by Vivien K Burt, MD, Ph.D. (Bio)
Professor Emeritus of Psychiatry,
The David Geffen School of Medicine at UCLA.
Founder and Co-Director
The Women’s Life Center
Resnick UCLA Neuropsychiatric Hospital
Los Angeles, California
Question from a Member:
1. A few years ago I had a perimenopausal patient with
2. A second patient of mine age 48 years and still menstruating, has not responded to medications. She is also on clozapine but remains psychotic, anxious, and depressed, and so far refuses ECT. I spoke with her husband recently and he said her symptoms began to worsen about 3 years ago. He also said she had been taking birth control pills all of her adult life, until about 3 years ago. He was unclear why these were stopped.
Both of these women are smokers on clozapine.
Is there evidence that resuming hormone replacement therapy (in the first case, at age 58) or birth control pills (in the second case, age 48) could be useful?
Editor: In both these cases, the estrogen may have increased clozapine levels (see this page). But, aside from that, does estrogen have a potential role as an adjunctive treatment for schizophrenia?
Why do we think estrogen has anything to do with schizophrenia?
Several gender differences related to schizophrenia, listed below, suggest that estrogen may have a protective effect against schizophrenia (Riecher-Rössler, 2017).
- Women have a slightly lower incidence of schizophrenia than men, which may suggest a protective role for estrogen.
- Unlike men, women have a second (smaller) peak in the incidence of schizophrenia after the age of 40 years. Twice as many women as men develop schizophrenia after the age of 40 years.
- Women with earlier onset schizophrenia (before age 40) tend to have worsening of the illness after menopause.
- Women are more vulnerable to psychotic episodes during periods of estrogen withdrawal (premenstrually, postpartum, and post-menopause).
Is estrogen neuroactive?
Estrogen has a number of important effects in the brain that may be relevant to its potential role in schizophrenia (Kulkarni et al., 2012; Riecher-Rössler et al., 2017):
- Promotes neuronal sprouting and myelination
- Enhances synaptic density and plasticity
- Facilitates neuronal connectivity
- Inhibits neuronal death
- Improves cerebral blood flow and glucose metabolism
- Modulates dopaminergic and other neurotransmitter systems relevant to schizophrenia (e.g., serotonergic, glutaminergic, noradrenergic, and cholinergic systems)
- Modulates the sensitivity and number of dopamine receptors.
SPMH is grateful to Erik Messamore, MD, PhD, for peer-reviewing this article and offering helpful suggestions. Dr. Messamore is an Associate Professor of Psychiatry at the Northeast Ohio Medical University (NEOMED) in Rootstown, Ohio.
Estrogen as a treatment for schizophrenia?
Selective estrogen receptor modulators (SERMs) for schizophrenia?
Can oral contraceptives affect clozapine levels?
Potential risks of estrogen therapy
Brzezinski A, Brzezinski-Sinai NA, Seeman MV. Treating schizophrenia during menopause. Menopause. 2017 May;24(5):582-588.
Chua WL, de Izquierdo SA, Kulkarni J, Mortimer A. Estrogen for schizophrenia. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD004719. Review. PubMed PMID: 16235377.
Kulkarni J. Oestrogen–a new treatment approach for schizophrenia? Med J Aust. 2009 Feb 16;190(4 Suppl):S37-8. Review. PubMed PMID: 19220172.
Kulkarni J, Gavrilidis E, Worsley R, Hayes E. Role of estrogen treatment in the management of schizophrenia. CNS Drugs. 2012 Jul 1;26(7):549-57.
Kulkarni J, Hayes E, Gavrilidis E. Hormones and schizophrenia. Curr Opin Psychiatry. 2012 Mar;25(2):89-95. doi: 10.1097/YCO.0b013e328350360e. Review. PubMed PMID: 22249082.
Riecher-Rössler A. Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses. Lancet Psychiatry. 2017 Jan;4(1):63-72.
Riecher-Rössler A, Butler S, Kulkarni J. Sex and gender differences in schizophrenic psychoses-a critical review. Arch Womens Ment Health. 2018 May 16.
Liao DL, Chen H, Lee SM, Tsai SJ. Estrogen supplementation for female schizophrenics treated with atypical antipsychotics. Gen Hosp Psychiatry. 2002 Sep-Oct;24(5):357-9. PubMed PMID: 12220803. Small case series. Not considered in this article.
Lindamer LA, Buse DC, Lohr JB, Jeste DV. Hormone replacement therapy in postmenopausal women with schizophrenia: positive effect on negative symptoms? Biol Psychiatry. 2001 Jan 1;49(1):47-51. PubMed PMID: 11163779. Very small, observational study.
Last revised February 22, 2019
Copyright 2019, Rajnish Mago, MD. All rights reserved. May not be reproduced in any form without express written permission.
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