While patients with major depressive disorder (MDD) and bipolar disorder (BD) often exhibit aberrant hormones, it is still unknown whether the hormones differ between MDD and BD across the age spectrum. We aimed to investigate the differences in testosterone and stress hormones between depressed patients with MDD and BD in adolescents and adults, and the impact of suicidal ideation on these.

A total of 432 depressed patients (270 MDD and 162 BD) were recruited, including 177 adolescents and 255 adults. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol (CORT), testosterone (T), and prolactin (PRL) were measured in all patients. Suicidal ideation was assessed by item 3 of the Hamilton Depression Rating Scale.

In adolescents, plasma T levels were higher in MDD than in BD (p=0.018), MDD patients with suicidal ideation exhibited higher T levels than BD patients with suicidal ideation (p=0.036), and plasma T levels were associated with diagnosis (ORadjus=0.777, p=0.023). In adults, plasma ACTH levels were elevated in MDD versus BD (p=0.012) and were also diagnosis-related (ORadjus=0.972, p=0.019). Plasma levels of other hormones were not significantly different between MDD and BD in adolescents or adults (all p>0.05).

There was an age-specific difference in the T and ACTH between depressed patients with MDD and BD. Suicidal ideation was linked to T in adolescents.

Depression and metabolic syndrome could exacerbate the risks of the other, leading to a series of severe coexisting conditions. One notable comorbidity that must be mentioned is obstructive sleep apnea (OSA). Current studies suggested that depression increases susceptibility to OSA. As the prevalence of depression rises, it becomes critical to prevent and manage its complications or comorbidities, including OSA. Predictive models, non-invasive electroencephalogram monitoring, genetic research, and other promising technologies are being applied to the prevention, diagnosis, and personalized treatment of depression and OSA.

Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR).

Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators.

The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (ORivw = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (ORivw = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (ORivw = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (ORivw = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA.

These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA.

Several lines of evidence indicate that the neurosteroid dehydroepiandrosterone (DHEA) is involved in anxiety. BNN27 is a new DHEA derivative lacking steroidogenic effects. The beneficial effects exerted by BNN27 in preclinical models of schizophrenia and memory disorders have been recently reported.

The present study was designed to investigate the effects of this DHEA novel analog on anxiety-like behavior in rats.

To this end, the light/dark box, the open field, the contextual fear conditioning, and the excessive self-grooming induced by the serotonin 5-HT2c receptor agonist mCPP tests were utilized.

Animals treated acutely with BNN27 (1, 3, and 6 mg/kg) dose dependently spent more time in the bright compartment of the light/dark box and in the central zone of the open field with respect to their vehicle-treated cohorts. Further, BNN27 reduced freezing behavior and weakened the mCPP-induced excessive self-grooming.

Our data indicate that BNN27 is a highly potent anxiolytic agent, as in all studied paradigms it showed anxiolytic-like effects in male rats.

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA_A receptor (GABA_A R). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be "fine-tuned" by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative properties and, at relatively high doses, induced a state of general anaesthesia, a profile consistent with their interaction with GABA_A Rs. However, realising the therapeutic potential of either endogenous neurosteroids or synthetic "neuroactive" steroids has proven challenging. Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat postpartum depression has rekindled enthusiasm for exploring their potential as new medicines. Although neurosteroids are selective for GABA_A Rs, they exhibit little or no selectivity across the many GABA_A R subtypes. Nevertheless, a relatively minor population of receptors incorporating the δ-subunit (δ-GABA_A Rs) appears to be an important contributor to their behavioural effects. Here, we consider how neurosteroids acting upon GABA_A Rs influence neuronal signalling, as well as how such effects may acutely and persistently influence behaviour, and explore the case for developing selective PAMs of δ-GABA_A R subtypes for the treatment of psychiatric disorders.

