The cardiovascular safety of tricyclic antidepressants in overdose and in clinical use.

Tricyclic antidepressants (TCAs) remain widely prescribed for depression and many other conditions. There may be important differences between individual TCA in regard to their overdose toxicity and their cardiac toxicity in clinical use. We conducted a systematic review to compare the toxicity of individual TCA in overdose and the risk of serious adverse cardiac events occurring with therapeutic doses. We used the fatal toxicity index (FTI) and case fatality ratio as markers of fatality in overdose, and hazard ratios or odds ratios for the risk of cardiovascular adverse events during normal clinical use. In all, 30 reports of mortality in overdose and 14 observational studies assessing the risk of cardiovascular adverse events in clinical use were included. FTI values were of the same order of magnitude (101-102) for all TCAs except lofepramine. Desipramine appears to be somewhat more likely than other TCAs to lead to death in overdose. Amitriptyline, clomipramine, dothiepin/dosulepin, doxepin, trimipramine and imipramine showed broadly similar toxicity and were usually reported to be less toxic than desipramine. Data on nortriptyline were contradictory. Lofepramine had the lowest risk of death in overdose. The rank order of overdose toxicity was broadly consistent between different FTI definitions and between markers used. With respect to the risk of cardiovascular events at clinically relevant exposure, amitriptyline, nortriptyline and lofepramine were associated with a greater risk of in-use cardiotoxicity. All measures of overdose toxicity were subject to external influences and confounding. The continued use of TCAs in depression and other conditions should be minimized when considering their undoubted toxicity in overdose and possible toxicity in normal clinical use.

Older tricyclic antidepressants and their toxicity in overdose and in clinical use Tricyclic antidepressants were first used in the 1950s. Their use for depression has gone down in the past 20 or so years. This is because newer antidepressants are better tolerated and less toxic in overdose. Certain tricyclics - dosulepin and amitriptyline - have been identified as being particularly toxic tricyclics and their use has been restricted. However many other tricyclics remain widely used for depression and many other conditions. We examined all the evidence we could find on tricyclic toxicity. We found that, with one exception, all tricyclics are toxic and dangerous when taken in overdose. The exception is lofepramine - a tricyclic used in the UK and some other countries. When looking at toxicity in clinical use, we found no consistent evidence of difference between individual tricyclics. It is possible that most or all tricyclics do not increase the risk of heart attack or sudden cardiac death when used at normal clinical doses.

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.

The lived experience of clozapine discontinuation in patients and carers following suspected clozapine-induced neutropenia.

BACKGROUND: Clozapine is the treatment of choice in refractory psychosis. In most countries, clozapine must be stopped indefinitely if white blood cells fall below a defined threshold during routine monitoring. Despite evidence of severe adverse consequences of clozapine discontinuation, published accounts on the lived experiences and perspectives of patients and carers are scarce. METHOD: We completed semi-structured interviews with patients (n = 4) and family carers (n = 4) on experiences of clozapine cessation following suspected drug-induced neutropenia. Interviews were audio-recorded, transcribed and analysed thematically. RESULTS: The two overarching themes comprised:(i) stress of clozapine below threshold neutrophil results and (ii) patient and carer priorities. CONCLUSIONS: There is a suggested need for evidence-based pharmacological and psychological approaches to support patients and carers after clozapine cessation. Such approaches will minimise the potentially negative physical and emotional sequela in the aftermath of a below threshold neutrophil result and reduce the likelihood of experiencing additional health and social inequalities after clozapine discontinuation.

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.

Clozapine augmentation with cariprazine for negative symptoms: a case series and literature review.

Only about 50% of patients with treatment-resistant schizophrenia respond to clozapine, and many more patients continue to experience ongoing and prominent negative symptoms. These negative symptoms, for which there are limited pharmacological options, may represent the greatest barrier to functional recovery. Cariprazine is a novel antipsychotic drug that is a partial agonist at dopamine D2 and D3 receptors with preferential binding to the D3 receptor, antagonism of 5HT2B receptors, and partial agonism at 5HT1A receptors. Cariprazine is currently licenced for the treatment of schizophrenia in Europe and the United States and has also been approved for bipolar disorder in the United States. There is a limited body of evidence to suggest clinical effectiveness as an augmentation strategy for negative symptoms in those treated with clozapine. In this case series, we present five cases of successful treatment of negative symptoms by clozapine combined with cariprazine in treatment-resistant psychosis.

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.

Newer Formulations of Risperidone: Role in the Management of Psychotic Disorders.

Antipsychotic long-acting injections improve relapse prevention in psychotic disorders. Three new risperidone formulations have been developed that offer advantages over currently available risperidone-based long-acting injections. Risperidone ISM® is a monthly intramuscular injection that does not require loading doses or concurrent oral risperidone. RBP-7000 is a monthly subcutaneous injection not requiring loading or oral supplementation. BB0817 is a 6-monthly implant of risperidone injected subcutaneously. All three preparations have been shown to be effective and well tolerated in clinical trials. A fourth formulation (TV-46000), which can be given subcutaneously every 1 or 2 months, has recently begun trials.