Deprescribing antipsychotics in patients with schizophrenia: findings from a specialized clinic.

BACKGROUND: While antipsychotic medication reduces the risk of relapse for patients with schizophrenia, high prevalence of adverse effects results in low adherence. Lower doses of antipsychotics have been associated with increased level of function but also with increased risk of relapse. This study presents findings from a specialized deprescribing clinic. In addition, we aim to identify clinical predictors for relapse. METHODS: Patients diagnosed with schizophrenia were referred to the clinic, which offers a six-month guided tapering program. Antipsychotic dose was reduced by 10% every four weeks. Patients were monitored closely for symptom progression or decrease in level of function, with defined cut-offs prompting a pause in or cessation of dose reduction. RESULTS: After 12 months, the antipsychotic dose was reduced from 404 (±320 mg) to 255 (±236 mg) chlorpromazine equivalent. Of the 88 patients included, 22 (27%) experienced relapse during the six-month tapering period, while 29 (37%) experienced relapse at the 12-month follow-up visit and nine patients were antipsychotic free. Patients who remained stable experienced a slightly increased level of functioning and markedly fewer side effects (p < 0.001). Following relapse, patients were clinically stabilized and showed an improved attitude toward antipsychotic medication. The predictive models were weak. CONCLUSIONS: We show that most patients undergoing guided antipsychotic tapering remained stable after one year and improved in level of function, while most patients who relapsed were quickly stabilized. Our inability to create strong predictive models could be due to limitations in the study design, warranting future studies exploring tapering of antipsychotics in patients with schizophrenia.

Liraglutide 3.0 mg once daily for the treatment of overweight and obesity in patients hospitalised at a forensic psychiatric department: A 26-week open-label feasibility study.

INTRODUCTION: Overweight and obesity constitute a major concern among patients treated at forensic psychiatric departments. The present clinical feasibility study aimed at investigating the extent to which glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with once-daily liraglutide 3.0 mg could be a feasible pharmacological treatment of these conditions in patients with schizophrenia spectrum disorders hospitalised in forensic psychiatry. METHODS: The 26-week, open-label feasibility study included participants aged 18-65 years diagnosed with a severe mental illness and hospitalised at a forensic psychiatric department. At the time of inclusion, all participants fulfilled the indication for using liraglutide as a treatment for overweight and obesity. Participants' baseline examinations were followed by a 26-week treatment period with liraglutide injection once daily according to a fixed uptitration schedule of liraglutide, with a target dose of 3.0 mg. Each participant attended seven visits to evaluate the efficacy and adverse events. The primary endpoint was the number of "completers", with adherence defined as >80% injections obtained in the period, weeks 12-26. Determining whether liraglutide is a feasible treatment was pre-defined to a minimum of 75% completers. RESULTS: Twenty-four participants were included in the study. Sex, male = 19 (79.2%). Mean age: 42.3 [25th and 75th percentiles: 39.1; 48.4] years; body mass index (BMI): 35.7 [31.7; 37.5] kg/m2; glycated haemoglobin (HbA1c): 37 [35; 39] mmol/mol. Eleven out of 24 participants (46%) completed the study. For the completers, the median net body weight loss after 26 weeks of participation was -11.4 kg [-15.4; -5.9]. The net difference in HbA1C and BMI was -2.0 mmol/mol [-4; -1] and -3.6 kg/m2 [-4.7; -1.8], respectively. The weight change and reduction in HbA1c and BMI were all statistically significant from baseline. CONCLUSION: The study did not confirm our hypothesis that liraglutide is a feasible treatment for a minimum of 75% of the patients initiating treatment with liraglutide while hospitalised in a forensic psychiatric department. The high dropout rate may be due to the non-naturalistic setting of the clinical trial. For the proportion of patients compliant with the medication, liraglutide 3.0 mg was an efficient treatment for overweight.

Clinical experiences of guided tapering of antipsychotics for patients with schizophrenia- a case series.

