Aim of the study was to identify neuropsychological predictors of the clinical response to cognitive behavioral therapy (CBT) in patients with major depression. 19 unmedicated patients underwent neuropsychological testing at baseline and subsequently were assigned randomly to CBT over 3 weeks either as monotherapy or combined with sleep deprivation (SD) therapy (two nights of total SD / week). Hierarchical regression analysis revealed that parameters of declarative verbal memory and a word fluency task predicted the clinical response (percentage improvement of Hamilton depression scores) to CBT monotherapy, whereas no such prediction was obtained in the combination group. The results suggest that certain cognitive performances have a unique predictive value for the response to CBT, which appears to be abolished by additive treatments with cognitive side effects (e. g. SD).

BACKGROUND:There is some evidence that stress-induced cortisol increase leads to a decrease in pain, while lowering cortisol levels enhances pain sensitivity, but no study has yet investigated both pharmacological enhancement and reduction of cortisol levels in the same individuals.METHODS:Firstly, we tested in 16 healthy individuals whether the treatment with hydrocortisone and dexamethasone, respectively, results in altered pain thresholds. Secondly, we aimed to test whether hormone effects are different across the pain range by using ratings for pain stimuli with varying intensity; and thirdly, we tested whether cortisol levels influence the discrimination ability for painful stimuli.RESULTS:Despite substantial effects of dexamethasone and hydrocortisone administration on cortisol levels, no effect of these drugs was seen in terms of pain sensitivity (pain threshold, pain rating, pain discrimination ability), although comprehensively examined. However, in the placebo condition, a significant negative correlation between cortisol and pain thresholds was seen. Similarly, there were also strong negative associations between cortisol levels in the placebo condition and pain thresholds after drug treatment (especially after hydrocortisone).CONCLUSION:These findings suggest that short-term variations of cortisol do not influence pain sensitivity whereas, in general, high levels of cortisol are associated with increased pain sensitivity, at least for weak to moderate stimuli.

Cognitive-behavioral therapy (CBT) and sleep deprivation (SD) are both effective in treating major depression (MD). Since patients with MD often have deficits in various cognitive domains, the study aimed to clarify whether these variables also contribute to the prediction of clinical outcome following CBT without vs. with additional SD. According to randomization, 19 drug-free and middle-aged inpatients with DSM-IV diagnosis of MD received CBT over 3 weeks (5 sessions/week) either as monotherapy or combined with additional SD (2 nights of total SD/week). At baseline, patients underwent neuropsychological testing and ratings of depressive symptomatology (Hamilton Depression Rating Scale, HDRS), the latter were also conducted after each treatment week. Irrespective of assignment to mono- or combination therapy, over 50% of patients showed a clinical meaningful improvement of depressive symptomatology. Significant positive relationships between measures of cognitive performance and clinical improvement were specifically observable in the CBT monotherapy group. Hierarchical regression revealed that performance in delayed recognition and word fluency predicted 71% of the variance in HDRS improvement following CBT monotherapy whereas no such prediction was obtained in the combination group. These results suggest a predictive role of cognitive functioning in MD for benefiting from CBT, which appears to be abolished by additive treatments with cognitive side effects such as SD. This study was supported by BMBF

Polysomnograhic (PSG) studies in Alzheimer’s disease (AD) show REM sleep abnormalities, which may be indicative for the deterioration of cholinergic pathways and probably closely linked to declarative memory impairment. To clarify the specificity of the association between sleep and cognitive impairment in dementia, we compared AD patients with patients suffering from frontotemporal dementia (FTD) with regard to PSG and neuropsychological variables. 15 AD and 6 FTD patients underwent polysomonography and a neuropsychological battery (CERAD-NB). Group differences (age: AD > FTD; education level: AD < FTD) were considered as covariates. Polysomnography revealed a trend towards increased REM latency and reduced REM sleep in AD, as well as a decrease of stage 2 sleep, however, at least partly due to effects of age. Declarative memory was more impaired in AD than in FTD, but this difference disappeared when adjusted for covariates. While no relationship was found between REM sleep and CERAD-NB parameters, strong positive correlations between stage 2 sleep and declarative memory measures were observed, which were also detectable when analyzing both groups separately. Based on these results we conclude that REM sleep alterations may be specific for AD, distinguishable from other dementia diagnoses, whereas NonREM stage 2 sleep may be related to declarative memory formation in dementia independent of subtype.

A dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis represents a prominent finding in major depression, possibly related to a dysfunction of the corticosteroid receptor system. Antidepressants are involved in the restoration of the altered feed-back mechanism of the HPA-axis, probably via normalization of corticosteroid receptor functions. Since Hypericum perforatum has antidepressive properties, we here examined its putative actions on glucocorticosteroid receptor mRNA levels in human blood cells as a peripheral model for neuroendocrine effects in human brain cells.Our data show that Hypericum (LI 160) affects the cellular mRNA levels of both, the glucocorticoid receptor (GR)-alpha and its inhibitory counterpart, the GR-beta, at clinically-relevant concentrations. Under these conditions, a bimodal effect was observed. Dose-response studies suggest a rather small effective concentration range and time-effect data show a primary and transient up-regulation of GR-alpha mRNA levels and a down-regulation of GR-beta mRNA levels after 16 h of treatment. The sodium channel blocker benzamil neutralized the effects of Hypericum, pointing to an at least partial mechanism of action via this pathway.In conclusion, Hypericum treatment differentially affects GR-mRNA levels in the human system. Our data suggest a bimodal effect on GR, resulting in a time-and dose-related modification of GR-mediated cellular effects. Such a mechanism has been alleged as an important way of action for a number of antidepressants. It is the first time that a specific effect on both receptors, especially on the subtype of GR-beta, is shown under antidepressive treatment in a human system under in vitro conditions. (C) 2011 Elsevier Ltd. All rights reserved.

Several studies have shown that glucocorticoids can impair declarative memory retrieval and working memory (WM) performance. The aim of the present study was to investigate the impact of a high dose of hydrocortisone on WM, as well as to examine the effects of cortisol suppression via treatment with a high dose of dexamethasone (DEX). We hypothesized that hydrocortisone treatment results in an impaired cognitive function compared with placebo. We further expected that dexamethasone treatment is also followed by cognitive impairment, due to the hypothesis that very low levels of cortisol are also associated with alterations in memory performance.

Because there are reports on cytotoxic and cytoprotective effects of antipsychotics, the aim of the present study was to evaluate the impacts of different concentrations (1.6—50 μg/mL) of atypical antipsychotics on the survival of human neuronal (neuroblastoma SH-SY5Y) and immune (monocytic U-937) cells and on energy metabolism (ATP level after the incubation with antipsychotics in the concentration of 25 μg/mL). Statistical analysis showed that incubation for 24 h with the antipsychotics quetiapine, risperidone, 9-hydroxyrisperidone and ziprasidone led to a significantly enhanced cell survival in both cell lines in the lower concentrations. Higher concentrations exerted in part cytotoxic effects with the exception of quetiapine, but therapeutically relevant concentrations of the drugs were not cytotoxic in our experiments. Measurement of ATP contents in the neuronal cell line showed significantly increased levels after a 24-h treatment with 25 μg/mL risperidone and 9-hydroxyrisperidone. The other substances produced no effects. Our results show that the antipsychotic substances under investigation exert concentration-dependent effects on cell survival in both cell lines examined.

Plant extracts such as Hypericum perforatum and Pycnogenol® have been tested as alternatives to the classical ADHD drugs. It has been possible to describe neuroprotective effects of such plant extracts. A reduction of ADHD symptoms could be shown in clinical studies after the application of Pycnogenol®, which is a pine bark extract. The impacts of the standardized herbal extracts Hypericum perforatum, Pycnogenol® and Enzogenol® up to a concentration of 5000 ng/mL on cell survival and energy metabolism in human SH‐SY5Y neuroblastoma cells has been investigated in the present examination. Hypericum perforatum significantly decreased the survival of cells after treatment with a concentration of 5000 ng/mL, whereas lower concentrations exerted no significant effects. Pycnogenol® induced a significant increase of cell survival after incubation with a concentration of 32.25 ng/mL and a concentration of 250 ng/mL. Other applied concentrations of Pycnogenol® failed to exert significant effects. Treatment with Enzogenol® did not lead to significant changes in cell survival.

P>Background and objective:In our original study based on five monozygotic twin pairs and seven same-sex sib pairs, we previously showed that genetic factors contribute to body weight gain induced by the atypical antipsychotic clozapine. We aim to study this further by including patients treated with the atypical antipsychotics olanzapine or risperidone as well as opposite-sex sib pairs.Methods:Twin and sib pairs were identified by a telephone screening. Measured data on weight and other clinical variables were obtained cross-sectionally and retospectively from medical records. In seven monozygotic twin pairs and 12 sib pairs (total number of patients treated: n = 38, mean age 29 center dot 5 +/- 9 center dot 5, range 13 center dot 7-54 center dot 3 years), the similarity in BMI (kg/m2) change under these atypical antipsychotics (atypical delta BMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total delta BMI) was explored.Results:For total delta BMI we found greater similarity in antipsychotic-induced BMI change in MZ twin pairs than in sib pairs (intrapair difference) with a heritability of h2 = 0 center dot 6, but not for atypical delta BMI, possibly because of a genetically influenced weight plateau achieved under antipsychotic medication.Conclusion:The results of the present and our previous report suggest a contribution of genetic factors in antipsychotic-induced weight gain of 60-80%.

