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In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.
This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).
A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n = 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.
The model showed an age-related reduction in risperidone clearance (P < 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2) v. 7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–Whitney U-test, P < 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P < 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P < 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.
Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
Neuroleptic malignant syndrome (NMS) is a rare and potentially fatal adverse reaction to drugs. In psychiatric practice, it is mainly associated with antipsychotics. The classic presentation is that of hyperpyrexia, muscle rigidity, mental state changes and autonomic instability. Subtle forms are difficult to recognise owing to symptom overlap with other conditions. This article discusses the clinical presentation of the syndrome, its differential diagnosis and use of supportive care, medication and electroconvulsive therapy in its treatment. It also explores prevention of NMS and reinstatement of treatment after an episode. It is stressed that all but the mildest forms of NMS should be considered a medical emergency that is properly managed in an acute hospital.
Delusional infestation (delusional parasitosis) is a relatively rare condition but it has been of interest to a wide range of professionals, including entomologists, zoologists and dermatologists, as patients predominantly seek help from specialties other than psychiatrists. The illness requires a multidisciplinary approach and a strong bond of trust between the treating clinician and the patient to ensure the best possible outcome. This article discusses how clinicians in all specialties should approach patients presenting with the disorder and outlines differential diagnosis and associated laboratory tests. It considers the evidence base for treatment and the success of psychodermatology clinics that provide a ‘neutral setting’ for consultation to address the problem of patients’ non-engagement. Such clinics are few, and there is a need to develop disease-specific pathways in primary care and hospital settings to improve prognosis.
In the past 15 years, researchers utilizing prescription databases to assess medication usage have concluded that antipsychotics reduce mortality in patients diagnosed with schizophrenia and other psychotic disorders. These findings stand in contrast to studies in non-psychiatric patients that have found that antipsychotics, because of their adverse effects on physical health, increase the risk of early death. A critical review of the evidence reveals that the worry remains. There is reason to conclude that antipsychotics contribute to the ‘mortality gap’ between the seriously mentally ill and the general population and that the database studies are plagued with methodological and reporting issues. Most importantly, the database studies tell of mortality rates within a drug-centered paradigm of care, which confounds any comparison of mortality risks when patients are on or off antipsychotics.
This random-effects model meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups.
We conducted systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. We calculated risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH). Primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. We also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months.
We identified 22 studies (n = 5462) receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. Mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs (95% confidence interval, NNTB/NNTH) of recurrence rate at 6 months were 0.61 (0.54–0.70, 5) for any mood episode, 0.72 (0.60–0.87, 13) for depressive episodes, and 0.45 (0.36–0.57, 6) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (0.61–0.82, 6).
Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.
To explore the beliefs and understanding of staff and patients at a secure mental health unit regarding clozapine monitoring, and to identify barriers to and facilitators of monitoring. Qualitative semi-structured interviews and focus groups were conducted with 17 staff members and six patients.
Six key themes were identified. The key facilitator of effective monitoring was the motivation of staff to help patients to become independent and facilitate recovery. An important barrier was a lack of clarity around the roles of different staff groups in monitoring. Staff and patients widely supported the establishment of an in-patient clozapine clinic and perceived that it would prepare patients for discharge.
An in-patient clozapine clinic is a robust mechanism for clozapine monitoring in secure settings. The barriers and facilitators identified here could be applied to other secure units to guide their systems of clozapine monitoring.
A high proportion of adults with intellectual disabilities are prescribed off-licence antipsychotics in the absence of a psychiatric illness. The National Health Service in England launched an initiative in 2016, ‘Stopping over-medication of people with a learning disability [intellectual disability], autism or both’ (STOMP), to address this major public health concern.
To gain understanding from UK psychiatrists working with adults with intellectual disabilities on the successes and challenges of withdrawing antipsychotics for challenging behaviours.
An online questionnaire was sent to all UK psychiatrists working in the field of intellectual disability (estimated 225).
Half of the 88 respondents stated that they started withdrawing antipsychotics over 5 years ago and 52.3% stated that they are less likely to initiate an antipsychotic since the launch of STOMP. However, since then, 46.6% are prescribing other classes of psychotropic medication instead of antipsychotics for challenging behaviours, most frequently the antidepressants. Complete antipsychotic discontinuation in over 50% of patients treated with antipsychotics was achieved by only 4.5% of respondents (n = 4); 11.4% reported deterioration in challenging behaviours in over 50% of patients on withdrawal and the same proportion (11.4%) reported no deterioration. Only 32% of respondents made the diagnosis of psychiatric illness in all their patients themselves. Family and paid carers’ concern, lack of multi-agency and multidisciplinary input and unavailability of non-medical psychosocial intervention are key reported factors hampering the withdrawal attempt.
