Neurosteroid and neurotransmitter alterations in Parkinson's disease.

Parkinson's disease (PD) is associated with a massive loss of dopaminergic cells in the substantia nigra leading to dopamine hypofunction and alteration of the basal ganglia circuitry. These neurons, are under the control, among others, of the excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA) systems. An imbalance between these systems may contribute to excitotoxicity and dopaminergic cell death. Neurosteroids, a group of steroid hormones synthesized in the brain, modulate the function of several neurotransmitter systems. The substantia nigra of the human brain expresses high concentrations of allopregnanolone (3α, 5αtetrahydroprogesterone), a neurosteroid that positively modulates the action of GABA at GABAA receptors and of 5α-dihydroprogesterone, a neurosteroid acting at the genomic level. This article reviews the roles of NS acting as neuroprotectants and as GABAA receptor agonists in the physiology and pathophysiology of the basal ganglia, their impact on dopaminergic cell activity and survival, and potential therapeutic application in PD.

Neurosteroids as neuromodulators in the treatment of anxiety disorders.

Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered as first-line treatment but have a slow onset of action. Neurosteroids are powerful allosteric modulators of GABA(A) and glutamate receptors. However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance. Moreover, novel drugs interfering with neurosteroidogenesis such as ligands of the translocator protein (18 kDa) may represent an attractive pharmacological option for novel anxiolytics which lack the unwarranted side effects of benzodiazepines. Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders.

Mirtazapine does not influence tetrahydrodeoxycorticosterone levels in depressed patients.

BACKGROUND: Among the neuroactive steroids, 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) is at least in part produced in the adrenal gland and is therefore under the control of the hypothalamic-pituitary-adrenocortical (HPA) system. The antidepressant mirtazapine has been shown to attenuate HPA axis activity and to increase the concentrations of 3alpha-reduced metabolites of progesterone in depressed patients. In the present study, the impact of mirtazapine on 3alpha,5alpha-THDOC levels was investigated in relation to clinical response in depressed patients. METHOD: A total of 23 drug-free inpatients suffering from a major depressive episode (DSM-IV criteria) underwent 5-week treatment with mirtazapine (45 mg/day). Plasma samples were taken weekly at 08:00 h and were quantified for 3alpha,5alpha-THDOC levels. RESULTS: 3alpha,5alpha-THDOC levels were not correlated with demographic and clinical parameters such as age and severity of depression. Moreover, 5-week treatment with mirtazapine did not influence the 3alpha,5alpha-THDOC in the depressed patients, neither in responders nor in non-responders. CONCLUSION: Putative increasing effects of mirtazapine on 3alpha-reduced neuroactive steroids such as 3alpha,5alpha-THDOC which may be mediated via an impact on the neurosteroidogenic enzyme 3alpha-hydroxysteroid dehydrogenase seem to be counterbalanced by the mirtazapine-induced inhibition of ACTH secretion which directly influences the 3alpha,5alpha-THDOC release of the adrenal cortex.

Changes in CCK-4 induced panic after treatment with the GABA-reuptake inhibitor tiagabine are associated with an increase in 3alpha,5alpha-tetrahydrodeoxycorticosterone concentrations.

There is evidence that gamma-amino-butyric acid type A (GABA(A))-receptor modulating neuroactive steroids play a role in the pathophysiology of panic disorder. Antidepressant treatment has been suggested to stabilize the concentrations of neuroactive steroids. In this pilot study we investigated neuroactive steroid concentrations during GABAergic treatment, which might represent an alternative anxiolytic pharmacotherapeutic strategy. Neuroactive steroid concentrations were determined in 10 healthy subjects treated with tiagabine. To evaluate the anxiolytic effects of tiagabine a cholecystokinin-tetrapeptide (CCK-4) challenge was performed before and after treatment. Treatment with tiagabine led to a significant increase in 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) from 0.49 to 1.42 nmol/l (Z=-2.80, p=.005), which was significantly correlated with a decrease of panic symptoms in the CCK-4 challenge. Thus, it might be hypothesized that the anxiolytic effects of GABAergic treatment might in part be mediated by their influence on 3alpha,5alpha-THDOC concentrations.

The complex roles of neurosteroids in depression and anxiety disorders.

The role of neurosteroids in neuropsychiatric disorders has been thoroughly investigated in many research studies that have stressed their significant pathophysiological function in neuropsychiatry. In this review, we will focus mainly on the steroids active on the GABA(A) receptors studied in anxiety and depression. The aim is to discuss the controversial results reported in research on anxiety and depressive disorders. We suggest the combined use of biological parameters linked to psychopathological dimensions to make more homogeneous diagnoses and to develop more precise therapies for the treatment of depression and anxiety disorders. We discuss the role of neurosteroids in the pathophysiology and therapy of anxiety and depression. Finally, we consider the possibility of using quantification of mRNA expression of steroidogenic enzymes from peripheral sources in neuropsychiatry.