BACKGROUND: 80% of patients value information on treatment options as an important part of recovery, further patients with a history of psychotic episodes feel excluded from decision making about their antipsychotic treatment, and on top of that, mental health staff is prone to be reluctant to support shared decision making and medication tapering for patients with schizophrenia. This case series aims to demonstrate the tapering of antipsychotic medication and how guided tapering affects the patient's feeling of autonomy and psychiatric rehabilitation. CASE PRESENTATION: We present six patients diagnosed with schizophrenia (International Classification of Mental and Behavioral Disorders- 10th Edition codes F20.0-5, F20.7-9) who underwent professionally guided tapering in our clinic. The clinic aims to guide the patients to identify the lowest possible dose of antipsychotic medication in a safe setting to minimise the risk of severe relapse. Two patients completely discontinued their antipsychotic medication, two suffered a relapse during tapering, one chose to stop the tapering at a low dose, and one patient with treatment resistant schizophrenia, which is still tapering down. CONCLUSIONS: Reducing the antipsychotic dose increased emotional awareness in some patients (n = 4) helping them to develop better strategies to handle stress and increased feelings of recovery. Patients felt a greater sense of autonomy and empowerment during the tapering process, even when discontinuation was not possible. Increased awareness in patients and early intervention during relapse may prevent severe relapse. IMPACT AND IMPLICATIONS: Some patients with schizophrenia might be over medicated, leading to unwanted side effects and the wish to reduce their medication. The patients in our study illustrate how guided tapering of antipsychotic medication done jointly with the patient can lead to improved emotional awareness and the development of effective symptom management strategies. This may in turn lead to a greater sense of empowerment and identity and give life more meaning, supporting the experience of personal recovery.

Mental Health Staff's Perspectives on Tapering of Antipsychotic Medication: A Focus Group Study.

Contemporary practices of long-term antipsychotic maintenance treatment for schizophrenia are being challenged, and clinicians must consider the possibilities of reducing long-term maintenance use. However, research indicates that people with schizophrenia receive little support from mental health staff to reduce antipsychotic medication. This article reports a study which aimed to investigate interdisciplinary mental health staff's accounts of tapering of antipsychotic medication and to explore different positions that mental health staff assign to themselves and others. Six focus groups were conducted with 39 mental health staff from outpatient clinics, inpatient units, forensic mental health units, and community mental health services. The data analysis combined analyses of the interactions during focus groups and the thematic content. Results were considered from a discourse analytic perspective considering the function and consequence of accounts applied by the mental health staff. The mental health staff accounted for their perspectives on tapering from the following three distinctive positions: 1) No, patients will eventually realize that they need the medication, 2) Yes, but tapering means running a big risk of relapse in symptoms, and 3) Yes, we need to welcome risks to support personal recovery. Our findings indicated that there was reluctance among interdisciplinary mental health staff to let service users make decisions and limited possibilities for people with schizophrenia to have their request for tapering of their antipsychotic medication met by mental health staff.

Antipsychotic prescribing practices for outpatients with schizophrenia and reasons for non-clozapine treatment - Data from a Danish quality assessment audit.

BACKGROUND: Clozapine is the gold standard for treating treatment-resistant schizophrenia (TRS) although widely underutilised. Both organisational, patient- and clinician related reasons for the underutilisation have been reported, however, the clinical impact of either in real-world settings is not fully elucidated. AIM: This audit aimed to evaluate the local antipsychotic (AP) prescribing practices for outpatients with schizophrenia and to assess the spectrum and prevalence of journalised reasons for non-clozapine treatment amongst eligible outpatients. METHODS: Data on demographics, current and former AP treatments, as well as documented reasons for non-clozapine treatment, was extracted through chart audit. RESULTS: Of the 668 affiliated outpatients with schizophrenia, 43% were treated with AP polytherapy (APP) and 19.6% with clozapine. The most prevalent reason for clozapine discontinuation was related to side effects whereas the most prevalent reason for refusal or omission of clozapine treatment was related to the associated monitoring regimen. CONCLUSIONS: This audit showed that APP prescribing is a highly prevalent practice in our services when treating outpatients with schizophrenia and that clozapine is underutilised in a 'last resort' manner. The blood-monitoring regimen associated with clozapine treatment was found to be an important factor in the underutilisation. It seemed, however, that the monitoring constituted a barrier for different reasons, requiring different approaches to remedy. Future studies, directly involving both patients and clinicians in the identification and management of the most clinically relevant barriers and their corresponding facilitators, are warranted.

An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels.

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas' original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300-600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75-150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175-300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100-200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250-400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150-300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300-600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Clozapine and mortality: A comparison with other antipsychotics in a nationwide Danish cohort study.