Adverse childhood experiences (ACEs) has been associated not only with an increased vulnerability for stress-related psychiatric disorders but also with distinct alterations of the hypothalamic-pituitary-adrenal (HPA) axis function and the immune system. The aim of this study is to examine differences in the HPA axis between major depressive disorder (MDD) patients with and without ACEs, and to explore differences in efficacy and HPA changes after long term antidepressant treatment between these two groups. A cohort of 803 patients with MDD were recruited. After the determination of cortisol (COR) and adrenocorticotropic hormone (ACTH), Hamilton Rating Scale for Depression (HAMD), Hamilton Rating Scale for Anxiety (HAMA), the Childhood Trauma Questionnaire (CTQ), 403 subjects were recruited for the following treatment study. Finally 330 MDD patients finished the monotherapy treatments of four antidepressants (Fluoxetine, Sertraline, Venlafaxine-extended release (XR), Duloxetine hydrochloride) for 12 weeks. Of 403 patients, 226 (56%) patients reported ACEs. Total score of HAMD in MDD with ACEs were higher than those in MDD without ACEs. There were significant differences for both ACTH and COR between MDD patients with and without ACEs that MDD patients with any types of maltreatment had higher level. Both COR and ACTH was positively and significantly correlated with the total scores of CTQ, HAMD, HAMA. After 12 weeks treatment of antidepressants monotherapy, the mean (SD) changes in HAMD and HAMA total scores was greater in MDD without ACEs than those in MDD with ACEs. At the 12-week end point, response was achieved by 37.2% in the MDD with ACEs group, 59.0% in the MDD without ACEs group respectively, with significant difference. Remission was achieved by 15.2% in the MDD with ACEs group and 32.2% in the MDD without ACEs group, with significant difference. The change in ACTH level in MDD without ACEs was also greater than that in MDD with ACEs, which was positively and significantly correlated with the HAMD total score only in MDD patient without ACEs. Logistic regression analysis showed that the total scores of CTQ, level of COR and ACTH at baseline were significantly associated with the response and remission. These findings indicated that exposure to ACEs for MDD could influence the HPA function and severity of symptoms. ACEs, ACTH and COR could be used as predictors of long term antidepressant treatment, suggested that are poor prognostic signs for antidepressants monotherapy in MDD with ACEs.

Psychiatric disorders are severe, debilitating conditions with unknown etiology and are commonly misdiagnosed, when based solely on clinical interviews, because of overlapping symptoms and similar familial patterns. Until now, no valid and objective biomarkers have been used to diagnose and differentiate between psychiatric disorders. We compared clinically tested serum indicators in terms of inflammation (C-reactive protein, complement proteins C3 and C4, and serum Immunoglobulins A, M, and G), nutrients (homocysteine, folate, and vitamin B12), and neurohormones (adrenocorticotropic hormone and cortisol) in patients with schizophrenia (SCZ, n = 1659), bipolar disorder (BD, n = 1901), and major depressive disorder (MDD, n = 1521) to investigate potential biomarkers. A receiver operating characteristic (ROC) curve was used to analyze the diagnostic potential of these analytes. We found that compared with MDD, serum levels of C-reactive protein, C3, C4, and homocysteine were higher in SCZ and BD groups, and folate and vitamin B12 were lower in SCZ and BD groups. In contrast with BD, adrenocorticotropic hormone and cortisol increased in patients with MDD. Although ROC analysis suggested that they were not able to effectively distinguish between the three, these biological indicators showed different patterns in the three disorders. As such, more specific biomarkers should be explored in the future.

There are few studies that explore the relationship of neuroendocrine hormones of the HPA, HPT and HPG axes with major depressive disorder (MDD) with comorbid obstructive sleep apnea (OSA). The aim of this study is to examine neuroendocrine abnormalities and the relationship in untreated first episode patients of MDD comorbided with OSA. Polysomnography, neuroendocrine hormones were determined for 111 patients. After excluding the influences of age and BMI, phase I in non-REM sleep (N1)% increased significantly in MDD with OSA when compared with non-OSA. In the OSA group, cortisol increased and exceeded the normal standard, and for the numbers of patients exceeding the normal range, there were significant difference between two groups. In MDD with OSA, adrenocorticotropic hormone was significantly negatively correlated with slow wave sleep (SWS)%, while thyroxine was significantly correlated with phase II in non-REM sleep (N2)%, and prolactin was significantly negatively correlated with N1%. This study revealed that for untreated first episode MDD patients with OSA, the HPA axis was hyperfunctional. Cortisol and adrenocorticotropic hormone may be increased along with disturbed sleep structure and less slow-wave sleep time. Concurrently prolactin was decreased and thyroxine increased during the N1 and N2 phase of sleep.

