Schizophrenia in Women – Role of Estrogen and Novel Treatments
Prof Jayashri Kulkarni, Professor of Psychiatry and Director of Monash Alfred Psychiatry Research Centre, discusses the unique aspects of schizophrenia in women.
Estrogen is a gonadal hormone that can exert powerful effects in numerous regions of the brain, consequently affecting mood, cognition, and behaviour. We covered the neurosteroidal effects of estrogen in this post.
Women with schizophrenia show a lower level of circulating estrogens. It is only in females that there is a second peak in incidence of schizophrenia (40-50 yrs) which is attributed to decreasing estrogen levels. 
Estrogen is thus, thought to be protective for the development of schizophrenia. Some studies have specifically shown an inverse correlation between circulating estrogen levels and symptoms of schizophrenia, particularly the positive symptoms. 
Estrogens act on various parts of the brain and have excitatory and inhibitory effects on various neurotransmitters. As a neurosteroid it also facilitates neuroprotection.
Estrogen receptors ERα and ERβ are widely distributed in the brain with ERα situated in the hippocampus, hypothalamus, amygdala and brain stem.
Estrogen interacts with the dopamine, glutamate and serotonin systems. Read more
The ADEPT study is the first large-scale randomised-controlled trial in women with treatment-resistant schizophrenia.
Both estradiol groups had greater decreases in PANSS positive, general and total symptoms compared with the placebo group (P<0.01), with a greater effect seen for 200 μg than 100 μg estradiol.
The largest effect size was for the positive subscale of PANSS in the estradiol 200 μg treatment group (effect size 0.44, P<0.01).
Raloxifene hydrochloride is a selective estrogen receptor modulator (SERM) with mixed agonist and antagonist activity.
Raloxifene exerts similar neurotransmitter effects to estradiol within the brain, while acting primarily as an estrogen antagonist in breast tissue and the endometrium.
Raloxifene influences multiple neurotransmitter pathways including serotonin in the frontal cortex, striatum and basal ganglia.
The addition of raloxifene to regular antipsychotic treatment in postmenopausal women with schizophrenia exhibiting prominent negative symptoms significantly improved the negative symptoms, as well as general psychopathological symptoms, compared with women receiving antipsychotic medication alone. 
Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of clinical response in women with refractory schizophrenia. 
Considering the important role of hormones in psychiatric illness in general in women a gender-based treatment approach is essential, and clinicians should take into account the powerful role estrogen plays in the brain.