Andrea Pfennig

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.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care

These practical guidelines for the biological treatment of unipolar depressive disorders in primary care settings were developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). They embody the results of a systematic review of all available clinical and scientific evidence pertaining to the treatment of unipolar depressive disorders and offer practical recommendations for general practitioners encountering patients with these conditions. The guidelines cover disease definition, classification, epidemiology and course of unipolar depressive disorders, and the principles of management in the acute, continuation and maintenance phase. They deal primarily with biological treatment (including antidepressants, other psychopharmacological and hormonal medications, electroconvulsive therapy, light therapy).

Combined Dexamethasone/Corticotropin Releasing hormone test predicts treatment response in major depression--a potential biomarker?

BACKGROUND Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. METHODS We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. RESULTS We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. CONCLUSIONS The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta‐analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view.

World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders

Abstract Objectives. This 2013 update of the practice guidelines for the biological treatment of unipolar depressive disorders was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal has been to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. The guidelines are intended for use by all physicians seeing and treating patients with these conditions. Methods. The 2013 update was conducted by a systematic update literature search and appraisal. All recommendations were approved by the Guidelines Task Force. Results. This first part of the guidelines (Part 1) covers disease definition, classification, epidemiology, and course of unipolar depressive disorders, as well as the management of the acute and continuation phase treatment. It is primarily concerned with the biological treatment (including antidepressants, other psychopharmacological medications, electroconvulsive therapy, light therapy, adjunctive and novel therapeutic strategies) of adults. Conclusions. To date, there is a variety of evidence-based antidepressant treatment options available. Nevertheless there is still a substantial proportion of patients not achieving full remission. In addition, somatic and psychiatric comorbidities and other special circumstances need to be more thoroughly investigated. Therefore, further high-quality informative randomized controlled trials are urgently needed.

Genome-wide association study reveals two new risk loci for bipolar disorder

Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

Pharmacological and Nonpharmacological Factors Influencing Hypothalamic–Pituitary–Adrenocortical Axis Reactivity in Acutely Depressed Psychiatric In-patients, Measured by the Dex-CRH Test

The most consistent biological findings in patients with depression are abnormalities in the hypothalamic–pituitary–adrenal (HPA)-axis, which can be measured using the combined dexamethasone-suppression/CRH-stimulation (Dex-CRH) test. The reactivity of the HPA-axis in this test, however, ranges over several orders of magnitude in depressed patients with comparable severity of symptoms. In this present study, we investigate which factors influence the magnitude of the response in the Dex-CRH test in 235 acutely depressed in-patients. We first examined the effects of common confounders shown to influence the HPA-axis, such as caffeine and nicotine consumption, acute stressors during the test, weight, gender, and age. Of all these variables, only female sex and nicotine consumption were positively correlated with the cortisol or ACTH response, respectively. As for the effects of psychopharmacological treatment, only the intake of carbamazepine and the fact of having relapsed under an established pharmacotherapy significantly increased the response in the Dex-CRH test, whereas the presence or absence of antidepressant treatment, the type of antidepressant treatment, or the number of ineffective antidepressant treatment trials during the index episode up to admission did not have any effect. We also found a positive correlation of the number of previous episodes, the overall HAM-D score and the severity of somatic/vegetative symptoms with the results in the Dex-CRH test. These results underline that in depressed patients this test is not majorly influenced by disease-unrelated factors. In addition, current antidepressant treatment does not appear to affect test outcome in the absence of clinical response. The influence of the number of previous episodes and relapse under pharmacotherapy suggests that HPA-axis reactivity may be altered by repetitive states of hypercortisolemia or continuous antidepressant treatment. Finally, more severe vegetative symptoms are associated with an enhanced HPA-axis activity.

