U. Hemmeter

Effects of Growth Hormone-Releasing Hormone and Somatostatin on Sleep EEG and Nocturnal Hormone Secretion in Male Controls

When applied centrally to animals, growth hormone-releasing hormone (GHRH) stimulates slow-wave sleep (SWS), whereas somatostatin (SRIF) increases REM sleep. We investigated whether these peptides also affect the sleep EEG in humans when given intravenously by comparing polysomnographically the effects of four boluses of (1) placebo, (2) 50 micrograms GHRH or (3) 50 micrograms SRIF administered at 22.00, 23.00, 24.00 and 1.00 h to 7 male controls. In addition, we collected blood samples through a long catheter every 20 min from 22.00 to 7.00 h and measured plasma cortisol and growth hormone (GH) levels. In comparison with SRIF and placebo, GHRH produced a significant increase in plasma GH concentration throughout the night (mean +/- SD: 10.8 +/- 2.0 ng/ml after GHRH; 3.0 +/- 1.7 ng/ml after SRIF and 3.2 +/- 2.0 ng/ml after placebo). SRIF failed to substantially attenuate the nocturnal GH release. Nocturnal cortisol secretion was blunted after GHRH but remained unaffected by SRIF (61.4 +/- 12.9 ng/ml after placebo; 46.6 +/- 19.7 ng/ml after GHRH and 70.8 +/- 12.6 ng/ml after SRIF). Quantitative sleep EEG staging showed a significant increase in SWS after GHRH administration but no change after SRIF (percent spent in SWS per night: 14.0 +/- 5.6 after placebo, 20.2 +/- 6.6 after GHRH and 15.1 +/- 8.2 after SRIF). Application of SRIF was accompanied by a trend toward increased REM density. The effects of episodic GHRH administration upon SWS, GH and cortisol secretion were opposite to those previously reported for corticotropin-releasing hormone, which supports the view that neuroregulation of human sleep involves an interaction of central GHRH and corticotropin-releasing hormone.

Sleep deprivation and bright light as potential augmenters of antidepressant drug treatment—Neurobiological and psychometric assessment of course

The present study was designed to investigate the clinical efficacy of trimipramine with adjunct sleep deprivation (SD) or bright light (BL) and to evaluate psychometric and neurobiological variables that might be of predictive value for treatment response. We used (1) the combined dexamethasone-corticotropin releasing hormone test (DEX-CRH test) to characterize alterations of the hypothalamic-pituitary-adrenal (HPA) system; (2) polysomnography to evaluate sleep disturbances; and (3) a standardized test battery to assess cognitive psychomotor functions after study initiation and after 5 weeks of treatment. The overall response rate (> or = 50% decrease in score on Hamilton Rating Scale for Depression [HRS]) was 55% (N = 42). The response rate in the group with trimipramine monotherapy (N = 14) was 79%, whereas in the groups with adjunct SD (N = 14) and BL (N = 14), respectively, it was only 43%. All three groups showed significant improvement at the end of the third week of treatment. Neither of the adjunct treatments hastened the onset of antidepressant action as measured by HRS. A significantly higher proportion of nonresponders than responders (p < .05) had HPA dysregulation, disturbed rapid eye movement (REM) sleep (REM latency, REM% first third of night) and decreased non-REM sleep (% stage 2). The non-responders showed significantly more corticotropin (ACTH) secretion after CRH stimulation in the DEX-CRH test than the responders and a less rapid normalization of the neuroendocrine dysregulation (cortisol secretion) (p < .01). In addition, REM latency was significantly shorter in the BL group than in the monotherapy group and estimated duration of illness significantly longer in the SD group than in the monotherapy group. REM latency, percentage of REM sleep during the first third of the total sleep period, percentage of non-REM sleep stage 2 and ACTH release after a DEX-CRH challenge predicted response across all three treatment groups. The neurobiological symptoms were unevenly distributed, among the three groups, thus creating heterogeneity in these measures. This heterogeneity may have contributed to the different treatment response rates as defined by psychopathology (HRS). In contrast, the neuropsychological tests and some of the sleep-EEG investigations revealed different response patterns for different groups: The onset of improvement in simple cognitive functions and in sleep continuity was earlier in the adjunct treatment groups. This study underlines the need for a multidimensional approach including use of neurobiological and neuropsychological measures to identify the therapeutic profiles of different treatment strategies and predictors of outcome.

