Side Effects Of Antipsychotics Research Articles

Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.

SummaryBackgroundLittle evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis.MethodsWe did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197.FindingsOf 138 patients referred to the study, 75 were recruited and randomly assigned—26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26–51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (–5·65 [95% CI −10·37 to −0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (–4·52 [95% CI −9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (–1·13 [95% CI −5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group).InterpretationA head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis.FundingNational Institute for Health Research.

F98. HYPOVITAMINOSIS D IN SCHIZOPHRENIA: ASSOCIATED CARDIOVASCULAR RISK

BackgroundVitamin D modulate the course of many neurologic diseases and conditions. Moreover, the prevalence of vitamin D deficiency might be higher in psychiatric patients, in particular with schizophrenia.Likewise, there is an inverse relationship between vitamin D levels and several cardiovascular risk factors, including the metabolic syndrome, that patients with schizophrenia are predisposed to develop. It is within this framework that this study aims to explore the relationship between vitamin D levels in a cohort of Tunisian patients with schizophrenia and to determine the cardiovascular risk according to whether they had hypovitaminosis D or not.MethodsA cross-sectional and retrospective descriptive study was conducted at the “F” psychiatry department at the Razi Hospital, Manouba over a twelve-month period from June 1st, 2015 to May 31st, 2016, including 80 patients with schizophrenia in period of clinical remission. The evaluation focused on anthropometric parameters and cardiovascular risk factors. A dosage of vitamin D was performed.ResultsThe patients had an average age of 42.5 years and 70% were male. 25 patients had metabolic syndrome. 49% of patients had vitamin D insufficiency and 51% had vitamin D deficiency. Vitamin D levels had not been affected by the clinical characteristics of the disease. However, there was no significant association between vitamin D levels and metabolic syndrome. A significant negative correlation was found between the total sum of the various cardiovascular risk factors and the vitamin D deficiency (p <0.001).DiscussionIn our study, all patients had vitamin D levels below the recommended levels. 25 patients (31%) met the criteria for metabolic syndrome. All our patients had at least one cardiovascular risk factor. The majority (33% and 27%) had respectively three or four FRCV. 10% had more than five concurrent FRCVs. This result has been described in many studies. Indeed, in patients with schizophrenia, the cardiometabolic risk seems to increase continuously. Several European studies have reported a prevalence of metabolic syndrome ranging from 28% to 37% in patients with schizophrenia. Higher rates of 43% and 46% were reported respectively in the United States and Canada. Moreover, with schizophrenia have an increased risk of sudden death and are 2 to 4 times more likely to die prematurely compared to the general population. These results have been explained with a multicausal model focusing on genetics, lifestyle, smoking, diet and sedentary behavior as well as by the side effects of antipsychotics known to induce weight gain and aggravate symptoms. risk factors for cardiometabolic disease, although studies in naïve patients reflect various abnormalities early on. However, several studies confirm that certain metabolic abnormalities may occur in schizophrenic patients naive to any antipsychotic treatment.This result is consistent with current literature data that highlight increased metabolic and cardiovascular risk in vitamin D deficiency. Indeed, in the general population, vitamin D deficiency is an important risk factor for cardiometabolic disease. The majority of cohort studies have reported an increase in the incidence of cardiovascular disease in people with low vitamin D levels.

F56. IMPACT OF SIDE EFFECTS DUE TO SECOND-GENERATION ANTIPSYCHOTICS ON THE FUNCTIONING OF PATIENTS WITH SCHIZOPHRENIA: AN OBSERVATIONAL, PATIENT CENTERED, WEB SURVEY

