associated with baseline or endpoint illness/symptom severity (all Ps ≥ 0.05). The results remained unchanged when adjusting for clinico-demographic characteristics. ConclusionAntipsychotic adherence, as measured by EAM, was not associated with illness/symptom severity at baseline and endpoint in patients with chronic schizophrenia, whose clinical status and adherence pattern were stabilized. This suggests that individuals may be able to achieve clinical stability in the face of maintenance antipsychotic treatment despite variations in adherence.

Predictors of Lack of Relapse After Random Discontinuation of Oral and Long-acting Injectable Antipsychotics in Clinically Stabilized Patients with Schizophrenia: A Re-analysis of Individual Participant Data.

To quantify the risk and predictors of relapse among individuals with schizophrenia randomly withdrawn from antipsychotic maintenance treatment. 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. 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. 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.

Self- and caregiver-perceived disability, subjective well-being, quality of life and psychopathology improvement in long-acting antipsychotic treatments: a 2-year follow-up study

Objective Switching to long-acting injectable (LAI) antipsychotic maintenance treatment (AMT) represents a valuable strategy for schizophrenia. In a recovery-oriented approach, patient-reported outcomes (PROs) such as perceived disability, subjective well-being, and quality of life cannot be neglected. Methods Forty clinically stable outpatients with schizophrenia treated with oral second-generation antipsychotics were enrolled at the time of switching to the equivalent dose of LAI. 35 subjects completed this 2-year longitudinal, prospective, open-label, observational study. Patients were assessed at baseline, after 1 year, and after 2 years of LAI-AMT, using psychometric scales (Positive And Negative Syndrome Scale, PANSS; Young Mania Rating Scale, YMRS; Montgomery-Åsberg Depression Rating Scale, MADRS), PROs (Subjective Well-Being under Neuroleptics short form, SWN-K; Short Form-36 health survey, SF-36; 12-item World Health Organisation Disability Assessment Schedule, WHODAS 2.0), and caregiver-reported outcomes (12-item WHODAS 2.0). Results No psychotic relapses were observed. Psychopathology measures (PANSS total and subscales – excluding negative symptoms), mood symptoms (YMRS, MADRS), perceived disability (patient- and caregiver-administered WHODAS 2.0), subjective well-being (SWN-K), and quality of life (SF-36) showed a concomitant amelioration after 1 year, without further significant variations. Discussion Switching to LAI-AMT may decrease perceived impairment, and increase subjective well-being and quality of life in clinically stable outpatients with schizophrenia. Highlights LAI treatment may improve outcomes by reducing psychopathology levels and relapses. In a recovery-oriented approach, patient-reported outcomes cannot be neglected. LAI antipsychotics may optimise the subjective experience of treatment. Switching to LAI therapy may result in a reduction in perceived disability. There is a significant correlation between proxy- and patient-reported disability.

Standard versus reduced dose of antipsychotics for relapse prevention in multi-episode schizophrenia: a systematic review and meta-analysis of randomised controlled trials