There are few studies that explore simultaneously the relationship of neuroendocrine hormones of the HPA, HPT and HPG axes with major depressive disorder (MDD) and bipolar disorder (BD). The aim of this study is to examine the relationship of neuroendocrine pathways with affective disorders by comparing the differences in measures of neuroendocrine function between untreated first episode patients with MDD and BD. A cohort of 679 MDD and 83 BD patients was recruited. Thyroid stimulating hormone (TSH), triiodothyronine (T3), free triiodothyronine (FT3), thyroxine (T4), free thyroxin (FT4), cortisol (COR), adrenocorticotropic hormone (ACTH), estradiol (E2) and testosterone (T) were determined by chemiluminesent immunoassay for all patients. COR and ACTH were both significantly higher in the MDD group than those in BD group. The incidences of high secretion of ACTH and COR, and low thyroid hormone secretion were significantly greater in MDD patients than in BD patients. Decreased T secretion was more common in BD than MDD patients. ACTH was significantly positively correlated with HAMD total score and negatively correlated with FT3 in MDD patients. FT3 and FT4 levels were significantly negatively correlated with the somatoform factor score of HAMD in MDD patients. Untreated first episode patients with MDD have a hyperactivity of the HPA axis, lower HPT compared with BD patients. BD patients had reduced testosterone secretion. These findings indicate that ACTH, FT3 and FT4 could be used as markers for severity and symptoms of untreated first episode patients with MDD.

Systemic sclerosis (SSc) can clinically present with psychological symptoms, including pain, depression, and distress about disfigurement, physical and social functioning. The existing small studies have reported a prevalence of depression ranging from 36% to 65% among SSc patients, likely reflecting the disease impact on the patient's self-image and function.

To investigate the association between SSc and depression using big data analysis methods.

We designed a nation-wide epidemiological survey relying on a large database of 2500 SSc patients and explored the relationship between SSc and depression, but also the impact of depression on the survival of SSc patients. Chi-squared and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis.

The proportion rate of depression among SSc patients was significantly higher than controls (16.2% vs 10.9%), and this proportion was even higher in female SSc patients and of low socioeconomic status. At the multivariate logistic regression, SSc was found to be an independent risk factor for depression with an OR of 1.55 (95%CI 1.29-1.88, p < 0.0001). No significant association was found between SSc-specific autoantibodies (anti-centromere, anti-Scl-70, anti-RNA polymerase III and anti-RNP) status and the risk of depression. Depression was not found to have a significant impact on the survival of SSc patients with an HR of 1.06 (0.80-1.42).

This study provides further support for the high prevalence of depression in SSc patients and therefore, SSc patients may benefit from a screening approach and a broad supportive care program.

Translocator protein has received attention for its involvement in the pathogenesis of depression. This study assessed the effects of the new translocator protein ligand, YL-IPA08, on alleviating inflammation-induced depression-like behavior in mice and investigated its mechanism of action. Mice were intracerebroventricularly injected with 1, 10, 100 or 1000 ng lipopolysaccharide. The tail-suspension test and the forced swimming test confirmed that 100 ng lipopolysaccharide induced depression-like behavior. A mouse model was then established by intraventricular injection of 100 ng lipopolysaccharide. On days 16-24 after model establishment, mice were intragastrically administered 3 mg/kg YL-IPA08 daily. Immunohistochemistry was used to determine BrdU and NeuN expression in the hippocampus. YL-IPA08 effectively reversed the depression-like behavior of lipopolysaccharide-treated mice, restored body mass, increased the number of BrdU-positive cells, and the number and proportion of BrdU and NeuN double-positive cells. These findings indicate that YL-IPA08 can attenuate lipopolysaccharide-induced depression-like behavior in mice by promoting the formation of hippocampal neurons.

