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The Massachusetts General Hospital Guide to Depression pp 147–151Cite as

Neuroactive Steroids and Depression

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Part of the book series: Current Clinical Psychiatry ((CCPSY))

Abstract

Neuroactive steroids are metabolites of gonadal steroids that act on the brain through traditional neurotransmitter mechanisms. The best studied is allopregnanolone, a metabolite of progesterone that is a potent GABAA receptor modulator. This article will discuss the evidence that relative neuroactive steroid deficiency may be a mechanism that contributes to depression. It will also discuss the recent positive but preliminary phase 2 data that suggests that intravenous allopregnanolone and/or oral allopregnanolone analogs may exert significant antidepressant effects. We further describe research into the effects of relative neuroactive steroid deficiency in post-traumatic stress disorder and the one, negative, trial of allopregnanolone analog therapy. Finally, we discuss that given the lack of definitive therapeutic studies in this area, and FDA-approved therapies, further research is needed before these medications can be recommended for clinical use.

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Author information

Authors and Affiliations

  1. Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

    Karen K. Miller

  2. Harvard Medical School, Boston, MA, USA

    Karen K. Miller

Authors
  1. Karen K. Miller
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Corresponding author

Correspondence to Karen K. Miller .

Editor information

Editors and Affiliations

  1. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Benjamin G. Shapero

  2. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    David Mischoulon

  3. Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Cristina Cusin

FAQs: Common Questions and Answers

FAQs: Common Questions and Answers

  • Q1. What is a “neuroactive steroid”?

  • A1. A neuroactive steroid is a metabolite of a gonadal steroid, such as progesterone, that acts through traditional neurotransmitter receptor pathways. The most commonly studied neuroactive steroid is allopregnanolone, a metabolite of progesterone that acts at GABAA receptors with approximately 20 times the potency of benzodiazepines.

  • Q2. Is a relative neuroactive steroid deficiency a cause of depression ?

  • A2. This is unknown. Small studies have suggested that mean CSF and blood levels of allopregnanolone are relatively lower in patients with depression than in non-depressed controls. Therefore, a relative deficiency of such endogenous neuroactive steroid levels is a possible contributor to depression symptom severity. Additional research is needed to determine whether this is the case.

  • Q3. Why would depressed patients develop a relative deficiency of neuroactive steroids?

  • A3. The answer to this question is not known but may involve relative blockades of enzymes that convert their precursor hormones (steroid hormones, such as progesterone) into neuroactive steroids.

  • Q4. Are neuroactive steroids available for prescription or over-the-counter?

  • A4. Pharmaceutical companies are developing and studying preparations of unaltered neuroactive steroids and neuroactive steroid analogs. None of these are FDA-approved or commercially available. Some neuroactive steroid preparations, such as pregnenolone, are available over-the-counter as supplements or through compounding pharmacies. However, none have been well studied, and side effects – especially with long-term use – are unknown. In addition, appropriate (safe and effective) doses have not been determined. In addition, over-the-counter and compounded products may have variable hormone content between batches and relative to what is stated on the label. Therefore, the use of these products cannot be recommended at this point in time.

  • Q5. Are neuroactive steroids “natural”?

  • A5. Yes. Neuroactive steroids are endogenous , meaning that they are made by the human body. Therefore, the concept that a relative deficiency may contribute to some affective disorders, and that replacement of these hormones may be developed therapeutically, has appeal. Some of the neuroactive steroid medications being developed have been altered chemically from the endogenous compound, for example, to prevent conversion back to precursor compounds, to increase their half-lives, or to make them bioavailable orally.

  • Q6. What are the next steps in understanding whether neuroactive steroids could be therapeutic options?

  • A6. Further research is needed and ongoing. Additional research funding and interest from patients in participating in clinical trials will advance the field more quickly. Such studies should elucidate normal physiology, delineate normal levels of these hormones, seek to understand whether blood levels accurately reflect brain levels, investigate specific brain targets, and elucidate mechanisms of action.

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Miller, K.K. (2019). Neuroactive Steroids and Depression. In: Shapero, B., Mischoulon, D., Cusin, C. (eds) The Massachusetts General Hospital Guide to Depression. Current Clinical Psychiatry. Humana Press, Cham. https://doi.org/10.1007/978-3-319-97241-1_11

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  • DOI: https://doi.org/10.1007/978-3-319-97241-1_11

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  • Publisher Name: Humana Press, Cham

  • Print ISBN: 978-3-319-97240-4

  • Online ISBN: 978-3-319-97241-1

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