Epidemiology of bipolar disorders

Summary:  Bipolar, or manic–depressive, disorders are frequent and severe mental illnesses associated with considerable morbidity and mortality. Epilepsy and bipolar disorder could probably share some aspects of pathophysiology because manic as well as depressive symptoms are seen in patients with seizures, and a number of antiepileptic drugs are effectively used in the acute and prophylactic treatment of bipolar disorder. Epidemiologic research suggests a dimensional composition of bipolar illness at the population level. Apart from the DSM‐IV diagnostic features of bipolar I (mania and depression) and bipolar II (hypomania and depression), the concept of bipolar spectrum disorders comprises a range of bipolar conditions with less obvious manifestations with estimated lifetime prevalence rates ranging from 2.8 to 6.5%. Expanding the definition of bipolar II disorders shows that half of the patients currently diagnosed with a unipolar depressive episode could suffer from unrecognized bipolar II disorder, and about the same number of mild depressive patients could be minor bipolars. Research efforts to refine the diagnostic criteria of bipolar disorder aim at an earlier and complete recognition of the disease to provide appropriate pharmacological and nonpharmacological treatment early in the course of the illness to anticipate individual suffering, suicidal behavior, and increased socioeconomic costs for society. This article also discusses risk factors, comorbid conditions, course of illness, as well as the individual and socioeconomic impact of bipolar disorders.

Hypothalamus-pituitary-adrenal system regulation and suicidal behavior in depression

BACKGROUND One of the most demanding tasks in psychiatry is to protect patients from suicidal attempts. Preventive strategies could be improved by increasing our knowledge on the pathophysiologic disturbances underlying this behavior. More than 70-80% of suicides occur in the context of depressive disorders, in which dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most prominent neurobiological findings. So far data on the involvement of the HPA axis in the pathophysiology of suicidal behavior in depressed patients are controversial. METHODS In this retrospective study, we administered the combined dexamethasone-suppression/CRH stimulation (Dex/CRH) test to 310 patients with a depressive syndrome characterized at admission for acute and past suicidal behavior within the first 10 days after hospitalization. RESULTS Suicidal behavior in depressed patients, including past and recent suicide attempts as well as suicidal ideation, was associated with a lower adrenocorticotropin and cortisol response in the combined Dex/CRH test, with lowest hormone levels observed in patients with a recent suicide attempt. DISCUSSION The findings suggest that suicidal behavior may alter HPA axis regulation in depressed patients. Large-scale prospective studies assessing neuroendocrine changes may help to develop predictors for an early identification of patients at risk for committing suicide.

HPA-axis regulation at in-patient admission is associated with antidepressant therapy outcome in male but not in female depressed patients

A concatenation of data implicates a hyperactivity of the hypothalamus pituitary adrenal (HPA)-axis in the pathogenesis of depression and its normalization as a necessary predecessor of clinical response to antidepressant drugs. In addition, regulation of the HPA-axis has been shown to be dependent on sex hormones. We therefore investigated gender differences in HPA-axis regulation in depression and its normalization during remission of clinical symptoms. We used the combined dexamethasone suppression/CRH stimulation (Dex-CRH) test to evaluate the degree of HPA-axis dysregulation in 194 in-patients with unipolar depression from the Munich Antidepressant Response Signature (MARS) study at both admission and discharge. The Hamilton Depression (HAM-D) Rating Scale was used to monitor clinical response to antidepressant treatment. For both genders, we observed a normalization of HPA-axis dysregulation in remitters but not in non-remitters, both after 5 weeks of treatment and at discharge. The pattern of HPA-axis normalization with remission of depressive symptoms, however, showed gender-specific differences. In male patients, remission after 5 weeks of in-patient treatment was associated with a significantly higher cortisol response in the Dex-CRH test at admission. In female patients, 5-week remitters and non-remitters had a comparable cortisol response at admission. Cortisol response at admission was not correlated with gonadal steroid levels at this time point and the results were similar for pre-menopausal women vs. post-menopausal women. Gender-associated biological characteristics, likely independent of circulating gonadal steroids, thus seem to influence HPA-axis regulation in depression. In male patients, a single measure of HPA-axis dysregulation at admission may serve as a predictor of response to antidepressant treatment in addition to the previously reported repeated measure of the Dex-CRH test.