OBJECTIVE: To compare the mortality in people using clozapine to that of people using other antipsychotics. METHODS: Danish incidence cohort of 22,110 patients with a first diagnosis of non-affective psychotic disorder (1995-2013) and a prevalence cohort of 50,881 patients ever diagnosed with such a disorder (1969-2013). Hazard ratios (HR) were calculated for the antipsychotic drug used at the time of death ("current use": incidence and prevalence cohort) and for the drug used for the longest at that moment ("cumulative use": incidence cohort), using a Cox model with adjustment for somatic comorbidity. Clozapine was the reference drug. RESULTS: As for current drug use, the risk of suicide was higher among users of other antipsychotics in the incidence (HRadj  = 1.76; 95% CI 0.72-4.32) and prevalence (HRadj  = 2.20; 95% CI 1.35-3.59) cohorts. There was no significant difference in all-cause or cardiovascular mortality in the two cohorts. Cumulative use of clozapine was not associated with an increased cardiovascular mortality. Cumulative use of other antipsychotics for up to 1 year was associated with a lower all-cause mortality and suicide risk than a similar period of clozapine use (all-cause: HRadj  = 0.73; 95% CI 0.63-0.85, suicide; HRadj  = 0.65; 95% CI 0.46-0.91). CONCLUSION: The results indicate that the use of clozapine is not associated with increased cardiovascular mortality. We found opposing trends toward a lower risk of suicide during current use of clozapine and a higher risk of suicide associated with cumulative use up to 1 year. This suggests that clozapine cessation marks a period of high risk of suicide.

Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms.

BACKGROUND: There is evidence of increased low grade inflammation (LGI) in schizophrenia patients. However, the inter-individual variation is large and the association with demographic, somatic and psychiatric factors remains unclear. Our aim was to explore whether levels of the novel LGI marker soluble urokinase plasminogen activator receptor (suPAR) were associated with clinical factors in schizophrenia and if such associations were sex-dependent. METHOD: In this observational study a total of 187 participants with schizophrenia (108 males, 79 females) underwent physical examination and assessment with clinical interviews (Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Alcohol Use Disorder Identification Test (AUDIT), and Drug Use Disorder Identification Test (DUDIT)). Blood levels of suPAR, glucose, lipids, and high sensitivity C-reactive protein (hsCRP) were determined and body mass index (BMI) calculated. Multivariable linear regression analyses were used adjusting for confounders, and sex interaction tested in significant variables. RESULTS: Adjusting for sex, age, current tobacco smoking and BMI, we found that levels of hsCRP and depressive symptoms (CDSS) were positively associated with levels of suPAR (p < 0.001). The association between suPAR and CDSS score was significant in females (p < 0.001) but not in males. Immune activation measured by hsCRP was not associated with depressive symptoms after adjusting for BMI. CONCLUSION: Our findings indicate that increased suPAR levels are associated with depressive symptoms in females with schizophrenia, suggesting aberrant immune activation in this subgroup. Our results warrant further studies, including longitudinal follow-up of suPAR levels in schizophrenia and experimental studies of mechanisms.

The use of stimulants in depression: Results from a self-controlled register study.

OBJECTIVE: To investigate the effectiveness of stimulants in patients with depression, by using naturalistic outcome measures, such as psychiatric admissions, psychiatric bed-days and incidents of intentional self-harm or suicide attempts. METHODS: Via linkage of the Danish nationwide health registers, we identified all patients with a diagnosis of depression initiating stimulants, including methylphenidate, modafinil, amphetamine, dexamphetamine or lisdexamphetamine, from 1995 to 2012. We used a mirror-image model to test whether redemption of a stimulant prescription was associated with a reduction in psychiatric admissions, inpatient days and incidents of intentional self-harm or suicide attempts. Specifically, the number of these outcomes in the 2 years leading up to redemption of a stimulant prescription was compared to the two subsequent years. Similar outcomes were used in a reverse mirror-image model to investigate the effect of stimulant termination. RESULTS: A total of 3354, 935 and 105 patients diagnosed with depression redeemed prescriptions for methylphenidate, modafinil or amphetamine/dexamphetamine/lisdexamphetamine, respectively. Initiation of methylphenidate was not associated with a significant change in psychiatric admissions (mean: -0.02 admissions, p = 0.11) or inpatient days (mean: 0.13 days, p = 0.74). Similar findings were made for modafinil and the amphetamines. In addition, no clinically relevant change in psychiatric admissions or inpatient days was found after termination of a stimulant. After initiation of methylphenidate, the incidents of self-harm or suicide attempts were reduced by 54%, from 68 to 31 events (p = 0.004). No significant change in incidents of self-harm or suicide attempts were found for modafinil or the amphetamines. CONCLUSION: This nationwide study, using naturalistic outcomes, does not support the use of stimulants in patients with depression. However, the use of methylphenidate was associated with a 54% reduction in incidents of self-harm or suicide attempts, indicating that methylphenidate may potentially be useful in patients with depression with suicidal- or self-harming behaviour. However, further studies are needed, before any firm conclusions can be made.