Increased trimipramine plasma levels during fluvoxamine comedication

A depressive patient, a non-responder to trimipramine (TRI), was comedicated first with citalopram (CIT) and then with fluvoxamine (FLUV). Both the TRI-CIT and TRI-FLUV combination treatments led to a worsening of the depressive state and to the appearance of panic attacks. The addition of FLUV to TRI resulted in a twofold increase of the plasma levels of TRI and to a slight increase of its N-demethylated and 2-hydroxylated metabolites. These results suggest that the interaction between FLUV and TRI occurred at the level of cytochrome P-450IID6 and cytochrome P-450meph in this patient, phenotyped as an extensive metabolizer of both dextromethorphan and mephenytoin. The adverse effects were possibly due to (a) a pharmacokinetic interaction between CIT and FLUV with TRI and/or (b) alterations in serotonergic and/or dopaminergic neurotransmission.

Antidepressive Response to Sleep Deprivation in Unipolar Depression Is Not Associated with Dopamine D3 Receptor Genotype

The psychostimulant theory of antidepressive sleep deprivation (SD) proposes a contribution of dopamine D3 receptors (DRD3) in the limbic system to the antidepressant effects of SD. Neuroendocrinological studies suggest a positive correlation of clinical response to SD and cortisol secretion. We hypothesized that the clinical response to SD and amount of cortisol secretion upon SD is associated with the 1-1 genotype of the Bal1 polymorphism of DRD3 on exon 1. In this study, aiming at evaluating the feasibility of screening large patient samples, 52 inpatients (19 males/33 females) with unipolar depression and a score of 18 or more on the 21-item Hamilton Depression Rating Scale were treated with 1 night of total SD. We found that 31% of our patients responded to SD. There was no association between response to SD and the genotype of the DRD3 Bal1 polymorphism (p < 0.879). There was also no association between increase in cortisol secretion after SD and DRD3 genotypes (p < 1.000) in a subgroup of patients. Statistical power analysis ruled out a major effect of the DRD3 Bal1 polymorphism on clinical response to SD. These results suggest that the DRD3 Bal1 polymorphism is not a promising lead to be followed up in larger patient samples.

Serial partial sleep deprivation as adjuvant treatment of depressive insomnia

1. Sleep disturbance is a prominent symptom of major depression. Despite specific treatment with antidepressants, there is a substantial number of patients who improve in depressed mood but remain sleep disturbed. 2. Polysomnographic sleep (PSG) data and self reported sleep measures were assessed at baseline and after one week in 18 patients (35-65 years) randomly assigned to treatment with either trimipramine alone 200 mg/d (group 1) or trimipramine (200 mg/d) and additional serial partial sleep deprivation in the second half of the night (3x/week) (group 2). 3. In group 1 no marked changes between baseline and after treatment were found. 4. In group 2 the PSG data showed a significant increase of slow wave sleep and a compensatory decrease in stage 1. Sleep continuity improved in terms of numbers of awakenings, sleep onset latency and total sleep time. These changes were in parallel with the subjective estimation of sleep in group 2. 5. There was no significant difference in the Hamilton rating scale scores neither at baseline nor after treatment. 6. These observed effects on sleep following additional serial PSD therapy seem to occur independent from the antidepressive effect.

Contingent negative variation and attention in schizophrenic and depressed patients.

Contingent negative variation (CNV) is supposed to be a psychophysiological indicator of attention and arousal. Both have been reported to be deteriorated in schizophrenic and depressed patients. Thirty-four patients with major depression, 43 patients with schizophrenia and 49 healthy subjects were investigated during acute illness with a complex three-stimulus go/no-go task which requires different states of attention: trials consisted of three complex figures that were tachistoscopically presented. Three identical figures had to be confirmed by pressing a button (target condition). CNV was measured: (1) after the first figure waiting for the second (baseline condition), (2) after two identical figures waiting for the third (response-relevant condition), (3) after two different figures waiting for the third (response-irrelevant condition). The response-relevant condition compared to baseline significantly intensified CNV in healthy controls and to a minor extent in depressed patients but not in schizophrenics. In the response-relevant conditions in healthy controls, CNV was significantly reduced compared to the response-relevant condition. This clear discrimination between response-relevant and response-irrelevant conditions was not observed in either group of patients. Thus, the applied CNV paradigm was able to discriminate schizophrenic and depressed patients from healthy controls. Furthermore, subtle differences between schizophrenic and depressed patients were detected, reflected by the different CNV development across experimental conditions.