[Gut microbiota and depression : Pathophysiology of depression: hypothalamic-pituitary-adrenal axis and microbiota-gut-brain axis]. / Darmflora und Depression : Pathophysiologie der Depression: Hypothalamus-Hypophysen-Nebennierenrinden- und Mikrobiota-Darm-Hirn-Achse.

Depression is a chronic disease with a complex multifactorial and still not fully clarified etiology. Due to new insights after recent investigations of the microbiota-gut-brain (MGB) axis, a relationship between a disrupted gut microbiota composition and the probability to develop a depression can be assumed. This hypothesis is supported by evidence that there is a strong communication between gut microbiota and the central nervous system (CNS) and that this communication is mediated through the MGB axis. Apparently, this bidirectional axis can be modulated by environmental factors, such as stress, pharmaceuticals (in particular antibiotics) and dietary habits. Moreover, modulation of this axis can also result in mood alterations. As the hypothalamic-pituitary-adrenal (HPA) axis is a key element regulating the MGB axis and is also related to the pathophysiology of depression, it is important to understand the relationship between both biological systems. An English language literature search was conducted using the biomedical database PubMed. We used combined terms, such as "gut microbiota", "depression", "hypothalamic-pituitary-adrenal axis" or "microbiota-gut-brain axis". The current literature supports the idea that the MGB axis has an impact on the risk to develop depression and that stress modulation through the HPA axis plays a key role in this context.

Translocator Protein (TSPO) Expression in Platelets of Depressed Patients Decreases during Antidepressant Therapy.

Introduction: A promising candidate in the field of pharmacological treatment options regarding major depressive disorder (MDD) is the mitochondrial translocator protein (18 kDa) (TSPO). TSPO is crucial for neurosteroid synthesis, which is in turn important for the regulation of emotions. It has already been shown that TSPO expression in platelets of depressed patients is reduced compared to healthy subjects. Methods: We measured TSPO levels in platelets of 37 depressed patients before and after 6 weeks of pharmacological treatment to test the hypotheses that i) such treatment would increase TSPO expression and ii) that this increase would be correlated with therapeutic response. Results: Surprisingly, TSPO levels in platelets of all patients were significantly reduced after 6 weeks of treatment (p=0.044). Within the responder group, a non-significant trend towards greater TSPO level reduction could be observed. Discussion: These results challenge our hypotheses that TSPO levels might increase during antidepressant therapy along with a decrease in depressive symptoms. Thus, we assume that TSPO expression in platelets is not a suitable state marker for MDD.

[Gut microbiome and major depressive disorder : The other side of ourselves]. / Dickdarmmikrobiom und Depression : Die andere Seite unseres Selbst.

Microbiological ecology and its ambition to describe the complete genome of complex living communities as a whole, have given us powerful tools to characterize the human gut microbiome on a genetic and, hence, taxonomic and abundance level; for a decade now, they have become sufficiently inexpensive, fast and feasible. Thus, opportunities arose to have a fresh and closer look at the microbiota-gut-brain-axis and its impact on human health; this axis comprises a complex multisystemic network of multidirectional interactions between brain and gut including influences beyond one generation. Gnotobiotic animal models have become essential for specific research targets. Combining gut microbiome analysis with observations on the hypothalamus-pituitary-adrenal axis and various aspects of inflammation helped to gain first insights into the role of the microbiota-gut-brain-axis in depressive disorders. Therapeutic endeavors with psychobiotics have not yet shown their value in clinical studies.

[Mirtazapine and hyperemesis gravidarum]. / Mirtazapin bei Hyperemesis gravidarum.

The case of a 29-year-old patient in the 21st gestational week with severe hyperemesis gravidarum which did not respond to conventional antiemetic treatment is reported. Nausea and vomiting improved within 48 h after i.v. administration of 30 mg mirtazapine/day. The pathophysiological and therapeutic implications are discussed.

[Psychotic and non-psychotic denial of pregnancy]. / Psychotische und nicht psychotische Verleugnung der Schwangerschaft.

We report about two patients with denial of pregnancy. While the first patient was free of psychopathological symptoms besides denial of pregnancy until rupture of the membranes, and was able to accomodate the new born, the second patient with psychotic denial of pregnancy could not accomodate the child because of the schizophrenia, so that an adoption was necessary. On the basis of the two cases aetiological, epidemiological, clinical und prognostic implications of psychotic and non-psychotic denial of pregnancy are discussed.