High prevalence of prediabetes and metabolic abnormalities in overweight or obese schizophrenia patients treated with clozapine or olanzapine.

OBJECTIVE: To assess the prevalence of prediabetes and metabolic abnormalities among overweight or obese clozapine- or olanzapine-treated schizophrenia patients, and to identify characteristics of the schizophrenia group with prediabetes. METHODS: A cross-sectional study assessing the presence of prediabetes and metabolic abnormalities in schizophrenia clozapine- or olanzapine-treated patients with a body mass index (BMI) ≥27 kg/m2. Procedures were part of the screening process for a randomized, placebo-controlled trial evaluating liraglutide vs placebo for improving glucose tolerance. For comparison, an age-, sex-, and BMI-matched healthy control group without psychiatric illness and prediabetes was included. Prediabetes was defined as elevated fasting plasma glucose and/or impaired glucose tolerance and/or elevated glycated hemoglobin A1c. RESULTS: Among 145 schizophrenia patients (age = 42.1 years; males = 59.3%) on clozapine or olanzapine (clozapine/olanzapine/both: 73.8%/24.1%/2.1%), prediabetes was present in 69.7% (101 out of 145). While schizophrenia patients with and without prediabetes did not differ regarding demographic, illness, or antipsychotic treatment variables, metabolic abnormalities (waist circumference: 116.7±13.7 vs 110.1±13.6 cm, P = 0.007; triglycerides: 2.3±1.4 vs 1.6±0.9 mmol/L, P = 0.0004) and metabolic syndrome (76.2% vs 40.9%, P<0.0001) were significantly more pronounced in schizophrenia patients with vs without prediabetes. The age-, sex-, and BMI-matched healthy controls had significantly better glucose tolerance compared to both groups of patients with schizophrenia. The healthy controls also had higher levels of high-density lipoprotein compared to patients with schizophrenia and prediabetes. CONCLUSION: Prediabetes and metabolic abnormalities were highly prevalent among the clozapine- and olanzapine-treated patients with schizophrenia, putting these patients at great risk for later type 2 diabetes and cardiovascular disease. These results stress the importance of identifying and adequately treating prediabetes and metabolic abnormalities among clozapine- and olanzapine-treated patients with schizophrenia.

In utero exposure to antiepileptic drugs is associated with learning disabilities among offspring.

OBJECTIVES: In utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk. METHODS: This population-based case-cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding. RESULTS: Of 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59). CONCLUSION: In utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.

Clozapine Rechallenge After Major Adverse Effects: Clinical Guidelines Based on 259 Cases.

BACKGROUND: Clozapine is widely prescribed for treatment-refractory schizophrenia, but its use is limited by many potentially life-threatening adverse effects. The risk of rechallenge after these complications has never been comprehensively assessed in controlled studies. Thus, clinical guidelines must rely on the published case reports. The number of such reports is likely to increase over time, and updated analyses of larger samples are needed, as they may lead to changes in clinical guidelines. STUDY QUESTIONS: How safe is the clozapine rechallenge after life-threatening adverse effects? STUDY DESIGN: The published case reports of clozapine rechallenge were identified in a MEDLINE search. We added 121 cases reported from 2012 through 2017 to the 138 cases reported from 1972 through 2011 analyzed by us in a previous publication. The 95% confidence intervals (CIs) of the successful rechallenge rate were calculated for each adverse effect with at least 5 published case reports. The rechallenge was considered a valid clinical option when the lower end of the CI range was at least 50%. RESULTS: A successful outcome was documented in 128/203 patients rechallenged after neutropenia (63.0%, CI, 56.0%-69.6%), 3/17 after agranulocytosis (17.7%, CI, 4.7%-44.2%), 11/17 after myocarditis (64.7%, CI, 38.6%-84.7%), and 7/7 after neuroleptic malignant syndrome (100%, CI, 56.1%-100%). Among the 15 patients with other clozapine-induced adverse effects, the rechallenge was successful in those with eosinophilia, cardiac complications other than myocarditis (QTc prolongation, pericarditis, cardiomyopathy, and atrial flutter), and gastrointestinal hypomotility. The rechallenge failed in patients who had developed pancreatitis or renal insufficiency. CONCLUSION: Clozapine rechallenge is a reasonable clinical option after return to baseline for patients who had developed neutropenia and neuroleptic malignant syndrome, but not after agranulocytosis or myocarditis. Data are insufficient to formulate rechallenge guidelines for any other clozapine-related adverse effects.

Diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes-naive population with schizophrenia: a nationwide nested case-control study.

AIMS/HYPOTHESIS: Diabetic ketoacidosis (DKA) is a potentially fatal metabolic emergency of both type 1 and type 2 diabetes. Although there is a reduced risk of type 1 diabetes in schizophrenia, the incidence of DKA is tenfold higher than that of the general population. Thus, we aimed to investigate associations between exposure to antipsychotic medication (within 3 months prior to event) and DKA, type 1 diabetes and type 2 diabetes. We also reported related, clinically relevant outcomes. METHODS: Using a nested case-control study design, we identified cases of DKA, type 1 diabetes and type 2 diabetes in a previously diabetes-naive population with schizophrenia in Denmark from 1995 to 2014. Cases were matched (by age, sex and year of schizophrenia onset) 1:5 to schizophrenic control individuals who were alive and had not emigrated prior to event. Conditional logistic regression was used to compute ORs with 95% CIs. Other outcomes included diabetes aetiology of DKA, in-hospital mortality, DKA readmissions and temporal trends of use of insulin and oral glucose-lowering agents. RESULTS: Of 29,955 individuals with schizophrenia, we identified 28 individuals with DKA, 90 with type 1 diabetes and 2140 with type 2 diabetes. These were matched to 137, 410 and 9861 individuals in the control group, respectively. Antipsychotic exposure was associated with DKA (OR 2.60; 95% CI 1.06, 6.38) and type 2 diabetes (OR 1.64; 95% CI 1.48, 1.83). A trend towards increased risk of type 1 diabetes was found but remained insignificant (OR 1.38; 95% CI 0.84, 2.29). Diabetes aetiology of DKA was type 1 in eight cases and type 2 in 14 cases. Of the remaining six cases of DKA, aetiology could not be determined, as four were fatal within 8 days and for two, no prescriptions for insulin and oral glucose-lowering agents were redeemed. Of all DKA cases, six had more than one episode of DKA, and of all type 1 diabetes and type 2 diabetes cases, four and 11, respectively, had at least one episode. Use of insulin and oral glucose-lowering agents was higher among individuals with DKA relative to those with type 1 diabetes and type 2 diabetes. CONCLUSIONS/INTERPRETATION: Antipsychotic exposure was associated with DKA and type 2 diabetes in a previously diabetes-naive schizophrenia population. Antipsychotic-associated DKA is relevant not only for psychiatrists but also for other physicians who may manage and admit such patients.

Antipsychotic-associated psoriatic rash - a case report.

BACKGROUND: Antipsychotics are a heterogeneous group of drugs. Although, antipsychotics have been used for years, unexpected side effects may still occur. With this case report we focus on a possible association between psoriasis and antipsychotics. Data on the patient's course of psychiatric disease, onset of psoriasis and its evolution were extracted from the patient's medical files. CASE PRESENTATION: We present a case of a 21-year-old female diagnosed with schizophrenia. She was initially treated with quetiapine, and later switched to aripiprazole due to weight gain. After initiation of antipsychotic treatment, the patient suffered from severe psoriasis lesions. CONCLUSIONS: Antipsychotics may possess immunological properties that may be involved in immune-mediated conditions, such as psoriatic rash. Further studies are warranted to determine causality and mechanism.

Minimal T-wave representation and its use in the assessment of drug arrhythmogenicity.

