Use of antipsychotic medication, benzodiazepines, and psychiatric hospitalization in cannabis-related versus cannabis-unrelated schizophrenia - a nationwide, register-based cohort study.

BACKGROUND: Evidence suggests that cannabis may be a causal factor for development of schizophrenia. We aimed to investigate whether use of antipsychotic medication, benzodiazepines, and psychiatric service use differs among patients with schizophrenia depending on whether psychosis was precipitated by a diagnosis of cannabis use disorder (CUD). METHODS: We utilized the nationwide Danish registries to identify all individuals with an incident diagnosis of schizophrenia from 1995 to 2016. We also collected information on whether first CUD diagnosis preceded schizophrenia and thus defined a group of potentially cannabis-related schizophrenia. We compared the cannabis-related schizophrenia group both with all non-cannabis-related patients with schizophrenia and with non-cannabis-related patients with schizophrenia that were propensity-score matched to cases using a range of potentially confounding variables. RESULTS: We included 35 714 people with incident schizophrenia, including 4116 (11.5%) that were cannabis-related. In the unmatched-comparison analyses, there were no clear differences over time in use of antipsychotics and benzodiazepines related to whether the diagnosis of schizophrenia was cannabis-related. After propensity-score matching, use of antipsychotics and benzodiazepines was significantly lower among cannabis-related cases of schizophrenia. In the unmatched comparison, the cannabis-related group had significantly more days admitted than the non-cannabis-related group. This was markedly attenuated after propensity-score matching. CONCLUSIONS: Our findings indicate the importance of considering cannabis-related cases of schizophrenia as a potentially distinct disorder in terms of prognosis. It is unclear, however, if these differences are due to different biological types of schizophrenia being compared or if they rather indicate behavioral differences such as reduced adherence and treatment-seeking.

Discontinuation of antipsychotics in individuals with first-episode schizophrenia and its association to functional outcomes, hospitalization and death: a register-based nationwide follow-up study.

BACKGROUND: Discontinuation of antipsychotic medication may be linked to high risk of relapse, hospitalization and mortality. This study investigated the use and discontinuation of antipsychotics in individuals with first-episode schizophrenia in relation to cohabitation, living with children, employment, hospital admission and death. METHODS: Danish registers were used to establish a nationwide cohort of individuals ⩾18 years with schizophrenia included at the time of diagnosis in1995-2013. Exposure was antipsychotic medication calculated using defined daily dose and redeemed prescriptions year 2-5. Outcomes year 5-6 were analysed using binary logistic, negative binomial and Cox proportional hazard regression. RESULTS: Among 21 351, 9.3% took antipsychotics continuously year 2-5, 38.6% took no antipsychotics, 3.4% sustained discontinuation and 48.7% discontinued and resumed treatment. At follow-up year 6, living with children or employment was significantly higher in individuals with sustained discontinuation (OR 1.98, 95% CI 1.53-2.56 and OR 2.60, 95% CI 1.91-3.54), non-sustained discontinuation (OR 1.25, 95% CI 1.05-1.48 and 2.04, 95% CI 1.64-2.53) and no antipsychotics (OR 2.00, 95% CI 1.69-2.38 and 5.64, 95% CI 4.56-6.97) compared to continuous users. Individuals with non-sustained discontinuation had more psychiatric hospital admissions (IRR 1.27, 95% CI 1.10-1.47) and longer admissions (IRR 1.68, 95% CI 1.30-2.16) year 5-6 compared to continuous users. Mortality during year 5-6 did not differ between groups. CONCLUSION: Most individuals with first-episode schizophrenia discontinued or took no antipsychotics the first years after diagnosis and had better functional outcomes. Non-sustained discontinuers had more, and longer admissions compared to continuous users. However, associations found could be either cause or effect.

Self-reported reasons for discontinuation or continuation of antipsychotic medication in individuals with first-episode schizophrenia.

