D. van Calker

Sleep and manipulations of the sleep-wake rhythm in depression.

Objective:  Disturbed sleep is typical for most depressed patients and complaints about disordered sleep are the hallmarks of the disorder. Polysomnographic sleep research has demonstrated that besides impaired sleep continuity, sleep in depression is characterized by a reduction of slow wave sleep and a disinhibition of random eye movement (REM) sleep, with a shortening of REM latency, a prolongation of the first REM period and increased REM density.

Regulation of K+ channel mRNA expression by stimulation of adenosine A2a-receptors in cultured rat microglia

Previous investigations suggest that the expression of K+ channels in cultured rat microglia is related to the activation status of these cells. Both, lipopolysaccharide (LPS) and agents that raise intracellular cyclic AMP have been shown to inhibit microglial proliferation. LPS also regulates the mRNA expression levels of K+ channels in cultured microglia, which led us to investigate possible regulatory interactions between K+ channels and adenosine A2a‐receptors, which are coupled to the cAMP‐signal transduction pathway. The selective adenosine A2a‐receptor agonist CGS 21680 induced enhanced mRNA expression of both Kv1.3 and ROMK1, as well as an elevation of Kv1.3 protein. The selective adenosine A2a‐receptor antagonist aminophenol (ZM 241385) and the nonselective antagonist 8‐phenyltheophylline (8‐PT) inhibited these effects. Elevations of cyclic AMP by use of dibutyryl cyclic AMP (dbcAMP), phosphodiesterase‐inhibitor (RO 20–1724), forskolin, or cholera toxin (CTX), strongly enhanced Kv1.3‐mRNA expression, but decreased ROMK1‐mRNA levels. Results from experiments with actinomycin D suggest that K+ channel mRNA levels in cultured microglia were regulated by altered mRNA synthesis. Evidently, the CGS 21680‐induced effects upon Kv1.3 were mediated via an increase in intracellular cyclic AMP, whereas ROMK1‐mRNA expression appeared to be regulated by coupling of adenosine A2a‐receptors to an alternative pathway, which involves activation of protein kinase C (PKC). It is concluded that the cyclic AMP second messenger system in microglia is not only involved in regulation of K+ channel activity, but also in regulation of de novo K+ channel synthesis. GLIA 25:120–130, 1999.

Abnormal G protein αs- and αi2-subunit mRNA expression in bipolar affective disorder

Disturbances of events associated with intracellular signaling pathways have been suspected of involvement in the development or progression of affective disorders. Often, heterotrimeric G proteins are located at the beginning of these pathways as modulators of extracellular messages. For this reason, messenger RNA expression of three G protein α-subunits and of phosphatidylinositol-3 kinase (PI-3 K) regulatory subunit p85 was examined in granulocytes from patients with bipolar or unipolar affective disorder and compared to healthy controls. Messenger RNA expression of the G protein subunit αq and of p85 was identical in unipolar and bipolar patients and in controls. Furthermore, mRNAs of G protein subunits αs and αi2 were not different in unipolar patients as compared to healthy controls. Alphas mRNA, however, was markedly increased in bipolar patients. This increase was observed in lithium-treated (more than 12 months) and in unmedicated patients. Elevated levels of αi2 mRNA in unmedicated bipolar patients did not reach statistical significance, whereas mRNA in bipolar patients receiving lithium was significantly above controls. Finally, long-term medication of unipolar patients with lithium had no influence on αi2 mRNA levels. The data reveal elevated mRNA levels of Gαs as a robust feature of bipolar affective disorder. Moreover, despite responsiveness of αi2 gene expression to cAMP-related events, no substantial upregulation of αi2 mRNA was observed in bipolar patients. The lack of αi2 mRNA upregulation, hence, could be an additional abnormality in these patients. Even though lithium was able to reinstate this upregulation, there was no feedback downregulation of αs. This strongly supports the notion of major disturbances of the cAMP signaling system in bipolar illness.

Effects of secretin on extracellular amino acid concentrations in rat hippocampus

Summary.In 1998, Horvath et al. (1998) observed a marked improvement in speech, eye contact, and attention in autistic children five weeks after treatment with secretin, which ocurred in the course of an endoscopic investigation. Since autism is hypothesized to be a hypoglutamatergic disorder we investigated the in vivo effects of secretin on extracellular amino acids in the rat brain. Studies were carried out on freely moving rats with microdialysis probes in the hippocampus. Amino acids were examined using tandem mass spectroscopy and HPLC/fluorometric detection. Following secretin injection (8.7 µg/kg i.p.), considerable increases in microdialysate glutamate and gamma-aminobutyric acid (GABA) levels were observed; other amino acids were not affected. The observed increased microdialysate concentrations of glutamate and GABA following secretin application may explain the results of the Horvath study.

