Clinical use of aripiprazole in patients with schizophrenia: a real-life setting results from the German Postmarketing Surveillance Study.

When aripiprazole (ABILIFY) received its approval in Germany for the treatment of schizophrenia, a hospital-based postmarketing surveillance study was initiated in order to gain further insights concerning safety and efficacy of the antipsychotic under real-life conditions. Efficacy was rated by using standard CGI, GAF, and SF-12 instruments, whereas safety was evaluated according to the reports on adverse effects. Data from 799 patients with schizophrenia from 122 psychiatric hospitals returned for evaluation. Eighty percent of the patients were treated for 4 weeks with 10-30 mg/day aripiprazole (mean modal dose 15 mg/day). Within the observation period significant improvements of CGI, GAF, and SF-12 ratings was observed. Aripiprazole was tolerated well by the patients. Most frequent adverse effects were insomnia, irritability, restlessness, nausea and vomiting, in general being moderate to mild and corresponding to the known tolerability profile of aripiprazole. The results demonstrate that the administration of aripiprazole can result in an improvement of the symptoms of schizophrenia within 4 weeks in a real-life hospital-based in- and outpatient setting.

Suppressed neuroendocrine stress response in depressed women on job-stress-related long-term sick leave: a stable marker potentially suggestive of preexisting vulnerability.

BACKGROUND: We recently reported marked hyporeactivity of the hypothalamo-pituitary-adrenal (HPA) axis in depressed women on job-stress-related long-term sick leave (LTSL). This unexpected finding prompted the question of whether HPA axis hypofunction in this group results from stress exposure or reflects preexisting vulnerability. Here, as a first step toward addressing this question, we assessed temporal stability of HPA axis reactivity in these subjects. METHOD: We used the combined dexamethasone/corticotropin-releasing hormone (DEX-CRH) test to retest HPA axis reactivity in 29 patients and 27 control subjects after 12 months of follow-up. Clinical status and cognitive performance was also retested. RESULTS: Despite marked clinical improvement and normalization of initially observed impairments in attention and working memory, marked HPA axis hyporeactivity persisted in patients. A high test-retest correlation was found both at the level of corticotropin (R = .85, p < .001) and cortisol (R = .76, p < .001) responses. CONCLUSIONS: Hyporeactivity of the HPA was stable over 12 months in LTSL subjects, independent of clinical improvement and normalized cognitive function. The stability of this response over time suggests that decreased DEX-CRH responses in this group may be a trait rather than a state marker. This finding is compatible with a hypothesis that HPA axis hyporeactivity may reflect a preexisting vulnerability in these subjects.

The Munich vulnerability study on affective disorders: microstructure of sleep in high-risk subjects.

Vulnerability markers for affective disorders have focused on stress hormone regulation and sleep. Among rapid eye movement (REM) sleep, increased REM pressure and elevated REM density are promising candidates for vulnerability markers. Regarding nonREM sleep, a deficit in amount of and latency until slow wave sleep during the first half of the night is a characteristic for depression. To further elucidate whether changes in the microstructure of sleep may serve as vulnerability markers we investigated the premorbid sleep composition in 21 healthy high-risk proband (HRPs) with a positive family history for affective disorders and compared HRPs with a control group of healthy subjects (HCs) without personal and family history for psychiatric disorders. The sleep electroencephalogram (EEG) was conventionally scored and submitted to a quantitative EEG analysis. The main difference in sleep characteristics between HRPs and HCs was an abnormally increased REM density. Differences in the spectral composition of sleep EEG were restricted to an increased power in the sigma frequency range. Since the HRP group comprised six unrelated and 15 related subjects we controlled for sibling effects. We could replicate the increased REM density in the group of HRPs whereas elevated power in the low sigma frequencies persisted only with approaching significance. The present study further supports elevated REM density as putative vulnerability marker for affective disorders. However, sleep EEG in our group of HRPs did not show slow wave sleep abnormalities. Ongoing follow up investigations of HRPs will clarify whether the observed increase in sigma EEG activity during nonREM sleep is of clinical relevance with respect to the likelihood to develop an affective disorder.

Blunted ACTH response to dexamethasone suppression-CRH stimulation in posttraumatic stress disorder.

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 microg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.

Dex/CRH-test response and sleep in depressed patients and healthy controls with and without vulnerability for affective disorders.