3α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as 3α-androstanediol, are neuroactive steroids and positive GABA_A receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic-pituitary-gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). AN were amenorrheic; HC and OW/OB were studied in the follicular phase. Fasting serum neuroactive steroids were measured by gas chromatography/mass spectrometry. Mean Hamilton depression and anxiety scores were highest in AN (p<0.0001). Mean serum allopregnanolone was lower in AN and OW/OB than HC (AN 95.3±56.4 vs OW/OB 73.8±31.3 vs HC 199.5±167.8 pg/ml, p=0.01), despite comparable mean serum progesterone. Allopregnanolone levels, but not progesterone levels, were negatively associated with depression and anxiety symptom severity, independent of BMI. Serum 3α-androstanediol levels did not differ among groups and were not associated with depression or anxiety scores, despite a significant negative association between free testosterone levels and both anxiety and depression severity. In conclusion, women at both extremes of the weight spectrum have low mean serum allopregnanolone, which is associated with increased depression and anxiety severity, independent of BMI. Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including AN.

Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily γ-aminobutyric acid type A (GABAA) receptors. Neuroactive steroids regulate many physiological processes including hypothalamic-pituitary-adrenal (HPA) axis function, ovarian cycle, pregnancy, aging, and reward. Moreover, alterations in neuroactive steroid synthesis are implicated in several neuropsychiatric disorders.

This review will summarize the pharmacological properties and physiological regulation of neuroactive steroids, with a particular focus on divergent neuroactive steroid responses to stress and ethanol in rats, mice, and humans.

GABAergic neuroactive steroids exert a homeostatic regulation of the HPA axis in rats and humans, whereby the increase in neuroactive steroid levels following acute stress counteracts HPA axis hyperactivity and restores homeostasis. In contrast, in C57BL/6J mice, acute stress decreases neurosteroidogenesis and neuroactive steroids exert paradoxical excitatory effects upon the HPA axis. Rats, mice, and humans also differ in the neuroactive steroid responses to ethanol. Genetic variation in neurosteroidogenesis may explain the different neuroactive steroid responses to stress or ethanol.

Rats and mouse strains show divergent effects of stress and ethanol on neuroactive steroids in both plasma and brain. The study of genetic variation in the various processes that determine neuroactive steroids levels as well as their effects on cell signaling may underlie these differences and may play a relevant role for the potential therapeutic benefits of neuroactive steroids.

Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely to be afflicted. Gonadal hormones may be a major factor in this disparity, given that women are more likely to experience mood disturbances during times of hormonal flux, and testosterone may have protective benefits against anxiety and depression. In this review we focus on the effects of testosterone in males and females, revealed in both human and animal studies. We also present possible neurobiological mechanisms underlying testosterone's mostly protective benefits, including the brain regions, neural circuits, and cellular and molecular pathways involved. While the precise underlying mechanisms remain unclear, both activational and organizational effects of testosterone appear to contribute to these effects. Future clinical studies are necessary in order to better understand when and how testosterone therapy may be effective in both sexes.

There has been a great deal of interest in the role of the neuroendocrine hormones of the hypothalamic-pituitary-adrenal (HPA) axis in the expression of stress-related psychopathology such as post-traumatic stress disorder (PTSD). This investigation examined the association of PTSD and childhood maltreatment with three key HPA axis hormones: cortisol, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). Regression analyses were undertaken on a sample of 43 participants with and 57 participants without PTSD. Results demonstrated that after controlling for age, sex, and PTSD status, exposure to childhood maltreatment was significantly associated with cortisol secretion [F(4,95)=11.68, ΔR(2)=0.11, P=0.0009] and cortisol/DHEA ratio [F(4,95)=6.20, ΔR(2)=0.05, P=0.01]. PTSD status was not associated with any of these neuroendocrine variables. Findings are discussed in the context of the complexity of the relationship of these neuroendocrine variables with trauma exposure and trauma-related psychopathology. It is suggested that DHEA(S) or cortisol/DHEA(S) ratios may not be biomarkers of specific forms of psychopathology per se, but that, instead, the severity and developmental timing of trauma may set the HPA axis in ways that are reflected in interactions among these neuroendocrine hormones. In adulthood, these HPA axis hormones may continue to be dynamically affected by personal and environmental resources.

