Neuroactive steroids in affective disorders: target for novel antidepressant or anxiolytic drugs?

In the past decades considerable evidence has emerged that so-called neuroactive steroids do not only act as transcriptional factors in the regulation of gene expression but may also alter neuronal excitability through interactions with specific neurotransmitter receptors such as the GABA(A) receptor. In particular, 3α-reduced neuroactive steroids such as allopregnanolone or allotetrahydrodeoxycorticosterone have been shown to act as positive allosteric modulators of the GABA(A) receptor and to play an important role in the pathophysiology of depression and anxiety. During depression, the concentrations of 3α,5α-tetrahydroprogesterone and 3α,5ß-tetrahydroprogesterone are decreased, while the levels of 3ß,5α-tetrahydroprogesterone, a stereoisomer of 3α,5α-tetrahydroprogesterone, which may act as an antagonist for GABAergic steroids, are increased. Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) or mirtazapine apparently have an impact on key enzymes of neurosteroidogenesis and have been shown to normalize the disequilibrium of neuroactive steroids in depression by increasing 3α-reduced pregnane steroids and decreasing 3ß,5α-tetrahydroprogesterone. Moreover, 3α-reduced neuroactive steroids have been demonstrated to possess antidepressant- and anxiolytic-like effects both in animal and human studies for themselves. In addition, the translacator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor, is the key element of the mitochondrial import machinery supplying the substrate cholesterol to the first steroidogenic enzyme (P450scc), which transforms cholesterol into pregnenolone, the precursor of all neurosteroids. TSPO ligands increase neurosteroidogenesis and are a target of novel anxiolytic drugs producing anxiolytic effects without causing the side effects normally associated with conventional benzodiazepines such as sedation or tolerance. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

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.

Effects of experimentally induced panic attacks on neuroimmunological markers.

Since little is known concerning regulation of immunological parameters in rapid changing psychiatric states like panic attacks, we measured cytokines at different time points in healthy subjects, which underwent experimental panic induction using the CCK-4 paradigm. Apart from a challenge related IL-6 increase, we could not observe any changes of neuroimmunological markers in relation to acute anxiety with regard to time and group. Herein we conducted for the first time a new approach to immunological research in panic disorder, suggesting immune changes are more related to long term disease stress.

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.

Independent component analysis applied to pharmacological magnetic resonance imaging (phMRI): new insights into the functional networks underlying panic attacks as induced by CCK-4.

Pharmacological magnetic resonance imaging (phMRI) is a method to study effects of psychopharmacological agents on neural activation. Changes of the blood oxygen level dependent (BOLD), the basis of functional MRI (fMRI), are typically obtained at relatively high sampling frequencies. This has more recently been exploited in the field of fMRI by applying independent component analysis (ICA), an explorative data analysis method decomposing activation into distinct neural networks. While already successfully used to investigate resting network and task-induced activity, its use in phMRI is new. Further extension of this method to tensorial probabilistic ICA (tensor PICA) allows to group similar brain activation across the anatomical, temporal, subject or session domain. This approach is useful for pharmacological experiments when no pharmacokinetic model exists. We exemplify this method using data from a placebo-controlled cholecystokinine-4 (CCK-4) injection experiment performed on 16 neuropsychiatrically and medically healthy males (age 25.6 +/- 4.2 years). Tensor PICA identified strong increases in activity in 12 networks. Comparison with results gained from the standard approach (voxelwise regression analysis) revealed good reproduction of areas previously associated with CCK-4 action, such as the anterior cingulate, orbitofrontal cortex, cerebellum, temporolateral, left parietal and insular areas, striatum, and precuneus. Several other components such as the dorsal anterior cingulate and medial prefrontal cortex were identified, suggesting higher sensitivity of the method. Exploration of the time courses of each activated network revealed differences, that might be lost when a fixed time course is modeled, e. g. neuronal responses to an acoustic warning signal prior to injection. Comparison of placebo and CCK-4 runs further showed that a proportion of networks are newly elicited by CCK-4 whereas other components are significantly active in the placebo conditions but further enhanced by CCK-4. In conclusion, group ICA is a promising tool for phMRI studies that allows quantifying and visualizing the modulation of neural networks by pharmacological interventions.

[Anticonvulsants in the treatment of anxiety--an alternative treatment option?]. / Antiepileptika in der therapie von angsterkrankungen--eine mögliche therapeutische alternative?

According to epidemiological studies anxiety disorders are among the most frequent psychiatric disorders. Depending on the diagnosis and severity, both cognitive behaviour therapy and pharmacological approaches are applied. In today's drug therapy antidepressants are the standard first-line treatment for most anxiety disorders, and enzodiazepines for the treatment of acute anxiety states. However, many patients do not respond to the first drug prescribed, prove to have conditions that are resistant to therapy or complain of side effects. There is therefore still a need for new medicamentous treatment strategies. There are numerous studies suggesting that anticonvulsants also have potentially anxiolytic properties and might therefore be an alternative treatment option in anxiety syndromes. This article gives an overview of investigations to date on the effects of various anticonvulsants in panic disorder, generalized anxiety disorder and social phobia.

