Side effects related to potentially inappropriate medications in elderly psychiatric patients under everyday pharmacotherapy.

PURPOSE: Potentially inappropriate medication (PIM) is suggested to give rise to adverse drug events. To study this suggestion for elderly psychiatric patients, an observational analysis related prescription of PRISCUS PIMs and drug-induced side effects in old aged (≥65 years) psychiatric inpatients and outpatients under conditions of everyday pharmacotherapy. METHODS: Request forms from a therapeutic drug monitoring (TDM) survey and medical files were screened for medication to identify PIMs of the PRISCUS list and assessed using the Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale. RESULTS: From 914 TDM request forms, data were available for 168 patients (64.3 % female). Patients (mean ± SD age 73.0 ± 5.5 years) received by mean 6.4 ± 3.9 drugs per day. More than half of them (53.0 %, n = 89) had at least one PIM, inpatients 0.9 ± 0.8 and outpatients 0.5 ± 0.7. Predominant PIMs were hypnotic drugs (69 %) in inpatients and antipsychotic drugs (35.6 %) in outpatients. The number of PIMs correlated with the total number of drugs administered per day (Spearman correlation coefficient 0.225, p < 0.01, CI 95 %). Side effects were documented for 106 patients (63 %). Severity of side effects did not correlate significantly (p > 0.05) with number of PIMs. However, only 6 of 77 patients who took no PRISCUS PIMs but 2 of 3 patients who took 3 PRISCUS PIMs exhibited severe side effects. CONCLUSIONS: Though the prevalence for PIMs and side effects was high in old aged psychiatric inpatients and outpatients, PIMs could not be identified as major determinants of overall unwanted side effects. Nevertheless, prescription of PIMs should be minimized, especially of hypnotic drugs, to improve safety.

Maintenance cognitive-behavioral therapy and manualized psychoeducation in the treatment of recurrent depression: a multicenter prospective randomized controlled trial.

OBJECTIVE: This multicenter study compared the relapse and recurrence outcomes of two active treatments, maintenance cognitive-behavioral therapy (CBT) and manualized psychoeducation, both in addition to treatment as usual, in patients in remission from depression. METHOD: This was a multicenter prospective randomized observer-blinded study with two parallel groups. The authors assessed 180 patients with three or more previous major depressive episodes who met remission criteria over a 2-month baseline period and who were randomly assigned to 16 sessions of either maintenance CBT or manualized psychoeducation over 8 months and then followed up for 12 months. The main outcome measure was time to first relapse or recurrence of a major depression, based on DSM-IV criteria, as assessed by blinded observers with the Longitudinal Interval Follow-Up Evaluation. RESULTS: Cox regression analysis showed that time to relapse or recurrence of major depression did not differ significantly between treatment conditions, but a significant interaction was observed between treatment condition and number of previous episodes (<5 or ≥5). Within the subsample of patients with five or more previous episodes, maintenance CBT was significantly superior to manualized psychoeducation, whereas for patients with fewer than five previous episodes, no significant treatment differences were observed in time to relapse or recurrence. CONCLUSIONS: The results indicate that maintenance CBT has significant effects on the prevention of relapse or recurrence only in patients with a high risk of depression recurrence. For patients with a moderate risk of recurrence, nonspecific effects and structured patient education may be equally effective.

Quetiapine and norquetiapine serum concentrations and clinical effects in depressed patients under augmentation therapy with quetiapine.

BACKGROUND: Quetiapine has been recently approved as an add-on therapy in the treatment of major depressive disorders in the case of inadequate response to antidepressant monotherapy. Thereby the antidepressant potential is attributed to the N-demethylated metabolite norquetiapine (NQ). The aim of this cross-sectional analysis was to relate quetiapine (Q) doses to serum concentrations of Q and its active metabolite and clinical effects. METHODS: Data were obtained from patients who had been treated with different antidepressants and augmented under naturalistic conditions with Q for whom blood level measurements were requested. RESULTS: For this analysis, 105 depressed patients were included who had been augmented with Q. The mean daily doses of Q were 222 ± 125 mg. Doses correlated significantly (P < 0.001) with the highly variable serum concentrations of both Q and NQ. Median serum concentrations of Q and NQ were 46 ng/mL (25th to 75th percentile 20-91 ng/mL) and 59 ng/mL (25th to 75th percentile 26-133 ng/mL), respectively. Concentrations per dose ranged from 0.10 to 0.58 ng·ml·mg for Q and from 0.17 to 0.59 ng·ml·mg for NQ. Most patients (55%) received comedications in addition to the antidepressant drug and Q. According to the clinical global impressions scale, 60% of the patients were either much (36%) or very much improved (24%). Receiver-operating characteristic analysis revealed no significant differences of serum concentrations between responders and nonresponders for NQ (P = 0.835) but a trend for Q (P = 0.056). CONCLUSIONS: Due to marked variability of Q and NQ concentrations in the blood, therapeutic drug monitoring may be helpful to identify pharmacokinetic peculiarities. The lack of correlation between serum concentrations of NQ and clinical improvement casts doubts on the concept that NQ is the pharmacologically active principle for the augmentation therapy.