Progesterone (P4) facilitates exploration, anxiety and social behaviors in estrogen (E2)-primed mice. Some of these effects may be due to actions of its 5α-reduced metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP). In order to address the role of P4 and its metabolite, 3α,5α-THP, a mouse model was utilized. We hypothesized that if P4's metabolism to 3α,5α-THP is essential to facilitate exploratory, anti-anxiety and social behaviors of mice, then wildtype, but not 5α-reductase knockout (5α-RKO), mice will have greater expression of these behaviors. Experiment 1: Mice were ovariectomized (ovx), E2-primed and administered P4 (0, 125, 250, or 500μg) subcutaneously and then tested 4h later in a battery of tasks: open field, elevated plus maze, and social interaction. Experiment 2: Ovx, E2-primed mice were administered P4 (4mg/kg), 3α,5α-THP (4mg/kg), medroxyprogesterone acetate (MPA, which does not convert to 3α,5α-THP; 4mg/kg), or vehicle subcutaneously and tested 4h later. There was a dose-dependent effect of P4 to wildtype, but not 5α-RKO, mice. Neither wildtype, nor 5α-RKO, mice had increased exploration, anti-anxiety or pro-social behavior with MPA administration. Progesterone only exerted effects on anti-anxiety behavior, and increased 3α,5α-THP in the prefrontal cortex and hippocampus, when administered to wildtype mice. 3α,5α-THP to both WT and 5α-RKO mice increased exploration, anti-anxiety and social interaction and 3α,5α-THP levels in the hippocampus and prefrontal cortex. Thus, metabolism of P4 by the 5α-reductase enzyme may be essential for enhancement of these behaviors.

Dysthymia is defined as a chronic mood disorder that persists for at least two years in adults, and one year in adolescents and children. According to DSM IV-TR, Dysthymia is classified into two subtypes: early-onset, when it begins before 21 years-old, and late onset Dysthymia, when it starts after this age. Before age 21, symptoms of conduct disorder, attention deficit disorder and hyperactivity with a few vegetative symptoms are usually present. It is important to distinguish it from other types of depression, as earlier as possible. This would allow providing these patients with the appropriate treatment to attenuate the impact of symptoms, such as poor awareness of self-mood, negative thinking, low self-esteem, and low energy for social and family activities, which progressively deteriorate their life quality. The etiology of Dysthymia is complex and multifactorial, given the various biological, psychological and social factors involved. Several hypotheses attempt to explain the etiology of Dysthymia, highlighting the genetic hypothesis, which also includes environmental factors, and an aminergic hypothesis suggesting a deficiency in serotonin, norepinephrine and dopamine in the central nervous system. From our point of view, dysthymia cannot be conceived as a simple mild depressive disorder. It is a distinct entity, characterized by a chronic depressive disorder which could persist throughout life, with important repercussions on the life quality of both patients and families.

There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD).

Participants included 90 inpatients with MDD at the psychiatric ward of Juntendo University Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls (based on sex and age) included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second, correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis.

Serum DHEA levels were significantly increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were significantly decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. Multiple regression analysis showed that both hormones were affected by the age at onset of depression.

All subjects in the present study were on antidepressant medications.

Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression, as DHEA administration has been found to be effective for the treatment of depression. Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression. However, DHEA/DHEA-S may be a poor indicator for evaluating severity of depression.

Progesterone is a neuroactive hormone with non-genomic effects on GABA(A) receptors (GABA(A)R). Changes in the expression of GABA(A)R subunits are related to depressive-like behaviors in rats. Moreover, sex differences and depressive behaviors have been associated with prefrontal brain asymmetry in rodents and humans. Thus, our objective was to investigate the effect of progesterone on the GABA(A)R α1 and γ2 subunits mRNA expression in the right and left prefrontal cortex of diestrus female and male rats exposed to the forced swimming test (FST). Male and female rats (n = 8/group) were randomly selected to receive a daily dose of progesterone (0·4 mg·kg⁻¹) or vehicle, during two complete female estrous cycles (8-10 days). On the experiment day, male rats or diestrus female rats were euthanized 30 min after the FST. Our results showed that progesterone significantly increased the α1 subunit mRNA in both hemispheres of male and female rats. Moreover, there was an inverse correlation between depressive-like behaviors and GABA(A)R α1 subunit mRNA expression in the right hemisphere in female rats. Progesterone decreased the GABA(A)R γ2 mRNA expression only in the left hemisphere of male rats. Therefore, we conclude that the GABA(A) system displays an asymmetric distribution according to sex and that progesterone, at lower doses, presents an antidepressant effect after increasing the GABA(A) R α1 subunit expression in the right prefrontal cortex of female rats.

