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Research Feature: Molecular Sex Differences in Psychiatry

Jordan M. Ramsey and Sabine Bahn (Cambridge Centre for Neuropsychiatric Research)

Background: Men and women exhibit a different prevalence, symptoms and prognosis in a number psychiatric and developmental disorders.  For instance, twice as many women are diagnosed with major depression and anxiety compared to men. On the other hand, women are generally diagnosed with schizophrenia at an older age compared to men and they show a better response to antipsychotic treatment with a more favourable course of illness (at least, prior to menopause). Figure 1 illustrates a number of distinct and overlapping sex differences in clinical features across a selection of these disorders.

Figure 1. A summary of distinct and overlapping gender differences present in autism spectrum disorders (ASD), schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD).

Our hypothesis that clinical sex differences in psychiatric conditions translate to molecular sex differences
My objective in this ongoing work is to determine how this heterogeneity in clinical features translates to molecular differences between men and women with psychiatric illnesses.

Methods: We recruited men and women with Asperger syndrome, schizophrenia, bipolar disorder, major depressive disorder, as well as healthy controls from a number of clinics across Europe. Patients from these clinics were matched to controls based on gender, age, body mass index (BMI), waist circumference, tobacco use and cannabis consumption, when these measurements were available. Demographic information for patients can be found in Table 1. Schizophrenia patients were first onset antipsychotic naive, individuals with Asperger syndrome were drug free, and bipolar disorder and major depression patients were receiving medication and were at various stages of illness.

Table 1. Demographic information for patients. Matched controls were used in analyses. Age in years is reported as mean ± standard deviation.

Asperger syndromeSchizophreniaBipolar disorderMajor depression
Male Female Male Female Male Female Male Female
Number 14 16 79 54 42 48 40 79
Age 31±9 33±9 28±8 31±11 40±14 43±13 44±12 40±13


Molecular serum concentrations in males and females were measured using a sandwich immunoassay in which analytes are identified and concentrations quantified by flow cytometry

After obtaining consent to take their blood, we measured the concentrations of 190 proteins and small molecules in the serum of these individuals using a multiplex immunoassay test panel. This panel consists of assays for immune factors, hormones, growth factors, transport molecules and enzymes. The platform has been used previously to explore molecular changes in cancer, autoimmune disorders and cardiovascular diseases, as well as in neurological disorders and various psychiatric illnesses such as schizophrenia.

Prior to analysing the molecular data, we log-transformed the data, removed individual molecular assays with excess missing values and imputed the remaining missing values, combined data from different clinics and removed outlying samples. We then used a linear statistical model to find sex-specific molecular markers associated with each psychiatric illness.

Results and Discussion: We found a number of distinct and overlapping sex-specific markers associated with each illness. Here, we will focus specifically on sex differences in markers for these disorders related to hormones and inflammatory and immune processes.

Figure 2. Sex-specific alterations in the levels of hormones in schizophrenia. Log10 transformed mean levels of markers are shown relative to control levels in males and females. Abbreviations: SHBG = sex hormone-binding globulin

Sex hormones play an important role in the organisation of brain circuits during early development and puberty. Receptors for sex hormones are widely distributed in the brain and influence neural signalling. Many researchers believe that sex hormones play a critical role regarding prevalence, symptoms and prognosis between men and women in psychiatric and developmental disorders. For example, researchers speculate that estrogen may have a protective effect in women with schizophrenia  [1]. We found levels of testosterone increased in females with schizophrenia and levels of sex hormone-binding globulin (SHBG) decreased.  These results are plotted in Figure 2. Since SHBG binds sex hormones, these findings point to higher overall levels of free testosterone in females with first onset schizophrenia. However, chronic schizophrenia and long-term antipsychotic use has been associated with hyperprolactinaemia in females and a hypogonadal state [1]. We found increased prolactin levels in females compared to males in first episode schizophrenia patients at a level reaching borderline significance (P=0.058) that agree with trends seen in chronic schizophrenia, shown in Figure 2. In a small study using a subset of antipsychotic naive first episode schizophrenia patients, prolactin levels increased and SHBG decreased after 6 weeks of antipsychotic use. In autism, the ‘extreme male brain theory’ postulates that this condition is an exaggeration of the typical male cognitive profile, accounting for the higher prevalence of males with autism and is possibly caused by high levels of prenatal testosterone [2]. We found that SHBG levels were reduced in females with Asperger syndrome, pointing again to higher levels of free testosterone. It is clear from these studies that sex-specific hormonal disturbances are associated with in Asperger syndrome, and with first episode and chronic schizophrenia.