BackgroundIn patients with schizophrenia, antipsychotic medications, including second-generation antipsychotics, may cause many side-effects (SE) often leading to treatment discontinuation, and possible relapse as a consequence. The impact of treatments on patient-centered outcomes such as health-related quality of life (HRQOL) is less well understood. Even less well understood is the impact of side effects on patient-centered outcomes such as daily functioning and HRQOL. Therefore, the study’s primary goal was to gain a deeper understanding of the impacts of SEs of second generation antipsychotics on patients’ day to day functioning.MethodsA cross-sectional, web-based, patient-reported survey was fielded in the United States between July and November 2017. The final survey included patient socio-demographics, a quality of life measure (Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, Q-LES-Q-SF), questions on treatment satisfaction, SEs experienced (Glasgow Antipsychotic Side-Effect Scale, GASS), and questions about the impact of SEs on functioning and emotions. Patients were recruited through patient advocacy and support groups, and medical research panels. Patient inclusion criteria: Self-reported schizophrenia diagnosis; 18 to 65 years old; stable for at least one month at time of screening; prescribed a second-generation antipsychotic medication for 1–12 months; the final sample consisted of those individuals who reported experiencing one or more side-effects based on the GASS.ResultsThe total sample (n=180) had a mean age of 35 (range 18–61) years old, of which 58.3% were females. Approximately a quarter (27.8%) of the sample had a college degree or higher; 69.4% identified as White, followed by 16.7% Black/ African American, and 6.1% Native Hawaiian/ Pacific Islanders. Most prevalent SEs reported on the GASS were ‘difficulty sleeping’ (81.1%), ‘feeling sleepy during the day’ (77.2%), ‘dry mouth’ (70.6%), and ‘feeling restless (60.6%). The SEs most commonly reported as distressing, for those patients experiencing that SE, were difficulty passing urine (23.3%), and feeling drugged/like a zombie (19.4%). The minimum impact from SEs on daily functioning was 53.2 on a 0–100 Visual Analogue Scale (higher number reflects more negative impact on daily functioning; 0=no impact and 100=very highly impacted). Across the SEs further probed about, the most severe impact was on one’s ‘ability to get or do a job’; specifically, for the SEs ‘shaky hands or arms’ the mean impact was 76.1, followed by 69.8 for restlessness. ‘Problems enjoying sex’ had the greatest effect on one’s ‘intimate relationships’ (mean 74.8), and feeling drugged/like a zombie had the greatest effect on one’s ‘ability to concentrate’ (mean 70.2).DiscussionThe study indicates the importance of incorporating the patient with schizophrenia’s perspective when assessing SE experiences and impact on functioning due to second generation antipsychotic agents. Findings suggest that both activating SEs (restlessness) and sedating SEs (feeling drugged and sleepiness) have pronounced undesirable impact on daily patient functioning.

Meta regression: Relationship between antipsychotic receptor binding profiles and side-effects

Our objective was to examine the association between antipsychotic receptor binding profiles and the magnitude of common side-effects. We used regression analysis to examine the association between the receptor binding affinities of antipsychotic agents (log Ki) and degree of specific antipsychotic side-effects. Data on magnitude of weight gain, prolactin increase and QTc prolongation (in Standardized Mean Difference) and risk of sedation and extrapyramidal symptoms (in Odds Ratio) between individual antipsychotic medications as compared to placebo was based on a recent network meta-analysis examining the treatment of schizophrenia. Receptor affinities (in log Ki) were examined for the D2, 5-HT1A, 5-HT2A, 5-HT2C, H1, alpha1, alpha2, M1, M3 and M4 receptors. Medications were weighted in the analysis using the generic inverse variance method utilizing variance estimates from the previous meta-analysis.Magnitude of weight gain was significantly associated with the affinity of antipsychotic medications to M1, M3, 5-HT2C and H1 receptors. Risk of sedation was significantly associated with the affinity to the M1 and M4 receptors. Magnitude of hyperprolactinemia was significantly associated with the affinity to M1 and M4 receptors. Risk of extrapyramidal side effects was associated with the affinity to 5-HT2C and M1 receptors. QT prolongation was not significantly associated with antipsychotic receptor affinities. Our meta-analysis demonstrated that increased affinity of antipsychotics for certain receptors are significantly associated with higher risk of sedation, hyperprolactinemia, extrapyramidal side effects and weight gain.