Fluctuations in the concentrations of the neuroactive steroid allopregnanolone are thought to influence γ-amino-butyric acid type A (GABA(A)) receptor gene expression and function. Long-term treatment with ethinyl estradiol (EE) plus levonorgestrel (LNG), two of the most widely used steroids in the hormonal contraceptive pill, decreases allopregnanolone levels in rat cerebral cortex and plasma, alters GABA(A) receptor expression and induces anxiety-like behavior. We evaluated which component of the hormonal contraceptive pill is responsible for the aforementioned changes. Female rats were injected subcutaneously (s.c.) with EE (0.030 mg) or LNG (0.125 mg) once a day for 4 weeks. Compared to the respective vehicle-treated control groups, EE decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 76, 72 and 33%, respectively and hippocampal levels by 52, 56 and 50%, respectively. Likewise, LNG decreased cerebral cortical levels of allopregnanolone, progesterone and pregnenolone by 75, 68 and 33%, respectively, and hippocampal levels by 55, 65 and 60%, respectively. Administration of LNG, but not EE, increased the abundance of the γ2 subunit peptide in cerebral cortex and hippocampus by 38 and 59%, respectively. Further, LNG, but not EE, decreased the time spent and the number of entries into the open arms of the elevated plus maze by 56 and 43%, respectively, an index of anxiety-like behavior. These results suggest that alterations in GABA(A) receptor subunit expression and anxiety-like behavior induced by long-term treatment with combined EE/LNG appear to be caused by LNG. Given that both EE and LNG decrease allopregnanolone levels in a similar manner, these results further suggest that changes in allopregnanolone levels are not associated with GABA(A) receptor expression.

Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are anabolic prehormones involved in the synthesis of testosterone. Both have been shown to exert neuroprotective effects during stress. In this randomized, controlled, double-blind field study, we examined the effects of a 12-day DHEA regimen on stress indices in military men undergoing survival training. Forty-eight men were randomized to either a DHEA treatment group or placebo control group. The treatment group received 50 mg of oral DHEA supplementation daily for 5 days during classroom training followed by 7 days of 75 mg during stressful field operations. Control subjects received identical placebo pills. Salivary assays (DHEA[S], testosterone, and cortisol) were conducted at four time points: distal pre-stress (T1), proximal pre-stress (T2), mock-captivity stress (T3), and 24 h recovery (T4). Subjective distress was also assessed at T1, T3, and T4. As expected, DHEA treatment resulted in higher salivary concentrations of DHEA and DHEAS during daily living, mock-captivity stress, and recovery. Similar patterns were observed for salivary markers of anabolic balance: DHEA/cortisol, DHEAS/cortisol, and testosterone/cortisol concentration ratios. Despite notable time effects, no group differences emerged for subjective distress. A brief, low dose DHEA regimen yielded large increases in salivary DHEA(S) concentrations and enhanced anabolic balance throughout sustained military stress. These physiological changes did not extrapolate to subjective distress.