Polymorphisms in the angiotensin-converting enzyme gene are associated with unipolar depression, ACE activity and hypercortisolism.

Angiotensin-converting enzyme (ACE) is assumed to influence the activity of the hypothalamic-pituitary-adrenocortical (HPA) system, which shows hyperactivity in the majority of patients with major depression. The ACE gene, known to be associated with cardiovascular disorders, which in turn are accompanied with an increased susceptibility for depression, is therefore a promising candidate gene for affective disorders. We investigated the genetic association between 35 single-nucleotide polymorphisms (SNPs) and an insertion/deletion (I/D)-polymorphism in the ACE gene and the susceptibility for unipolar major depression together with the genetic association with ACE serum activity and functional parameters of the HPA system. Two independent case/control samples with a total of 843 unrelated unipolar depressed patients and 1479 healthy controls were investigated. A case/control sample was screened to detect genetic associations with unipolar major depression. In addition, a replication sample was used to confirm the detected associations and to further investigate functional consequences of the genetic variants associated with depression. In the screening sample, two SNPs within the ACE gene were significantly associated with unipolar major depression. The association with unipolar major depression of one SNP (rs4291) located in the promoter region of the ACE gene was confirmed in our replication sample. The T-allele of this SNP was associated with depression and depressed T-allele carriers showed higher ACE serum activity and HPA-axis hyperactivity. Variants of the ACE gene such as SNP rs4291 are suggested susceptibility factors for unipolar major depression. We could show that SNP rs4291 influences ACE activity and HPA-axis hyperactivity and might therefore represent a common pathophysiologic link for unipolar depression and cardiovascular disease.

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.

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.

Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity.

Concentrations of 3alpha-reduced neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy with selective serotonin re-uptake inhibitors (SSRIs). We investigated the impact of mirtazapine on the activity of a key neurosteroidogenic enzyme, the 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD), and on the levels of neuroactive steroids in relation to clinical response. A total of 23 drug-free in-patients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 0800 and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. Enzyme activity was determined by assessment of steroid conversion rates. Irrespective of clinical outcome, there were significant increases in 3alpha,5alpha-tetrahydroprogesterone, 3alpha,5beta-tetrahydroprogesterone, 5alpha-dihydroprogesterone, and 5beta-dihydroprogesterone after mirtazapine treatment, whereas 3beta,5alpha-tetrahydroprogesterone levels were significantly decreased. In vitro investigations demonstrated a dose-dependent inhibitory effect of mirtazapine on the activity of the microsomal 3alpha-HSD in the oxidative direction (conversion of 3alpha,5alpha-tetrahydroprogesterone to 5alpha-dihydroprogesterone). Mirtazapine affects neuroactive steroid composition similarly as do SSRIs. The inhibition of the oxidative pathway catalyzed by the microsomal 3alpha-HSD is compatible with an enhanced formation of 3alpha-reduced neuroactive steroids. However, the changes in neuroactive steroid concentrations more likely reflect direct pharmacological effects of this antidepressant rather than clinical improvement in general.

SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression.

Tryptophan hydroxylase (TPH), being the rate-limiting enzyme in the biosynthesis of serotonin plays a major role as candidate gene in several psychiatric disorders. Recently, a second TPH isoform (TPH2) was identified in mice, which was exclusively present in the brain. In a previous post-mortem study of our own group, we could demonstrate that TPH2 is also expressed in the human brain, but not in peripheral tissues. This is the first report of an association study between polymorphisms in the TPH2 gene and major depression (MD). We performed single-nucleotide polymorphism (SNP), haplotype and linkage disequlibrium studies on 300 depressed patients and 265 healthy controls with 10 SNPs in the TPH2 gene. Significant association was detected between one SNP (P=0.0012, global P=0.0051) and MD. Haplotype analysis produced additional support for association (P<0.0001, global P=0.0001). Our findings provide evidence for an involvement of genetic variants of the TPH2 gene in the pathogenesis of MD and might be a hint on the repeatedly discussed duality of the serotonergic system. These results may open up new research strategies for the analysis of the observed disturbances in the serotonergic system in patients suffering from several other psychiatric 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.

Plasma gamma-amino-butyric acid (GABA) levels in cholecystokinine-tetrapeptide (CCK-4) induced anxiety.

INTRODUCTION: Dysregulation of the GABA system is supposed to play an important role in the pathophysiology of panic disorder. Moreover, prior investigations revealed an association between GABA plasma levels and experimental induced panic with lactate. To evaluate a possible relationship between plasma GABA and CCK-4 induced panic plasma GABA levels in healthy volunteers were investigated. METHODS: 12 healthy subjects were challenged with 50 micro g CCK-4. Blood samples for determination of plasma GABA were drawn at baseline, 5 and 10 minutes after CCK-4 injection. RESULTS: Plasma GABA levels did not change significantly during the CCK-4 challenge as revealed by ANOVA for repeated measurements. There was no correlation between baseline GABA levels and anxiogenic response to CCK-4. CONCLUSION: In contrast to previous findings with lactate our study does not suggest a possible relationship between plasma GABA levels and experimental induced panic with CCK-4.