Effects of the GABA-reuptake inhibitor tiagabine on panic and anxiety in patients with panic disorder.

INTRODUCTION: There is evidence that a decreased GABAergic tone plays a role in the pathophysiology of panic disorder (PD). Selective GABAergic treatment has been suggested as a new therapeutic strategy in PD. In this pilot-study anxiolytic effects of the GABA reuptake inhibitor tiagabine (TGB) were investigated in PD. METHODS: A total of 19 patients were treated with TGB (n=10) or placebo (n=9) for 4 weeks. PAS, HAM-A, and CGI ratings were administered every week. To further assess specific antipanic activity, panic challenges with CCK-4 were carried out in single subjects. RESULTS: Although there was a significant reduction of clinical rating scores over time, no differences were detected between the groups. However, during challenge experiments TGB treated subjects showed decreased sensitivity to CCK-4. DISCUSSION: Whereas tiagabine did not show beneficial effects on clinical symptoms in PD compared to placebo, results of challenge experiments suggest effects of TGB on sensitivity to experimentally induced panic.

[Core symptoms of depression. Effectiveness of antidepressant therapy]. / Depressive Kernsymptome. Wirksamkeit medikamentöser antidepressiver Therapieverfahren.

Core symptoms of depression are a combination of psychological and somatic symptoms, often associated with psychomotor and cognitive disturbances. The diagnostic classifications of depression include the concepts of melancholic, endogenous, or severe depression. All subgroups describe severely depressed patients suffering from most of the core symptoms of depression. In addition these patients exhibit the clinical characteristics of a recurrent unipolar or bipolar course, lower placebo response rates, or higher response rates to ECT, to antidepressant treatments with dually or mixed modes of action, or to lithium augmentation. Higher rates of HPA axis hyperactivity and specific EEG patterns may also occur in this patient group. This suggests a broad overlap of patient subgroups within the diagnostic classification of depression. Because the positive diagnosis of the core symptoms of depression may include clinical consequences, it would be useful to integrate all these concepts into the upcoming new versions of the diagnostic systems DSM-V and ICD-11.

[Antidepressive pharmacotherapy. In slight and severe disease, young and old]. / Antidepressive Pharmakotherapie. Bei leichter und schwerer Erkrankung, bei jung und alt.

During the past decade a variety of promising new compounds launched onto the market not only enhancing serotonergic and noradrenergic neurotransmission, but also influencing the dopamine and the melatonergic receptor system. In spite of misleading discussions both in the specialized and in the lay press the clinical effectiveness of antidepressants still is indisputable. The main advantages of the newer drugs are the broadening of the spectrum treatments and a far better tolerability profile in comparison to older compounds. Predominantly depression of medium to high severity should be treated pharmacologically. Especially severe depression seems to respond better to dually acting antidepressants. In children effectiveness of Omega3-fatty acids has been shown, in adolescents SSRI treatment was efficacious. Older patients respond to all antidepressant mechanisms, but more selective substances should be preferred due to a better tolerability. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.

Impact of gene-gender effects of adrenergic polymorphisms on hypothalamic-pituitary-adrenal axis activity in depressed patients.

OBJECTIVE: There is overwhelming evidence that activation of the hypothalamic-pituitary-adrenal (HPA) system plays a major role in depression and cardiovascular disease in genetically susceptible individuals. We hypothesized that due to the multiple interactions between the sympathetic and the HPA systems via adrenoceptors, polymorphisms in these genes could have an impact on HPA axis activity in major depression. METHODS: Using the dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test, we investigated the association of alpha(2)-adrenoceptor (ADRA2A -1291C-->G) and the beta(2)-adrenoceptor gene (ADRB2 Arg16Gly) in 189 patients with major depression during the acute state of the disease and after remission. RESULTS: Male ADRA2A -1291G allele homozygotes showed significant pretreatment HPA axis hyperactivity, with increased adrenocorticotropin (ACTH; F = 4.9, d.f. = 2, p = 0.009) and cortisol responses (F = 6.4, d.f. = 2, p = 0.003). In contrast, female ADRB2 Arg/Arg homozygotes had increased pretreatment ACTH (F = 7.17, d.f. = 2, p = 0.001) and cortisol (F = 8.95, d.f. = 2, p = 0.000) levels. Interestingly, in the respective genotypes, the stress hormones remained elevated in the second DEX/CRH test, despite a reduction in depressive symptoms. CONCLUSIONS: This study provides evidence that, depending on gender and polymorphisms, there is continuous HPA axis overdrive in a proportion of patients irrespective of the status of depression. Considering the importance of stress hormones for cardiovascular disorders, our data might suggest that these patients are at high risk of comorbidity between depression and cardiovascular disorders.

