The chemical question

Mapping the brain-biology frontier

‘IT’S MY HORMONES, doc. It’s my hormones, and no one’s listened to that.’

It was the late 1980s, in what was once Royal Park Psychiatric Hospital in inner-city Melbourne. A brash young registrar doing her training in psychiatry had arrived at her first hospital placement, full of ideas and enthusiasm. Perhaps to put a bit of scuff on that bright ambition, she was assigned to look after the female patients in the ‘back ward’.

Some of the women in that ward had been there for decades, institutionalised more or less indefinitely because existing treatments could not relieve the psychosis, hallucinations and schizophrenic symptoms that warped their reality.

So Jayashri Kulkarni listened. She listened as the women told her of the psychologically ordinary lives they had led until their children were born or they went through menopause. Psychiatry couldn’t tell them what happened, but those women knew. They knew instinctively that the healthy ebb and flow of hormones that women’s minds and bodies sway to throughout life had been disturbed for them, and had never recovered their rhythm. They knew that those key life events of birth and menopause had been the trigger for that disturbance.

‘I thought, “Yeah, you’re damn right, actually,”’ Kulkarni says. Her side interest in endocrinology – the study of hormones – had previously led her to the early, groundbreaking research work of Heinz Häfner in Germany and Mary Seeman in Canada, who separately had been exploring the effects of the female sex hormone oestrogen on the brain. Their work had provided early evidence of its possible protective effect against diseases such as schizophrenia.

‘That coalesced with what I was seeing in the women who I was asked to look after in this back ward,’ Kulkarni says. ‘I thought, “We need to look at this and do better.”’

Today, Kulkarni is Professor of Psychiatry at Monash University and The Alfred Hospital, and founder and director of the Monash Alfred Psychiatry Research Centre. She has authored countless research papers, reports and book chapters and is a world-renowned authority on the effect of reproductive hormones on mental health. But back then, she was just a registrar.

So with the help of colleagues, including the highly respected endocrinologist Henry Burger, she began a pilot study in which eleven pre-menopausal women with severe psychosis were treated with a daily dose of oestrogen, in the form of estradiol tablets, for eight weeks in addition to their usual schizophrenia treatments. That study, and a second larger study shortly after, took place at Dandenong Hospital – a small hospital, but one keen to support Kulkarni’s research.

Kulkarni remembers one participant clearly: a woman in her forties who had experienced continuous auditory hallucinations that incapacitated her so badly she had been an inpatient at the facility for many years.

She had been on the study’s estradiol therapy for just four days when one of the nurses accosted Kulkarni and asked, ‘What have you done?’

‘I said, “What do you mean?” And [the nurse] said, “She’s fine, she’s normal,”’ Kulkarni says. The two ran straight to the ward. ‘All her voices had stopped overnight.’

After the study had finished, Kulkarni was able to get that patient onto a form of hormone replacement therapy. The woman was discharged from hospital a few weeks later; she went on to find love and a job. She and Kulkarni stayed in touch until the woman’s death from an unrelated condition.

She was just one patient. And the results weren’t all quite so miraculous. But the studies found that women treated with the higher dose of estradiol had significantly greater improvements in their psychotic symptoms than those given an inactive placebo treatment. Kulkarni knew she was onto something important.


MOST WOMEN ARE acutely aware that hormones matter. ‘From the time you’re a teenager and you’re dealing with having your period, you are very much in tune with the fact that hormones play a role in lots of things,’ says Samantha Meltzer-Brody, a psychiatrist, scientist and director of the University of North Carolina Center for Women’s Mood Disorders in the United States. From the onset of menstruation through adolescence, for some through pregnancy and then menopause, women’s hormonal cycles are an ever-present biological tide.

For the vast majority of women, that current barely disturbs the surface. ‘Most women just live in that world, in a way that I think men don’t,’ Meltzer-Brody says. And nor, until surprisingly recently, did science.

Premenstrual dysphoric disorder (PMDD) – a severe and often crippling manifestation of premenstrual tension, which affects around 5 per cent of women – was not even recognised as a diagnosis until the 1990s. The first drug specifically to treat severe postnatal depression was only released two years ago. ‘For a very long time, there were huge barriers to having these things taken seriously,’ Meltzer-Brody says.

But that is starting to change. In 2019, US biopharmaceutical company Sage Therapeutics released a new antidepressant – the first truly novel antidepressant developed since the 1990s – to treat severe postnatal depression.

Brexanolone is a formulation of the neuroactive steroid – meaning that it has effects on brain chemistry – allopregnanolone, which is formed from the sex hormone progesterone. During pregnancy, women’s levels of allopregnanolone rise gradually and steadily, reaching a peak in the third trimester. Immediately after delivery, they crash. That crash in hormone levels is thought to be a contributor to the so-called ‘baby blues’ that hit most women a few days after they give birth.