Dose reduction of antipsychotic maintenance treatment in individuals with schizophrenia could be desirable to minimise adverse effects, but evidence for this strategy is unclear. We aimed to compare risks and benefits of reduced versus standard doses of antipsychotics. We searched Embase, Medline, PsycINFO, and the Cochrane Library from database inception until June 17, 2020, for randomised trials in adults with schizophrenia or schizoaffective disorder lasting at least 24 weeks, including individuals clinically stable at baseline, and comparing at least two doses of the same antipsychotic, excluding trials in first-episode psychosis or treatment-resistant schizophrenia. We compared low-dose (within 50-99% of the lower limit of the standard dose) and very-low dose (less than 50% of the lower limit) with standard dose, defined as doses higher than the lower limit of the treatment dose recommended by the International Consensus Study. Data from published reports on number of participants, treatment, sex, age, number of events, and changes in psychopathology scores were extracted independently by at least two authors. Investigators or sponsors were contacted by email to obtain missing information regarding outcomes. Co-primary outcomes were relapse and all-cause discontinuation. Study-level data were meta-analysed using random-effects models, calculating risk ratios (RRs) for dichotomous data, and Hedges' g for continuous data. The protocol was registered with OSF registries. 7853 references were identified in the database search and one additional reference from a manual review of relevant studies. 5744 abstracts were assessed for eligibility, and 101 references were assessed for full-text review. Of these, 79 were excluded for a variety of reasons, resulting in 22 studies being included in the meta-analysis, reporting on 24 trials and 3282 individuals. Study participants had a median age of 38 years (IQR 36-40) with 2166 (65·9%) males and 1116 (34·0%) females. Compared with standard dose, low dose increased the risk of relapse by 44% (16 trials, 1920 participants; RR 1·44, 95% CI 1·10-1·87; p=0·0076; I2=46%) and the risk of all-cause discontinuation by 12% (16 trials, 1932 participants; RR 1·12, 1·03-1·22; p=0·0085; I2=0%). Very low dose increased the risk of relapse by 72% (13 trials, 2058 participants; RR 1·72, 95% CI 1·29-2·29; p=0·0002; I2=70%) and all-cause discontinuation by 31% (11 trials, 1866 participants; RR 1·31, 1·11-1·54; p=0·0011; I2=63%). Compared with low dose, very low dose did not significantly increase the risk of relapse (five trials, 686 participants; RR 1·31, 95% CI 0·96-1·79; p=0·092; I2=51%) or all-cause discontinuation (five trials 686 participants; RR 1·11, 95% CI 0·95-1·30; p=0·18; I2=43%). Subgroup analyses comparing double-blind versus open-label studies, first-generation versus second-generation antipsychotics, and oral versus long-acting injectable antipsychotics were consistent with the overall results. Most studies were classified as having some concerns in the risk of bias assessment, which was mainly caused by absence of publicly available study registrations. During maintenance treatment in multi-episode schizophrenia, antipsychotic doses should probably not be reduced below the standard dose range recommended for acute stabilisation, because reducing the dose further is associated with an increased risk of both relapse and all-cause discontinuation. None.

Editorial introductions

Editorial introductions

Predictors of long-acting injectable antipsychotic treatment discontinuation in outpatients with schizophrenia: relevance of the Drug Attitude Inventory-10.

Given the importance of patients' subjective experience and attitudes in the management of severe mental illness, the present study evaluated their potential role as predictors of future continuation of long-acting injectable antipsychotic maintenance treatment (LAI-AMT) in clinically stable outpatients with schizophrenia switching from an oral therapy. Retrospective data from 59 subjects receiving LAI-AMT for at least 6 months were collected. Patients who continued LAI treatment (n = 32) were compared to those who discontinued it (n = 27), assessing baseline socio-demographic and clinical characteristics, psychopathological features (Positive And Negative Syndrome Scale, Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale) and patient-reported experience of treatment through Drug Attitude Inventory 10-item (DAI-10) and Subjective Well-being under Neuroleptics short form. Binary logistic and Cox regression analyses explored the predictive role of the mentioned variables on treatment discontinuation. The Kaplan-Meier estimator compared dropout from LAI treatment in subsamples with different characteristics. Unemployment and lower baseline DAI-10 scores predicted LAI-AMT discontinuation. No major differences were detected in other socio-demographic, clinical or psychometric indexes. When switching from oral to LAI-AMT, the preliminary assessment of attitude towards drug might be clinically relevant, allowing the identification of patients at risk for treatment discontinuation.