AIM: Many individuals with schizophrenia discontinue initially prescribed antipsychotics. Knowledge on reasons for discontinuation among individuals with first-episode schizophrenia is sparse. We aimed to describe reasons for discontinuation and continuation, differences between individuals discontinuing and continuing, and factors predicting reasons for discontinuation or continuation. METHODS: This was a prospective cohort study with a post hoc design. Individuals with first-episode schizophrenia were included from early intervention teams in Denmark from 2009-2012. Sociodemographic and clinical variables were collected at baseline and reasons for discontinuation and continuation of antipsychotics were assessed at 3.5-year follow-up. RESULTS: Among 215 patients, 76 reported reasons for discontinuation and 139 for continuation. The most frequent reasons for discontinuation were "side effects" and "patient believed he/she no longer needed the medication because he/she was now better". The most frequent reasons for continuation were "benefits for positive symptoms" and "another person told them to". Individuals who discontinued antipsychotics were at baseline younger, had longer DUP, less negative symptoms, better social function, lower compliance, higher self-belief of coping, and fewer used antipsychotics compared to those continuing antipsychotics. CONCLUSIONS: The effect of antipsychotics is the main reason to continue, whereas side effects were the main reason to discontinue. Knowledge of reasons to discontinue or continue is helpful in shared decision-making, identifying individuals with high odds of discontinuation, improving adherence, and helping with safe discontinuation.

Tapered discontinuation vs. maintenance therapy of antipsychotic medication in patients with first-episode schizophrenia: Obstacles, findings, and lessons learned in the terminated randomized clinical trial TAILOR.

Aim: Evidence is insufficient regarding the consequences of discontinuing vs. maintaining antipsychotic medication in patients with first-episode schizophrenia. Our aim was to examine tapered discontinuation vs. maintenance treatment regarding remission of psychotic symptoms and impact on other areas. Methods: Patients included had a diagnosis of schizophrenia, were treated with antipsychotic medication, and were in remission of psychotic symptoms. Participants were randomized to tapered discontinuation or maintenance treatment with antipsychotic medication. Assessments were undertaken at baseline and after 1-year. The primary outcome was remission of psychotic symptoms without antipsychotic medication. Results: The trial was terminated due to insufficient recruitment. In total, 29 participants were included: 14 in the tapering/discontinuation group and 15 in the maintenance group. Adherence to maintenance treatment was poor. At 1-year follow-up, remission of psychotic symptoms without antipsychotic medication for 3 months was observed in five participants in the tapering/discontinuation group and two in the maintenance group. Conclusion: Due to insufficient recruitment this study does not provide a conclusion on whether unfavorable outcomes or advantages follow tapering of antipsychotic medication. Recruitment and adherence to maintenance treatment encountered obstacles. Based on experiences from this trial, we discussed alternative study designs as consistent evidence is still needed on whether to continue or discontinue antipsychotic medication in remitted patients with first-episode schizophrenia. Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000565-23/DK, EU Clinical Trials Register-EudraCT no. 2016-000565-23.

Reversibility of Antipsychotic-Induced Weight Gain: A Systematic Review and Meta-Analysis.

Background and Aims: Weight gain is a major adverse effect of antipsychotic medication, negatively affecting physical and mental well-being. The objective of this study was to explore if dose reduction, discontinuation, switch to a partial agonist, or switch from polypharmacy to monotherapy will lead to weight loss. Methods: Controlled and uncontrolled studies reporting the effects of discontinuation, dose reduction, switch to a partial agonist, or switch from polypharmacy to monotherapy on weight were included. Primary outcome was difference in weight compared to maintenance groups based on controlled studies. Secondary outcome was change in weight from initiation of one of the included interventions until follow-up in a pre-post analysis. Results: We identified 40 randomized controlled trials and 15 uncontrolled studies including 12,279 individuals. The effect of the interventions, i.e. dose reduction, drug discontinuation, or switch to a partial agonis, reduced the weight with 1.5 kg (95% CI -2.03 to -0.98; P < 0.001) compared to maintenance treatment. The weight change from pre to post was a reduction of 1.13 kg (95% CI -1.36 to -0.90; P < 0.001). Conclusion: We found a significant but small reduction in weight, suggesting that antipsychotic-induced weight gain can be reversed to some degree. Only a few studies were designed to address the question as primary outcome, which limits the generalizability of our findings.

Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis.

BACKGROUND: Several studies and meta-analyses have shown that mortality in people with schizophrenia is higher than that in the general population but have used relative measures, such as standardised mortality ratios. We did a systematic review and meta-analysis to estimate years of potential life lost and life expectancy in schizophrenia, which are more direct, absolute measures of increased mortality. METHODS: We searched MEDLINE, PsycINFO, Embase, Cinahl, and Web of Science for published studies on years of potential life lost and life expectancy in schizophrenia. Data from individual studies were combined in meta-analyses as weighted averages. We did subgroup analyses for sex, geographical region, timing of publication, and risk of bias (estimated with the Newcastle-Ottawa Scale). FINDINGS: We identified 11 studies in 13 publications covering all inhabited continents except South America (Africa n=1, Asia n=1, Australia n=1, Europe n=7, and North America n=3) that involved up to 247 603 patients. Schizophrenia was associated with a weighted average of 14·5 years of potential life lost (95% CI 11·2-17·8), and was higher for men than women (15·9, 13·8-18·0 vs 13·6, 11·4-15·8). Loss was least in the Asian study and greatest in Africa. The overall weighted average life expectancy was 64·7 years (95% CI 61·1-71·3), and was lower for men than women (59·9 years, 95% CI 55·5-64·3 vs 67·6 years, 63·1-72·1). Life expectancy was lowest in Asia and Africa. Timing of publication and risk of bias had little effect on results. INTERPRETATION: The effects of schizophrenia on years potential life lost and life expectancy seem to be substantial and not to have lessened over time. Development and implementation of interventions and initiatives to reduce this mortality gap are urgently needed. FUNDING: None.

TAILOR - tapered discontinuation versus maintenance therapy of antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder in remission of psychotic symptoms: study protocol for a randomized clinical trial.

BACKGROUND: The aim of the TAILOR trial is to investigate the effect of closely monitored tapering/discontinuation versus maintenance therapy with antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder and with minimum 3 months' remission of psychotic symptoms. METHODS AND DESIGN: Two hundred and fifty patients will be included from the psychiatric early intervention program, OPUS, in two regions in Denmark. Inclusion criteria are: ICD-10 diagnoses schizophrenia (F20, except F20.6) or persistent delusional disorder (F22), minimum 3 months' remission of psychotic symptoms and in treatment with antipsychotic medication (except clozapine). The patients will be randomized to maintenance therapy or tapering/discontinuation with antipsychotic medication in a 1-year intervention. The tapering/discontinuation group will be using a smartphone application to monitor early warning signs of psychotic relapse. Patients will be assessed at baseline, 1-, 2- and 5-year follow-up regarding psychotic and negative symptoms, side-effects of antipsychotic medication, social functioning, cognitive functioning, perceived health status, patient satisfaction, substance and alcohol use, sexual functioning and quality of life. The primary outcome will be remission of psychotic symptoms and no antipsychotic medication after 1 year. Secondary outcome measures will include: co-occurrence of remission of psychotic symptoms and 0-1-mg haloperidol equivalents of antipsychotic medication after 1-year intervention; antipsychotic dose; antipsychotic side effects; negative symptoms; social functioning; cognitive functioning; and patient satisfaction. Exploratory outcomes will include remission, clinical recovery, substance and alcohol use, sexual functioning, quality of life, self-beliefs of coping and user experience of support from health workers. Safety measures will include death, admissions to psychiatric hospital, severe self-harm and psychotic relapses. DISCUSSION: The TAILOR trial will contribute knowledge about the effect of tapering/discontinuation of antipsychotic medication in the early phases of schizophrenia and related disorders and the results may guide future clinical treatment regimens of antipsychotic treatment. TRIAL REGISTRATION: EU Clinical Trials Register - EudraCT number: 2016-000565-23 . Registered on 5 February 2016.