Neuropsychopharmacological properties of neuroactive steroids in depression and anxiety disorders

Neuroactive steroids modulate neurotransmission through modulation of specific neurotransmitter receptors such as γ-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 3α-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.     

Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action

The naturally occurring 3α-reduced neurosteroids allopregnanolone and its isomer pregnanolone are among the most potent positive allosteric modulators of γ-aminobutyric acid type A receptors. They play a critical role in the maintenance of physiological GABAergic tone and display a broad spectrum of neuropsychopharmacological properties. We have reviewed existing evidence implicating the relevance of endogenous 3α-reduced neuroactive steroids to depression and to the mechanism of action of antidepressants. A wide range of preclinical and clinical evidence suggesting the antidepressant potential of 3α-reduced neuroactive steroids and a possible involvement of a deficiency and a disequilibrium of neuroactive steroid levels in pathomechanisms underlying the etiology of major depressive disorder have emerged in recent years. Antidepressants elevate 3α-reduced neurosteroid levels in rodent brain, and clinically effective antidepressant pharmacotherapy is associated with normalization of plasma and cerebrospinal fluid (CSF) concentrations of endogenous neuroactive steroids in depressed patients, unveiling a possible contribution of neuroactive steroids to the mechanism of action of antidepressants. In contrast, recent studies using nonpharmacological antidepressant therapy suggest that changes in plasma neuroactive steroid levels may not be a general mandatory component of clinically effective antidepressant treatment per se, but may reflect distinct properties of pharmacotherapy only. While preclinical studies offer convincing evidence in support of an antidepressant-like effect of 3α-reduced neuroactive steroids in rodent models of depression, current clinical investigations are inconclusive of an involvement of neuroactive steroid deficiency in the pathophysiology of depression. Moreover, clinical evidence is merely suggestive of a role of neuroactive steroids in the mechanism of action of clinically effective antidepressant therapy. Additional clinical studies evaluating the impact of successful pharmacological and nonpharmacological antidepressant therapies on changes in neuroactive steroid levels in both plasma and CSF samples of the same patients are necessary in order to more accurately address the relevance of 3α-reduced neuroactive steroids to major depressive disorder. Finally, proof-of-concept studies with drugs that are known to selectively elevate brain neurosteroid levels may offer a direct assessment of an involvement of neurosteroids in the treatment of depressive symptomatology.     

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.     

Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs.

Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg/kg, i.p., twice daily) or mirtazapine (10 mg/kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs.     

Potential clinical uses of neuroactive steroids

Neuroactive steroids rapidly modulate gamma-aminobutyric acid (GABA) and glutamate receptors. GABA-enhancing steroids have potential clinical utility as anesthetics, hypnotics, anticonvulsants and anxiolytics. Furthermore, GABAergic neurosteroids may participate in regulating mood and the effects of alcohol on the nervous system, suggesting a potential role in major psychiatric disorders. Neuroactive steroids that alter the function of glutamate receptors could be useful for treating neurodegenerative disorders, and as cognitive enhancers. Recent progress in developing water-soluble steroids and steroids with enhanced oral efficacy foster optimism that certain neuroactive steroids will be developed for clinical use.     

Potential clinical uses of neuroactive steroids

Neuroactive steroids rapidly modulate gamma-aminobutyric acid (GABA) and glutamate receptors. GABA-enhancing steroids have potential clinical utility as anesthetics, hypnotics, anticonvulsants and anxiolytics. Furthermore, GABAergic neurosteroids may participate in regulating mood and the effects of alcohol on the nervous system, suggesting a potential role in major psychiatric disorders. Neuroactive steroids that alter the function of glutamate receptors could be useful for treating neurodegenerative disorders, and as cognitive enhancers. Recent progress in developing water-soluble steroids and steroids with enhanced oral efficacy foster optimism that certain neuroactive steroids will be developed for clinical use.     

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.     

