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Reproductive hormones and schizophrenia

Schizophrenia Research, Volume 168, Issue 3, November 2015, Pages 601 - 602

Hormones clearly play a role in modulating the course and symptoms of schizophrenia, especially when one considers that stress hormones exaggerate symptoms and sex hormones attenuate symptoms. However, this viewpoint is likely overly simplistic as even a single hormone can have diverse actions depending on the context (concentration, time, genotype and prior history). Additionally, hormones do not act in isolation, but have complex interactions with one another and act in concert to orchestrate changes in gene expression and cell function. In this special issue, we have highlighted current studies on the impact of sex hormones (estrogen and testosterone), sex hormone modulators [5α reductase and selective estrogen receptor modulators (SERMs)] and down-stream effectors (oxytocin) on neurobiological and behavioural changes relevant to schizophrenia.

Although estrogens have perhaps received the most attention in schizophrenia to date, it is now clear that other hormones including testosterone and oxytocin may also play an important role in the development of schizophrenia or in the modulation of symptoms. We propose that a greater neurobiological and clinical understanding of how these hormones modulate behaviour and act in the brain may lead to beneficial adjunctive therapies, especially targeting cognitive symptoms, which are currently the most disabling or untreatable aspect of schizophrenia.

The articles in this special edition showcase hormones in schizophrenia research from both basic research and clinical studies to begin to build a bridge between these often disparate approaches. While clinical trials involving both sex hormone based strategies and oxytocin have been conducted for several years and have shown promise, the underlying neurobiological mechanisms behind their effectiveness are not yet clear. Perhaps, these trials will provide a foundation from which basic scientists can formulate questions around the mechanisms involved with the aim of developing even more efficacious treatment strategies. The basic research studies included in this issue provide insights into how changes in hormones may contribute to molecular changes in the brain and to behavioural alterations that mimic those found in schizophrenia, and also report on complimentary strategies for determining the full range of impact of novel hormone-modulating treatments and their future refinement.

We start our issue with a meta-analysis of sex hormone and oxytocin based clinical studies in people with schizophrenia. Heringa et al. provide an overview of the rationale behind sex hormone and oxytocin therapies in schizophrenia, and comprehensively review 24 studies involving 1149 patients. Studies included in this analysis involve not only oxytocin, estrogen and testosterone but also a selective estrogen receptor modulator raloxifene, and sex hormone precursors [dehydroepiandrosterone (DHEA) and pregnenolone] and examine positive, negative and general symptoms as well as cognitive measures. This article highlights that studies involving estrogens or raloxifene have dominated the field to date, and also concludes that most of the beneficial effects of estrogens are on positive and negative symptoms, reflecting that this was the primary outcome for the majority of studies. This stands in contrast to studies on oxytocin, which have heterogeneous results and their effectiveness on symptoms is less clear. The authors suggest that hormone based therapies may prove useful to improve cognition, as some positive findings, particularly in memory and attention domains were noted and are supported by a recent clinical trial by our group ( Weickert et al., 2015 ).

We follow with a more specific review on oxytocin, where existing observational and clinical studies in schizophrenia are covered. While the previous article suggests significant heterogeneity in the benefits of oxytocin on symptoms, Bartholomeusz et al. make the case for oxytocin therapy in schizophrenia, especially with regard to social cognition and social behaviour in healthy populations, and provide an in-depth introduction to the role of oxytocin in both health and illness. However, this article highlights that while there is evidence that oxytocin can improve a range of cognitive, positive and negative symptoms in people with schizophrenia; these studies have very mixed results and thus supports the conclusions of Heringa et al. earlier in this issue. Importantly, Bartholomeusz et al. raise the potential contribution of individual differences in oxytocin and oxytocin receptor genotypes on the outcomes of these previous studies. While the influence of these genotypes on social cognition has not been tested in psychotic populations, evidence from healthy populations is used to support that genetic factors may contribute to individual responses, and highlights the need for consideration of individual differences that may influence treatment response in clinical studies.

Following on from this review, we include a clinical trial focused on oxytocin in social functioning by Guastella et al. This study refines previous findings on the use of oxytocin for social cognition, and suggests that inconsistencies in tasks across studies may also contribute to mixed findings, highlighting the importance of trial design and careful consideration of outcome measures in this area of research. For example in this study, oxytocin treatment is shown to improve performance on complex social cognition tasks such as recognising social faux pas and indirect speech, but not less complex abilities such as emotional recognition. This information is not only useful in targeting future oxytocin treatment strategies, but it also may provide a framework to study the neurobiological systems involved in lower versus higher order social cognition in schizophrenia.

While we started our issue with evidence that sex hormone based therapies can be effective in schizophrenia, the mechanisms behind this benefit remain elusive. The next paper by Gogos et al. takes us an important step forward in this regard. These authors examine the action of estradiol and SERMs (raloxifene and tamoxifen) on the dopaminergic system in an experimental rat model. A dopamine agonist was used to disrupt pre-pulse inhibition (PPI), a measure of information processing that is disrupted in schizophrenia, and estradiol was able to prevent this disruption. Gogos et al. found that SERMs had a similar beneficial influence to estradiol on dopamine-mediated disruption of PPI, confirming that SERMs can act as estrogen agonists in brain and adding to a growing body of research suggesting estrogen-based therapies may act in part by modulation of dopamine.

