Lone Baandrup

Evaluation of a multifaceted intervention to limit excessive antipsychotic co‐prescribing in schizophrenia out‐patients

Baandrup L, Allerup P, Lublin H, Nordentoft M, Peacock L, Glenthoj B. Evaluation of a multifaceted intervention to limit excessive antipsychotic co‐prescribing in schizophrenia out‐patients.

Increased all-cause mortality with use of psychotropic medication in dementia patients and controls: A population-based register study

We aimed to evaluate all-cause mortality of middle-aged and elderly subjects diagnosed with dementia and treated with psychotropic drugs as compared with controls subjects. Using data from the Danish National Patient Registry, n=26,821 adults with a diagnosis of dementia were included. They were compared with 44,286 control subjects with a minimum follow-up of four years and matched on age, gender, marital status, and community location. Information about psychotropic medication use (benzodiazepines, antidepressants, antipsychotics) was obtained from the Danish Medicinal Product Statistics. All-cause mortality was higher in patients with dementia as compared to control subjects. Mortality hazard ratios were increased for subjects prescribed serotonergic antidepressant drugs (respectively, HR=1.355 (SD=0.023), P=0.001 in patients; HR=1.808 (0.033), P<0.001 in controls), tricyclic antidepressants (HR=1.004 (0.046), P=0.925; HR=1.406 (0.061), P<0.001), benzodiazepines (HR=1.131 (0.039), P=0.060); HR=1.362 (0.028), P<0.001), benzodiazepine-like drugs (HR=1.108 (0.031), P=0.078; HR=1.564 (0.037, P<0.001), first-generation antipsychotics (HR=1.183 (0.074), P=0.022; HR=2.026 (0.114), P<0.001), and second-generation antipsychotics (HR=1.380 (0.042), P<0.001; HR=1.785 (0.088), P<0.001), as compared with no drug use. Interaction analysis suggested statistically significantly higher mortality hazard ratios for most classes of psychotropic drugs in controls than in dementia patients. We found that use of psychotropic drugs is associated with increased all-cause mortality in both patients with dementia and control subjects. Thus, the frequently reported increased mortality with antipsychotic drugs in dementia is not restricted to subjects with impaired cognition and is not restricted to only one class of psychotropic drugs.

Treatment options for residual insomnia in schizophrenia.

It is well documented that patients with schizophrenia demonstrate disturbances in sleep continuity and sleep architecture as well as disrupted circadian rhythmicity. These sleep disturbances are associated with reduced quality of life and social functioning. Insomnia might be secondary to the hyperarousal caused by positive psychotic symptoms. However, in recent years, it has been acknowledged that insomnia often persists beyond adequately dosed antipsychotic treatment. Residual insomnia in schizophrenia, defined as insomnia persisting beyond otherwise adequate antipsychotic treatment, covers a range of insomnia symptoms that could be secondary to other potentially treatable conditions such as medical or psychiatric comorbidity, substance use, use of medication that might interfere with sleep or a primary sleep disorder. A thorough evaluation of the insomnia diagnosis is therefore warranted. This includes a careful patient history and examination that addresses sleep and wake function, as well as common medical, psychiatric and medication-/substance-related conditions. The complex problem of residual insomnia in schizophrenia is currently addressed by substituting or adding sedating drugs, but current treatment guidelines suffer from a lack of information on the best clinical practice. Substituting an otherwise efficient antipsychotic drug-therapy with a more sedating drug carries the risk of psychotic relapse during the switch, and adding another drug carries the disadvantages of polypharmacy including increased rate of side-effects, drug–drug interactions, patient non-compliance and medication errors. To investigate the evidence base for the different treatment options in residual insomnia in schizophrenia, we performed a systematic literature review. We searched the major bibliographic databases for randomized clinical trials (search terms: sleep and schizophren*) supplemented by review of reference lists of relevant articles. We found only five randomized clinical trials investigating pharmacological treatment options for residual insomnia in schizophrenia. Two trials examined the efficacy of switching antipsychotic drug to, respectively, risperidone (1) or its active metabolite, paliperidone (2). The data suggest that risperidone might be a good choice for this particular indication, but methodological limitations and the lack of comparison with other second-generation antipsychotics weaken the suggestion. Three studies evaluating the efficacy of melatonin showed improvement in certain sleep characteristics (e.g. sleep duration and sleep efficiency) (3–5), but two of the studies (3,4) came from the same group of researchers presumably using the same sample of patients. We found no published randomized clinical trials investigating non-pharmacological treatment of residual insomnia in schizophrenia. Thus, our attempt to review this clinically important subject was limited by the few interventions tested experimentally and difficulties making a thorough comparison of the tested interventions due to methodological limitations. These included small sample size, selective reporting, lack of specification of primary outcome measure and a high level of variability regarding assessment tools and allowed comedication. The benzodiazepines and benzodiazepine-like drugs (Z-drugs) are frequently prescribed as hypnotics, but they have not been investigated for residual insomnia in schizophrenia. These drugs are generally only recommended for short-term therapy due to the development of tolerance and dependence. Because residual insomnia in schizophrenia is a chronic condition, these drugs are generally not recommendable. An additional reason to avoid prescription of benzodiazepines is their deteriorating effect on cognitive function and their impairment (rather than correction) of sleep architecture. Particular care should be taken in patients’ comorbid for a sleep-related breathing disorder or a comorbid history of alcohol or drug abuse. Please see editorial comment to this paper by Chittaranjan Andrade and P. N. Suresh Kumar: Acta Psychiatr Scand 2013;127:11.