[Delirium caused by nonconvulsive status epilepticus]. / Nonkonvulsiver Status epilepticus als Ursache eines Delirs.

We report about a patient (66 years) who was referred to our psychiatric hospital because of a progressive confusional state with acute onset. The colleagues of the referring psychiatric hospital considered a first manic episode as the cause of the symptoms and under therapy with haloperidol the confusional state had shown a progression.The clinical examination's findings were a mild central facial paresis on the right side and a mild hemiparesis on the right side with elevated reflex levels.The patient was disoriented, he had cognitive and mnestic deficits. His reasoning was slowed, incoherent and perseverating. The patient had a slight euphoria.An EEG recording showed a continuous regional EEG-seizure pattern. In combination with the clinical symptoms we diagnosed a nonconvulsive status epilepticus. Under anticonvulsive treatment with Lorazepam and Valproic acid the status epilepticus sustended but a control EEG recording showed signs of a Valproate-encephalopathy. Under treatment with Topiramate symptoms ameliorated but due to a vascular dementia the patient still showed fluctuating symptoms of cognitive and mnestic disturbances.

Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder--the EMC trial.

BACKGROUND: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome. METHODS/DESIGN: The EMC trial is a phase IV, multi-centre, multi-step, randomized, observer-blinded, actively controlled parallel-group clinical trial to investigate for the first time prospectively, whether non-improvers after 14 days of antidepressant treatment with an early medication change (EMC) are more likely to attain remission (HAMD-17

Perception of sleep: subjective versus objective sleep parameters in patients with Parkinson's disease in comparison with healthy elderly controls. Sleep perception in Parkinson's disease and controls.

INTRODUCTION: Subjective sleep perception, as measured against objective parameters such as those obtained by polysomnography, have not been examined thoroughly to date. Little is known about subjective sleep perception in patients with chronic somatic diseases. PATIENTS AND METHODS: Patients with Parkinson's disease (PD) and healthy elderly controls filled in a sleep log over 14 days, which included a self-rating questionnaire concerning sleep and quality of time awake, sleep times and somatic complaints. All participants underwent polysomnography in the sleep lab on nights 7 and 8, and slept all other nights at home. RESULTS: Seventeen patients with PD (64 +/- 6 years, 6 female, Hoehn and Yahr median = 2), and 62 healthy controls of the same age without sleep disturbances (64 +/- 8 years, 36 female) were included. Patients with PD showed reduced subjective sleep (p = 0.001) and quality of time awake (p = 0.02), decreased sleep duration (p = 0.01) and reduced sleep efficiency (p = 0.004) compared with the controls. Subjective sleep efficiency at home was no different from that in the sleep lab for both groups. Patients with PD reported more somatic complaints (p = 0.001) than controls but did not show a firstnight effect. CONCLUSION: In summary, patients with PD have subjectively and objectively disturbed sleep as compared to healthy controls of the same age. However, they may not rate this poor sleep as much changed from their baseline sleep at home, and they have more somatic complaints. Increasing sleep efficiency might be of importance in PD patients, as it shows an association with subjective quality of time awake in the morning.

Influence of age on the interrelation between EEG frequency bands during NREM and REM sleep.

The age-dependence of temporal interrelations between distinct frequency bands of sleep EEG was investigated in a group of 59 healthy young and middle-aged males via cross correlation analysis. Based on global evaluation throughout the entire night, a highly significant decline of the delta/theta correlation with increasing age was found. A separate analysis for non-rapid eye movement (NREM) and rapid eye movement (REM) sleep revealed different changes with aging. During NREM sleep, the correlation between the delta and theta frequency bands decreased with increasing age. In contrast, during REM sleep, a stronger correlation became obvious between the theta, alpha, and beta frequency bands with increasing age, whereas the lower frequency components were not affected. These findings indicate that aging processes seem to interact with sleep EEG rhythms in a complex manner, where most conspicuous is a disintegration of the activities in the lower frequency range, both concerning the successive sleep cycles across the night and the micro-structure of NREM sleep.

