Clinical outcomes with paliperidone palmitate 3-monthly injection as monotherapy: observational 3-year follow-up of patients with schizophrenia.

BACKGROUND: Paliperidone palmitate 3-monthly (PP3M) has been tested in 1-year controlled studies. The aim of this study was to examine the relapse outcomes with PP3M monotherapy at 3 years in patients with schizophrenia. METHODS: This was an observational, non-interventional study of patients started on PP3M according to their clinical need. All patients had a diagnosis of schizophrenia (ICD-10 F20) and were between 18 and 65 years of age. The study took place in a mental health facility in South East London, UK. RESULTS: Among the 166 patients who started PP3M, 97 (58%) met inclusion criteria and were observed for 36 months. In total, five patients (5%) experienced a relapse (defined as step-up in clinical care) while on PP3M. There were no relapses between months 18 and 36. Of the original 97 patients, 56 (58%) remained on PP3M monotherapy at 3 years, and 71 (73%) remained on either PP3M or paliperidone palmitate one-monthly. Reasons for discontinuation of PP3M included patient refusal (n = 11, 33% of discontinuations) and adverse effects in (n = 8, 24%). CONCLUSION: PP3M is a highly effective monotherapy treatment for reducing relapse in people with schizophrenia.

Meta-analysis and systematic review of vesicular monoamine transporter (VMAT-2) inhibitors in schizophrenia and psychosis.

RATIONALE: Dopamine antagonists induce dopamine receptor supersensitivity. This may manifest in late-appearing movement disorders (tardive dyskinesia (TD). VMAT-2 inhibitors reduce dopaminergic transmission but have limited activity at postsynaptic receptors and so may have antipsychotic activity with lower risk of tardive dyskinesia. METHODS: We conducted a systematic database search from inception to September 2022 for articles describing the use of VMAT-2 inhibitors in psychosis. Inclusion criteria were as follows: Population: adults diagnosed with psychosis or schizophrenia; Intervention: treatment with tetrabenazine, deutetrabenazine or valbenazine; Comparison: comparison with placebo or/and antipsychotic drug; Outcomes: with efficacy outcomes (e.g. Brief Psychiatric Rating Scale (BPRS) change or clinician assessment) and adverse effects ratings (e.g. rating scale or clinician assessment or dropouts); and Studies: in randomised controlled trials and non-randomised studies. RESULTS: We identified 4892 records relating to VMAT-2 inhibitor use of which 5 (173 participants) met our a priori meta-analysis inclusion criteria. VMAT-2 inhibitors were more effective than placebo for the outcome 'slight improvement' (risk ratio (RR) = 1.77 (95% CI 1.03, 3.04)) but not for 'moderate improvement' (RR 2.81 (95% CI 0.27, 29.17). VMAT-2 inhibitors were as effective as active comparators on both measures for-'slight improvement' (RR 1.05 (95% CI 0.6, 1.81)) and 'moderate improvement' (RR 1.11 (95% CI 0.51, 2.42). Antipsychotic efficacy was also suggested by a narrative review of 37 studies excluded from the meta-analysis. CONCLUSIONS: VMAT-2 inhibitors may have antipsychotic activity and may offer promise for treatment of psychosis with the potential for a reduced risk of TD.

A case-control study of antipsychotic use and pneumonia-related mortality in the United Kingdom.

