Finding the ideal place for a psychotherapeutic intervention in a stepped care approach--a brief overview of the literature and preliminary results from the Project PREDICT.

AIMS: To provide an overview over empirical evidence regarding stepped care approaches that include psychotherapies. To present own preliminary study results in alcohol dependent patients. METHODS: Publications were searched in the databases Medline, PsycINFO and the internet search engine Google Scholar. Inclusion criteria were psychosocial treatment and psychiatric disorders. Our own study consists of two steps. In step 1 patients receive anti-craving medication or placebo and Medical Management (MM). After a relapse to heavy drinking patients can step up and after randomization they either continue with the same treatment or they receive additional alcoholism specific psychotherapy (ASP). RESULTS: Evidence suggests that stepped care might be efficacious in patients with obsessive-compulsive behavior and depression. There is no evidence for efficacy in problem drinkers. Results of our own study show that the completer rate in MM alone is higher than in ASP with MM, but there are no significant differences concerning age, sex and disease severity between completer and non-completer in both study arms. CONCLUSIONS: Further research with regard to stepped care in alcohol dependent patients is needed. An introduction of the psychotherapy at earlier stages might be sensible.

Growth hormone response to growth hormone-releasing hormone and clonidine in depression.

Growth hormone (GH) responses to the alpha 2-adrenoceptor agonist clonidine and to GH-releasing hormone (GHRH) were measured in 12 patients fulfilling DSM-III-R criteria for major depressive disorder and in 12 age- and sex-matched controls. GH responses to clonidine correlated significantly with the GH responses to GHRH in the depressed patients as well as in the controls. Neither the responses to clonidine nor the responses to GHRH were significantly lower in depressed patients than in controls. Similarly, somatomedin-C (Sm-C) plasma concentrations and baseline GH concentrations were not different between the two groups. The data do not suggest that blunted GH responses to clonidine and/or GHRH represent specific features of depression.

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.

The effects of biperiden on nap sleep after sleep deprivation in depressed patients.

Sixteen patients with a major depressive disorder were allowed to take a nap at 5 A.M. after a period of total sleep deprivation. The patients were randomly assigned to biperiden or placebo treatment prior to the nap to test the hypothesis that anticholinergic medication is capable of preventing a nap-related worsening of mood. Total sleep deprivation positively influenced mood for the whole group. Contrary to expectations, the rate of nap-related relapses of mood did not differ between placebo- and biperiden-treated individuals, and biperiden did not significantly suppress rapid eye movement (REM) sleep. There was only a tendency for lower REM time after administration of biperiden compared to placebo. This unexpected result may be due to a high cholinergic tone in the patient group investigated and a high REM propensity in the early morning hours. Studies with more selective M1/M2 receptor antagonists are necessary to clarify whether nap-related changes of mood can be prevented by anticholinergic blockade.

Cholinergic REM induction test: muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia.

Disinhibition of rapid eye movement (REM) sleep (e.g. shortening of REM latency, heightened REM density) is frequently encountered in patients with a major depressive disorder (MDD). Administration of cholinomimetics prior to or during sleep leads to a more pronounced advance of REM sleep in depressed patients compared to healthy controls and patients with other psychiatric disorders. The present study tested whether the cholinergic REM induction test (CRIT) with 1.5 mg RS 86 (an orally acting muscarinic agonist) differentiates patients with MDD (n = 40) from those with schizophrenia (n = 43) and healthy controls (n = 36). The most pronounced shortening of REM latency after cholinergic stimulation occurred in patients with MDD. However, a significant number of patients with schizophrenia also displayed short REM latencies (REM latency < 25 minutes) under placebo conditions and after cholinergic stimulation. REM density measures more clearly differentiated patients with MDD from those with schizophrenia. It is concluded that a subgroup of patients suffering from schizophrenia displays signs of a muscarinic receptor supersensitivity.

The sleep structure of patients with anxiety disorders in comparison to that of healthy controls and depressive patients under baseline conditions and after cholinergic stimulation.

