The link between Schizophrenia and the sex hormone oestrogen

Schizophrenia, a complex mental illness, causes affected individuals to experience positive symptoms, including hallucinations and delusions, in addition to negative symptoms, such as apathy and social withdrawal. Schizophrenia is known to be subject to gender differences in age of onset, severity, and effectiveness of treatment. Of the numerous gonadal steroids, the action of oestrogen is the most researched; the oestrogen hypothesis postulates that oestrogen exerts a protective effect in females against the development and severity of the illness. Thus, whilst schizophrenia usually onsets in young adulthood, there is a peak in women around menopause, resulting from a decline of oestrogen levels. This poses the question: Can oestrogen have a therapeutic use in the treatment of schizophrenia?

Whilst the cause of schizophrenia is currently unknown, and likely to be a combination of genetic, psychological and environmental factors, the major neurotransmitter systems involved in schizophrenia are the dopamine, serotonin, and glutamate systems. In the pharmacological treatment of schizophrenia, antipsychotics are the therapeutic choice, and target the dysregulation of dopaminergic circuits involved in the illness. Positive symptoms result from excess dopaminergic activity in the mesolimbic pathway, whereas negative symptoms result from reduced dopaminergic signalling in the meso-cortical pathway. Evidence for this dopamine hypothesis comes from the effects of D2- class dopamine receptor antagonists and agonists in precipitating and reducing psychotic symptoms. 

The gonadal steroid, oestrogen, is thought to interact with the neurotransmitter serotonin, and has such been implicated in the modulation of mood and cognition. When oestrogen levels decrease in post-menopausal females, there is a subsequent peak in the onset of schizophrenia. Oestrogen acts as a protective buffer against the development and severity of the illness. As such, given that treatment of schizophrenia with antipsychotic medication targets the dopaminergic system, oestrogen must affect the neurotransmitter dopamine. This also poses the idea that oestrogen can be used therapeutically in the treatment of schizophrenia; evidence from a recent study (1) shows oestrogen to be an effective adjunctive therapy for women with treatment-resistant schizophrenia, especially for positive symptoms.

1. Kulkarni J¹, Gavrilidis E¹, Wang W¹, Worsley R¹, Fitzgerald PB¹, Gurvich C¹, Van Rheenen T¹, Berk M², Burger H. Estradiol for treatment-resistant schizophrenia: a large-scale randomized-controlled trial in women of child-bearing age.Mol Psychiatry. 2015 Jun; 20(6): 695-702. Epub 2014 April 15.
2. Gogos A, Sbisa AM, Sun J, Gibbons A, Udawela M, Dean B. A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings. Int J Endocrinol. 2015; 2015: 615356. doi:10.1155/2015/615356
3. Tandon R. Antipsychotics in the treatment of schizophrenia: an overview. J Clin Psychiatry. 2011; 4-8. 
4. Lally J, MacCabe JH. Antipsychotic medication in schizophrenia: a review. British Medical Bulletin, Volumer 114, Issue 1, June 2015, Pages 169-179
5. Amin Z¹, Canli T, Epperson CN. Effect of estrogen-serotonin interactions on mood and cognition. Behav Cogn Neurosci Rev. 2005 Mar;4(1):43-58.

Why are the symptoms of depression not alleviated immediately after treatment by an SSRI antidepressant?

The selective serotonin reuptake inhibitors, or SSRIs, are a class of antidepressants often used in the treatment of depression. SSRIs work by increasing the level of availability of the neurotransmitter serotonin in the synaptic cleft. Their pharmacological action achieves this by blocking the reuptake of serotonin and norepinephrine. The monoamine theory of depression, which proposes that depression results from a depletion in the levels of serotonin, norepinephrine, and/ or dopamine in the central nervous system, supports the proposed mechanism of action of SSRI antidepressants.

When SSRIs are used as treatment, they become pharmacologically active at their molecular sites of action almost immediately. Their action, which blocks the re-uptake of serotonin and norepinephrine by the monoamine transporter SERT, causes an increase in neurotransmitter availability at the synaptic cleft. However, the antidepressant effects of SSRIs are generally not seen until 2 to 4 weeks of continuous treatment, thus limiting the monoamine theory of depression. Ultimately there is a discrepancy between immediate inhibition of serotonin reuptake and clinical effects. Why are the clinical symptoms of depression not alleviated immediately after treatment by an SSRI?

One of the 14 subtypes of serotonin receptor, the 5-HT1A receptor, works as an auto-receptor that inhibits serotonergic activity. In simpler terms, this means that a 5HT1A receptor stimulated by the presence of the neurotransmitter serotonin inhibits the firing of serotonergic neurons. These 5HT1A receptors are expressed in the somato-dendritic region of a serotonergic (5-HT) neuron; here they act as inhibitory auto-receptors. 

Image depicting the synaptic cleft between a serotonergic neuron terminal and a postsynaptic membrane. The neurotransmitter serotonin is present as 5-HT. The addition of SSRI blocks the 5-HT re-uptake transporter (SERT), thus increasing serotonin levels in the synaptic cleft and resulting in the down-regulation of the 5-HT inhibitory auto-receptor.