Effects of combination treatment with mood stabilizers and mirtazapine on plasma concentrations of neuroactive steroids in depressed patients.

Antidepressants such as SSRIs or mirtazapine have been demonstrated to increase the concentrations of 3alpha-reduced neuroactive steroids throughout several weeks of treatment. However, no data are available on the impact of mood stabilizers such as lithium or carbamazepine on neuroactive steroid levels in depressed patients. Study 1 was performed in 26 drug-free depressed inpatients who were treated with either mirtazapine monotherapy (n=13) or combination therapy with mirtazapine and addition of lithium (n=13). Twenty drug-free depressed inpatients were included in study 2, receiving either mirtazapine monotherapy (n=10) or combination treatment with mirtazapine and carbamazepine (n=10). Plasma samples were taken weekly at 0800 h in the morning and quantified for neuroactive steroids by means of combined gas chromatography/mass spectrometry analysis. In study 1, the mirtazapine-induced rises in 3alpha,5alpha-tetrahydroprogesterone and 3alpha,5beta-tetrahydroprogesterone were abolished by additional lithium administration, as compared to mirtazapine monotherapy. In study 2, the mirtazapine-evoked increase in 3alpha,5alpha-tetrahydroprogesterone was reversed after additional administration of carbamazepine, presumably due to lowered mirtazapine levels after induction of cytochrome P450 enzymes. Apparently, the mood stabilizers lithium and carbamazepine do not enhance but rather reverse the increase in plasma concentrations of 3alpha-reduced neuroactive steroids in depressed patients pretreated with antidepressants such as mirtazapine.

Neuroactive steroids in depression and anxiety disorders: clinical studies.

Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the gamma-aminobutyric acid type A (GABA(A)) receptor. During major depression, there is a disequilibrium 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 nonpharmacological 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 steroid concentrations 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 to those seen in depression. However, during experimentally induced panic induction either with cholecystokinine-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. The modulation of GABA(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.

Comparative non-radioactive RT-PCR assay: an approach to study the neurosteroids biosynthetic pathway in humans.

Polymerase chain reaction (PCR) is a powerful tool for qualitative evaluation of nucleic acid expression. PCR has been widely applied to measure DNA and RNA messages expression. Neurosteroids synthesized in the nervous system are potent modulators of synaptic activity and have been implicated in several neuropsychiatric disorders. To examine the possibility of an altered expression of the neurosteroidogenic metabolic enzymes in neurological diseases (like Parkinson's disease, PD) we developed a comparative non-radioactive RT-PCR assay to detect the mRNA levels of the peripheral benzodiazepine receptor, the 5alpha-reductase type 1 and 3alpha-hydroxysteroid-oxidoreductase type 1 and 2 in lymphocytes obtained from PD patients. The results were compared with that obtained from simultaneous quantification of progesterone, 5alpha-dihydroprogesterone and 3alpha,5alpha-tetrahydroprogesterone in the plasma and cerebro-spinal fluid of the same individuals using a gas chromatography mass spectrometry (GC/MS) technique. We found a significant decrease of the rate-limiting enzyme 5alpha-R1 along with a significant decrease in plasma and CSF of the 3alpha,5alpha-tetrahydroprogesterone and of the 5alpha-dihydroprogesterone. Comparative RT-PCR assay, along with complimentary techniques (i.e. GC/MS), has the sensitivity, selectivity and dynamic range to allow specific and reliable quantization of the enzymes involved in the neurosteroids pathway and represent a valuable tool to assess their expression in human neuropsychiatric conditions.

Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders.

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as gamma-aminobutyric acid type A (GABAA) 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 3alpha-reduced neuroactive steroids have been observed during major depression. This disequilibrium can be corrected by successful treatment with antidepressant drugs. However, non-pharmacological antidepressant treatment strategies did not affect neuroactive steroid composition independently from the clinical response. Further research is needed to clarify whether enhancement of neuroactive steroid levels might represent a new therapeutical approach in the treatment of affective disorders. Nevertheless, the first studies investigating the therapeutical effects of exogenously administered dehydroepiandosterone revealed promising results in the treatment of major depression. In addition, in various anxiety disorders alterations of neuroactive steroid levels have been observed. In panic disorder, in the absence of panic attacks, neuroactive steroid composition is opposite to that seen in depression, which may represent counter-regulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimentally induced panic attacks, there was a pronounced decline in GABAergic neuroactive steroids, which might contribute to the pathophysiology of panic attacks. In conclusion, neuroactive steroids contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. They are important endogenous modulators of depression and anxiety and may provide a basis for the development of novel therapeutic agents in the treatment of affective disorders.