This study investigated sleep EEG during placebo and after cholinergic stimulation with RS 86 in 36 healthy subjects, 34 patients with major depression and 20 patients with anxiety disorders. Cholinergic stimulation with RS 86 led to a decrease of slow wave sleep and REM latency. RS 86 had a more profound impact on REM latency in patients with major depression than in healthy controls and patients with anxiety disorders. Six out of 36 healthy controls, three out of 20 patients with anxiety disorders and 24 of 34 patients with depression displayed sleep onset REM periods after cholinergic stimulation. Also effects on REM density and duration of the first REM period were more pronounced in major depression. Even in those patients with anxiety disorders and a secondary major depression no depression-like sleep abnormalities could be provoked. The results underline the usefulness of the cholinergic REM induction test to differentiate patients with major depression from those with other psychiatric disorders. The results can be interpreted as further evidence for the cholinergic-aminergic imbalance model of depression and for the reciprocal interaction model of nonREM-REM regulation.

48-hour rapid cycling: results of psychopathometric, polysomnographic, PET imaging and neuro-endocrine longitudinal investigations in a single case.

We report a 64-year-old patient suffering from rapid cycling bipolar disorder who was studied by means of polysomnography, neuroendocrine tests and PET (positron emission tomography) imaging. In a manner only partly compatible with the cholinergic-aminergic imbalance model of mania and depression, a linkage of REM sleep disinhibition and depressive mood was observed, but no decisive REM sleep delay was seen on manic days. Growth hormone secretion after clonidine stimulation was blunted on depressive and hypomanic days. A series of total sleep deprivations led to a positive effect on psychopathology for about two weeks. Carbamazepine treatment normalized REM sleep variables, damped the amplitude of mood cycling of the patient, increased TSH and decreased FT4.

Cholinergic neurotransmission, REM sleep and depression.

It is known from animal experiments that the regulation of REM and Non-REM sleep is governed by cholinergic and serotonergic/adrenergic neurons in the brain stem. Cholinergic neurons in the gigantocellular field of the tegmentum seem to be responsible for the triggering and maintenance of REM sleep. These findings are of special interest for interpreting abnormalities of REM sleep in depression. Psychiatric sleep research in the last two decades has demonstrated that an early onset of REM sleep and heightened REM density frequently occurs in patients suffering from depression. Extrapolating from animal data on REM sleep regulation, the premature onset of REM sleep in depression may be interpreted as the consequence of a central nervous cholinergic overactivity or muscarinic supersensitivity. In our experimental work we have tested assumptions of the so-called reciprocal interaction model of NonREM and REM sleep by cholinergic/anticholinergic stimulation strategies of sleep in healthy subjects. Furthermore, the impact of cholinergic stimulation on sleep in depression, healthy control subjects and other psychopathological conditions was investigated. These studies demonstrated that the most pronounced REM sleep response to cholinergic stimulation occurred in depression.

Agonist-stimulated Ca2+ response in neutrophils from patients with primary alcoholism and alcoholized healthy subjects.

The sensitivity of the inositol phosphate (IP)/Ca2+-second messenger generating system was assessed in neutrophils from healthy volunteers before and after ingestion of approximately 1%o ethanol for 2 h. In addition, isolated neutrophils from healthy subjects were incubated with ethanol in vitro. Furthermore, the sensitivity of the IP/Ca2+ system was evaluated in neutrophils from alcoholic patients in the state of active drinking, and after 2-3 weeks and 6 months of abstinence. EC50 values of the concentration-response curves obtained by agonist stimulation with formyl-methionyl-leucylphenylalanine (fMLP) of the intracellular Ca2+ accumulation were determined as an indicator of the sensitivity of the system. Ingestion of ethanol by healthy volunteers (both in the ex vivo and in vitro experiments) induced a rightward shift of the concentration-response curve (higher EC50 values) in neutrophils, indicating a reduced sensitivity to agonist stimulation evoked by ethanol. The sensitivity of the Ca2+ response in neutrophils from alcoholic patients decreased intraindividually after a period of 2-3 weeks of abstinence (higher EC50 values) and was at this time also significantly lower compared to a group of matched healthy controls In contrast, the maximal Ca2+ release induced by a saturating concentration of fMLP was increased after 2-3 weeks of abstinence, both intraindividually and in comparison to healthy controls. These alterations of the EC50 values and the maximal Ca2+ response were normalized after 6 months of abstinence. It is concluded that ethanol attenuates the sensitivity of the IP/Ca2+ system in neutrophils in healthy subjects. In neutrophils from alcoholic subjects complex alterations appear to persist up to several weeks, which are only normalized after a prolonged period of abstinence.

Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep.

Evidence from animal experiments has suggested that the triggering and maintenance of rapid eye movement (REM) sleep is mainly under the control of cholinergic neurons in the brain stem. Correspondingly, studies in humans have demonstrated that the application of cholinergic agonists or cholinesterase inhibitors provokes an earlier onset of REM sleep. The present study investigated the influence of galanthamine hydrobromide, a reversible cholinesterase inhibitor, on REM sleep regulation in 18 healthy volunteers. After an adaptation night, the subjects were given two doses of galanthamine (10 mg and 15 mg) or placebo at 10 p.m. in a randomized double-blind design. Both doses of galanthamine shortened REM latency (with statistical significance depending on the definition of REM latency used), increased REM density, and reduced slow wave sleep mainly in the first non-REM cycle. Higher doses of galanthamine (15 mg) seem to be accompanied by unwanted side effects that warrant the application of a peripheral antidote. These results are comparable to those for other cholinomimetics and stress the usefulness of galanthamine for pharmacological challenge studies in healthy subjects and depressed patients.

Interaction of MnO and ZnO nanomaterials with biomedically important proteins and cells.

Zinc and manganese nanomaterials may have potential for biomedical nanotechnology. Here first generation Zn and Mn oxide nanomaterials were prepared as determined by XRD. Transmission electron microscopy confirmed their nanoscale in two dimensions and revealed a rod or belt-like morphology for MnO or ZnO respectively. Association of MnO and ZnO to three model biomedically important proteins (albumin, protamine and thrombin) has been characterized by ultra-violet and dynamic laser light spectroscopy, UVS and DLLS respectively. UVS demonstrated a concentration-dependent loss of protein from the supernatant upon sedimentation of MnO or ZnO. Shifts in the surface charge of the MnO or ZnO by DLLS confirmed the protein's adsorption to the surface. MnO and ZnO were incubated with live human cells in culture (HeLa, A375 or 1321N1). A marked difference was observed for the two nanomaterials behavior in cell culture where the MnO could be discerned associating at the cell surface whereas the ZnO caused the cells to exhibit a rounded up morphology. Trypan blue dye exclusion studies demonstrated cytotoxicity of the ZnO at high concentrations 62.5-31.5 microg/mL whereas surprisingly the MnO demonstrated no cytotoxicity at any of the concentrations tested.

[The importance of sleep for healthy alcohol consumers and alcohol dependent patients]. / Die Bedeutung des Schlafs für gesunde Alkoholkonsumenten und alkoholabhängige Patienten.

This 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. Pre-existing 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.

Growth-hormone response to clonidine in panic disorder patients in comparison to patients with major depression and healthy controls.

Growth-hormone (GH) responses to the alpha 2-adrenoceptor agonist clonidine were measured in 9 panic disorder patients, in 9 patients fulfilling DSM-III-R criteria for major depressive episode, and in 9 age- and sex-matched controls. GH responses to clonidine were not significantly different between the groups. The data do not agree with the assumption that blunted GH responses to clonidine represent a general feature of panic disorder or major depression.

Platelet and lymphocyte free intracellular calcium in affective disorders.