The mechanism of allopregnanolone’s mood effects lie in its interaction with a class of receptors in the brain called gamma-aminobutyric acid type A (GABA-a) receptors, which play a role in generating anxiety disorders, schizophrenia and insomnia, and are the receptors that interact with sedatives and alcohol. GABA-a receptors are part of an inhibitory – as opposed to excitatory – brain mechanism. Put simply, the GABA system calms things down and keeps a check on fear and anxiety.

The sudden drop in allopregnanolone after delivery precipitates a sometimes drastic change in mood for many women. Most recover, but some don’t. Meltzer-Brody, who has received funding from Sage Therapeutics, has been involved in studies of brexanolone in severely postnatally depressed women. Like Kulkarni, she saw some stunning results in women who had previously been totally withdrawn, not eating or interacting with anyone, and profoundly depressed.

Brexanolone was approved in the US in 2019 as an intravenous drug treatment for severe postnatal depression; it has to be administered in a hospital setting. It is yet to be released in Australia. But the mere fact of its existence points to a possible renaissance in our understanding of how reproductive hormones influence the brain and in potential management of the mental illnesses to which such an influence can contribute.

PMDD also stems from changes in allopregnanolone levels. In contrast to postnatal depression, the problem in PMDD may be too much allopregnanolone rather than too little. Allopregnanolone levels rise just after ovulation,[i] and this rise is associated with the mood changes that can be one of the symptoms of premenstrual tension. For a small number of women, this excess of allopregnanolone sends the GABA network into overdrive, and the effect can be devastating. Kulkarni recalls the case of a young woman who experienced such severe psychotic symptoms around the time of her period that she would have to be hospitalised and treated with multiple antipsychotics.

The current treatment options for PMDD range from antidepressants – which benefit around 70 per cent of people – to medically induced menopause. The most intractable cases may be treated by removing the ovaries to stop the cyclical surge in progesterone – which is released by the ovaries after ovulation – and the resulting rise in allopregnanolone. These are hardly attractive options for a condition that may first appear in adolescence.

Endocrinologist Rosie Worsley from Jean Hailes for Women’s Health – a not-for-profit policy, research and public health services centre in Melbourne – believes women with the condition deserve better. ‘The issue with something like PMDD is a lot of women get symptoms from when they’re a teenager, and if you’re not going to have menopause until you’re fifty-one, that’s a long time on SSRIs [antidepressants] or other drugs,’ she says.

With the discovery of the effects of allopregnanolone on the GABA system, researchers have been exploring whether this might also be an avenue of treatment in women with PMDD. One drug – sepranolone – is designed to reduce the hormone’s effects by blocking the action of allopregnanolone. A study funded by the manufacturer Asarina Pharma showed an 80 per cent improvement in symptoms in women who received the drug compared with those who were treated with an inert placebo. But a subsequent study found the same reduction in symptoms in both the treated women and those given a placebo.

That doesn’t mean it’s the end of this avenue of scientific enquiry: other drugs that target allopregnanolone are also being developed and trialled, and sepranolone is being investigated to treat menstrual migraine, a condition that is believed to affect one in ten women overall and around 60 per cent of women who experience migraines.


IT’S JUST THAT time of the month. It’s only the baby blues. It’s the change, it’ll pass. It’s just your hormones. Most women have experienced a dismissal like this at some stage in their lives, whether for a genuine mental health issue or for something as minor as offering a differing opinion.

But the trivialising of issues deemed ‘hormonal’, and the dismissal of associated mood disorders, can have fatal consequences.

‘What keeps me up are the mothers [who] end their lives because they have such horrendous symptoms,’ Meltzer-Brody says. Between 2009 and 2018 in Australia, twenty-three women suicided within forty-two days of giving birth,[ii] making suicide the third highest cause of maternal mortality after heart disease and haemorrhage. In the US, suicide rates in women are highest among those aged forty-five to sixty-four – around menopause; in men, the peak is in those aged over seventy-five years.[iii] In Australia, suicide rates in women have long been highest among those aged forty-five to fifty-nine years.[iv]

But there’s a simmering tension between those who want the role of hormones in women’s mental health to be taken seriously and those who caution against tarring all women’s mental health with the hormonal brush.

Clinical psychologist Jane Fisher, the Finkel Professor of Global Health at Monash University, argues against the notion that women’s hormonal cycles make them more vulnerable to mental health problems at times of life such as menopause. ‘I think it’s part of the medicalisation of women’s mental health that has led to neglect of the things that really contribute to the disproportionate burden carried by women,’ Fisher says.

Things such as women’s greater exposure to violence and discrimination and reduced access to income-generating work and education play major role. The times of life when women are more likely to experience mental health issues – such as around pregnancy, birth and menopause – are also times of psychologically demanding adjustments for women, when they may not be receiving adequate support from partner, parents or friends.