There is an urgent need to develop national guidelines to provide a framework for systematic psychotropic drug reviews and withdrawal where possible.
To assess the effects of treatment with lurasidone on risk for metabolic syndrome (MetS) in patients with schizophrenia.
Rates of metabolic syndrome during treatment with lurasidone (40-160 mg/d) were analyzed using pooled, short-term data from three randomized, double-blind, placebo-controlled studies (vs olanzapine and quetiapine XR); long-term data from two active-comparator-controlled studies (vs risperidone and quetiapine XR); and data from two open-label studies in which patients were switched from olanzapine or risperidone to lurasidone.
MetS was defined based on the National Cholesterol Education Program criteria. In short-term studies, the odds of meeting criteria for MetS at week 6 LOCF (adjusted for baseline metabolic syndrome status) was similar for the lurasidone and placebo groups (OR = 1.18; [95% CI, 0.81-1.71]; P = .39), but the odds (vs placebo) were significantly greater for olanzapine (OR = 2.81; [95% CI, 1.53-5.15]; P < .001) and quetiapine (OR = 3.49; [95% CI, 1.93-6.29]; P < .0001). No dose effect was observed for lurasidone across the dose range of 40-160 mg/d. In long-term studies, the odds of MetS after 12 months of treatment was significantly higher for risperidone compared with lurasidone (OR = 2.12; 95% CI, 1.15-3.90; P = .016) and for quetiapine XR compared with lurasidone (OR = 3.92; 95% CI, 1.15-13.40; P = .029). In open-label extension studies, the rate of MetS decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone.
In this analysis of lurasidone clinical trials, the odds of developing metabolic syndrome were minimal during short- and long-term treatment with lurasidone (40-160 mg/d).
Vitamin D deficiency is associated with an increased risk of acute respiratory infection. There is an excess of respiratory infections and deaths in schizophrenia, a condition where vitamin D deficiency is especially prevalent. This potentially offers a modifiable risk factor to reduce the risk for and the severity of respiratory infection in people with schizophrenia, although there is as yet no evidence regarding the risk of COVID-19. In this narrative review, we describe the prevalence of vitamin D deficiency in schizophrenia, report the research examining the relationship between vitamin D levels and COVID-19 and discuss the associations between vitamin D deficiency and respiratory infection, including its immunomodulatory mechanism of action.
The purpose of this review was to establish whether the prescription of antipsychotic medication in HMP Low Newton was safe, rational and consistent with current best practice. A search of the electronic healthcare records was performed on 14 March 2018 to identify all the women in the prison who were prescribed antipsychotic medication, and then data were collected from the records.
A total of 46 out of 336 prisoners (13.7%) had been prescribed antipsychotic medications; 29 of the 46 patients (84.8%) were also prescribed other psychotropic medications at the same time. Quetiapine was the most frequently prescribed antipsychotic and was also the most likely to be prescribed for off-label indications. Less than one-third of all antipsychotic prescriptions were for psychotic disorders.
The rationale for prescribing all antipsychotic medication, especially for off-label indications, should be clearly documented and reviewed regularly within the prison by the mental health team and psychiatrist.
Clozapine, an antipsychotic with unique efficacy in treatment-resistant psychosis, is associated with increased susceptibility to infection, including pneumonia.
To investigate associations between clozapine treatment and increased risk of COVID-19 infection in patients with schizophrenia-spectrum disorders who are receiving antipsychotic medications in a geographically defined population in London, UK.
Using information from South London and Maudsley NHS Foundation Trust (SLAM) clinical records, via the Clinical Record Interactive Search system, we identified 6309 individuals who had an ICD-10 diagnosis of schizophrenia-spectrum disorders and were taking antipsychotics at the time of the COVID-19 pandemic onset in the UK. People who were on clozapine treatment were compared with those on any other antipsychotic treatment for risk of contracting COVID-19 between 1 March and 18 May 2020. We tested associations between clozapine treatment and COVID-19 infection, adjusting for gender, age, ethnicity, body mass index (BMI), smoking status and SLAM service use.