Many studies have demonstrated pharmacologic similarities between platelet and brain 5-HT2 binding sites. Therefore it may be possible to use platelets as a model for the central serotonergic neuron. Accordingly, a previous report (Kusumi et al. 1991b) about elevated [Ca2+]i after serotonin stimulation in platelets of depressed patients was interpreted as further evidence for enhanced serotonergic sensitivity in depression. However, a very recent study showed an enhanced thrombin-induced platelet Ca2+ response, rather suggesting abnormalities of intracellular Ca2+ regulation in affective disorders. In the present study we have determined 5-HT2- and thrombin-induced Ca2+ responses in platelets and additionally phytohemagglutin (PHA)-induced Ca2+ increase in lymphocytes of medicated depressed patients (8 mono- and 2 bipolar, HRSD > 17) and of ten sex- and age-matched controls. The results showed no significant difference in basal calcium levels between the two groups and no significant difference in the Ca2+ response to thrombin although the response was higher in the patients. The Ca2+ increase after serotonin stimulation in depressed patients was significantly (P < 0.05) higher than in healthy controls. By contrast, the Ca2+ response to PHA in lymphocytes was significantly decreased in the patients. Our data confirm elevated Ca2+ responses after 5-HT2 receptor activation even in mediated depressed patients. However, Ca2+ responses in lymphocytes were decreased. Together with the observations of an enhanced Ca2+ response in platelets after thrombin stimulation, we speculate that the findings rather suggest alterations of [Ca2+]i regulation in depression than specific changes of serotonergic sensitivity.

Auditory and visual event-related potentials in alcoholics: abnormalities of components and brain electrical field.

Alterations of ERPs recorded over midline scalp sites have frequently been reported in alcoholics. To assess the P3 and other ERP components topographically, auditory and visual ERPs were recorded from 33 scalp electrodes in abstinent alcoholics and healthy controls using an oddball paradigm. At the Cz electrode the alcoholics showed decreased visual N1 and increased auditory N2 amplitudes. Topographically, the negative centroids of the visual N1 and P3 and the auditory N2 differed between groups, and the positive centroid of the visual P3 was displaced toward the right hemisphere. While no valid diagnostic classification could be obtained by using the traditional ERP component P3 recorded from Pz, the combination of visual N1 and auditory N2 amplitudes at Cz with centroid parameters amounted to 51% explained variance and 92% correct discrimination of alcoholics from controls. Abnormalities of N1 amplitude and P3 topography similar to the current findings in alcoholics have previously been described for schizophrenics.

The effect of carbamazepine on endocrine and sleep EEG variables in a patient with 48-hour rapid cycling, and healthy controls.

Carbamazepine treatment of a patient with 48-hour rapid cycling led to a dampening of mood cycling, and prolonged rapid eye movement (REM) sleep latency. No effect on central alpha-receptors as measured by growth hormone (GH) secretion after clonidine stimulation or on spontaneous 48-hour GH secretion was observed. In 12 healthy subjects given 400 mg carbamazepine daily for a period of 5 days, improved sleep continuity and increased slow-wave sleep occurred with treatment. REM sleep percentage and REM latency remained uninfluenced, whereas REM density decreased. GH secretion after clonidine stimulation was not altered. Data from the single-case longitudinal study emphasize that carbamazepine is effective in treating rapid-cycling affective psychosis. Furthermore, neuroendocrine and sleep EEG data from the study in healthy subjects indicate a different profile of action for carbamazepine compared to most other antidepressants or antimanic drugs.

Cholinergic and noradrenergic neurotransmission: impact on REM sleep regulation in healthy subjects and depressed patients.

The reciprocal interaction model of NonREM- and REM sleep regulation suggests that the cycling alternating pattern of Non-REM- and REM sleep is under the control of noradrenergic/serotonergic and cholinergic neuronal networks. This model was tested in healthy humans by administration of cholinergic agonists/antagonists and noradrenergic antagonists prior to or during sleep. Cholinomimetics like physostigmine, RS 86 and galanthamine provoked an earlier onset of REM sleep, whereas subchronic treatment with scopolamine, a cholinergic antagonist, only led to a heightening of REM density. Simultaneous administration of noradrenergic antagonists with a cholinergic agonist did not provoke a more pronounced REM sleep advance. Comparative studies with the cholinergic agonist RS 86 in depressed patients, schizophrenic patients and patients with other psychiatric disorders revealed the most pronounced REM sleep response in the depressed group. The REM sleep response to cholinergic stimulation in depression did however not predict the treatment response to a differential-therapeutic strategy.