Neuroactive steroids as modulators of depression and anxiety.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

Neuroactive steroids and affective disorders.

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABA(A)) receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behaviour and may contribute to the therapeutical effects of antidepressant drugs. Attenuations of such neuroactive steroids have been observed during major depression and in several anxiety disorders, suggesting a pathophysiological role in such psychiatric conditions. In panic disorder patients a dysequilibrium of neuroactive steroid composition has been observed, which may represent a counterregulatory mechanism against the occurrence of spontaneous panic attacks. Furthermore, alterations of 3alpha-reduced pregnane steroids during major depression were corrected by successful treatment with antidepressant drugs. However in contrast, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. In addition, changes in neuroactive steroid concentrations after mirtazapine therapy occurred independently from the clinical response, thereby suggesting that changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of antidepressants rather than clinical improvement in general. Nevertheless, the effects of antidepressant pharmacotherapy on the composition of neuroactive steroids may contribute to the alleviation of certain depressive symptoms, such as amelioration of anxiety, inner tension or sleep disturbances. Moreover, first studies investigating the therapeutical effects of dehydroepiandrosterone revealed promising results in the treatment of major depression. In conclusion, neuroactive steroids are important endogenous modulators of depression and anxiety and may provide a basis for development of novel therapeutic agents in the treatment of affective disorders.

Effects of alprazolam on cholecystokinin-tetrapeptide-induced panic and hypothalamic-pituitary-adrenal-axis activity: a placebo-controlled study.

Cholecystokinin-tetrapeptide (CCK-4) induces panic attacks both in patients with panic disorder (PD) and healthy volunteers. It has been shown that panic elicited by CCK-4 is improved after treatment with antidepressants. Moreover, a reduction of CCK-4-induced panic has also been demonstrated after treatment with lorazepam in single subjects and after selective GABAergic treatment with vigabatrin. Although benzodiazepines are widely used as anxiolytics, no controlled study on the effects of benzodiazepines on CCK-4-induced panic symptoms is available so far. Therefore, we investigated the effects of alprazolam and placebo on CCK-4-induced panic symptoms in a double-blind, placebo-controlled study. A total of 30 healthy subjects were challenged with 50 microg CCK-4. Out of these 30 subjects, 26 showed a marked panic response to CCK-4. Subjects were rechallenged after a 7-day interval and treated with 1 mg alprazolam or placebo 1 h prior to the second CCK-4 challenge. Panic was assessed using the acute panic inventory (API) and a DSM-IV-derived panic symptom scale (PSS). Moreover, the number of reported symptoms and self-rated anxiety and arousal were recorded. We found a significant reduction of the API and PSS scores and of the number of reported symptoms compared to placebo. Moreover, compared to placebo the CCK-4-induced ACTH and cortisol release were significantly attenuated during the CCK-4 challenge after alprazolam treatment. However, also placebo treatment reduced CCK-4-induced anxiety and HPA-axis activation to a certain extent. In conclusion, our data show that alprazolam reduces CCK-4-induced panic, which supports the hypothesis of a possible interaction between the GABA and the CCK system.

Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers.

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 microg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4-induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD.

The combined dexamethasone-CRH test before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

BACKGROUND: Hypothalamic-pituitary-adrenocortical (HPA) dysregulation assessed by the combined dexamethasone corticotropin releasing hormone test (DEX/CRH test) has been demonstrated to normalize after successful antidepressant pharmacotherapy. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) also leads to a normalization of HPA system activity in depressed patients. METHODS: Thirty-seven medication free patients suffering from a major depressive episode (DSM-IV) underwent a DEX/CRH test before and after 13 daily sessions of left prefrontal rTMS in an open trial. RESULTS: There was an overshoot of CRH-induced cortisol release that was not affected by rTMS treatment. Postdexamethasone cortisol levels prior to CRH challenge decreased in responders after rTMS treatment, whereas no change of CRH-induced adrenocorticotropic hormone (ACTH) and cortisol release in responders or nonresponders was observed. CONCLUSIONS: The persisting HPA system hyperactivity after rTMS suggests a high risk for relapse and therefore argues for an immediate maintenance therapy in patients responding to this treatment.