Effectiveness of Planned Teaching about Knowledge Regarding side Effects of Typical Antipsychotics among the Primary care givers of Psychiatric Patient in selected Hospital

Effectiveness of Planned Teaching about Knowledge Regarding side Effects of Typical Antipsychotics among the Primary care givers of Psychiatric Patient in selected Hospital

Perioperative management of patients with schizophrenia

This article is a review of publications on clinical research and recommendations for managing patients with schizophrenia in the perioperative period in surgical interventions not associated with psychopathology. An anesthesiologist may face behavioral, cognitive and emotional problems in patients with schizophrenia at all stages of the perioperative period. When anesthetizing such patients, it is necessary to take into account the undesirable side effects of antipsychotics, as well as the risk of their interaction with anesthetics. It is also known that schizophrenia often combines with cardiovascular and endocrine diseases, which further increases the risk of anesthesia. The article gives a description of the main groups of drugs for the treatment of schizophrenia — typical and atypical antipsychotics, a tactic of withdrawal or continuation of their admission during the perioperative period. The problem of neuroleptic malignant syndrome is considered — a potentially lethal complication of therapy with these drugs.

Prevention of antipsychotic side effects in elderly populations

The elderly, especially women, are at risk for severe side effects from antipsychotic medication. There are a number of reasons for this. This paper lists the reasons, the nature of the effects, and provides clinical recommendations for prevention and treatment.

Antipsychotic polypharmacy in older Australians.

A cross-sectional study was conducted using Australian Department of Veterans' Affairs (DVA) administrative claims data for the period 1 March 2014 to 30 June 2014. Veterans dispensed at least one antipsychotic medicine during the study period was included. We determined the number of participants dispensed antipsychotic polypharmacy and the number of participants dispensed medicines to manage antipsychotic side effects. There were 7,412 participants with a median age of 86 years. Fifty-one percent (n=3,784) were women and 48% (n=3,569) lived in residential aged-care. Fifty one participants (0.7%) were dispensed anticholinergic medicines indicated for the management of antipsychotic-associated extrapyramidal movement disorders and eight (0.1%) were dispensed medicines for the management of hyperprolactinemia. Five percent of participants (n=365) received dual antipsychotics. Dual antipsychotic users were more likely to be under the care of a psychiatrist or to have had a mental health hospitalization than those using a single antipsychotic. Antipsychotic polypharmacy occurred in one in 20 elderly persons, indicating that there is room for improvement in antipsychotic use in elderly patients.

The Glasgow antipsychotic side-effects scale for clozapine in inpatients and outpatients with schizophrenia or schizoaffective disorder

Background: The inconsistency in clinician and patient ratings of clozapine-induced side effects underscore the need to supplement clinician-based estimates of side effects with patient-reported ones.Aims: The main aims of the study are validation of the Glasgow antipsychotic side-effects scale for clozapine (GASS-C) in Serbian inpatients/outpatients with schizophrenia or schizo-affective disorder and recommendations for its future use, based on common and rare clozapine-associated side-effects.Methods: The GASS-C was administered to 95 outpatients/inpatients diagnosed with schizophrenia, schizoaffective, or chronic psychotic disorder.Results: The scale showed good overall reliability, with an internal consistency coefficient of α = 0.84, an average retest coefficient of rho = 0.76, and a Spearman–Brown coefficient of validity of 0.81. Side effects were absent or mild in 64.2% of the patients, moderate in 31.6%, severe in 4.2%; 14% of the subjects considered their symptoms distressing. The most commonly reported side-effects were drowsiness, thirst, frequent urination, and dry mouth. Women reported more side effects than men, and patients not in a relationship reported significantly fewer side effects than patients in a relationship. Results indicate a weak positive correlation (rho = 0.231; p = .025) between severity of side effects and clozapine dose.Conclusions: The GASS-C showed good psychometric characteristics in clinical population of patients on clozapine. In future studies, clozapine serum concentrations should be measured when using the GASS-C to monitor side effects.