‘Those factors explain so much of the variability in estimates of women’s mental health problems that I think it’s a great pity that yet again we’re going down a line that says give women a pill or an infusion and that will fix things,’ Fisher says.

She points out that profits can be made from pharmaceutical interventions, not from social and psychological ones. ‘The pharmaceutical industry has a huge interest in this being a medical illness that they can sell us an expensive drug to fix,’ she says. ‘They don’t have any interest in violence prevention, occupational fatigue, crying babies, coinciding with your mother being diagnosed with breast cancer; all of that stuff which I think is the murky reality.’

Kulkarni agrees that ‘biology isn’t destiny’, but argues biology can have a significant effect on mental health and wellbeing. ‘It’s that woman who suddenly falls apart, who is suddenly unable to use all the strengths and the resources that she normally has to deal with matters,’ she says. ‘Then you think “What’s the biology doing here?” Because that is the other X factor that is not there for men.’

She says biology is a fundamental part of the trio of bio-psycho-social influences on mental health – and one that needs to be taken into account. Unfortunately, because of the siloed nature of science, medicine and health, each speciality tends to focus on its own area of expertise and often to the exclusion of others: psychologists work in the psychosocial domains of mental health but less so the biological, while psychiatrists ‘are blind to the biology’, says Kulkarni, ‘because they say, “hang on, that’s endocrinology” or “that’s some other branch of medicine, that’s not my thing”.’

Both, Kulkarni says, are leaving out a whole chapter of what causes mental illness and what can therefore be undone. But she highlights the fact that the opposite situation can also occur: a woman can be treated for depression with little consideration for the fact that her partner is abusing her on a regular basis. ‘Prescribing Zoloft is not going to cut the mustard there.’

Mental health has to take a broad bio-psycho-social approach, she says. That means examining what has happened to a woman in early life; has she experienced sexual or physical or emotional abuse; what is happening in her workplace? ‘Because there’s a whole bunch of effects.’


AS FAR BACK as the ancient Egyptians and Greeks, the uterus was seen as the locus of ‘hysteria’ – moods and mental illness that only blighted women. Women were believed to be vulnerable to the whims of this organ, which could be restored to its rightful place and state by a range of cures from marriage to removal to burning its host at the stake. That viewpoint – thankfully without the option of burning at the stake – stuck around for a remarkably long time: it wasn’t until 1980 that ‘hysterical neurosis’ was removed as a potential diagnosis from the Diagnostic and Statistical Manual of Mental Disorders.

However, it’s hard to dispute the scientific evidence that hormones do influence brain chemistry and mood. Does this mean that by endorsing the theory that hormones do influence women’s mental health – leaving aside any part they may play in treating mental illness – scientists such as Kulkarni and Meltzer-Brody are inadvertently supporting a narrative that women are vexed by their hormones? Does this revive the historical stereotype of the hormonal, hysterical creature?

‘We sometimes have problems with criticisms [such as] “you can’t say this is hormonal, because then we’ll never have a female president, we’ll never have a female pilot, because God! she might do something if the hormones are astray,”’ Kulkarni says. These criticisms come from men, but they also come from women – from feminists, with whom Kulkarni herself identifies – who worry that the focus on hormones and their psychological effects is a regression back to the time when women were viewed as biologically flawed and when that position was used to justify denying them education, jobs and agency.

The irony is that men are hormonal creatures too – all mammals are. Testosterone, the dominant male reproductive hormone, is also known to influence mood when levels are either too high or too low[v] Men also produce oestrogen, progesterone and allopregnanolone. Kulkarni’s research suggests that raising men’s oestrogen levels may improve psychotic symptoms, and a trial is also underway to explore whether brexanolone could treat major depression in both men and women.

For Meltzer-Brody, one way to combat the ‘hormonal and hysterical’ stereotype is to emphasise that the women whose symptoms of PMDD, postnatal depression or menopause are so severe as to require medical interventions represent a very small percentage of women.

‘The reality then is that we see women functioning and being incredible athletes and leaders and excelling broadly, and they’re not all being made “hysterical” by any of this,’ she says. To Meltzer-Brody, the fact that women have these hormonal cycles and fluctuations, and that these are what enable menstruation and pregnancy, ‘is what makes women remarkable’.

Kulkarni’s response is to put the patient – the woman – and her whole bio-psycho-social history and experience front and centre. ‘Because she’s the one who’s saying, “I’m not coping; I want to feel and be in situations better than this, and I want to be able to get back to doing what I want to do.”’

To feminist critics, Kulkarni says, ‘you fought for women to have the right to do what they want to do’, yet here is a group of women who are being held back. To psychiatry, whose conservatism and rigidity has made it difficult for Kulkarni’s ideas to gain traction, she says ‘step up’. ‘Embrace the bio-psycho-social approach, because that then means you will look at everything and you’ll end up doing better for the individual that you’re trying to help.’








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