There is evidence that reactive oxygen species (ROS) are involved in the pathophysiology of psychiatric disorders such as schizophrenia. Indirect biochemical alterations of ROS formation have been shown for patients treated with antipsychotics as well as for untreated patients. Only one study measured directly the ROS formation after treatment with antipsychotics by using electron spin resonance spectroscopy. The aim of the present examination was to demonstrate the effects of haloperidol, clozapine and olanzapine in concentrations of 18, 90 and 180 μg/mL on the formation of ROS in the whole blood of rats by using electron spin resonance spectroscopy after incubation for 30 min. To test the protective capacity of vitamin C we incubated the highest concentration of each drug with vitamin C (1 mM). Under all treatment conditions, olanzapine led to a significantly higher formation of ROS compared with control conditions, whereas in the cases of haloperidol and clozapine the two higher concentrations induced a significantly enhanced formation of ROS. Vitamin C reduced the ROS production of all drugs tested and for haloperidol and clozapine the level of significance was reached. Our study demonstrated that antipsychotics induce the formation of ROS in the whole blood of rats, which can be reduced by the application of vitamin C.

Oxidative DNA damage as one sign of reactive oxygen species induced oxidative stress is an important factor in the pathogenesis of various psychiatric disorders. Altered levels of DNA base damage products as well as the expression of the main repair enzyme 8-hydroxyguanine glycosylase 1 have been described. The aim of the present study was to examine the effects of drugs (amphetamine, methylphenidate and atomoxetine) used in the treatment of attention deficit-hyperactivity disorder on the expression of this enzyme via reverse transcriptase-polymerase chain reaction in human neuroblastoma SH-SY5Y and human monocytic U-937 cells at concentrations of 50, 500 and 5,000 ng/ml. We observed decreased expression of this enzyme for all applied substances. In U-937 cells, the significance level was reached after treatment with 5,000 ng/ml amphetamine as well as after treatment with 50, 500 and 5,000 ng/ml atomoxetine. Incubation of SH-SY5Y cells with 50 and 5,000 ng/ml amphetamine and 5,000 ng/ml methylphenidate led to significant decreases of 8-hydroxyguanine glycosylase 1. As a positive correlation between the expression of 8-hydroxyguanine glycosylase 1 and the level of oxidative DNA damage products has been described, we accordingly consider these substances (amphetamine, methylphenidate and atomoxetine) to possibly play a protective role in this process.

The oxidative and antioxidative properties of psychostimulants such as methylphenidate and amphetamine are discussed controversially. The aim of the present study was to evaluate the impact of psychostimulants and atomoxetine in different concentrations between 31.25 and 5000 ng/ml on the survival of human neuronal (neuroblastoma SH-SY5Y) and immune (monocytic U-937) cells and the impact of psychostimulants and atomoxetine in different concentrations between 500 and 5000 ng/ml on energy metabolism (adenosine triphosphate [ATP] content) in SH-SY5Y cells. Statistical analysis revealed that incubation for 24 h with amphetamine led to a significantly enhanced cell survival in both cell lines after treatment with various (32.5, 125, 250 and 1250 ng/ml) concentrations. Methylphenidate and atomoxetine induced a significantly enhanced cell survival at lower concentrations in the SH-SY5Y cell line, whereas in the U-937 cell line higher concentrations increased the cell survival. Incubation with the highest concentration of methylphenidate (5000 ng/ml) caused a significant reduction of cell survival in both cell types. Measurement of ATP contents in the neuronal cell line revealed no significant effects of the investigated compounds. Our results show that the examined substances exert concentration-dependent effects on cell survival in both applied cell lines.

Sleep deprivation (SD) is a powerful antidepressant treatment that shows antidepressant responses within hours in 40–60% of depressed patients. In more than 80% of responders to SD, a relapse into depression occurred after the recovery night. In addition, it serves as an excellent tool to examine the neurobiological disturbance of depression and may profoundly contribute to the development of new specific and more rapidly acting antidepressants. The reason why SD works and relapses occur is still unclear. A key to solve this problem is to include the current knowledge about the neurobiological disturbance of depression in research, with a focus on neurobiological aspects of sleep and SD (sleep EEG, neuroendocrinology, neurochemistry and chronobiology). Based on findings from these different areas, different strategies to stabilize the antidepressant effect of SD have been applied. This article provides an overview of clinical and neurobiological responses related to SD in depression.