Objective and subjective sleep quality: Melatonin versus placebo add-on treatment in patients with schizophrenia or bipolar disorder withdrawing from long-term benzodiazepine use

Benzodiazepines are frequently long-term prescribed for the treatment of patients with severe mental illness. This prescribing practice is problematic because of well-described side effects including risk of dependence. We examined the efficacy of prolonged-release melatonin on objective and subjective sleep quality during benzodiazepine discontinuation and whether sleep variables were associated with benzodiazepine withdrawal. Eligible patients included adults with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and long-term use of benzodiazepines in combination with antipsychotics. All participants gradually tapered the use of benzodiazepines after randomization to add-on treatment with melatonin versus placebo. Here we report a subsample of 23 patients undergoing sleep recordings (one-night polysomnography) and 55 patients participating in subjective sleep quality ratings. Melatonin had no effect on objective sleep efficiency, but significantly improved self-reported sleep quality. Reduced benzodiazepine dosage at the 24-week follow-up was associated with a significantly decreased proportion of stage 2 sleep. These results indicate that prolonged-release melatonin has some efficacy for self-reported sleep quality after gradual benzodiazepine dose reduction, and that benzodiazepine discontinuation is not associated with rebound insomnia in medicated patients with severe mental illness. However, these findings were limited by a small sample size and a low retention rate.

Mortality and use of psychotropic medication in patients with stroke: a population-wide, register-based study

Objectives The study sought to describe whether psychotropic medication may have long-term side effects in patients with stroke compared with controls. Setting Use of national register data from healthcare services were identified from the Danish National Patient Registry in Denmark. Information about psychotropic medication use was obtained from the Danish Register of Medicinal Product Statistics. Objectives We aimed to evaluate all-cause mortality in relation to the use of benzodiazepines, antidepressants and antipsychotics in patients with stroke and matched controls. Participants Patients with a diagnosis of stroke and either no drug use or preindex use of psychotropic medication (n=49 968) and compared with control subjects (n=86 100) matched on age, gender, marital status and community location. Primary outcome measure All-cause mortality. Results All-cause mortality was higher in patients with previous stroke compared with control subjects. Mortality HRs were increased for participants prescribed serotonergic antidepressant drugs (HR=1.699 (SD=0.030), p=0.001 in patients; HR=1.908 (0.022), p<0.001 in controls, respectively), tricyclic antidepressants (HR=1.365 (0.045), p<0.001; HR=1.733 (0.022), p<0.001), benzodiazepines (HR=1.643 (0.040), p<0.001; HR=1.776 (0.053), p<0.001), benzodiazepine-like drugs (HR=1.776 (0.021), p<0.001; HR=1.547 (0.025), p<0.001), first-generation antipsychotics (HR=2.001 (0.076), p<0.001; HR=3.361 (0.159), p<0.001) and second-generation antipsychotics (HR=1.645 (0.070), p<0.001; HR=2.555 (0.086), p<0.001), compared with no drug use. Interaction analysis suggested statistically significantly higher mortality HRs for most classes of psychotropic drugs in controls compared with patients with stroke. Conclusions All-cause mortality was higher in patients with stroke and controls treated with benzodiazepines, antidepressants and antipsychotics than in their untreated counterparts. Our findings suggest that care should be taken in the use and prescription of such drugs, and that they should be used in conjunction with adequate clinical controls.

Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo

Chronic benzodiazepine use is common in patients with mental illness and is associated with cognitive impairment. It is unclear whether benzodiazepine-induced cognitive impairment is reversible. Amelioration of cognitive dysfunction may be facilitated during benzodiazepine tapering by add-on melatonin due to its anti-inflammatory and neuroprotective properties. We examined how melatonin and benzodiazepine withdrawal affect cognition, subjective well-being, and psychosocial functioning. Eighty patients with schizophrenia or bipolar disorder were randomized to add-on treatment once daily with either prolonged-release melatonin or placebo in a 24-week, double-blind clinical trial. All participants gradually tapered usual benzodiazepine dosage in a closely monitored treatment setting. We used the Brief Assessment of Cognition in Schizophrenia (BACS) to assess neurocognitive performance with additional assessments of subjective well-being and psychosocial functioning. BACS composite and subscale scores (except motor speed) significantly improved in parallel with benzodiazepine dose reduction, but there was no additional effect of melatonin. Cognitive performance was still markedly impaired post-tapering compared with normative data. Neither benzodiazepine withdrawal nor treatment group affected subjective well-being or psychosocial functioning. In conclusion, add-on melatonin does not seem to affect cognition, well-being, or psychosocial functioning in patients with severe mental illness. The observed improvement in cognitive performance could not be distinguished from retest effects, which may in turn have been facilitated by the benzodiazepine tapering.

Circadian rest-activity rhythms during benzodiazepine tapering covered by melatonin versus placebo add-on: data derived from a randomized clinical trial

BackgroundPatients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short-term usage. Melatonin, a naturally occurring nocturnal hormone, has the potential to stabilize disrupted circadian rhythmicity. Our aim was to investigate how prolonged-release melatonin affects rest-activity patterns in medicated patients with severe mental illness and if benzodiazepine dose reduction is associated with changes in circadian rhythm parameters.MethodData were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage was gradually tapered. Here we report the results of 72 h of actigraphic assessment of activity-rest cycles performed pre and post tapering. Changes in rest-activity rhythm parameters between the melatonin and placebo group were analyzed using the univariate general linear model. Change in activity counts per 6 h, from baseline to follow-up, in the whole sample was analyzed using paired samples t-test.ResultsA subsample of 48 patients participated in the actigraphic assessment: 20 in the melatonin group and 28 in the placebo group. Rest-activity cycles varied from regular to highly disrupted. Melatonin significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre tapering, but differences did not reach statistical significance.ConclusionOur data suggest melatonin as an aid during benzodiazepine withdrawal for patients distressed by disrupted circadian rest-activity cycles. Benzodiazepine tapering might result in diminished sedentary behavior but further research is needed.Trial registrationClinicalTrials NCT01431092, clinicaltrials.gov. Registered 31 August 2011.

Familial Hemiplegic Migraine and Recurrent Episodes of Psychosis: A Case Report

Familial hemiplegic migraine (FHM) is a rare autosomal dominant form of migraine with motor aura. We present a case report of a father and son with very similar attacks of hemiplegic migraine and recurrent episodes of accompanying psychoses. Previously, such episodes led to hospitalization and extended clinical examinations, which further worsened the psychoses. Since the episodes were recognized as related to the hemiplegic migraine, a treatment strategy combining sleep and sedation was initiated and progression onto psychosis was almost completely avoided in both father and son. Genetic analyses found no causal gene mutation in the three known FHM genes, suggesting that the phenotype is caused by a yet unidentified mutation.

P.3.c.005 Association of antipsychotic polypharmacy with health service cost – a Danish register-based cost-minimisation analysis

Lone Baandrup, MD, PhD1; Jan Sørensen, MSc2; Henrik Lublin, MD, DMSc1; Merete Nordentoft, MD, PhD, DMSc3; and Birte Glenthoj, MD, DMSc1 1Center for Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Psychiatric Centre Glostrup, Glostrup, Denmark; 2Centre for Applied Health Services Research and Technology Assessment, University of Southern Denmark, Odense, Denmark; 3Copenhagen University Hospital, Psychiatric Centre Bispebjerg, Copenhagen NV, Denmark