Evidence for an association between a G-protein beta3-gene variant with depression and response to antidepressant treatment.

Abnormal signal transduction pathways have been implicated in the pathogenesis of bipolar disorder and major depression. G-proteins are key elements of these pathways in the regulation of cellular responses by transmission of signals from receptors to effector proteins. In recent years several studies have reported altered levels and activities of G-protein alpha subunits in depressive patients. A recently identified polymorphism of a G-protein beta3 subunit (C825T) has been shown to be associated with increased signal transduction and ion transport activity. Therefore, we investigated whether this Gbeta3 polymorphism is associated with affective disorders or with the response to antidepressant treatment in 88 depressive patients (10 bipolar disorder, 78 major depression) compared with 68 schizophrenic patients and 111 healthy controls. We found a significantly higher frequency of the T allele in depressive patients than in healthy controls (genotype: chi2 = 9.571, df = 2, p = 0.008; alleles: p = 0.004, OR = 1.87, 95% CI 1.23-2.84; Fisher's exact test, two sided) and schizophrenic patients (genotype: chi2 = 8.037, df = 2, p = 0.018; alleles: p = 0.009, OR = 1.94, 95% CI 1.99-3.14; Fisher's exact test, two sided). We also found a statistical significant association between TT homozygosity and response to antidepressant treatment after four weeks (p = 0.01). The results of this study suggest that the investigated G-protein beta3 subunit seems to be a susceptibility factor for major depression and maybe even for bipolar disorder, but not for schizophrenia. Further, the presence of the T allele could be an indicator for treatment response.

Serotonin-2A-receptor and -transporter polymorphisms: lack of association in patients with major depression.

Disturbances in serotonergic neurotransmission system have been implicated in the etiology of mood disorders. As the importance of genetic factors is well established, genes encoding for proteins of the serotonergic pathway are important candidates to unravel the underlying genetic contribution. We examined two polymorphisms in the serotonin-2A-receptor gene (5-HT2A; T102C and His452Tyr) and the insertion/deletion polymorphism in the promoter region of the serotonin transporter (5-HTTLPR) in a sample of 173 patients with major depression and 121 healthy controls. No statistical significant differences between patients and controls were found for any of the three investigated polymorphisms, neither in the distribution of the genotypes nor in allele frequencies. However, concerning the 5-HTTLPR polymorphism, the frequency of S/S (short allele) homozygotes was higher (23.1%) than in the control group (14.0%), but this failed to reach significance. Moreover we observed a different treatment response in patients with one or two C-alleles of the T102C polymorphism, with a significantly higher decrease in HAMD-17 (ANOVA: d.f. = 1, F = 5,288, P = 0.023) after 4 weeks of antidepressant treatment. Overall our results suggest that the investigated 5-HT2A and 5-HTTLPR polymorphisms are not major susceptibility factors in the etiology of major depression. However, subtypes might be identified at least on a basis of differential treatment response.

Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile.

Anxiety disorders are frequent and highly disabling diseases with considerable socio-economic impact. In the treatment of anxiety disorders, benzodiazepines (BZDs) as direct modulators of the GABA(A) receptor are used as emergency medication because of their rapid onset of action. However, BZDs act also as sedatives and rather quickly induce tolerance and abuse liability associated with withdrawal symptoms. Antidepressants with anxiolytic properties are also applied as first line long-term treatment of anxiety disorders. However, the onset of action of antidepressants takes several weeks. Obviously, novel pharmacological approaches are needed that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. Neurosteroids are potent allosteric modulators of GABA(A) receptor function. The translocator protein (18 kDa) (TSPO) plays an important role for the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Etifoxine not only exerts anxiolytic effects as a TSPO ligand by enhancing neurosteroidogenesis, but also acts as a weak direct GABA(A) receptor enhancer. The TSPO ligand XBD173 enhances GABAergic neurotransmission via the promotion of neurosteroidogenesis without direct effects at the GABA(A) receptor. XBD173 counteracts pharmacologically-induced panic in rodents in the absence of sedation and tolerance development. Also in humans, XBD173 displays antipanic activity and does not cause sedation and withdrawal symptoms after 7 days of treatment. XBD173 therefore appears to be a promising candidate for fast-acting anxiolytic drugs with less severe side-effects than BZDs. In this review, we focus on the pathophysiology of anxiety disorders and TSPO ligands as a novel pharmacological approach in the treatment of these disorders.