Sleep electroencephalographic (EEG) abnormalities and increased hypothalamo-pituitary-adrenal (HPA) axis activity are the most prominent neurobiological findings in depression and were suggested as potential biomarker for depression. In particular, increased rapid eye movement sleep (REM) density, deficit in slow wave sleep and excessive stress hormone response are associated with an unfavorable long-term outcome of depression. Recent studies indicate that the sleep and endocrine parameters are related to each other. This study investigated the association of sleep structure including a quantitative EEG analysis with the results of the combined dexamethasone (Dex)/corticotropin-releasing hormone (CRH)-test in 14 patients with a severe major depression, 21 healthy probands with a positive family history of depression (HRPs) and 12 healthy control subjects without personal and family history for psychiatric disorders. As expected patients with depression showed an overactivity of the HPA axis, disturbed sleep continuity and prolonged latency until slow wave sleep in the first sleep cycle. Differences in microarchitecture of sleep were less prominent and restricted to a higher NonREM sigma power in the HRP group. Dexamethasone suppressed cortisol levels were positively associated with higher NonREM sigma power after merging the three groups. We also observed an inverse association between the ACTH response to the Dex/CRH-test and rapid eye movement sleep (REM) density in HRPs, with suggestive evidence also in patients, but not in controls. This contra-intuitive finding might be a result of the subject selection (unaffected HRPs, severely depressed patients) and the complementarity of the two markers. HRPs and patients with high disease vulnerability, indicated by an elevated REM density, seem to have a lower threshold until an actual disease process affecting the HPA axis translates into depression, and vice versa. To summarize, our findings provide further evidence that the HPA axis is involved in the sleep regulation in depression. These associations, however, are not unidimensional, but dependent on the kind of sleep parameters as well as on the selection of the subjects.

Rapid eye movement (REM) sleep: an endophenotype for depression.

Disturbed sleep is one of the hallmark signs of depression. After successful treatment, many of these signs disappear; however, changes in rapid eye movement (REM) sleep may persist and even predict recurrence of depression. High-risk studies have established these alterations to be not only biological scars but true endophenotypes for depression. REM sleep changes are mediated by the noradrenergic, serotonergic, and cholinergic systems and are under strong genetic control. REM sleep has a crucial role for brain maturation and is inhibited during ontogeny. Lack of this inhibition may predispose an individual to depression. Findings regarding the CREB gene support REM sleep's role in depression. The combination of psychopathology and neurobiological measures, such as REM sleep parameters, will help to improve genetic studies and therefore increase the knowledge of relevant pathways for depression. This could facilitate development of preventive and therapeutic measures.

Neuroendocrine, cognitive and structural imaging characteristics of women on longterm sickleave with job stress-induced depression.

BACKGROUND: A recent increase in long-term sick leave (LTSL) in Sweden affects mostly women in the public sector. Depression-related diagnoses account for most of the increase, and work-related stress has been implicated. METHODS: We examined dexamethasone/corticotropin-releasing hormone (dex/CRH) test responses, magnetic resonance imaging measures of prefrontocortical and hippocampal volumes, and cognitive performance in 29 female subjects fulfilling three core criteria: 1) LTSL > 90 days; 2) unipolar depression or maladaptive stress reaction with depressed mood; 3) job-related stress given as a reason for disability. This group was compared with 28 healthy matched controls. RESULTS: The cortisol response to CRH differed markedly between the two groups (p = .002), with a dampened response in patients. This difference remained after removing subjects on antidepressant drugs (p = .006) or smokers (p = .003). Neither hippocampal nor prefrontocortical volumes differed. Performance on hippocampus-dependent declarative memory tests did not differ between groups, but the LTSL group had impaired working memory. CONCLUSIONS: Our most salient finding is an attenuated dex-CRH response in patients on LTSL due to job-stress related depression. This is opposite to what has been described in major depression. It remains to be established whether this impairment is the end result of prolonged stress exposure, or a pre-existing susceptibility factor.

Paroxetine treatment improves motor symptoms in patients with multiple system atrophy.

PURPOSE: In view of the putative role of serotonergic neurotransmission in basal ganglia circuitry we investigated the effects of paroxetine (PXT) as a selective serotonin reuptake inhibitor (SSRI) on the motor performance in n=19 patients clinically diagnosed as MSA using a double-blind placebo-controlled randomized study design. In addition, we assessed the effects on the psychopathological status of the patients. RESULTS: The short-term add-on treatment with PXT up to 30 mg tid for two weeks resulted in a significant improvement of the motor abilities of the upper limbs and speech when compared to placebo. The treatment with PXT was generally well tolerated. The degree of depressive symptoms was not significantly influenced by PXT or placebo during the observation period. CONCLUSIONS: Previous observations suggest that serotonergic projections may modulate the neuronal excitability of the mesolimbic system and cerebellar system. The observed effects of PXT on motor performance may therefore be due to a direct action of the drug on the motor system. However, these results should be regarded as preliminary, and further research is suggested to evaluate the long-term outcome and clinical relevance of SSRI co-medication in MSA.