Sleep under exposure to high-frequency electromagnetic fields.

The controversy about potential health hazards associated with the exposure to electromagnetic fields (EMF) has been recently stimulated by the increasing use of mobile telecommunication devices. Attention has focused here on non-thermal effects of low-level high-frequency radiation, which does not lead to a heating of tissue. Scientific literature on the effects of high-frequency EMFs on sleep is reviewed. The epidemiological studies provide no evidence that sleep disturbances are a relevant complaint under exposure to such fields. Recent sleep laboratory studies have revealed a number of slight effects. Despite their heterogeneity, there seems to be some consistency regarding a slight sleep-promoting effect and an increase of the alpha power of the sleep EEG induced by high-frequency EMFs. However, for both the epidemiological and sleep laboratory studies, the database concerning sleep is up to now very limited. At the present level of knowledge, no final conclusions can be drawn from the available data concerning potential health hazards. Although there seem to be some biological effects, these do not provide evidence for any adverse health consequences. However, further research is needed for a better understanding of the interaction between EMFs and the sleep process.

A confirmatory study on the mechanisms behind reduced P300 waves in depression.

A single-trial analysis of event-related potentials (P300) of 21 depressives was performed in comparison with matched controls. The purpose was to confirm previous results revealing an overall reduction of the single-trial P300 amplitude in depression despite fewer elicited single-trial P300 waves in schizophrenics. The result of the present study is in line with our previous investigation implicating a general reduced P300 amplitude on single trials of depressive patients. Therefore, it appears possible to differentiate depressives and schizophrenics by measuring event-related potentials and applying a single-trial analysis of them.

Temporal relationship between nocturnal erections and rapid eye movement episodes in healthy men.

The exact temporal relationship between spontaneous nocturnal erections and rapid eye movement (REM) sleep was studied in healthy men with the aim of creating a basis for a more sophisticated analysis of nocturnal erection measurements in physiological research and clinical applications. The vast majority of erectile events was coupled to REM episodes, where the latency between the beginning of erections and REM episodes showed a large variability. Moreover, a correlation analysis revealed a highly significant decrease of the latency over the course of the night. The time variant properties of the coupling between erections and REM sleep point to more complex dynamics of the central control of erections with regard to sleep regulation, indicating that REM sleep and REM-related erections are not completely interdependent. Beside the possibility of obtaining further insight into the physiological mechanisms underlying erectile function, the consideration of dynamic aspects in the assessment of nocturnal erection measurements might have potential clinical implications regarding both the diagnosis and the evaluation of therapies for erectile dysfunction.

Covariation of spectral and nonlinear EEG measures with alpha biofeedback.

This study investigated how different spectral and nonlinear EEG measures covaried with alpha power during auditory alpha biofeedback training, performed by 13 healthy subjects. We found a significant positive correlation of alpha power with the largest Lyapunov-exponent, pointing to an increased dynamical instability of the EEG accompanying alpha enhancement. Alpha power amplification, moreover, was significantly correlated with a decrease of spectral entropy within the alpha range. This outcome reflects a sharpening of the alpha peak during biofeedback training. The fact that the sharpening effect clearly preceded the increase of alpha amplitude could be exploited in future biofeedback settings.

Is the nonREM-REM sleep cycle reset by forced awakenings from REM sleep?

In selective REM sleep deprivation (SRSD), the occurrence of stage REM is repeatedly interrupted by short awakenings. Typically, the interventions aggregate in clusters resembling the REM episodes in undisturbed sleep. This salient phenomenon can easily be explained if the nonREM-REM sleep process is continued during the periods of forced wakefulness. However, earlier studies have alternatively suggested that awakenings from sleep might rather discontinue and reset the ultradian process. Theoretically, the two explanations predict a different distribution of REM episode duration. We evaluated 117 SRSD treatment nights recorded from 14 depressive inpatients receiving low dosages of Trimipramine. The alarms were triggered by an automatic mechanism for the detection of REM sleep and had to be canceled by the subjects themselves. The REM episodes were determined as in undisturbed sleep-they had to include the remaining REM activity and were separated by 30 min without REM epochs. The frequency histogram of REM episodes declined exponentially with episode duration for each of the first four sleep cycles. The duration of nonREM intervals revealed bimodal distributions. These results were found consistent with the model assuming a reset of the ultradian cycle upon awakening. Whether REM or nonREM activity is resumed on return to sleep can be modeled by a random decision whereby the probability for REM sleep might depend on the momentary REM pressure.