The involvement of nitric oxide (NO) in the effects of dehydroepiandrosterone sulphate (DHEAS) on restraint stress induced neurobehavioral and brain oxidative/nitrosative stress markers was investigated in rats. Exposure of rats to restraint stress suppressed behavioral activity in the elevated plus maze and this was associated with increases in malondialdehyde (MDA) and decrease in reduced glutathione (GSH) and brain NO metabolite (NOx) levels in brain homogenates. Pretreatment with DHEAS (5-40mg/s.c.) reversed the stress induced changes in behavioral and oxidative stress markers and also brain NOx levels. The beneficial effect of DHEAS (40mg/kgs.c.) was blocked by pretreatment with nitric oxide synthase inhibitor, L-NAME (50mg/kgi.p.) while pretreatment of rats with NO-precursor l-Arginine (100mg/kg i.p.) produced potentiation of action of sub effective dose of DHEAS (5mg/kgs.c.). The DHEAS effects were stress specific as these behavioral and biochemical parameters were not much influenced in non-stressed rats. These observations suggest that pretreatment with DHEAS has a protective effect on restraint stress induced alteration of neurobehavioral changes and brain oxidative injury in rats and NO-dependent mechanisms may be involved in this effect.

Nicotine and cocaine each stimulate hypothalamic-pituitary-adrenal and -gonadal axis hormones, and there is increasing evidence that the hormonal milieu may modulate the abuse-related effects of these drugs. This review summarizes some clinical studies of the acute effects of cigarette smoking or IV cocaine on plasma drug and hormone levels and subjective effects ratings. The temporal covariance between these dependent measures was assessed with a rapid (2 min) sampling procedure in nicotine-dependent volunteers or current cocaine users. Cigarette smoking and IV cocaine each stimulated a rapid increase in LH and ACTH, followed by gradual increases in cortisol and DHEA. Positive subjective effects ratings increased immediately after initiation of cigarette smoking or IV cocaine administration. However, in contrast to cocaine's sustained positive effects (<20 min), ratings of "high" and "rush" began to decrease within one or two puffs of a high-nicotine cigarette while nicotine levels were increasing. Peak nicotine levels increased progressively after each of three successive cigarettes smoked at 60 min intervals, but the magnitude of the subjective effects ratings and peak ACTH and cortisol levels diminished. Only DHEA increased consistently after successive cigarettes. The possible influence of neuroactive hormones on nicotine dependence and cocaine abuse and the implications for treatment of these addictive disorders are discussed.

Alterations in hormone concentrations, including adrenocorticotropin, corticotropin releasing hormone, and cortisol have been reported in patients with obsessive compulsive disorder (OCD). Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S, have not been assessed in patients with OCD. We report 24-h serum DHEA, DHEA-S, and cortisol concentrations in a young man with OCD and 15 healthy young men. Circadian patterns of DHEA and cortisol were markedly different in the subject with OCD than in the control subjects. DHEA and DHEA-S concentrations were substantially higher in the OCD subject than in the control subjects. In contrast, cortisol concentrations were similar in the OCD subject and the control subjects. Future clinical studies are needed to evaluate the significance of DHEA and DHEA-S in OCD.

DHEA and DHEAS are steroids synthesized in human adrenals, but their function is unclear. In addition to adrenal synthesis, evidence also indicates that DHEA and DHEAS are synthesized in the brain, further suggesting a role of these hormones in brain function and development. Despite intensifying research into the biology of DHEA and DHEAS, many questions concerning their mechanisms of action and their potential involvement in neuropsychiatric illnesses remain unanswered. We review and distill the preclinical and clinical data on DHEA and DHEAS, focusing on (i) biological actions and putative mechanisms of action, (ii) differences in endogenous circulating concentrations in normal subjects and patients with neuropsychiatric diseases, and (iii) the therapeutic potential of DHEA in treating these conditions. Biological actions of DHEA and DHEAS include neuroprotection, neurite growth, and antagonistic effects on oxidants and glucocorticoids. Accumulating data suggest abnormal DHEA and/or DHEAS concentrations in several neuropsychiatric conditions. The evidence that DHEA and DHEAS may be fruitful targets for pharmacotherapy in some conditions is reviewed.

This review assesses the parallel data on the role of gamma-aminobutyric acid (GABA) in depression and anxiety. We review historical and new data from both animal and human experimentation which have helped define the key role for this transmitter in both these mental pathologies. By exploring the overlap in these conditions in terms of GABAergic neurochemistry, neurogenetics, brain circuitry, and pharmacology, we develop a theory that the two conditions are intrinsically interrelated. The role of GABAergic agents in demonstrating this interrelationship and in pointing the way to future research is discussed.