BACKGROUND AND AIM: There is increasing evidence linking antipsychotic use with pneumonia, but limited evidence of an effect on pneumonia-related outcomes such as mortality. In this study, we aimed to examine the association of pneumonia-related death with specific antipsychotic exposure. METHOD: Deaths analysed were those reported to a UK-based drug-related deaths database, the National Programme on Substance Abuse Deaths (NPSAD), between 1997 and September 2020. We conducted a case-control study with cases defined as pneumonia-related deaths and controls as cases with alternative causes of death. Cases were analysed by considering drugs detected at post-mortem (PM) and by drugs prescribed to the deceased at the time of their death with calculated odds ratios (ORs) adjusted to account for confounders. RESULTS: There were 2467 PM cases and 40,128 controls; 1818 prescribed cases and 28,018 controls. Second generation antipsychotics (SGAs) were robustly associated with an increased risk of pneumonia-related death compared with those not prescribed or taking antipsychotics (PM detection adjusted OR [AOR] 1·34 [95% CI 1·15-1·55]; prescribed AOR 1·28 [95% CI 1·11-1·49]). First generation antipsychotics had no clear association with death from pneumonia (PM detection AOR 1·06 [95% CI 0·77-1·47]; prescribed AOR 0·91 [95% CI 0·71-1·17]). Amongst SGAs, olanzapine was associated with an increased risk of death due to pneumonia (PM detection AOR 1·49 [95% CI 1·22-1·82]; prescribed AOR 1·44 [95% CI 1·18-1·76]) as was quetiapine (PM detection AOR 1·34 [95% CI 1·07-1·66]; prescribed AOR 1·28 [95% CI 1·01-1·64]). CONCLUSION: Olanzapine and quetiapine were found to increase the risk of pneumonia-related death in this NPSAD sample to a clinically important extent.

Intermittent selective serotonin reuptake inhibitors for premenstrual syndromes: A systematic review and meta-analysis of randomised trials.

BACKGROUND: Intermittent (luteal phase) dosing of selective serotonin reuptake inhibitors is one treatment strategy for premenstrual syndromes such as premenstrual dysphoric disorder. This avoids the risk of the antidepressant withdrawal syndrome associated with long-term continuous dosing. AIMS: To compare intermittent dosing to continuous dosing in terms of efficacy and acceptability. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO, PubMed and CINAHL for randomised trials of intermittent compared with continuous dosing of selective serotonin reuptake inhibitors in premenstrual syndromes. We extracted response rates, dropout rates and changes in symptom scores. We used random effects meta-analyses to pool study-level data and calculated odds ratio for dichotomous data and standardised mean difference for continuous data. Risk of bias was assessed using the Cochrane risk-of-bias tool. The study was registered with PROSPERO (CRD42020224176). RESULTS: A total of 1841 references were identified, with eight studies being eligible for analysis, consisting of a total of 460 participants. All included studies provided response rates, six provided dropout rates and five provided symptom scores. There was no statistically significant differences between intermittent and continuous dosing in terms of response rate (odds ratio: 1.0, 95% confidence interval (CI): 0.23-4.31, I2 = 71%), dropout rate (odds ratio 1.26, 95% CI: 0.39-4.09, I2 = 33%) or symptom change (standardised mean difference: 0.04, 95% CI: -0.27 to 0.35, I2 = 39%). All studies had a moderate or high risk of bias. CONCLUSION: Since intermittent dosing avoids the potential for withdrawal symptoms, it should be considered more commonly in this patient population.

Effect of 3-monthly paliperidone palmitate on hospitalisation in a naturalistic schizophrenia cohort - A five-year mirror image study.

PURPOSE/BACKGROUND: Currently the longest-acting antipsychotic formulation widespread clinical use is paliperidone 3-monthly injection (PP3M). While its efficacy has been shown in rigorous trials, there are few data relating to its effect on hospitalisation in normal clinical practice. METHODS/PROCEDURES: This was a mirror-image study (3 years before; 2 years after) of hospitalisations before and after beginning paliperidone 1-monthly (PP1M) and switching to 3-monthly within 18 months. All consecutive patients prescribed paliperidone long-acting injections with its licence (F20 schizophrenia diagnosis; 18-65 years) were included. The setting was an urban, specialist mental health organisation In London, UK. FINDINGS/RESULTS: In total 378 patients were initiated on PP3M during the study period. After applying inclusion criteria, 76 patients were retained and followed-up for 2 years. Mean duration of PP1M use before starting 3-monthly injections was 6 months (range 3-18 months). Of the 76 patients initiated, 13 patients discontinued PP3M within 2 years of starting PP1M or were lost to follow-up. Mean hospitalisations per patient per year fell from 0.55 (SD 0.46) before paliperidone to 0.05 (SD 0.19) after initiation (p < 0.001). Only 5 of 76 PP1M/PP3M participants were hospitalised during the 2-year follow up. The mean number of bed days per year before paliperidone initiation was 32.2 (SD 44.3) and after paliperidone initiation it was 23.0 (SD 53.2) (p = 0.004). Almost all of the bed days after initiation were associated with the index admission during which PP1M was started. IMPLICATIONS/CONCLUSIONS: In patients stabilised on PP1M and switched to PP3M in normal clinical practice, rehospitalisation is very uncommon and much reduced compared with previous treatments.

