Abstract
Background: Many people with psychosis discontinue antipsychotic treatment due to a perceived lack of efficacy or problematic side effects.[1] Treatment discontinuation is associated with a significantly increased risk of relapse.[2] However, less is known about the incidence and associations of side effects with treatment discontinuation in people with first episode psychosis (FEP), who may be particularly sensitive to antipsychotic side effects in the early phase of illness.[3] We analysed electronic health record (EHR) data to estimate the proportion of patients with FEP who experience antipsychotic side effects and the associations of specific side effects with treatment discontinuation.
Methods: A retrospective cohort study was performed using data from the South London and Maudsley (SLaM) Biomedical Research Centre (BRC) Case Register.[4] De-identified EHR data were assembled from adults (16-65 years old) who received care from Early Intervention Services for psychosis between 1st April 2008 and 31st March 2019, and who had at least two years of follow-up (up to 31st March 2021). Unstructured free text records were manually reviewed by three researchers (including one psychiatrist) to ascertain the presence or absence of clinician-recorded side effects (extrapyramidal; hyperprolactinemia; sedation; sexual; weight gain). The associations of side effects with discontinuation of the first-prescribed antipsychotic were investigated using multivariable Cox regression with age, gender, ethnicity, and prescription setting (inpatient vs community) as covariates. A further analysis was conducted to investigate the associations of side effects with discontinuation of antipsychotics prescribed at any point during the follow-up period.
Results: 2,309 adults with FEP were included in the study with a mean follow-up duration of 34.2 months and a total study follow-up of 6,830.8 person years. The mean age of patients was 26.7 years. 1,492 (64.6%) were male and 817 (35.4%) were female. Olanzapine (n=1,013), risperidone (n=571) and aripiprazole (n=460) were the most frequently first-prescribed antipsychotics. First prescribed antipsychotics were discontinued earlier when commenced in inpatient settings than in community settings (HR=1.41, 95%CI=1.27-1.60) and later in male patients than in female patients (HR=0.81, 95%CI=0.73-0.90). Among first-prescribed antipsychotics, extrapyramidal (n=125, HR=1.33, 95%CI=1.08-1.64) and sexual side effects (n=24, HR=1.59, 95%CI=1.03-2.46) were associated with significantly faster treatment discontinuation, whereas multiple side effects (n=365, HR=0.85, 95%CI=0.74-0.98) were associated with significantly slower treatment discontinuation. Among antipsychotics prescribed at any point during the follow-up period, sedation (n=898, HR=0.89, 95%CI=0.81-0.97), weight gain (n=374, HR=0.73, 95%CI=0.64-0.83), or multiple side effects (n=873, HR=0.83, 95%CI=0.76-0.90) were associated with significantly delayed treatment discontinuation.
Conclusions: We found that clinician-reported side effects had varying associations with time to antipsychotic treatment discontinuation. Extrapyramidal and sexual side effects were associated with faster treatment discontinuation among first-prescribed antipsychotics. This may reflect the relatively fast onset of these side effects leading to earlier treatment discontinuation. In contrast, sedation, weight gain and multiple side effects were associated with slower treatment discontinuation. This could reflect the propensity for antipsychotics with relatively high efficacy to be associated with these side effects.[5] These findings highlight the importance of the balance of efficacy and side effect profiles when considering potential therapeutic approaches for people with FEP.
References
1. Rubio JM, Taipale H, Tanskanen A, et al. Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study. Schizophr Bull 2021;47:1611–20. doi:10.1093/schbul/sbab063 2. Winton-Brown TT, Elanjithara T, Power P, et al. Five-fold increased risk of relapse following breaks in antipsychotic treatment of first episode psychosis. Schizophr Res 2017;179:50–6. doi:10.1016/j.schres.2016.09.029 3. Keating D, McWilliams S, Boland F, et al. Prescribing pattern of antipsychotic medication for first-episode psychosis: A retrospective cohort study. BMJ Open 2021;11:40387. doi:10.1136/bmjopen-2020-040387 4. Stewart R, Soremekun M, Perera G, et al. The South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLAM BRC) case register: Development and descriptive data. BMC Psychiatry 2009;9:51. doi:10.1186/1471-244X-9-51 5. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019;394:939–51. doi:10.1016/S0140-6736(1931135-3)
Conflict of interest:
Disclosure statement: RP has received grant funding from the National Institute for Health and Care Research (NIHR301690), the Medical Research Council (MR/S003118/1), the Academy of Medical Sciences (SGL015/1020) and Janssen, personal fees from Holmusk, and honoraria from Boehringer Ingelheim. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Mindstrong, Proxymm Science.