Oral contraceptives and neuroactive steroids

A deregulation in the peripheral and brain concentrations of neuroactive steroids has been found in certain pathological conditions characterized by emotional or affective disturbances, including major depression and anxiety disorders. In this article we summarize data pertaining to the modulatory effects of oral contraceptive treatment on neuroactive steroids in women and rats. Given that the neuroactive steroids concentrations are reduced by oral contraceptives, together with the evidence that a subset of women taking oral contraceptives experience negative mood symptoms, we propose the use of this pharmacological treatment as a putative model to study the role of neuroactive steroids in the etiopathology of mood disorders. Moreover, since neuroactive steroids are potent modulators of GABA(A) receptor function and plasticity, the treatment with oral contraceptives might also represent a useful experimental model to further investigate the physiological role of these steroids in the modulation of GABAergic transmission.     

Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics.

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n = 14-15 per group, 59-60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABA(A) and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.     

An investigation of endogenous neuroactive steroid-induced modulation of ethanol's discriminative stimulus effects

Neuroactive steroids exhibit rapid non-genomic central nervous system activity, including modulation of GABAA and NMDA receptors, two receptors known to mediate the effects of methanol. Neuroactive steroids that modulate GABAA receptors in a manner similar to ethanol were expected to potentiate the discriminative stimulus and/or rate-suppressing effects of ethanol. In contrast, neuroactive steroids that modulate GABAA or NMDA receptors in a manner opposite to ethanol were hypothesized to attenuate the effects of ethanol. Adult male rats were trained to discriminate 1.0 or 2.0 g/kg ethanol (i.g.) from water (i.g.). Animals were pretreated with subthreshold doses (i.p.) of ethanol and neuroactive steroids and exposed to an acute stressor (n = 5), prior to conducting ethanol cumulative-dosing (i.p.) tests. Only ethanol and 3 beta, 5 beta-P pretreatments potentiated the discriminative stimulus effects of ethanol. None of the six neuroactive steroid manipulations attenuated the effects of ethanol. These results demonstrate that a neuroactive steroid, endogenous in humans, can enhance the interoceptive effects of ethanol.     

Interaction of steroids with the GABA(A) receptor

Over the last two decades there has been a resurgence of interest in steroids as potential therapeutics for central nervous system disorders. This interest followed the discovery that neurosteroids and neuroactive steroids are potent modulators of GABA(A) receptor function. This article traces those developments focussing particularly on the structure-activity relationships that have been identified through synthetic modification of established ligands, but also examines the influence of GABA(A) receptor subunit composition for steroid modulation. The review then covers some of the physiological effects such steroids are liable to exert and their therapeutic potential for treating central nervous system disorders including epilepsy, anxiety and insomnia.     

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.     

Discriminative stimulus effects of pregnanolone in rhesus monkeys

Rationale

Neuroactive steroids and benzodiazepines can positively modulate GABA by acting at distinct binding sites on synaptic GABA_A receptors. Although these receptors are thought to mediate the behavioral effects of both benzodiazepines and neuroactive steroids, other receptors (e.g., extrasynaptic GABA_A, N-methyl-d-aspartate (NMDA), σ₁, or 5-HT₃ receptors) might contribute to the effects of neuroactive steroids, accounting for differences among positive modulators.

Objective

The current study established the neuroactive steroid pregnanolone as a discriminative stimulus to determine whether actions in addition to positive modulation of synaptic GABA_A receptors might contribute to its discriminative stimulus effects.

Methods

Four rhesus monkeys discriminated 5.6 mg/kg pregnanolone while responding under a fixed-ratio 10 schedule of stimulus-shock termination.

Results

Positive modulators acting at benzodiazepine, barbiturate, or neuroactive steroid sites produced ≥80 % pregnanolone-lever responding, whereas drugs acting primarily at receptors other than synaptic GABA_A receptors, such as extrasynaptic GABA_A, NMDA, σ₁, and 5-HT₃ receptors, produced vehicle-lever responding. Flumazenil antagonized the benzodiazepines midazolam and flunitrazepam, with Schild analyses yielding slopes that did not deviate from unity and pA₂ values of 7.39 and 7.32, respectively. Flumazenil did not alter the discriminative stimulus effects of pregnanolone.

Conclusion

While these results do not exclude the possibility that pregnanolone acts at receptors other than synaptic GABA_A receptors, they indicate a primary and possibly exclusive role of synaptic GABA_A receptors in its discriminative stimulus effects. Reported differences in the effects of benzodiazepines and neuroactive steroids are not due to differences in their actions at synaptic GABA_A receptors.     