Several studies reported a decreased pain sensitivity in patients with depression, but the underlying neurobiological mechanisms of this phenomenon are unclear. While there is extensive evidence that the serotoninergic system plays a key role in pain modulation, especially in pain inhibitory mechanisms via descending pathways, as well as in the pathophysiology of depression, no study so far has examined its potential relevance in mediating the alteration of pain processing. The present study addresses the question of whether indices of serotoninergic dysfunction, as investigated by a neuroendrocine challenge paradigm, are related to pain sensitivity. Nineteen drug-free inpatients with unipolar major depression underwent a neuroendocrine challenge test by measuring cortisol and prolactin in response to intravenously administered clomipramine (12.5mg). Heat/cold pain thresholds, warmth/cold detection thresholds, measures of current pain complaints and mood were assessed the day before and three day after challenge procedure. When patients were classified in subgroups based on a median split of their cortisol response values, the low-responsive group showed significantly elevated heat pain thresholds and nearly significantly elevated cold pain thresholds compared to the high-responsive group. No such group differences were found with regard to somatosensory thresholds, measures of pain complaints and mood. Subgrouping on the basis of prolactin responsiveness did not reveal significant differences in any parameter. In summary, a decreased pain sensitivity was demonstrated in patients characterized by a reduced neuroendocrine responsiveness to clomipramine, suggesting an involvement of serotoninergic dysfunction underlying altered pain perception in depression.

Atypical antipsychotics are nowadays the most widely used drugs to treat schizophrenia and other psychosis. Unfortunately, some of them can cause major metabolic adverse effects, such as weight gain, dyslipidemia and type 2 diabetes. The underlying lipogenic mechanisms of the antipsychotic drugs are not known, but several studies have focused on a central effect in the hypothalamic control of appetite regulation and energy expenditure. In a functional convergent genomic approach we recently used a cellular model and demonstrated that orexigenic antipsychotics that induce weight gain activate the expression of lipid biosynthesis genes controlled by the sterol regulatory element-binding protein (SREBP) transcription factors. We therefore hypothesized that the major genes involved in the SREBP activation of fatty acids and cholesterol production ( SREBF1, SREBF2, SCAP, INSIG1 and INSIG2 ) would be strong candidate genes for interindividual variation in drug-induced weight gain. We genotyped a total of 44 HapMap-selected tagging single nucleotide polymorphisms in a sample of 160 German patients with schizophrenia that had been monitored with respect to changes in body mass index during antipsychotic drug treatment. We found a strong association ( P =0.0003–0.00007) between three markers localized within or near the INSIG2 gene (rs17587100, rs10490624 and rs17047764) and antipsychotic-related weight gain. Our finding is supported by the recent involvement of the INSIG2 gene in obesity in the general population and implicates SREBP-controlled lipogenesis in drug-induced metabolic adverse effects.

While data dealing with neurobiological effects of sleep deprivation (SD) are mainly restricted to the acute effects of a single night, only few studies have investigated mid-term effects after repeated SD. We therefore examined the clinical and hormonal characteristics of depressive patients before and after serial SD to determine potential sustained effects, focusing especially on serotoninergic functions. One tool to investigate serotoninergic dysfunction in depression is the use of serotoninergic agents to stimulate hormonal secretion, which is assumed to normalize during a clinically effective therapy. Eighteen drug-free inpatients with unipolar major depression received cognitive-behavioral treatment for three weeks and – according to a randomized control design – additional SD therapy (six nights of total SD within three weeks, separated by nights of recovery sleep) or no SD therapy (control group). Serotoninergic function was assessed by measuring cortisol and prolactin in response to intravenously administered clomipramine (12.5mg) before and after the treatment period. The post-treatment challenge test was performed three days after the last SD night. Apart from of a transient overnight improvement of mood induced by SD, both groups showed a comparable clinical course during the three-week treatment period. Compared to the control group, the SD-treated patients exhibited significantly decreased pre-stimulation cortisol levels and significantly increased cortisol responses to clomipramine, whereas no treatment effects were observed for prolactin. In conclusion, our findings suggest that the mid-term effects of serial SD therapy lead to a normalization of serotoninergic dysfunction, although an obvious impact on clinical symptoms was not detected.

In major depressive disorder (MDD), there is increasing evidence of a relationship between neuroendocrine and immunological alterations. Therefore, we investigated the influence of cortisol and dexamethasone on the in vitro production of TNF-α and IL-6 in blood cells of depressed inpatients at admission, in the course of MDD and in healthy controls. Patients were psychopathologically classified as responders and non-responders after a 6-week antidepressant treatment. At admission in the responder subgroup, incubation with both steroids under basal conditions resulted in an increase of TNF-α levels, which decreased after treatment. After stimulation with phytohemagglutinin, an enhancement of TNF-α suppression by steroids was detectable after successful antidepressive treatment. A significant relationship was seen between the cortisol-induced modulation of TNF-α levels and the psychopathology in this subgroup. Under basal conditions, IL-6 levels were increased after treatment with both steroids. The data suggest a normalization of the altered effects of glucocorticoids on TNF-α production in the responder subgroup only.