Zuclopenthixol decanoate 500mg/1ml solution for injection ampoules

Background: Reducing the dose of psychosis drugs in a gradual hyperbolic manner may minimise withdrawal effects and risk of relapse. There is presently limited guidance on tapering decanoate-based long-acting injectable dopamine antagonists (LIDAs). Objectives: We aimed to apply hyperbolic principles of tapering to the decanoate-based LIDAs flupentixol, zuclopenthixol and haloperidol to develop withdrawal regimens. Design: We used in silico methodology to predict plasma drug levels and D 2 occupancy for different LIDA regimens. Methods: Existing pharmacokinetic and receptor occupancy data from nuclear neuroimaging studies were used to power modelling. Abrupt discontinuation was examined as a potential strategy, and dose reduction was modelled with pre-defined constraints used in similar work of 10 (fast regimens), 5 (moderate) and 2.5 (slow) percentage points of D 2 occupancy change per month. Results: Abrupt discontinuation of decanoate-based LIDAs leads to excessive change in D 2 occupancy which violated our pre-defined constraints, potentially resulting in withdrawal symptoms and increased risk of relapse. Reduction of LIDA dose allowed hyperbolic reduction in plasma level consistent with imposed constraints on receptor occupancy reduction rate. For equivalent per-weekly LIDA dosing, more frequent administration allowed a more gradual reduction of D 2 occupancy. However, switching to oral forms is required to continue hyperbolic tapering to full discontinuation; reduction to zero using only LIDA produces too large a reduction in D 2 occupancy. Guidance for reduction and cessation of LIDAs according to slow, moderate and fast criteria is provided. Conclusion: Abrupt cessation of decanoate LIDAs is not consistent with gradual hyperbolic tapering, despite their longer half-lives compared with oral formulations. Reduction to the point of full discontinuation can only be achieved by switching to oral therapy to complete the taper. These results are limited by the in silico and theoretical nature of the study, and there is a need to confirm these findings through real-world observational and interventional studies.

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BACKGROUND: Priapism is a prolonged penile erection that is described as a rare but serious event that constitutes a medical emergency. Drug-induced is commonly cited in the aetiology of priapism with several drug classes implicated in its onset (e.g. antipsychotics, antidepressants, anticonvulsants (gabapentinoids) and antihypertensives). The underlying mechanisms are thought to involve alterations in vascular tone and smooth muscle regulation, which may precipitate the onset of priapism. CASE PRESENTATION: This report describes a 36-year-old male with schizophrenia and a history of chronic substance misuse including crack cocaine, heroin, methamphetamine and pregabalin, who developed ischaemic priapism during an acute psychotic episode on a psychiatric intensive care unit. At the time of the event, his regular medication regimen included a stable long-term dose of zuclopenthixol decanoate (500 mg weekly) and a recent initiation of low dose pregabalin (75 mg twice daily) for previously diagnosed neuropathic pain. The Naranjo adverse reaction probability scale score of eight suggested a probable association between the prescribed psychotropics and ischaemic priapism. CONCLUSIONS: Priapism requires urgent recognition and management to prevent long-term complications. In psychiatric settings, clinicians should exercise caution when combining gabapentinoids alongside antipsychotics, as this may increase the risk of priapism. This case highlights the need for careful monitoring when prescribing gabapentinoids to patients on long-term antipsychotics, particularly in psychiatric inpatient settings where delayed recognition may increase morbidity. CLINICAL TRIAL NUMBER: Not applicable.

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Background The rate at which psychosis drugs can be reduced in dose remains unclear. Anecdotal reports exist of people experiencing worsening of mental state before their next dose of long-acting injectable antipsychotic. No research has previously explored this phenomenon, but understanding this may advise on the rate of receptor occupancy change that provokes the emergence of psychotic symptoms. Aims Exploring the relationship between psychotic symptoms and variations in plasma concentration (and calculated receptor occupancy) of long-acting injectable antipsychotics. Method This longitudinal study monitored mental state variation within dosing cycles of people taking depot flupentixol and zuclopenthixol. The Positive and Negative Syndrome Scale (PANSS) monitored global mental state changes, and was stratified into domains according to a five-factor model. Plasma assays at maximal and minimal concentrations allowed prediction of striatal D 2 occupancy from published data. We examined correlations between receptor occupancy and the emergence of psychotic symptoms. Results Preliminary results from ten participants with psychotic disorders suggest that global mental state deterioration may correlate with increased rate of D 2 occupancy reduction. Increased rate of D 2 occupancy reduction led to deterioration in ‘positive’ ( r = 0.637 [CI: 0.013, 0.904], P = 0.047) and ‘resistance’ ( r = 0.726 [CI: 0.177, 0.930], P = 0.018) PANSS clinical domains at minimal concentrations. PANSS score differences were not related to absolute reduction in D 2 occupancy. Conclusions Our novel observational study design has been demonstrated to be feasible and practicable. Faster reductions in D 2 occupancy may increase the risk of increased positive psychotic symptoms and irritability. Slower reductions may minimise this effect. Further recruitment is required before this can be confirmed.

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Psychotic symptoms in Graves’ disease are relatively uncommon and may mimic primary psychiatric disorders which may result in delayed diagnosis and management especially in limited resource settings.We report the case of a 22-year-old male, who presented with gradual onset of psychotic symptoms which were auditory hallucinations, visual hallucinations and psychomotor agitation. Medical therapy with maximum doses of carbimazole, propranolol, and antipsychotics (haloperidol, risperidone, zuclopenthixol decanoate) administered over 18 weeks resulted in only a mild reduction in thyroid hormone levels with no improvement in psychotic symptoms.Following multidisciplinary evaluation, the patient underwent total thyroidectomy. Psychotic symptoms resolved completely within two weeks post-thyroidectomy. Follow-up thyroid hormone monitoring demonstrated normalization of free T3, free T4, and thyroid-stimulating hormone levels.This case emphasizes the importance of routine thyroid function screening in patients presenting with psychotic symptoms, particularly in resource-limited settings. It also highlights the need for timely escalation to surgical management when medical therapy fails.

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Background: Compound lipophilicity is a fundamental physicochemical property for determining the pharmacokinetic and pharmacodynamic profiles of therapeutic substances. It is successfully used in the early stages of drug candidates’ design and development. Aim: Taking into account the importance of this parameter, we aimed to assess and compare the utility of a hybrid procedure based on calculation methods and an experimental one for rapid and simple estimation of the lipophilicity of selected neuroleptics such as fluphenazine, triflupromazine, trifluoperazine, flupentixol and zuclopenthixol and their potential new derivatives. Methods: Log P values of the studied compounds were predicted by means of different platforms and algorithms: AlogPs, ilogP, XlogP3, WlogP, MlogP, milogP, logPsilicos-it, logPconsensus, logPchemaxon and logPACD/Labs. The experimental determination of lipophilicity was carried out by reverse-phase thin-layer chromatography (RP-TLC) using three types of stationary phases—RP-2F254, RP-8F254 and RP-18F254—and mobile phases consisted of acetone, acetonitrile and 1,4-dioxane as organic modifiers. Results: Our results provide a confident proposal of optimal chromatographic conditions to experimentally determine the lipophilicity of neuroleptic drugs, including new derivatives. Conclusions: Additionally, for the first time, the paper shows the application of selected topological indices in determining lipophilicity factors and other ADMET parameters of neuroleptics and, in the future, the newly synthesized quinoline derivatives of the studied compounds.

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