Creating more effective antidepressants: clues from the clinic

Antidepressant medications have eased the suffering of millions of people. In addition to treating depression, antidepressant drugs also treat several anxiety disorders. Unfortunately, there are problematic limitations with antidepressant agents, including a delayed therapeutic response and insufficient efficacy. Emerging evidence shows that atypical antipsychotic agents can be used as augmentation therapy in patients with poor responses to antidepressants. Future drugs combining key features of antidepressant and atypical antipsychotic agents could offer new promise for patients suffering from obsessive-compulsive disorder, post-traumatic stress disorder, panic disorder, generalized anxiety disorder and depression.     

Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies

Rationale

Neuroactive steroids are endogenous or synthetic steroids that rapidly alter neuronal excitability via membrane receptors, primarily γ-aminobutyric acid type A (GABA_A) 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.

Objectives

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.

Results

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.

Conclusions

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.     

Potential role of the 5-HT6 receptor in depression and anxiety: an overview of preclinical data

Mental disorders, such as depression and anxiety, pose both medical and social challenges. The clinical efficacy of current antidepressant/anxiolytic therapies is unsatisfactory; both antidepressant and anxiolytic drugs induce a variety of unwanted effects and have delayed onsets of action. Thus, a search for better and safer agents is continuously in progress. Preclinical results published so far have brought new insights into the possible role of recently discovered serotonin 5-HT(6) receptors in these disorders. This review surveys the current state of knowledge regarding potential antidepressant and anxiolytic activities of selective 5-HT(6) receptor ligands, namely, full agonists and antagonists, in animal models commonly used to predict such activity. Evidence indicates that both 5-HT(6) agonists and antagonists may evoke identical responses in animal models of depression and anxiety; however, the possible mechanisms of these effects seem to be diverse and are not clearly understood. Especially interesting are the augmented effects achieved by combining antidepressants or diazepam with a selective 5-HT(6) receptor antagonist.     

Recent developments in potential anxiolytic agents targeting GABAA/BzR complex or the translocator protein (18kDa) (TSPO)

Anxiety disorders are frequent and disabling disorders. For short-term treatment, benzodiazepines are useful due to their rapid onset of anxiolytic action. However, these compounds have sedative properties and may induce tolerance, abuse liability and withdrawal symptoms. First-line choices for the long-term treatment are selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. The major disadvantage of these compounds is their delayed onset of action. It is obvious that there is a need for novel pharmacological approaches that combine a rapid anxiolytic efficacy with the lack of tolerance induction, abuse liability and withdrawal symptoms. A very important target for the development of such compounds is the -amino-butyric-acid (GABA)A receptor. Subtype specific benzodiazepines are being developed, but also phytotherapeutic agents experience a renaissance as GABAA receptor modulators. On the other hand, GABA related compounds, e.g. tiagabine, did not show pronounced anxiolytic efficacy. Neuroactive steroids such as allopregnanolone and tetrahydrodeoxycorticosterone (THDOC) are potent modulators of GABAA receptors. To date synthetic neuroactive steroids could not be established in the treatment of anxiety disorders. Regarding endogenous neurosteroidogenesis, recently the translocator protein (18kDa) (TSPO) has been identified as a potential novel target. TSPO is supposed to play an important role for the synthesis of neuroactive steroids. TSPO ligands may promote the synthesis of neuroactive steroids via induction of cholesterol translocation to the inner mitochondrial membrane. First clinical studies revealed promising results. In this review, we discuss putative compounds affecting the GABAergic system which may provide the basis for fast acting anxiolytics with a favorable side effect profile.     

Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment.