PREMORBID PERSONALITY IN PATIENTS WITH UNI- AND BIPOLAR AFFECTIVE DISORDERS AND CONTROLS : ASSESSMENT BY THE BIOGRAPHICAL PERSONALITY INTERVIEW (BPI)

The relationship between premorbid personality and subtypes of affective disorder was investigated by means of the Biographical Personality Interview (BPI) and by a self-rating scale. Interview and rater (BPI) were blind to diagnosis. A total of 52 patients with unipolar depression or bipolar II disorder (D/Dm), 32 bipolar-I patients (DM) and 39 control subjects (C) were examined. Expert rating of “typus melancholicus” features (BPI) were found to be more pronounced in D/Dm than in DM and C. “Typus manicus” features were also distinguished between both clinical groups, whereas anxious-insecure features were not significantly different between the groups of patients. In contrast to the expert-rated personality variants, self-rating of personality features did not reveal any significant differences between the two clinical groups. Potential sources of the discrepancies between the questionnaire data and the interview data are discussed. It is concluded that premorbid features of “typus manicus” and “typus melancholicus” predicted, respectively, a predominant manic and a predominant depressive course of an affective disorder.

Lithium-induced inositol depletion in rat brain after chronic treatment is restricted to the hypothalamus

The influence of acute and chronic lithium administration on inositol content was examined in five different regions of the rat brain: caudate, cerebellum, cortex, hippocampus and hypothalamus. After acute administration of lithium at doses of 3, 6 or 10 mEq kg−1, no significant reductions of inositol were found in any brain region. Also no significant changes were observed in cortex, caudate, hippocampus and cerebellum after chronic treatment with lithium-containing diet, which led to brain concentrations of lithium in the therapeutic range. However, a moderate but significant reduction of inositol was under these conditions observed in the hypothalamus. At basal conditions, ie in control rats not treated with lithium, the inositol content in various brain areas was different, the hypothalamus containing the highest inositol concentration (4.4 mmol kg−1 wet weight) and the cortex the lowest (2.3 mmol kg−1 wet weight). It is concluded that chronic lithium treatment at therapeutically relevant brain concentrations does not evoke major changes in the inositol content of the brain but induces a moderate decrease which is restricted to the hypothalamus. The results are discussed with respect to the potential function of the hypothalamus in affective disorders.

Die Bedeutung des Schlafs für gesunde Alkoholkonsumenten und alkoholabhängige Patienten

ZusammenfassungDie Auswirkungen von Alkohol auf den Schlaf und das Schlaf-EEG bei Gesunden und Alkoholabhängigen in den verschiedenen Phasen der Abhängigkeit werden dargestellt. Gesunde schlafen zunächst besser. Eine höhere Dosis kann aber zur Durchschlafstörung in der 2. Nachthälfte führen. Alkohol interagiert mit einer vorhergehenden Schlafdeprivation oder -restriktion.Schlafstörungen finden sich häufiger bei Alkoholkranken als bei Gesunden und können die Entwicklung einer Alkoholerkrankung begünstigen. Bei Alkoholkranken finden sich in allen Phasen der Erkrankung Einschlafstörungen und eine verminderte Gesamtschlafzeit sowie überzufällig häufig andere Schlafstörungen, wie Schlafapnoe-Syndrom oder periodische Beinbewegungen im Schlaf. . Es fanden sich Prädiktoren für ein erhöhtes Rückfallrisiko bei abstinenten Alkoholkranken.Die Neurobiologie des Schlafs und der Alkoholabhängigkeit wird diskutiert. Eine wichtige Bedeutung kommt hierbei dem cholinerg-aminergen reziproken Interaktionsmodell der REM- und Non-REM-Schlafregulation zu. Therapeutische Implikationen werden diskutiert.SummaryThis article deals with the effects of alcohol on sleep and sleep EEG of healthy individuals and alcohol-dependent patients during different phases of alcohol dependency.Healthy individuals initially experience an improvement in sleep, although a greater quantity of alcohol can lead to problems of sleep maintenance during the second half of the night. Preexisting sleep deprivation or sleep restriction potentiates the effects of alcohol.Alcohol-dependent patients are found to be more prone to sleep problems than healthy individuals, which can facilitate the development of alcoholism. These patients experience difficulty falling asleep and suffer from a reduced total sleep time during all phases of the disorder, often accompanied by other sleep disorders such as sleep apnea syndrome or periodic leg movements during sleep. Certain predictors for the risk of relapse in abstinent alcoholics have been identified.Neurobiological findings in sleep and alcohol dependency are discussed. The cholinergic-aminergic reciprocal interaction model of REM and non-REM sleep regulation is significant in this context. Therapeutic implications are discussed.

Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression

Abstract.Complex neurobiological models based on animal research have been formulated in an attempt to explain the cyclic pattern of nonREM and REM sleep. The “reciprocal interaction model” of nonREM and REM sleep regulation, which has been updated to incorporate new evidence is still the most convincing. Therefore it is reasonable to apply this model also to REM sleep abnormalities such as shortened REM latency and increased REM density, observed in patients with depression and alcohol dependency.In a retrospective analysis baseline data from 40 subjects with primary alcohol dependency are compared with a group of 40 patients diagnosed with major depression (diagnoses according to DSM-III-R) and healthy subjects. All alcohol dependent patients were examined in the sleep laboratory during subacute withdrawal at least 7 days off medication and after at least 14 days of abstinence. The patients with major depression (at least 7 days off psychoactive medication) and the healthy subjects had been examined previously by polysomnography during the last few years in the context of various studies and were assembled from our database to match the group of alcohol dependent patients with respect to age and sex.Alcohol dependent patients exhibited similar disturbances in sleep continuity and REM sleep as depressed patients in comparison to healthy controls while parameters of sleep architecture were even more strongly disturbed in alcohol dependence.While enhanced sensitivity of cholinergic receptors is the most likely explanation for the increase in “REM pressure” in depressives, this appears not to apply to alcoholics, who rather exhibit a decreased response to cholinergic stimulation. Thus, according to the reciprocal interaction model of nonREM- and REM sleep regulation and in contrast to the interpretation of the findings in depressed patients, an impaired aminergic rather than an increased cholinergic neurotransmission might be responsible for the increased REM sleep pressure in alcohol dependent patients. Alternatively or in addition the REM anomalies in alcoholic patients could also be due to adaptive regulatory processes during chronic alcohol consumption that lead to downregulation of GABAA- and upregulation of NMDA-receptors or their intracellular signalling and become apparent with alcohol withdrawal. Such adaptive counterregulation might also explain the alterations in slow wave sleep found in alcoholics that are even more pronounced in these patients than in patients with major depression.

Decreased agonist-stimulated Ca2+ response in neutrophils from patients under chronic lithium therapy

SummaryThe agonist-stimulated increase in the intracellular concentration of free Ca2+ ([Ca2+]i) was determined in neutrophils from patients under chronic lithium therapy and a control group of age- and sex-matched healthy drug-free subjects. Cells were stimulated with the chemotactic peptide formylmethionylleucylphenylalanin (fMLP) and the Ca2+ concentrations measured with the fluorescent Ca2+ indicator Fura-2. The Ca2+ response to stimulation with fMLP was significantly attenuated in neutrophils from patients chronically treated with lithium. The data suggest that lithium treatment inhibits the inositol phospholipid second messenger generating system in human cells and support the results of earlier inositol phosphate measurements in fMLP-stimulated neutrophils.

Datengestützte Qualitätszirkel in der stationären Depressionsbehandlung

BACKGROUND Several quality assurance initiatives in health care have been undertaken during the past years. The next step consists of systematically combining single initiatives in order to built up a strategic quality management. METHODS In a German multicenter study, the quality of inpatient depression treatment was measured in ten psychiatric hospitals. Half of the hospitals received comparative feedback on their individual results in comparison to the other hospitals (bench marking). Those bench markings were used by each hospital as a statistic basis for in-house quality work, to improve the quality of depression treatment. RESULTS According to hospital differences concerning procedure and outcome, different goals were chosen. There were also differences with respect to structural characteristics, strategies, and outcome. The feedback from participants about data-based quality circles in general and the availability of bench-marking data was positive. The necessity of carefully choosing quality circle members and professional moderation became obvious. CONCLUSIONS Data-based quality circles including bench-marking have proven to be useful for quality management in inpatient depression care.