Efficacy and Tolerability of Clozapine versus Quetiapine in Treatment-resistant Schizophrenia.

Objectives:To compare the efficacy and tolerability of clozapine and quetiapine in patients with treatment-resistant schizophrenia (TRS).Patients and Methods:In this prospective, randomized, open label study of 14 weeks, 53 patients with schizophrenia diagnosed as per ICD-10 and fulfilling the modified version of Conley and Kelly's criteria of TRS were randomly assigned to receive clozapine or quetiapine as per a computer-generated random table. After 2-weeks of dose-titration phase, doses were fixed at minimum therapeutic dose and subsequently adjusted according to the clinical improvement. All patients received dosage of respective drug in therapeutic range. 13 patients were lost to follow up. Treatment efficacy and side effects were evaluated with standardized rating scales.Results:Clozapine group (reduction in total score: mean=14.45, SD=10.39) had significantly greater reductions (P=0.004; CI=3.541-17.059) in the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive subscale and PANSS general psychopathology subscale at 14 weeks in comparison to the quetiapine group (reduction in total score: mean=4.15, SD=10.71). Significant reduction in PANSS negative subscale was seen with both drugs but no significant difference was present between the two drugs. At 14 weeks, 30% patients in clozapine group and 15% patients in quetiapine group showed response. Clozapine led to significantly greater side effects (P< 0.001, CI=2.241-6.059) on Glassgow Antipsychotic Side-effect Scale (GASS) than quetiapine.Conclusions:Clozapine was found to be more efficacious than quetiapine in patients with TRS but was associated with greater side effects. Both the drugs were found to be equally effective in reducing the negative symptoms.

Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number of observations made across several decades and under different experimental conditions. Here we show that association rates, but not dissociation rates, correlate with EPS. We measured the kinetic binding properties of a series of typical and atypical APDs in a novel time-resolved fluorescence resonance energy transfer assay, and correlated these properties with their EPS and prolactin-elevating liabilities at therapeutic doses. EPS are robustly predicted by a rebinding model that considers the microenvironment of postsynaptic D2 receptors and integrates association and dissociation rates to calculate the net rate of reversal of receptor blockade. Thus, optimizing binding kinetics at the D2 receptor may result in APDs with improved therapeutic profile.

C.09.02 - Antipsychotic side effects may have a negative impact on patient functioning

C.09.02 - Antipsychotic side effects may have a negative impact on patient functioning

Antipsychotic-induced encephalopathy and re-examining the schizophrenic brain from the viewpoint of it

Background: There is inadequate understanding of chronic encephalopathy as one of the irreversible side effects of antipsychotics.

TAILOR \u2013 tapered discontinuation versus maintenance therapy of antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder in remission of psychotic symptoms: study protocol for a randomized clinical trial