Of 6309 participants, 102 tested positive for COVID-19. Individuals who were on clozapine had increased risk of COVID-19 infection compared with those who were on other antipsychotic medication (unadjusted hazard ratio HR = 2.62, 95% CI 1.73–3.96), which was attenuated after adjusting for potential confounders, including clinical contact (adjusted HR = 1.76, 95% CI 1.14–2.72).
These findings provide support for the hypothesis that clozapine treatment is associated with an increased risk of COVID-19 infection. Further research will be needed in other samples to confirm this association. Potential clinical implications are discussed.
In this overview we discuss the role of psychiatry in managing delirium in acute hospital admissions. We briefly discuss the role psychiatry can offer in four main domains: (a) assessment; (b) management; (c) recovery; and (d) paradigm, education and research. In the assessment section we discuss accurately detecting delirium in the context of comorbid mixed neuropsychiatric syndromes, including depression and dementia, and the clinical importance of delirium subtyping. The management section briefly outlines pharmacological and non-pharmacological approaches to delirium and their evidence-based rationale. The recovery section focuses on the effect delirium can have on cognitive decline, mental health and long-term health, including functional outcome and need for institutional care after hospital discharge. Finally, we outline the role of psychiatry in delirium research and education. We hope that this article will encourage clinicians to reflect on their current practice and consider holistic and evidence-based care for this vulnerable population in the acute hospital setting.
This is a report of a joint World Psychiatric Association/International College of Neuropsychopharmacology (WPA/CINP) workgroup concerning the risk/benefit ratio of antipsychotics in the treatment of schizophrenia. It utilized a selective but, within topic, comprehensive review of the literature, taking into consideration all the recently discussed arguments on the matter and avoiding taking sides when the results in the literature were equivocal. The workgroup’s conclusions suggested that antipsychotics are efficacious both during the acute and the maintenance phase, and that the current data do not support the existence of a supersensitivity rebound psychosis. Long-term treated patients have better overall outcome and lower mortality than those not taking antipsychotics. Longer duration of untreated psychosis and relapses are modestly related to worse outcome. Loss of brain volume is evident already at first episode and concerns loss of neuropil volume rather than cell loss. Progression of volume loss probably happens in a subgroup of patients with worse prognosis. In humans, antipsychotic treatment neither causes nor worsens volume loss, while there are some data in favor for a protective effect. Schizophrenia manifests 2 to 3 times higher mortality vs the general population, and treatment with antipsychotics includes a number of dangers, including tardive dyskinesia and metabolic syndrome; however, antipsychotic treatment is related to lower mortality, including cardiovascular mortality. In conclusion, the literature strongly supports the use of antipsychotics both during the acute and the maintenance phase without suggesting that it is wise to discontinue antipsychotics after a certain period of time. Antipsychotic treatment improves long-term outcomes and lowers overall and specific-cause mortality.
Delirium is a state of global disturbance of cerebral function, and is common, affecting over 30% of inpatients. Readers are invited to explore the causes of delirium, how to assess patients with this condition and its initial management, including both pharmacological and nonpharmacological measures. The chapter includes advice on prescribing antipsychotics and benzodiazepines in this vulnerable group of patients.
Advocating for good physical healthcare for their patients is of the utmost importance to psychiatrists. This narrative review focuses on one part of this large goal, the topic of hyperprolactinaemia from the perspective of mental healthcare. For psychiatrists this often includes managing raised prolactin levels in the context of medication. However, they must consider the wider differentials of a raised prolactin level and the possible impact of treatments. For that reason, in this review we start with an overview of prolactin physiology before considering hyperprolactinaemia both in the context of antipsychotic therapy and its wider differentials, including prolactinoma. Investigation and management are considered and key practice points developed.
Individuals with tardive dyskinesia (TD) who completed a long-term study (KINECT 3 or KINECT 4) of valbenazine (40 or 80 mg/day, once-daily for up to 48 weeks followed by 4-week washout) were enrolled in a subsequent study (NCT02736955) that was primarily designed to further evaluate the long-term safety of valbenazine.
Participants were initiated at 40 mg/day (following prior valbenazine washout). At week 4, dosing was escalated to 80 mg/day based on tolerability and clinical assessment of TD; reduction to 40 mg/day was allowed for tolerability. The study was planned for 72 weeks or until termination due to commercial availability of valbenazine. Assessments included the Clinical Global Impression of Severity-TD (CGIS-TD), Patient Satisfaction Questionnaire (PSQ), and treatment-emergent adverse events (TEAEs).