Methods: A retrospective cohort study was performed using data from the South London and Maudsley (SLaM) Biomedical Research Centre (BRC) Case Register.[4] De-identified EHR data were assembled from adults (16-65 years old) who received care from Early Intervention Services for psychosis between 1st April 2008 and 31st March 2019, and who had at least two years of follow-up (up to 31st March 2021). Unstructured free text records were manually reviewed by three researchers (including one psychiatrist) to ascertain the presence or absence of clinician-recorded side effects (extrapyramidal; hyperprolactinemia; sedation; sexual; weight gain). The associations of side effects with discontinuation of the first-prescribed antipsychotic were investigated using multivariable Cox regression with age, gender, ethnicity, and prescription setting (inpatient vs community) as covariates. A further analysis was conducted to investigate the associations of side effects with discontinuation of antipsychotics prescribed at any point during the follow-up period.
Results: 2,309 adults with FEP were included in the study with a mean follow-up duration of 34.2 months and a total study follow-up of 6,830.8 person years. The mean age of patients was 26.7 years. 1,492 (64.6%) were male and 817 (35.4%) were female. Olanzapine (n=1,013), risperidone (n=571) and aripiprazole (n=460) were the most frequently first-prescribed antipsychotics. First prescribed antipsychotics were discontinued earlier when commenced in inpatient settings than in community settings (HR=1.41, 95%CI=1.27-1.60) and later in male patients than in female patients (HR=0.81, 95%CI=0.73-0.90). Among first-prescribed antipsychotics, extrapyramidal (n=125, HR=1.33, 95%CI=1.08-1.64) and sexual side effects (n=24, HR=1.59, 95%CI=1.03-2.46) were associated with significantly faster treatment discontinuation, whereas multiple side effects (n=365, HR=0.85, 95%CI=0.74-0.98) were associated with significantly slower treatment discontinuation. Among antipsychotics prescribed at any point during the follow-up period, sedation (n=898, HR=0.89, 95%CI=0.81-0.97), weight gain (n=374, HR=0.73, 95%CI=0.64-0.83), or multiple side effects (n=873, HR=0.83, 95%CI=0.76-0.90) were associated with significantly delayed treatment discontinuation.
Conclusions: We found that clinician-reported side effects had varying associations with time to antipsychotic treatment discontinuation. Extrapyramidal and sexual side effects were associated with faster treatment discontinuation among first-prescribed antipsychotics. This may reflect the relatively fast onset of these side effects leading to earlier treatment discontinuation. In contrast, sedation, weight gain and multiple side effects were associated with slower treatment discontinuation. This could reflect the propensity for antipsychotics with relatively high efficacy to be associated with these side effects.[5] These findings highlight the importance of the balance of efficacy and side effect profiles when considering potential therapeutic approaches for people with FEP.
References
1. Rubio JM, Taipale H, Tanskanen A, et al. Long-term Continuity of Antipsychotic Treatment for Schizophrenia: A Nationwide Study. Schizophr Bull 2021;47:1611–20. doi:10.1093/schbul/sbab063 2. Winton-Brown TT, Elanjithara T, Power P, et al. Five-fold increased risk of relapse following breaks in antipsychotic treatment of first episode psychosis. Schizophr Res 2017;179:50–6. doi:10.1016/j.schres.2016.09.029 3. Keating D, McWilliams S, Boland F, et al. Prescribing pattern of antipsychotic medication for first-episode psychosis: A retrospective cohort study. BMJ Open 2021;11:40387. doi:10.1136/bmjopen-2020-040387 4. Stewart R, Soremekun M, Perera G, et al. The South London and Maudsley NHS Foundation Trust Biomedical Research Centre (SLAM BRC) case register: Development and descriptive data. BMC Psychiatry 2009;9:51. doi:10.1186/1471-244X-9-51 5. Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019;394:939–51. doi:10.1016/S0140-6736(1931135-3)
Conflict of interest:
Disclosure statement: RP has received grant funding from the National Institute for Health and Care Research (NIHR301690), the Medical Research Council (MR/S003118/1), the Academy of Medical Sciences (SGL015/1020) and Janssen, personal fees from Holmusk, and honoraria from Boehringer Ingelheim. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantic. PFP has received research funds or personal fees from Lundbeck, Angelini, Menarini, Sunovion, Boehringer Ingelheim, Mindstrong, Proxymm Science.
| Original language | English |
|---|---|
| Article number | 103327 |
| Pages (from-to) | 11 |
| Number of pages | 12 |
| Journal | Neuroscience Applied |
| Volume | 2 |
| Issue number | S2 |
| DOIs | |
| Publication status | Published - 26 Dec 2023 |