Neuroactive steroids as modulators of depression and anxiety.

In addition to the well-known genomic effects of steroid molecules, certain neuroactive steroids control neurotransmission through the modulation of specific neurotransmitter receptors. Preclinical studies suggested that neuroactive steroids may modulate anxiety and depression-related behavior and may contribute to the therapeutic effects of antidepressant drugs. However, nonpharmacological antidepressant treatment strategies did not affect neuroactive steroid composition. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy probably reflect distinct pharmacological properties of antidepressants, rather than the clinical response. Nevertheless, initial studies investigating the antidepressive effects of exogenously administered dehydroepiandosterone revealed promising results. In addition, in various anxiety disorders, alterations of neuroactive steroid levels have been observed. In conclusion, neuroactive steroids contribute to the pathophysiology of affective disorders and the mechanisms of action of antidepressants. They are important endogenous modulators of depression and anxiety and might offer new targets for the development of novel anxiolytic compounds.

Plasma concentrations of neuroactive steroids before and after electroconvulsive therapy in major depression.

There is evidence that both cerebrospinal fluid (CSF) and plasma concentrations of 3alpha-reduced neuroactive steroids are decreased in major depressive disorder. Successful antidepressant pharmacotherapy, for example, with selective serotonin reuptake inhibitors (SSRIs), over several weeks is accompanied by an increase in CSF and plasma concentrations of these neuroactive steroids. However, no such increase has been observed during nonpharmacological treatments such as partial sleep deprivation or repetitive transcranial magnetic stimulation. In order to investigate whether concentration changes in neuroactive steroids are an important component of clinically effective antidepressant treatment, we examined plasma concentrations of the neuroactive steroids 3alpha,5alpha-tetrahydroprogesterone, 3alpha,5beta-tetrahydroprogesterone, 3beta,5alpha-tetrahydroprogesterone, and their precursors progesterone, 5alpha-dihydroprogesterone, and 5beta-dihydroprogesterone in 31 pharmacotherapy-resistant depressed in-patients before and after unilateral electroconvulsive therapy (ECT) as a monotherapy over 4 weeks. Samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. In all, 51.6% of the patients were treatment responders. There was no influence of ECT on the plasma concentrations of any neuroactive steroid studied. Moreover, neuroactive steroid levels did not differ between treatment responders and nonresponders. Our study shows that changes in neuroactive steroid plasma levels are not a mandatory factor for successful antidepressant treatment by ECT. Thus, the previously observed changes in plasma concentrations of neuroactive steroids following treatment with antidepressants such as SSRIs more likely reflect distinct pharmacological properties of these compounds rather than clinical improvement.

Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia.

Dehydroepiandrosterone has been recently recognized as neuroactive steroid with several vital neurophysiological activities on membrane receptors, such as N-methyl-d-aspartate, and gamma-aminobutyric acid receptors and on genomic androgen receptors. DHEA does also have an antiglucocorticoid effect. So far, the relevance of this neuroactive steroid to psychiatric disorders is not well known. In this study, plasma levels of DHEA were determined with a highly sensitive and specific gas-chromatography/mass-spectrometry method in 23 outpatients suffering from Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia compared with 23 healthy control subjects matched for age and sex. Plasma levels of DHEA were found to be strongly elevated in the group of schizophrenic patients (mean+/-SD=90.9+/-61.4 nmol/l) compared to that of control subjects (mean+/-SD=24.0+/-17.9 nmol/l) and the difference was highly significant (t=5.018, df=44, p<0.0001). This statistically significant difference was also found when we divided the groups of schizophrenics and controls in subgroups of males (t=4.536, df=24, p=0.0001) and females (t=2.777, df=18, p=0.0124). These results suggest that DHEA may have some role in the pathophysiology of schizophrenia due to its complex mechanism of action in the brain involving genomic and non-genomic components. Therefore, its study may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment.

Preliminary evidence for an association between aggressive and hostile behaviour and 3alpha,5alpha-tetrahydroprogesterone plasma levels in schizophrenia.