Human scalp recorded sigma activity is modulated by slow EEG oscillations during deep sleep.

The EEG during deep sleep exhibits a distinct cortically generated slow oscillation of around and below 1 Hz which can be distinguished from other delta (0.5-3.5 Hz) activity. Intracranial studies showed that this slow oscillation triggers and groups cortical network firing. In the present study, we examined whether the phases of the slow oscillation during sleep stage 4 are correlated with the magnitude of sigma (12-16 Hz) and gamma (> 20 Hz) scalp activity. For this purpose, 10-min segments of uninterrupted stage 4 sleep EEG from 9 subjects were analyzed by applying wavelet techniques. We found that scalp recorded sigma, but not gamma, activity is modulated by the phases of the slow oscillation during deep sleep. Enhancement of sigma activity was observed to be triggered by the peak of the surface positive slow wave component, whereas reduction of sigma activity started around the peak of the negative component.

Effects of REM sleep awakenings and related wakening paradigms on the ultradian sleep cycle and the symptoms in depression.

In 1975 Vogel and coworkers published their classical study where they compared selective rapid eye movement (REM) sleep deprivation by brief awakenings to a control intervention paradigm in depressed patients. The superior antidepressive impact of the first procedure was attributed to the REM pressure accumulating during the treatment period. The laborious procedure and the considerable effort necessary to evaluate the sleep profiles in real time have prevented similar experiments so far. Based on artificial neural networks we developed a software for the real time detection of REM sleep. In combination with an alarm system the algorithm allowed us to wake up subjects automatically and to reduce REM sleep by about 50%. The procedure was then compared to a modified nonREM intervention paradigm for a treatment period of ten consecutive nights in depressed patients (n(1)=14, n(2)=13). These simultaneously received moderate dosages of Trimipramine. We found a strong and robust but not significantly different reduction of the average Hamilton rating scores (33 and 41% of baseline levels). While the REM sleep awakenings shortened the sleep cycle duration considerably, our nonREM intervention paradigm lengthened the ultradian alternations. Both effects might be interpreted as a challenge imposed on the nonREM-REM alternating mechanism possibly responsible for the antidepressive impact. A different timing of the control interventions might have caused the discrepancy between our findings and those of Vogel and coworkers.

The sleep EEG's microstructure in depression: alterations of the phase relations between EEG rhythms during REM and NREM sleep.

OBJECTIVE: We investigated the microstructure of sleep electroencephalograms (EEGs) of 13 unmedicated depressive inpatients and 13 healthy controls matched in sex and age, hypothesizing that depressives depict an alteration of certain EEG oscillations across the night. METHODS: We digitized the sleep EEGs with a sampling rate of 100 Hz (bipolar derivation C(z)-P(z), 1440 single sweeps; 2048 data points each), calculated the time course of delta (1-3.5 Hz), theta (3.5-7.5 Hz), alpha (7.5-15 Hz), and beta (15-35 Hz) activity over the night, and determined the correlation coefficients of these different EEG rhythms separately for rapid eye movement (REM) and non-rapid eye movement (NREM) sleep. RESULTS: For both groups we detected a clear difference between REM and NREM sleep cycles at certain frequency bands. The most impressive changes occurred for the delta/beta and theta/beta correlations, which change their signs between NREM (negatively correlated) and REM (positively correlated) sleep cycles. Following an analysis of variance model with repeated measurement design, a statistically significant group effect (P=0.024) between depressives and controls was observable during NREM sleep for the delta/beta (P=0.010) and theta/beta (P=0.018) interactions. CONCLUSION: We detected alterations of certain sleep EEG oscillations during the NREM sleep cycle, where the delta/beta as well as the theta/beta activities were higher (negatively) compared to healthy controls. Together with previous investigations on the influence of antidepressants on the microstructure of sleep EEGs, this is another hint that the NREM sleep cycle plays a major role in depression.