BackgroundThe aim of the TAILOR trial is to investigate the effect of closely monitored tapering/discontinuation versus maintenance therapy with antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder and with minimum 3 months’ remission of psychotic symptoms.Methods and designTwo hundred and fifty patients will be included from the psychiatric early intervention program, OPUS, in two regions in Denmark. Inclusion criteria are: ICD-10 diagnoses schizophrenia (F20, except F20.6) or persistent delusional disorder (F22), minimum 3 months’ remission of psychotic symptoms and in treatment with antipsychotic medication (except clozapine). The patients will be randomized to maintenance therapy or tapering/discontinuation with antipsychotic medication in a 1-year intervention. The tapering/discontinuation group will be using a smartphone application to monitor early warning signs of psychotic relapse. Patients will be assessed at baseline, 1-, 2- and 5-year follow-up regarding psychotic and negative symptoms, side-effects of antipsychotic medication, social functioning, cognitive functioning, perceived health status, patient satisfaction, substance and alcohol use, sexual functioning and quality of life. The primary outcome will be remission of psychotic symptoms and no antipsychotic medication after 1 year. Secondary outcome measures will include: co-occurrence of remission of psychotic symptoms and 0–1-mg haloperidol equivalents of antipsychotic medication after 1-year intervention; antipsychotic dose; antipsychotic side effects; negative symptoms; social functioning; cognitive functioning; and patient satisfaction. Exploratory outcomes will include remission, clinical recovery, substance and alcohol use, sexual functioning, quality of life, self-beliefs of coping and user experience of support from health workers. Safety measures will include death, admissions to psychiatric hospital, severe self-harm and psychotic relapses.DiscussionThe TAILOR trial will contribute knowledge about the effect of tapering/discontinuation of antipsychotic medication in the early phases of schizophrenia and related disorders and the results may guide future clinical treatment regimens of antipsychotic treatment.Trial registrationEU Clinical Trials Register – EudraCT number: 2016-000565-23. Registered on 5 February 2016.

A pilot randomised controlled trial of community-led ANtipsychotic Drug REduction for Adults with Learning Disabilities.

Data suggest that approximately 50,000 adults with learning disabilities (LDs) in England and Wales are currently prescribed antipsychotic medication. Illness in this population is common, including significant rates of challenging behaviour and mental illness, but there is particular concern over the use of antipsychotics prescribed for reasons other than the treatment of psychosis. Control of challenging behaviour is the primary reason why such medications are prescribed despite the absence of good evidence for any therapeutic effect for this purpose. To assess the feasibility of recruitment and retention and to explore non-efficacy-based barriers to a blinded antipsychotic medication withdrawal programme for adults with LDs without psychosis compared with treatment as usual. A secondary objective was to compare trial arms regarding clinical outcomes. A two-arm individually randomised double-blind placebo-controlled drug reduction trial. Recruitment was through community learning disability teams (CLDTs) in south Wales and south-west England. Adults with LDs who are prescribed risperidone for treatment of challenging behaviour with no known current psychosis or previous recurrence of psychosis following prior drug reduction. A double-blind drug reduction programme leading to full withdrawal within 6 months. Treatment in the intervention group was gradually reduced over a 6-month period and then maintained at the same level for a further 3 months, still under blind conditions. In the control group, the baseline level of medication was maintained throughout the 9-month period. The blind was broken at 9 months, following final data collection. Feasibility outcomes were (1) the number and proportion of general practices/CLDTs that progressed from initial approach to recruitment of participants and (2) the number and proportion of recruited participants who progressed through the various stages of the study. Trial arms were also compared regarding clinical outcomes, the Modified Overt Aggression Scale, the Aberrant Behaviour Checklist, the Psychiatric Assessment Schedule for Adults with Developmental Disability checklist, the Antipsychotic Side-effect Checklist, the Dyskinesia Identification System Condensed User Scale, the Client Service Receipt Inventory, use of other interventions to manage challenging behaviour, use of as-required (pro re nata) medication and level of psychotropic medication use. Of the 22 participants randomised (intervention, n = 11; control, n = 11), 13 (59%) achieved progression through all four stages of reduction. Follow-up data at 6 and 9 months were obtained for 17 participants (intervention, n = 10; and control, n = 7; 77% of those randomised). There were no clinically important changes in participants' levels of aggression or challenging behaviour at the end of the study. There were no expedited safety reports. Four adverse events and one serious adverse event were reported during the trial. Recruitment was challenging, which was largely a result of difficulty in identifying appropriate persons to consent and carer concerns regarding re-emergence of challenging behaviour. Reduced recruitment meant that the full trial became an exploratory pilot study. The results indicate that drug reduction is possible and safe. However, concerns about taking part were probably exacerbated by limited availability of alternative (behavioural) interventions to manage behaviour; therefore, focused support and alternative interventions are required. The results of the qualitative study provide important insights into the experiences of people taking part in drug reduction studies that should influence future trial development. We recommend that further work focuses on support for practitioners, carers and patients in reducing antipsychotic medication. Current Controlled Trials ISRCTN38126962. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 47. See the NIHR Journals Library website for further project information.