OBJECTIVE: Because it has been suggested that agents acting on the gamma-aminobutyric acid-A (GABA(A)) receptor complex, such as the neuroactive steroid 3!#!alpha;,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), may be biologic modulators of aggression, we aimed to measure 3alpha,5alpha-THP plasma concentrations in subjects with schizophrenia in order to investigate a possible relation with aggressive and hostile behaviour. METHODS: Eight outpatients with schizophrenia diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), were included. Aggression and hostility were assessed using the Modified Overt Aggression Scale and the paranoid/belligerence symptom cluster of the Positive and Negative Syndrome Scale. Plasma samples were obtained 1 hour before psychometric assessment and were quantified for 3alpha,5alpha-THP using a highly sensitive and specific combined analysis by gas chromatography-mass spectrometry. RESULTS: Increased aggressiveness and hostility were associated with increased 3alpha,5alpha-THP plasma levels (Pearson r = 0.72, p = 0.043 and Pearson r = 0.72, p = 0.041, respectively). CONCLUSIONS: These preliminary results suggest that the neuroactive steroid 3alpha,5alpha-THP may affect aggression and hostility in humans.

Panic induction with cholecystokinin-tetrapeptide (CCK-4) Increases plasma concentrations of the neuroactive steroid 3alpha, 5alpha tetrahydrodeoxycorticosterone (3alpha, 5alpha-THDOC) in healthy volunteers.

3alpha-reduced neuroactive steroids such as 3alpha, 5alpha-tetrahydroprogesterone (3alpha, 5alpha-THP) and 3alpha, 5alpha-tetrahydrodeoxycorticosterone (3alpha, 5alpha-THDOC) are potent positive allosteric modulators of gamma-aminobutyric acid type A (GABAA) receptors and display pronounced anxiolytic activity in animal models. Experimental panic induction with cholecystokinin-tetrapeptide (CCK-4) and sodium lactate is accompanied by a decrease in 3alpha, 5alpha-THP concentrations in patients with panic disorder, but not in healthy controls. However, no data are available on 3alpha, 5alpha-THDOC concentrations during experimental panic induction. Therefore, we quantified 3alpha, 5alpha-THDOC concentrations in 10 healthy volunteers (nine men, one woman) before and after panic induction with CCK-4 by means of a highly sensitive and specific gas chromatography/mass spectrometry analysis. CCK-4 elicited a strong panic response as assessed by the Acute Panic Inventory. This was accompanied by an increase in 3alpha, 5alpha-THDOC, ACTH and cortisol concentrations. This increase in 3alpha, 5alpha-THDOC might be a consequence of hypothalamic-pituitary-adrenal (HPA) axis activation following CCK-4-induced panic, and might contribute to the termination of the anxiety/stress response following challenge with CCK-4 through enhancement of GABAA receptor function.

Neuroactive steroids in responders and nonresponders to sleep deprivation.

Evidence from preclinical and clinical studies indicates that concentrations of neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy. However, data on the impact of sleep deprivation on concentrations of neuroactive steroids are not available. Therefore, 29 drug-free patients (12 men, 17 women) with major depression according to DSM-IV criteria were treated with partial sleep deprivation (PSD). Response to PSD was defined as a reduction of at least 30% according to the 6-item version of the Hamilton Depression Scale (6-HAMD). Plasma samples were taken the day before and the day after PSD (day 0 and 1) and after one night of recovery sleep (day 2) at 8:00 am. Samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. PSD did not influence concentrations of neuroactive steroids in either PSD responders (n = 20) or nonresponders (n = 9). However, nonresponders showed significantly higher concentrations of 3alpha,5alpha-tetrahydroprogesterone, 3alpha,5beta-tetrahydroprogesterone, and dehydroepiandrosterone before or after PSD compared to responders. In contrast to antidepressant drugs which correct the dysequilibrium of neuroactive steroids in major depression within several weeks, PSD does not affect the concentrations of neuroactive steroids in either responders or nonresponders.

Influence of sleep deprivation on neuroactive steroids in major depression.

There is evidence from preclinical and clinical studies that concentrations of neuroactive steroids are altered in depression and normalize after antidepressant pharmacotherapy. However, no data are available concerning the impact of sleep deprivation on the concentrations of neuroactive steroids. A total of 29 drug-free patients (12 men, 17 women) suffering from major depression according to DSM-IV criteria were treated with partial sleep deprivation (PSD). Response to PSD was defined as a reduction of at least 30% according to the six-item version of the Hamilton depression scale (6-HAMD). Plasma samples were taken the day before and after PSD (days 0 and 1) and after one night of recovery sleep (day 2) at 8:00 am. The samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was no influence of PSD on the concentrations of neuroactive steroids either in PSD responders (n=20) or in nonresponders (n=9). However, nonresponders showed significantly higher concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta-tetrahydroprogesterone (3alpha,5beta-THP), and dehydroepiandrosterone (DHEA) before or after PSD compared to responders. In contrast to antidepressant drugs, which correct the dysequilibrium of neuroactive steroids in major depression within several weeks, PSD does not affect the concentrations of neuroactive steroids either in responders or in nonresponders.