Figure 3. Male-specific alterations in the levels of inflammatory markers in schizophrenia (SCZ; left) and Asperger syndrome (AS; right). Log 10 transformed mean levels of markers are shown relative to control levels in males and females. Abbreviations: Il-5 = interleukin-15; AAT = alpha-1 antitrypsin; IL-8 = interleukin-8; C3 = complement 3; MDC = macrophage-derived chemokine; ICAM-1 = intercellular adhesion molecule-1; MIP-1-alpha = macrophage inflammatory protein 1 alpha; ENA-78 = epithelial-derived neutrophil-activating peptide 78; CTGF = connective tissue growth factor; IL-12p70 = interleukin-12p70; IL-16 = interleukin-16; TENA = tenascin C; TF = tissue factor; TNF = tumor necrosis factor alpha
Immunological abnormalities have been widely reported in a number of psychiatric illnesses. Increased levels of peripheral inflammatory markers are prominent in several psychiatric disorders and many studies have shown a bi-directional relationship between psychiatric illnesses and diseases related to inflammation such as obesity, cardiovascular disease and autoimmune disorders [3]. These inflammatory processes have been associated with breakdown of the blood-brain barrier and can interfere with production of neurotransmitters thought to be important in major depression, schizophrenia and other psychiatric illnesses. In our study, we found male-specific increases in the levels of several inflammatory markers in schizophrenia, major depression and Asperger syndrome. Figure 3 illustrates these results for schizophrenia and Asperger syndrome. Interestingly, two of these male-specific markers of schizophrenia (IL-15 and AAT) were negatively correlated with symptom severity in females only. It is possible that immune response and inflammation behave differently in men and women with schizophrenia. Sex differences in immune response and production of inflammatory markers are well established [4]. However, further research will need to be done to elucidate the role of these processes in schizophrenia and other conditions in both men and women.

For more details on the results of our work, check out our most recent publications, Distinct Molecular Phenotypes in Male and Female Schizophrenia Patients (Ramsey et al (2013) PLoS ONE 8(11): e78729. ) and Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome (Steeb et al (2014) Molecular Autism 5:4:). 

This may imply that different treatments are needed for male and female patients
Conclusions and Future Work: We have seen that men and women show different molecular alterations in various neuropsychiatric and developmental disorders. Our findings have implications for how we study and treat these conditions, since they may indicate that different molecular mechanisms are involved in how men and women develop these conditions.

Therefore, it may be appropriate to provide different treatments depending on the sex of a patient. We are currently trying to better understand sex differences in schizophrenia, bipolar disorder and major depression by investigating post-mortem prefrontal cortex gene expression and proteomic changes. This region of the brain is involved in regulation of higher functions such as cognition, working memory, desires, mood and emotional responses. This will give us more insight into chronic mechanisms of these illnesses in men and women. A great deal of work remains to be done in this area, but through our work we hope that by increasing our knowledge of these illnesses we can begin to improve the lives of the men and women who suffer with them. 


1.     Canuso CM, Pandina G (2007) Gender and Schizophrenia. Psychopharmacol Bull 40: 178–190.
2.     Baron-Cohen S (2002) The extreme male brain theory of autism. Trends Cogn Sci 6: 248–254.
3.     Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O (2013) Neuroinflammation and psychiatric illness. J Neuroinflammation 10: 43.
4.     Fish EN (2008) The X-files in immunity: Sex-based differences predispose immune responses. Nat Rev Immunol 8: 737–744.