At study termination, 85.7% (138/161) of participants were still active. Four participants had reached week 60, and none reached week 72. The percentage of participants with a CGIS-TD score ≤2 (normal/not ill or borderline ill) increased from study baseline (14.5% [23/159]) to week 48 (64.3% [36/56]). At baseline, 98.8% (158/160) of participants rated their prior valbenazine experience with a PSQ score ≤2 (very satisfied or somewhat satisfied). At week 48, 98.2% (55/56) remained satisfied. Before week 4 (dose escalation), 9.4% of participants had ≥1 TEAE. After week 4, the TEAE incidence was 49.0%. No TEAE occurred in ≥5% of participants during treatment (before or after week 4).
Valbenazine was well-tolerated and persistent improvements in TD were found in adults who received once-daily treatment for >1 year.
Previous literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.
A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.
Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.
CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.
Antipsychotic medications may reduce hostile and aggressive behavior in schizophrenia. This study compared the effectiveness of antipsychotics in the treatment of aggression.
The Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study compares the effectiveness of antipsychotic treatments in practice setting. Schizophrenia outpatients who initiated or changed to a new antipsychotic are followed in this non-interventional, prospective observational study for up to 3 years, with 6-months data now available on the entire cohort (N = 7655). The presence or absence of verbal or physical hostility/aggression was assessed retrospectively for the period of 6 months before enrollment, and prospectively in the period of 6 months after enrollment (the study treatment period). At baseline, patients in five monotherapy treatment groups (combined N = 3135) were prescribed one of the treatments: clozapine, olanzapine, quetiapine, risperidone, or haloperidol, and had complete data.
Hostile/aggressive behavior was reduced during the treatment period. Olanzapine and risperidone were significantly superior to haloperidol and to clozapine in this respect. These results remained essentially unchanged when adjusting for baseline imbalances in age, gender, age of onset, and substance abuse.
As monotherapy, both olanzapine and risperidone were superior to haloperidol and clozapine in reducing aggression. The relative lack of effectiveness of clozapine may be specific to this study population.
Interest exists in identifying the factors that specifically contribute to the increased prevalence of cardiovascular disease observed in psychiatric disease. The apolipoprotein-E (APOE) gene codes for a protein that has a key role in metabolism of cholesterol and triglycerides, with increased levels of apoE found in specific areas of post-mortem schizophrenic brains. This study investigated whether apoE variants influence the prevalence of cardiovascular risk factors (obesity, diabetes and dyslipidaemia), in patients receiving antipsychotic treatment, due to extension of the risk seen in the general population, but also due to the role of the APOE gene in mediating antipsychotic-induced side effects. Seven polymorphisms (rs741780, rs483082, rs429358, rs7412, rs10119, rs439401 and rs405509) were genotyped in 427 American Caucasian patients who were either receiving, or had been prescribed risperidone. Our results support the hypothesis that APOE gene variants influence the prevalence of diabetes and possibly overweight in psychiatric patients. Unfortunately, due to the cross sectional nature of this study, the contribution of antipsychotic treatment was not determined. These associations warrant prospective study to assess interaction between APOE gene variants and the propensity of antipsychotics to induce cardiovascular risk factors.
The prevalence of Diabetes Mellitus (DM) is becoming a serious public health problem. The use of atypical antipsychotics has been associated with disruption of the glucose metabolism and therefore with causing DM. The underlying mechanisms are unknown, but knowledge of the differences between the pharmacological features of various antipsychotics combined with their diabetogenic profile might help us to understand those mechanisms. This article describes how the binding of various essential receptors or transporters in essential body tissues, adipose tissue, pancreatic tissue and liver and skeletal muscle tissue can cause disruption of the glucose metabolism. With such knowledge in mind one can try to explain the differences between the diabetogenic propensities of various antipsychotics. It is well known that clozapine and olanzapine cause weight gain and DM, whereas aripiprazole and ziprasidone have much less disruptive clinical profiles. The most significant risk factor for adiposity seems to be strong blocking of histaminergic receptors. An agonistic activity on serotonergic-1a receptors, with a very low affinity for muscarinergic-3 receptors, might protect against the development of DM. More data will become available which may help to solve the puzzle.