Drug attitude inventory is relevant to LAI treatment persistence in schizophrenia: Preliminary results

IntroductionPatients’ attitudes and subjective experience are crucial in the management of severe mental illness, but their practical value is overlooked.ObjectivesTo identify predictors of future adherence to LAI antipsychotic maintenance treatment of schizophrenia among socio-demographic, clinical, and psychometric characteristics – including Drug Attitude Inventory-10 (DAI-10) and Subjective Well-being under Neuroleptics short form (SWN-K) scores.MethodsRetrospective baseline data from 53 clinically stable outpatients with schizophrenia switched from oral to LAI therapy were collected. Patients continuing treatment at the time of analysis (n=29) were compared to those who had discontinued it (n=24). Selected variables were further evaluated in survival analyses.ResultsBetween-group differences are presented in Table 1 (**: p&lt;0.01; *: p&lt;0.05).Continued treatmentDiscontinued treatmentχ2 or tTreatment persistence (months)63.79±21.0123.88±25.806.21**Age (years)39.17±10.1135.58±13.391.11Male15 (51.7%)13 (54.1%)0.03Single20 (69.0%)15 (62.5%)0.25Instruction (years)13.28±3.3111.83±3.561.53Employed20 (69.0%)7 (29.2%)8.32**Illness duration (years)17.69±10.5313.42±11.361.42Previous hospitalisations2.10±1.322.67±1.86-1.29MADRS13.59±9.0614.67±8.99-0.43YMRS5.52±5.576.00±9.94-0.22p-PANSS12.17±5.2014.38±6.13-1.41n-PANSS10.90±5.3915.63±7.93-2.48*g-PANSS29.38±10.3333.63±10.26-1.49PANSS52.66±17.5763.96±20.61-2.15*DAI-103.86±4.96-1.13±5.803.38**SWN-K74.93±23.0781.00±15.60-1.09Cox regression analysis included instruction, employment, hospitalisations, PANSS subscales and DAI-10 scores: a protective role against treatment discontinuation was outlined only for employment (HR 0.16; 95%CI 0.05-0.50) and higher DAI-10 scores (HR 0.85; 95%CI 0.78-0.94). DAI-10 scores delineated distinct adherence trajectories (Figure 1).ConclusionsBaseline DAI-10 scores may identify patients at risk of dropout after switching to LAI.DisclosureNo significant relationships.

Twenty-year effects of antipsychotics in schizophrenia and affective psychotic disorders.

Studies that examine course and outcome in psychosis have reported considerable heterogeneity in terms of recovery, remission, employment, symptom presentation, social outcomes, and antipsychotic medication effects. Even with demonstrated heterogeneity in course and outcome, prophylactic antipsychotic maintenance therapy remains the prominent practice, particularly in participants with schizophrenia. Lack of efficacy in maintenance antipsychotic treatment and concerns over health detriments gives cause to re-examine guidelines. This study was conducted as part of the Chicago follow-up study designed as a naturalistic prospective longitudinal research study to investigate the course, outcome, symptomatology, and effects of antipsychotic medication on recovery and rehospitalization in participants with serious mental illness disorders. A total of 139 participants with 734 observations were included in the analysis. GEE logistic models were applied to adjust for confounding factors measured at index hospitalization and follow-ups. Our data show that the majority of participants with schizophrenia or affective psychosis experience future episodes of psychosis at some point during the 20-year follow-up. There was a significant diagnostic difference between groups showing an increase in the number of future episodes of psychosis in participants with schizophrenia. Participants with schizophrenia not on antipsychotics after the first 2 years have better outcomes than participants prescribed antipsychotics. The adjusted odds ratio of not on antipsychotic medication was 5.989 (95% CI 3.588-9.993) for recovery and 0.134 (95% CI 0.070-0.259) for rehospitalization. That is, regardless of diagnosis, after the second year, the absence of antipsychotics predicted a higher probability of recovery and lower probability of rehospitalization at subsequent follow-ups after adjusting for confounders. This study reports multiple findings that bring into question the use of continuous antipsychotic medications, regardless of diagnosis. Even when the confound by indication for prescribing antipsychotic medication is controlled for, participants with schizophrenia and affective psychosis do better than their medicated cohorts, strongly confirming the importance of exposing the role of aiDSP and antipsychotic drug resistance.

APA Releases Practice Guideline on Schizophrenia

APA Releases Practice Guideline on Schizophrenia