BACKGROUND: Recently, numerous models and techniques have been developed for analyzing and extracting features from the T wave which could be used as biomarkers for drug-induced abnormalities. The majority of these techniques and algorithms use features that determine readily apparent characteristics of the T wave, such as duration, area, amplitude, and slopes. METHODS: In the present work the T wave was down-sampled to a minimal rate, such that a good reconstruction was still possible. The entire T wave was then used as a feature vector to assess drug-induced repolarization effects. The ability of the samples or combinations of samples obtained from the minimal T-wave representation to correctly classify a group of subjects before and after receiving d,l-sotalol 160 mg and 320 mg was evaluated using a linear discriminant analysis (LDA). RESULTS: The results showed that a combination of eight samples from the minimal T-wave representation can be used to identify normal from abnormal repolarization significantly better compared to the heart rate-corrected QT interval (QTc). It was further indicated that the interval from the peak of the T wave to the end of the T wave (Tpe) becomes relatively shorter after IKr inhibition by d,l-sotalol and that the most pronounced repolarization changes were present in the ascending segment of the minimal T-wave representation. CONCLUSIONS: The minimal T-wave representation can potentially be used as a new tool to identify normal from abnormal repolarization in drug safety studies.

Neurological, Metabolic, and Psychiatric Adverse Events in Children and Adolescents Treated With Aripiprazole.

Aripiprazole is a partial dopamine agonist with only minor neurological and psychiatric adverse effects, making it a potential first-line drug for the treatment of psychiatric disorders. However, the evidence of its use in children and adolescents is rather sparse. The aim of this case study is to discuss adverse drug reaction (ADR) reports concerning aripiprazole-associated neurological and psychiatric events in children and adolescents. The ADR report database at Danish Medicines Agency was searched for all ADRs involving children and adolescents (<18 years) reported by the search term [aripiprazole] AND all spontaneous reports since the introduction of aripiprazole in 2003 until December 31, 2015. Nineteen case reports were included in the study and included both patients with psychotic disorders (PS group) and nonpsychotic disorders (non-PS group). The PS group consisted of 5 patients with schizophrenia and psychoses, not otherwise specified; and the non-PS group consisted of fourteen cases including autism spectrum disorders, attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and Tourette syndrome. The main reported adverse effects in the non-PS group were chronic insomnia, Parkinsonism, behavioral changes psychoses, and weight gain, whereas the adverse effects in the PS group was predominantly anxiety, convulsions, and neuroleptic malignant syndrome. Although aripiprazole is considered safe and well tolerated in children and adolescents, severe adverse events as neuroleptic malignant syndrome, extreme insomnia, and suicidal behavior has been reported to health authorities. Clinicians should pay attention to these possible hazards when prescribing aripiprazole to this vulnerable group of patients.

Eosinophilic myocarditis during treatment with olanzapine - report of two possible cases.

BACKGROUND: Drug-induced eosinophilic myocarditis is a life-threatening and frequently overlooked condition. The prevalence of myocarditis in clozapine-treated patients may be as high as 3 %. An association between olanzapine and myocarditis has not previously been described, but given the chemical similarity between olanzapine and clozapine, we hypothesized the existence of such an association. We searched the spontaneous adverse drug reports database of the Danish Health and Medicines Authority for olanzapine and myocarditis in the period from October 21, 1996 to - June 03, 2015. We identified two fatal cases of eosinophilic myocarditis associated with the use of olanzapine. CASE PRESENTATION: Case 1 was a 39-year-old Caucasian man with known substance abuse and schizophrenia. He was found dead in his home. Olanzapine was prescribed at day -54, and dose at time of death was 40 mg/day. Post-mortem toxicological examination demonstrated presence of olanzapine, morphine, venlafaxine and oxazepam. Syringes indicating substance abuse were found in his home. Case 2 was a 36-year-old Caucasian man diagnosed with schizophrenia was found dead unexpectedly. There was no history of substance abuse. Current treatment was olanzapine 20 mg/day +5 mg as PRN (prescribed for almost 4 years), aripiprazole 30 mg/day (prescribed for 6 months) and mirtazapine 30 mg/day (prescribed for 6 months). Both cases of eosinophilic myocarditis were confirmed by autopsy findings and both patients received olanzapine in doses exceeding the recommendations. CONCLUSION: Olanzapine may have contributed to and/or worsened the two reported fatal cases of myocarditis. Additional studies are required to establish a causal link between olanzapine and eosinophilic myocarditis.