Induced panic attacks shift gamma-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results.

BACKGROUND: Certain metabolites of progesterone such as 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP; allopregnanolone) and 3alpha,5beta-THP (pregnanolone) are potent, positive allosteric modulators of gamma-aminobutyric acid type A receptors. Although animal studies suggest anxiolytic properties of these endogenous modulators of central nervous excitability, no clinical data indicate whether they are also involved in the pathophysiology of anxiety disorders and panic attacks. METHODS: We quantified the concentrations of 3alpha,5alpha-THP, 3alpha,5beta-THP, the isomer 3beta,5alpha-THP, and their precursors in the plasma of 10 patients with panic disorder and matched control subjects during panic attacks induced by means of sodium lactate and cholecystokinin tetrapeptide administration, using a highly sensitive gas chromatography-mass spectrometry analysis. RESULTS: Panic attacks induced by sodium lactate and cholecystokinin tetrapeptide in patients with panic disorder were accompanied by pronounced decreases in the concentrations of 3alpha,5alpha-THP and 3alpha,5beta-THP and a concomitant increase in the concentrations of the functional antagonistic isomer 3beta,5alpha-THP, findings that are compatible with a decreased gamma-aminobutyric acid-ergic tone. No changes in neuroactive steroid concentrations were observed after placebo administration in patients with panic disorder or after placebo, sodium lactate, or cholecystokinin tetrapeptide administration in controls. CONCLUSIONS: The association between changes in plasma neuroactive steroid concentrations and experimentally induced panic attacks and the well-documented pharmacological properties of these compounds as gamma-aminobutyric acid type A receptor modulators suggest that neuroactive steroids may play a role in the pathophysiology of panic attacks in patients with panic disorder.

Plasma concentrations of neuroactive steroids before and after repetitive transcranial magnetic stimulation (rTMS) in major depression.

There is evidence for altered levels of neuroactive steroids in major depression that normalize after successful antidepressant pharmacotherapy. Currently it is not known whether this is a general principle of clinically effective antidepressant therapy or a pharmacological effect of antidepressants. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) may affect plasma concentrations of neuroactive steroids in a similar way as antidepressant pharmacotherapy. Progesterone, 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta- tetrahydroprogesterone (3alpha,5beta-THP), 3beta,5alpha-tetrahydroprogesterone (3beta, 5alpha-THP) and dehydroepiandrosterone (DHEA) were quantified in 37 medication-free patients suffering from a major depressive episode before and after 10 sessions of left prefrontal rTMS. Plasma samples were analyzed by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. There was a significant reduction of depressive symptoms after rTMS. However, plasma concentrations of neuroactive steroids were not affected by rTMS and not related to clinical response. Clinical improvement after extended daily treatment with rTMS is not accompanied by changes in neuroactive steroid levels. Changes in neuroactive steroid levels after antidepressant pharmacotherapy more likely reflect specific pharmacological effects of antidepressant drugs and are not necessary for the amelioration of depressive symptoms.

GABA(A) receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment.

OBJECTIVE: Previous studies have shown that neuroactive steroids modulate anxiety and stress reactivity. However, no data on the possible role of these gamma-aminobutyric acid(A) (GABA(A)) receptor-modulating neuroactive steroids in patients with anxiety disorders are available. METHOD: The concentrations of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP), 3alpha,5beta-THP, 3beta,5alpha-THP, and their precursors were studied in the plasma of 10 patients with panic disorder and 10 matched healthy comparison subjects. In addition, the effects of paroxetine treatment on neuroactive steroid concentrations were studied in the panic disorder patients over a 24-week period. RESULTS: Unexpectedly, patients with panic disorder had significantly greater concentrations of the positive allosteric modulators 3alpha,5alpha-THP and 3alpha,5beta-THP and significantly lower concentrations of 3beta,5alpha-THP (a functional antagonist for GABA(A) agonistic steroids), which might result in greater GABA(A) receptor-mediated neuronal activity. Paroxetine treatment did not affect neuroactive steroid concentrations, which were highly stable over 24 weeks. CONCLUSIONS: Differences in neuroactive steroid composition in patients with panic disorder were the opposite of those seen in patients with major depression and may reflect counterregulative mechanisms against the occurrence of spontaneous panic attacks.