Chronic stress is a risk factor for the development of many psychopathological conditions in humans, including major depression and anxiety disorders. There is a high degree of comorbidity of depression and anxiety. Moreover, cognitive impairments associated with frontal lobe dysfunction, including deficits in cognitive set-shifting and behavioral flexibility, are increasingly recognized as major components of depression, anxiety disorders, and other stress-related psychiatric illnesses. To begin to understand the neurobiological mechanisms underlying the cognitive and emotional consequences of chronic stress, it is necessary to employ an animal model that exhibits similar effects. In the present study, a rat model of chronic unpredictable stress (CUS) consistently induced a cognitive impairment in extradimensional set shifting capability in an attentional set shifting test, suggesting an alteration in function of the medial prefrontal cortex. CUS also increased anxiety-like behavior on the elevated plus-maze. Further, chronic treatment both with the selective norepinephrine reuptake blocker, desipramine (7.5 mg/kg/day), and the selective serotonin reuptake blocker, escitalopram (10 mg/kg/day), beginning 1 week before CUS treatment and continuing through the behavioral testing period, prevented the CUS-induced deficit in extradimensional set-shifting. Chronic desipramine treatment also prevented the CUS-induced increase in anxiety-like behavioral reactivity on the plus-maze, but escitalopram was less effective on this measure. Thus, CUS induced both cognitive and emotional disturbances that are similar to components of major depression and anxiety disorders. These effects were prevented by chronic treatment with antidepressant drugs, consistent also with clinical evidence that relapse of depressive episodes can be prevented by antidepressant drug treatment.     

Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABAA-related mechanistic probes

Rationale A disordered regulation of neuroactive steroids release in response to acute stress could induce GABAergic dysfunctions underlying anxiety disorders. Objectives First, we conducted studies indicating that a short immobilization stress in anxious Balb/cByJ mice produced an anticonvulsive effect. Second, the effects of different positive allosteric modulators (etifoxine, progesterone, clonazepam, and allopregnanolone) of GABA_A receptors were compared in a mouse model mimicking the disruption of the acute stress-induced neuroactive steroids release with finasteride (types I and II 5α-reductase inhibitor). Results The acute stress-induced anticonvulsive effect, expressed by the threshold dose of t-butylbicyclophosphorothionate-producing clonic seizures, was time-dependent. The extent of the enhancement of acute stress-induced anticonvulsive effect was lowered in the presence of finasteride. The same effect was observed with PK11195, which behaves as an antagonist of the peripheral benzodiazepine receptor in the dose range used in this study. Picrotoxin reduced the acute stress anticonvulsive effect, proving that this effect operates through the GABA_A receptor. Contrary to progesterone (up to 30 mg/kg), etifoxine (50 mg/kg), allopregnanolone (10 mg/kg), and clonazepam (10 μg/kg) inhibited the finasteride effect in stressed animals. The effect of etifoxine was blocked in the presence of finasteride and picrotoxin combined in stressed animals. Conclusions These findings support the hypothesis suggesting an involvement of neuroactive steroids in the anticonvulsive effect of restraint stress. The dual and complementary mechanisms of action of etifoxine (directly on the GABA_A receptor and indirectly via the neuroactive steroids) may represent a therapeutic benefit in the treatment of various anxiety disorders with abnormal production of neuroactive steroids.     

Serotonergic drugs in the treatment of depressive and anxiety disorders

Serotonergic dysfunction has been implicated in the aetiology of several psychiatric conditions, including depressive and anxiety disorders. Much of the evidence for the role of serotonin (5-HT) in these disorders comes from treatment studies with serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), 5-HT(1A) agonists and 5-HT antagonists. This review considers the place of these drugs in the treatment of panic disorder, obsessive-compulsive disorder (OCD), social phobia, and generalized anxiety disorder (GAD). Among these agents, the SSRIs stand out with proven efficacy in the treatment of a spectrum of disorders, such as depression, panic disorder, OCD and social phobia. They may also be a suitable treatment for GAD. 5-HT(1A) agonists have been used extensively for the treatment of depression and GAD but evidence of their efficacy in other anxiety disorders is equivocal. 5-HT antagonists are the least well studied of these agents: while they may have activity in depression, their efficacy has not been fully investigated in anxiety disorders. However, preliminary reports suggest that they may be useful as adjuvants to SSRIs in treatment-refractory OCD. The high incidence of comorbidity amongst psychiatric disorders means that pharmacotherapy that is effective against a range of disorders, such as the SSRIs, is of considerable use to clinicians. Future research into the biological mechanisms underlying such disorders is likely to further enhance pharmacotherapy. Copyright 2000 John Wiley & Sons, Ltd.