Neurosteroids in the Treatment of Anxiety

Neurosteroids as Neuromodulators in the Treatment of Anxiety Disorders free full-text /PMC3356011/ – Front Endocrinol (Lausanne). Oct 2011

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 GABAA 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.

Currently six primary anxiety disorders are identified in DSM-IV-R:

  1. panic disorder (characterized by recurrent panic attacks),
  2. generalized anxiety disorder (characterized by frequent worrying)
  3. posttraumatic stress disorder (the result of a traumatic experience),
  4. obsessive–compulsive disorder (characterized by repetitive obsessions and the urge to perform specific acts or rituals) and
  5. specific phobia (in which specific stimuli trigger fear and/or anxiety)

I’ve checked and double-checked but I still see only 5 anxiety disorders in the list. I’m shocked to find such a glaring error (not a typo!) in an official scientific study.

Low levels of γ-aminobutyric acid (GABA) have been attributed to the occurrence of anxiety disorders such as panic disorder

The term “neurosteroids” (NS) indicates steroids that modulate the action of the central nervous system (CNS), thereby regulating synaptic transmission at different targets (rapid non-genomic effect on presynaptic receptors and long-term genomic action).

The most important effect of NS occur at the GABAA receptor, but NS may exert various effects at the

  • N-methyl-d-aspartate (NMDA),
  • alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA),
  • kainate,
  • glycine,
  • serotonin,
  • sigma type-1, and
  • nicotinic acetylcholine receptors

Thus, NS represent promising compounds modulating both the pathophysiology and the pharmacotherapy of anxiety disorders. Here, we provide a review of the different actions of NS and discuss the evidence given by pre-clinical and clinical data.

Serotoninergic System

Deficient serotonergic neurotransmission in various brain regions is thought to be involved in the development of depression and anxiety disorders.

Serotonin is involved in a variety of physiological and behavioral functions such as

  • mood,
  • affect,
  • learning,
  • aggression, and
  • stress response.

SSRIs inhibit the reuptake of serotonin into the presynaptic nerve terminal, thereby increasing 5-HT concentrations in the synaptic cleft and prolonging its activity at postsynaptic receptor sites.

GABAergic System

γ-Aminobutyric acid is the most abundant inhibitory neurotransmitter in the CNS.. GABAA receptors are one of the most important targets for the treatment of anxiety symptoms, because reduced GABAA receptor function may be related to the pathophysiology of anxiety.

Numerous compounds can potentiate the GABA action through positive modulation of GABAA receptor function. GABAA agonists, such as BDZs, are widely used for the acute treatment of anxiety symptoms, such as panic, agitation, tension, hyperarousal, sensation of lack of control, phobia, insomnia, since they exert their efficacy much more quickly than SSRIs

Barbiturates are GABAA agonists as well and have been used in the past in view of their anticonvulsant, anxiolytic, sedative, and hypnotic actions. However, due to their serious side effects, such as a profound depression of CNS activity with the induction of pronounced sedation and a lethal risk in case of overdose, they are considered obsolete for the treatment of anxiety disorders

Neurosteroids, in particular 3α, 5α-THP, represent the most potent endogenous positive allosteric modulator of GABAA receptors, with a BDZ- and barbiturates-like action.

When administered systemically, 3α, 5α-THP possesses anxiolytic and anticonvulsant properties and at the highest doses, sedative and hypnotic actions, similar to those elicited by other GABAA receptor agonists

NS replacement is a potential therapeutic approach, but natural NS have poor bioavailability and may be converted to metabolites with undesired progestational activity.


A growing body of evidence suggests that glutamatergic neurotransmission may also be involved in the biological mechanisms underlying stress response and anxiety-related disorders.

It is well established that NS regulate gene expression (genomic effect) and can alter neuronal excitability by interacting with specific neurotransmitter receptors

pregnenolone sulfate (PREGS) has been described as both a

  • positive NMDA receptor modulator and
  • negative GABAA receptor modulator.

NS that act as positive allosteric modulators of GABAA receptors have been described as anxiolytic, sedative, and anticonvulsive substances


Neurosteroids are powerful modulators within the CNS and they affect numerous neurophysiological processes.

They exert their action already at low concentrations and they may act on different neurotransmitter pathways.

Their ability to modulate different pathways that also interact with each other makes them interesting candidates for the pharmacotherapy of anxiety disorders, in the case of comorbidity with other mental diseases such as mood disorders.

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