Polymorphisms of the glucocorticoid receptor gene and major depression.

BACKGROUND: The most consistent biological finding in patients with depression is a hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis, which might be caused by impaired glucocorticoid signaling. Glucocorticoids act through the glucocorticoid receptor (GR) for which several polymorphisms have been described. The N363S and BclI polymorphisms have been associated with hypersensitivity to glucocorticoids, whereas the ER22/23EK polymorphism is related to glucocorticoid resistance. METHODS: We studied whether the susceptibility to develop a depression is related to these polymorphisms by comparing depressive inpatients (n = 490) and healthy control subjects (n = 496). Among depressed patients, we also investigated the relation between GR variants and dysregulation of the HPA-axis, as measured by the combined dexamethasone suppression/corticotropin-releasing hormone (CRH)-stimulation test, clinical response to antidepressive treatment, and cognitive functioning. RESULTS: Homozygous carriers of the BclI polymorphism and ER22/23EK-carriers had an increased risk of developing a major depressive episode. We found no genetic associations with functional HPA-axis measures in depressed patients. The ER22/23EK-carriers, however, showed a significantly faster clinical response to antidepressant therapy as well as a trend toward better cognitive functioning during depression. CONCLUSIONS: The BclI and ER22/23EK polymorphisms were associated with susceptibility to develop major depression. In addition, the ER22/23EK polymorphism is associated with a faster clinical response to antidepressant treatment. These findings support the notion that variants of the GR gene might play a role in the pathophysiology of a major depression and can contribute to the variability of antidepressant response.

The Munich vulnerability study on affective disorders: premorbid polysomnographic profile of affected high-risk probands.

BACKGROUND: The most characteristic alterations in the sleep electroencephalogram (EEG) during major depression are a shortened latency to rapid eye movement (REM) sleep and an elevated REM density. Because these changes persist in remission, they might represent vulnerability markers. To identify vulnerability markers, we investigated premorbid sleep EEG parameters in healthy high-risk probands (HRPs) with a positive family history of affective disorders. METHODS: We identified 136 depressed inpatients from referrals to our hospital who had first-degree relatives with an affective disorder as well as first-degree relatives with no current or lifetime history of psychiatric disorders. The latter (the HRP group) were investigated by polysomnography. During the follow-up period, 20 HRPs developed an affective disorder. Their premorbid sleep data were analyzed. RESULTS: Premorbid sleep EEG of affected HRPs showed an increased REM density (total night and first REM period) compared with the control group without personal or family history of a psychiatric disorder. CONCLUSIONS: Increased REM density can be observed not only in patients with depression, but also in their healthy relatives. Moreover, it is predictive for the onset of a psychiatric disorder. Therefore, it can be recommended as a possible endophenotype of these diseases.

The combined dexamethasone/CRH test as a potential surrogate marker in depression.

There is compelling evidence that impaired corticosteroid receptor function is the key mechanism in the pathogenesis of depression resulting in a dysfunctional stress hormone regulation, which can be most sensitively detected with the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. Treatment with different kinds of antidepressants is associated with a reduction of the hormonal responses to the combined dex/CRH test suggesting normalization of impaired corticosteroid receptor signaling as the final common pathway of these drugs. Consequently, the combined dex/CRH test is suggested as a screening tool to decide whether new compounds designed as antidepressants provide sufficient efficacy to normalize corticoid receptor signaling in depressed patients. We summarize own data and findings from the literature suggesting that (1) the neuroendocrine response to the combined dex/CRH test is elevated during a major depressive episode, but (2) tends to normalize after successful treatment. (3) Favorable response to antidepressant treatment can be predicted by determining the dex suppresser status on admission. For optimal prediction of non-response to antidepressant treatment, however, the results of a second dex/CRH test are necessary. These findings, together with the fact that impaired corticosteroid receptor signaling is considered as key mechanism of the pathogenesis in depression, support the suitability of the combined dex/CHR test as a surrogate marker for treatment response in depression. In conclusion, the combined dex/CRH test is a promising candidate to serve as a screening tool for the antidepressive effects of new compounds in clinical drug trials. Furthermore, the test appears to be capable of predicting the individual likelihood to respond to a current antidepressant treatment. If a drug treatment fails to normalize the outcome of the combined dex/CRH test, a change of the treatment strategy is recommended. Further systematic research is required and already ongoing to confirm the suitability of the combined dex/CRH test as a surrogate marker in depression.

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder.

Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression, knowledge of factors related to response remains scanty. Findings with the combined dexamethasone/corticotropin-releasing hormone (DEX/CRH) test are associated with response to treatment with a tricyclic antidepressant. This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder. The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks. Response status was assessed weekly using the Hamilton Rating Scale for Depression. For multivariate prediction, a logistic regression analysis was performed. Eleven (37%) patients responded to lithium augmentation within 4 weeks. Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test, but results were not statistically significant. However, non-responders had a statistically significant higher cortisol/ACTH peak ratio (3.43+/-1.75) compared to responders (2.18+/-1.38) (P=0.027). This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH. A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders. In conclusion, results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation. The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group, because chronic depression is known to cause enlargement of the adrenal gland with a subsequent hypersensitivity to ACTH. Results of this study should be confirmed in a larger study group.

The Munich Vulnerability Study on Affective Disorders: risk factors for unipolarity versus bipolarity.

BACKGROUND: An individual with a high genetic load for psychiatric disorders is subject to a considerable risk factor for an affective illness. Family studies usually try to distinguish between bipolar and unipolar disorders since it was suggested that they might show different modes of inheritance. The aim of this study was to differentiate between healthy members of unipolar and bipolar families without a previous history of any psychiatric disorder according to the neurobiological and psychometric findings. METHODS: We first analysed the results obtained from neurobiological and psychometric measurements taken from 75 healthy subjects who had at least two close relatives with a unipolar and a bipolar disorder. In a second step we examined the subjects with a parental affective disorder; finally, we compared the members of 'pure' unipolar, bipolar and of mixed families to each other. RESULTS: The first-degree relatives of unipolar patients showed a significantly higher REM density and scored higher on scales of 'neuroticism' and 'vegetative lability' than the controls. No significant differences could be noticed between the relatives of unipolar and bipolar patients, either when considering the degree of relationship, or the parental type of affective disorder and the 'purity' of the respective families. CONCLUSIONS: We found some distinct neurobiological and psychometric differences between the relatives of unipolar patients and the control probands. No obvious differences, however, were ascertained between relatives of unipolar and bipolar patients. Therefore, we consider it to be possible that these findings represent potential vulnerability markers for affective disorders in general.

The Munich Vulnerability Study on Affective Disorders: stability of polysomnographic findings over time.

BACKGROUND: Some of the sleep abnormalities found in depression also persist in remission, suggesting that these parameters could represent trait or vulnerability markers. In a previous study, we found that about one third of a group of high-risk probands (HRPs) showed sleep patterns that were comparable to those of depressed patients. In the present study, we re-investigated a subsample of these HRPs to evaluate the stability of these findings over time. METHODS: We investigated the sleep-electroencephalograms of 82 healthy subjects with a high genetic load of affective disorders. We were able to re-investigate 26 of these HRPs after a mean interval of 3.5 years. Thirty-five unrelated control probands and 33 unrelated depressed inpatients that were recruited at the first investigation served as reference groups. RESULTS: At index investigation, we found that the HRPs showed a significantly increased rapid eye movement (REM) sleep density compared to control subjects. At the second examination, no changes of the polysomnographic observations over time could be observed; in particular, the REM density remained elevated. CONCLUSIONS: The increased REM density in high-risk subjects for an affective disorder at index investigation was stable over time, so that one of the requirements for a true vulnerability marker is fulfilled.

Lithium augmentation increases the ACTH and cortisol response in the combined DEX/CRH test in unipolar major depression.

Lithium augmentation is a well established strategy for treatment-resistant depression. The exact mode of its action is unknown, but an enhancement of serotonergic transmission is hypothesized. The authors investigated changes in the hypothalamic-pituitary-adrenocortical (HPA) system during lithium augmentation and their correlation to clinical response by means of the combined dexamethasone/CRH test (DEX/CRH test). Thirty patients with unipolar major depressive episodes (DSM IV) who had not responded to an adequate trial with an antidepressant were assessed on the day before lithium augmentation (baseline) with the DEX/CRH test (pretreatment with 1.5 mg dexamethasone p.o. at 11 P.M. and CRH stimulation at 3 P.M. on the next day). Twenty-four patients were re-assessed after response was determined or, in cases of non-response, four weeks after initiation of lithium augmentation. Response to lithium augmentation was measured by weekly ratings on the Hamilton Depression Rating Scale (HDRS 17-item version). Response was defined as a DeltaHDRS of > or =50% and an endpoint score of < 10. Patients had a significantly higher ACTH and cortisol response to CRH stimulation during lithium augmentation compared with the values at baseline. There was no difference in ACTH and cortisol reaction between responders and non-responders to lithium augmentation. This increase is in contrast to the known normalization of HPA-axis overdrive after treatment with a tricyclic antidepressant like amitriptyline. Because the effect was independent of response status we suggest that this increase reflects an effect of lithium that is independent from the psychopathological state or its change. This effect might be explained by the serotonergic effects of lithium.