When one considers sex hormone action in brain, one needs to consider that often one hormone can serve as a precursor to others in the biosynthetic pathway, and that changes in activity of enzymes will change the balance of hormones that neurons in the brain are exposed to. The next paper in this issue highlights the inter-relationships of sex steroids (or neurosteroids as they are also termed due to local production from enzymes within the brain) synthesised in the brain. This study by Frau et al. also examines the effects of sex hormones on PPI, this time focusing on disrupting sex hormone synthesis as a target for reversing disruptions in PPI. Inhibition of 5α-reductase, a key rate-limiting enzyme in neurosteroid production, has antipsychotic effects in schizophrenia ( Koethe et al., 2008 ) and can modulate dopaminergic systems. In this study, the 5α-reductase inhibitor finasteride was shown to reduce PPI deficits caused by psychosocial stress, and the authors suggest that this reversal may be due to increases in pregnenolone in the nucleus accumbens. This study suggests that finasteride may have similar antipsychotic effects to estrogen-based therapies, and illustrates how changing the activity of enzymes capable of altering the balance of steroids in the brain may be an avenue to advance or refine hormone-based therapies in schizophrenia.

The next manuscript in our special issue also examines relationships between sex hormones and dopamine, this time examining correlations of circulating levels of testosterone and brain activity in humans. The study by Morris et al. employs neuroimaging to examine dopamine-governed prediction error in healthy men and men with schizophrenia. Negative symptoms of schizophrenia are related to abnormal fronto-striatal activity during reward processing, and seem to be exaggerated with low testosterone levels. However, the relationships between testosterone and regions involved with reward processing have so far been unexplored. Morris et al. used blood oxygen level dependent (BOLD) responses as a proxy for midbrain dopamine neuron activity, and found that striatal activity was positively associated with circulating testosterone levels. However, this relationship was not found in men with schizophrenia, which may be due to disease-related alterations in sex steroid signalling. This work is supported by molecular evidence that midbrain dopamine neurons are directly responsive to testosterone and that midbrain androgen receptor mRNA levels correlate with mRNA encoding a dopamine synthesis enzyme. These results highlight that some aspects of the normal androgenic response may be intact in schizophrenia while others may be disrupted, and that hormonal manipulation studies in healthy animals may need to be constructed and interpreted with this in mind.

One of the major mysteries about schizophrenia revolves around why there is a peak of onset during adolescence, especially in males. While adolescence involves many changes one obvious one is the change in circulating testosterone, raising the question as to how testosterone impacts the adolescent brain in a schizophrenia-sensitive context. Thus, the cortical effects of normal and disrupted circulating sex steroids during adolescence are the focus of the last article in this edition. Deficits in certain types of cortical interneurons are among the most replicated changes found in the neuropathology of schizophrenia. These cortical interneuron deficits may be related to a lack of trophic support due to reduced levels of brain derived neurotrophic factor (BDNF) and its receptor TrkB which correlate with interneuron markers. Purves-Tyson et al. found that removal of testosterone can increase BDNF expression in both rat and monkey cortex. The presence of testosterone also influenced the ratio of the full length TrkB receptor to the truncated version with no overall change in interneuron markers. This paper suggests that adolescent testosterone may normally attenuate BDNF leading to changes in trophic dependence of interneurons across maturation.

Together these seven articles give us an enhanced insight of the potential therapeutic value of oxytocin and sex hormone based treatments in schizophrenia, while highlighting the need for personalised treatment strategies to overcome genotype (and possible gender) effects. The value of reverse translational research (from the clinic back to the laboratory) to determine the mechanism of action of potential hormone based treatments in preclinical models to further optimise therapeutic efficacy is also evident. This special edition indicates that with continued effort and cross fertilisation within the field of hormone research in schizophrenia, we are drawing closer to potentially promising new reproductive hormone-based adjunctive treatment strategies for schizophrenia that could lead to not only symptom improvement but also to enhancement of cognition and social cognition, some of the most intractable, debilitating and untreatable aspects of schizophrenia.

Role of funding source

N/A.

Contributors

Katherine Allen, Tertia Purves-Tyson and Cynthia Shannon Weickert wrote and edited the manuscript.

Conflict of interest

No author has a conflict of interest to declare.

Acknowledgements

N/A.

References

  • Koethe et al., 2008 D. Koethe, M. Bortolato, D. Piomelli, F.M. Leweke. Improvement of general symptoms in a chronic psychotic patient treated with finasteride: case report. Pharmacopsychiatry. 2008;41(3):115-116 Crossref
  • Weickert et al., 2015 T.W. Weickert, D. Weinberg, R. Lenroot, S.V. Catts, R. Wells, A. Vercammen, M. O'Donnell, C. Galletly, D. Liu, R. Balzan, B. Short, D. Pellen, J. Curtis, V.J. Carr, J. Kulkarni, P.R. Schofield, C.S. Weickert. Adjunctive raloxifene treatment improves attention and memory in men and women with schizophrenia. Mol. Psychiatry. 2015;20(6):685-694 Crossref

Footnotes

a Schizophrenia Research Institute, Darlinghurst, NSW, Australia

b Neuroscience Research Australia, Randwick, NSW, Australia

c School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

d School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Corresponding author at: Neuroscience Research Australia, Barker St., Randwick 2031, NSW, Australia.