Treating schizophrenia during menopause.

The aim of this review is to examine three questions: What are the risks and benefits of treating women with schizophrenia with hormone therapy (HT) at menopause? Should the antipsychotic regimen be changed at menopause? Do early- and late-onset women with schizophrenia respond differently to HT at menopause? MEDLINE databases for the years 1990 to 2016 were searched using the following interactive terms: schizophrenia, gender, menopause, estrogen, and hormones. The selected articles (62 out of 800 abstracts) were chosen on the basis of their applicability to the objectives of this targeted narrative review. HT during the perimenopause in women with schizophrenia ameliorates psychotic and cognitive symptoms, and may also help affective symptoms. Vasomotor, genitourinary, and sleep symptoms are also reduced. Depending on the woman's age and personal risk factors and antipsychotic side effects, the risk of breast cancer and cardiovascular disease may be increased. Antipsychotic types and doses may need to be adjusted at menopause, as may be the mode of administration. Both HT and changes in antipsychotic management should be considered for women with schizophrenia at menopause. The question about differences in response between early- and late-onset women cannot yet be answered.

Rat brain CYP2D enzymatic metabolism alters acute and chronic haloperidol side-effects by different mechanisms

Risk for side-effects after acute (e.g. parkinsonism) or chronic (e.g. tardive dyskinesia) treatment with antipsychotics, including haloperidol, varies substantially among people. CYP2D can metabolize many antipsychotics and variable brain CYP2D metabolism can influence local drug and metabolite levels sufficiently to alter behavioral responses. Here we investigated a role for brain CYP2D in acutely and chronically administered haloperidol levels and side-effects in a rat model.Rat brain, but not liver, CYP2D activity was irreversibly inhibited with intracerebral propranolol and/or induced by seven days of subcutaneous nicotine pre-treatment. The role of variable brain CYP2D was investigated in rat models of acute (catalepsy) and chronic (vacuous chewing movements, VCMs) haloperidol side-effects.Selective inhibition and induction of brain, but not liver, CYP2D decreased and increased catalepsy after acute haloperidol, respectively. Catalepsy correlated with brain, but not hepatic, CYP2D enzyme activity. Inhibition of brain CYP2D increased VCMs after chronic haloperidol; VCMs correlated with brain, but not hepatic, CYP2D activity, haloperidol levels and lipid peroxidation. Baseline measures, hepatic CYP2D activity and plasma haloperidol levels were unchanged by brain CYP2D manipulations.Variable rat brain CYP2D alters side-effects from acute and chronic haloperidol in opposite directions; catalepsy appears to be enhanced by a brain CYP2D-derived metabolite while the parent haloperidol likely causes VCMs. These data provide novel mechanistic evidence for brain CYP2D altering side-effects of haloperidol and other antipsychotics metabolized by CYP2D, suggesting that variation in human brain CYP2D may be a risk factor for antipsychotic side-effects.

What side effects are problematic for patients prescribed antipsychotic medication? The Maudsley Side Effects (MSE) measure for antipsychotic medication.