Factors predicting relapse and treatment discontinuation with paliperidone 3-monthly long-acting injection: A 2-year naturalistic follow-up study.

BACKGROUND: Paliperidone 3-monthly (PP3M) long-acting injection has proven efficacy and effectiveness in schizophrenia. Little is known of its effectiveness in other diagnoses. METHODS: All patients starting PP3M were followed up for 2 years. Main outcome measures were relapse and discontinuation from PP3M. Post hoc we examined outcomes in those switched back to one monthly paliperidone (PP1M) long-acting injection. RESULTS: Overall, 186 patients were followed-up. At the 2-year end point, 110 patients (59%) were still receiving PP3M, and 129 (70%) were receiving some form of paliperidone long-acting injection. Discontinuation from paliperidone long-acting injections (PPLAIs) was more likely with a nonschizophrenia diagnosis (hazard ratio [HR] for continuation 0.429 [95% confidence intervals (CI) - 0.21, 0.87 p = 0.018)), and prior clozapine use [in PP3M patients; HR for discontinuation 1.87 [95% CI - 1.05, 3.30 p = 0.032]). Relapse occurred in 20 (11%) of those receiving PP3M. Relapse on PP3M and PPLAIs was more likely in nonschizophrenia diagnosis (HR 0.17 for remaining relapse-free [95% CI - 0.06, 0.50; p = 0.001]; HR 0.21 [95% CI - 0.08, 0.58 p = 0.002], respectively), polypharmacy in PP3M patients (HR for relapse 7.91 [95% CI - 3.73, 22.9; p < 0.001]) and PPLAI patients (HR for relapse 6.45 [95% CI - 2.49, 16.5; p < 0.001]), and prior clozapine use in PP3M patients (HR for relapse 6.11 [95% CI - 1.82, 20.5; p = 0.003]) and PPLAI patients (HR for relapse 4.52 (95% CI - 1.51, 13.5; p = 0.007). CONCLUSIONS: Outcomes with PP3M are excellent in practice, even when used outside its formal license. PP3M was relatively more effective in those with an F20 schizophrenia diagnosis and in those never before considered for or prescribed clozapine.

Discontinuation and relapse with paliperidone palmitate three-monthly for maintenance of schizophrenia: Two year follow-up of use in clinical practice.

BACKGROUND: The use of antipsychotic long-acting injections (LAI) aims to reduce risk of relapse and hospitalisation in patients with schizophrenia compared with oral medication. Paliperidone palmitate is currently the only LAI that can be administered at three-monthly intervals for maintenance treatment of schizophrenia. AIM: This prospective study aimed to evaluate relapse and continuation in licensed use of paliperidone palmitate three-monthly (PP3M) over a 2-year follow-up in clinical practice. METHOD: Non-interventional, observational study of patients treated in the South London and The Maudsley NHS Foundation Trust. RESULTS: A total of 166 patients initiated on PP3M, 55 were excluded from the study (non-F20 diagnosis (n = 43); F20 >65 years old (n = 12)). Of the 111 patients included, 67 (60%) continued PP3M for 2 years. Overall 102 patients received more than one dose of PP3M and 92 (90%) remained on the same dose of PP3M for the whole of their treatment duration. Relapse (defined as a step-up in clinical care) occurred in eight patients (7%) while on PP3M. The most common reason for discontinuation was patient refusal and the most frequent medication prescribed after discontinuation was paliperidone palmitate one-monthly (PP1M). Post hoc, we analysed outcome in those continuing any form of PPLAI (those continuing with PP3M and those switching back to PP1M). Continuation over 2 years with any PPLAI formulation was 73% (81/111) and relapse was recorded in 9% (10/111). CONCLUSION: Overall, PP3M was an effective maintenance treatment for schizophrenia after stabilisation on PP1M in a clinical setting.