An SSRI works by blocking the monoamine transporter protein SERT, which transports serotonin from synaptic spaces into presynaptic neurons. Thus, an SSRI causes an increased availability of serotonin in the synaptic space. This increase in serotonin levels downregulates 5HT1A receptors present on serotonergic neurons. This means that there are fewer 5HT1A receptors present. Downregulation is controlled by genomic mechanisms, hence the reduction of 5HT1A receptors occurs over a period of weeks, and is not immediate. This explains the discrepancy of the monoamine theory of depression previously discussed.

The serotonergic neuron is now disinhibited since there are fewer 5HT1A receptors expressed in the somato-dendritic region. Consequently, the firing rate of the serotonin-sensitive neuron increases. This in turn increases serotonin release to the synaptic space, which stimulates postsynaptic serotonin receptors.

To summarise, the monoamine theory of depression hypothesises that depression may result from a depletion in the levels of serotonin in the CNS. Treatment by an SSRI increases the concentration of serotonin in the synaptic cleft by blocking the SERT monoamine transporter. This decrease in serotonin degradation results in the down-regulation of the inhibitory auto receptor 5-HT (type 1A). A reduction in the presence of 5-HT1A receptors means that the serotonergic neuron is disinhibited, and hence neurotransmission by the serotonin-sensitive neuron increases. Ultimately, 2-4 weeks is required to alleviate clinical symptoms of depression since down-regulation of the 5-HT1A receptor is mediated by genomic processes. Although serotonin levels may increase immediately after administration of an SSRI, this is not the case for the 5-HT1A receptor.

An Overview of Bipolar Disorder

Bipolar disorder, formerly manic depression, is a typically chronic mental illness characterised by extreme changes in mood and energy. Depending on the type of bipolar and severity, an individual may experience periods of severe depression that alternate with manic, hypomanic or mixed episodes. Both ends of the bipolar spectrum are often so severe that they interfere with everyday tasks and can, at times, compromise an individual’s ability to function in the community. Ultimately, as with most mental illnesses, bipolar disorder results from a complex combination of both genetic and environmental factors, but causative research, and hence our understanding of the illness, is ever-developing.

There are several classifications of bipolar disorder, hence it can be considered a spectrum of severity: cyclothymia, bipolar II and Bipolar I disorder, in addition to bipolar NOS (not otherwise specified), where cyclothymia is the least severe and bipolar I the most severe. An individual with a milder form of bipolar disorder has an increased risk of progressing to a more severe variant of the disorder. Studies suggest that individuals with bipolar I disorder first experience less severe symptoms on average 12 years prior to being diagnosed (1). The median age for onset for bipolar disorder ranges from 17 to 31, with the first peak occurring between 15 and 19 years of age.

A person is thought to be born with a “vulnerability” to bipolar disorder, meaning that they are more prone to developing the disorder (2). In fact, there are specific abnormalities in emotional processing and regulation of neural circuitries in offspring at risk for bipolar disorder, i.e. offspring of a patient with bipolar disorder. A neuroimaging study showed there to be greater activity and functional connectivity during emotion regulation tasks (facial processing) in the anterior cingulate cortex that may help to distinguish youth at risk for bipolar disorder from healthy youth (3). 

The genetic component to bipolar disorder is still largely mis-understood. A study by UCLA used a new, innovative approach, far from the traditional clinical interview of symptoms in the diagnosis of bipolar disorder: Researchers combined the results from brain imaging, cognitive testing, and an array of temperament and behaviour measures (3). Whilst the specific genes that contribute towards the illness are still unidentified, about 50 brain and behavioural measures under strong genetic control were found to be associated with bipolar disorder. Interestingly, it was found that the thickness of the grey matter in the brain’s temporal and prefrontal regions were both genetically linked and associated with the disease. These structures are critical for language, self-control and problem-solving. This identifies a potential target trait for genetic mapping and identification of disrupted biological pathways vital for the disease.

To summarise, bipolar disorder has several variants of severity. Development of the more severe bipolar I disorder increases in likelihood should an individual present with the less severe symptoms of cyclothymia. The average age of emergence for bipolar disorder is 19, although many patients first experience symptoms prior to seeking treatment and obtaining a correct diagnosis. The cause of bipolar disorder is ultimately unknown; a combination of environmental ‘triggers’ and genetic factors are necessary for the development of the disorder. An individual may possess a genetic “vulnerability” to bipolar disorder, and present with abnormalities in emotional processing and regulation in neural circuitries. A previous study showed there to be 50 brain and behavioural measures, that are under strong genetic control, associated with bipolar disorder. Of particular interest, the thickness of the grey matter in the brain’s temporal and prefrontal regions were linked to the diease, and mark a potential target for genetic mapping.

1. History of illness prior to a diagnosis of bipolar disorder or schizoaffective disorder. Berk M, Dodd S, Callaly P, Berk L, Fitzgerald P, de Castella AR, Filia S, Filia K, Tahtalian S, Biffin F, Kelin K, Smith M, Montgomery W, Kulkarni.J Affect Disord. 2007 Nov; 103(1-3):181-6.
2. https://www.heretohelp.bc.ca/factsheet/bipolar-disorder-what-causes-bipolar-disorder
4. https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2697854?resultClick=1
5. http://newsroom.ucla.edu/releases/coming-soon-249997