Capturing service users' perspectives can highlight additional and different concerns to those of clinicians, but there are no up to date, self-report psychometrically sound measures of side effects of antipsychotic medications. Aim To develop a psychometrically sound measure to identify antipsychotic side effects important to service users, the Maudsley Side Effects (MSE) measure. An initial item bank was subjected to a Delphi exercise (n = 9) with psychiatrists and pharmacists, followed by service user focus groups and expert panels (n = 15) to determine item relevance and language. Feasibility and comprehensive psychometric properties were established in two samples (N43 and N50). We investigated whether we could predict the three most important side effects for individuals from their frequency, severity and life impact. MSE is a 53-item measure with good reliability and validity. Poorer mental and physical health, but not psychotic symptoms, was related to side-effect burden. Seventy-nine percent of items were chosen as one of the three most important effects. Severity, impact and distress only predicted 'putting on weight' which was more distressing, more severe and had more life impact in those for whom it was most important. MSE is a self-report questionnaire that identifies reliably the side-effect burden as experienced by patients. Identifying key side effects important to patients can act as a starting point for joint decision making on the type and the dose of medication.

Histone deacetylase inhibitors reverse age-related increases in side effects of haloperidol in mice.

Older patients can be especially susceptible to antipsychotic-induced side effects, and the pharmacodynamic mechanism underlying this phenomenon remains unclear. We hypothesized that age-related epigenetic alterations lead to decreased expression and functionality of the dopamine D2 receptor (D2R), contributing to this susceptibility. In this study, we treated young (2-3months old) and aged (22-24months old) C57BL/6 mice with the D2R antagonist haloperidol (HAL) once a day for 14days to evaluate HAL-induced motor side effects. In addition, we pretreated separate groups of young and aged mice with histone deacetylase (HDAC) inhibitors valproic acid (VPA) or entinostat (MS-275) and then administered HAL. Our results show that the motor side effects of HAL are exaggerated in aged mice as compared to young mice and that HDAC inhibitors are able to reverse the severity of these deficits. HAL-induced motor deficits in aged mice are associated with an age- and drug-dependent decrease in striatal D2R protein levels and functionality. Further, histone acetylation was reduced while histone tri-methylation was increased at specific lysine residues of H3 and H4 within the Drd2 promoter in the striatum of aged mice. HDAC inhibitors, particularly VPA, restored striatal D2R protein levels and functionality and reversed age- and drug-related histone modifications at the Drd2 promoter. These results suggest that epigenetic changes at the striatal Drd2 promoter drive age-related increases in antipsychotic side effect susceptibility, and HDAC inhibitors may be an effective adjunct treatment strategy to reduce side effects in aged populations.

Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances

Antipsychotic drugs are widely prescribed medications, used for numerous psychiatric illnesses. However, antipsychotic drugs cause serious metabolic side effects that can lead to substantial weight gain and increased risk for type 2 diabetes. While individual drugs differ, all antipsychotic drugs may cause these important side effects to varying degrees. Given that the single unifying property shared by these medications is blockade of dopamine D2 and D3 receptors, these receptors likely play a role in antipsychotic drug-induced metabolic side effects. Dopamine D2 and dopamine D3 receptors are expressed in brain regions critical for metabolic regulation and appetite. Surprisingly, these receptors are also expressed peripherally in insulin-secreting pancreatic beta cells. By inhibiting glucose-stimulated insulin secretion, dopamine D2 and dopamine D3 receptors are important mediators of pancreatic insulin release. Crucially, antipsychotic drugs disrupt this peripheral metabolic regulatory mechanism. At the same time, disruptions to circadian timing have been increasingly recognized as a risk factor for metabolic disturbance. Reciprocal dopamine and circadian signaling is important for the timing of appetitive/feeding behaviors and insulin release, thereby coordinating cell metabolism with caloric intake. In particular, circadian regulation of dopamine D2 receptor/dopamine D3 receptor signaling may play a critical role in metabolism. Therefore, we propose that antipsychotic drugs’ blockade of dopamine D2 receptor and dopamine D3 receptors in pancreatic beta cells, hypothalamus, and striatum disrupts the cellular timing mechanisms that regulate metabolism. Ultimately, understanding the relationships between the dopamine system and circadian clocks may yield critical new biological insights into mechanisms of antipsychotic drug action, which can then be applied into clinical practice.