PCOS and Depression

Individuals with PCOS are 2.5-8x more likely to experience depression,[1],[2] with particularly high rates amongst young women.[3] In this article, we explore the link between PCOS and Depression.

Depression is a persistent feeling of sadness and loss of interest in regular daily activities.[4] Some people may experience a single depressive episode in their lifetime but it is more likely that it will be a reoccurring issue.[5]

There are a variety of ways in which depression presents, including:[6]

Major depressive disorder (MDD) with severe symptoms which occur frequently and for at least 2 weeks;
Persistent depressive disorder (dysthymia or dysthymic disorder) with less severe symptoms that last for a longer period, usually at least 2 years;
Seasonal affective disorder (SAD) which varies with the seasons, usually starting in late fall or early winter and going away in spring and summer;
Depression with psychosis, a severe form of depression where the individual experiences symptoms such as delusions or hallucinations;
Bipolar disorder with depressive episodes but also manic (or hypomanic) episodes with elevated mood, increased irritability or increased activity levels;
Premenstrual dysphoric disorder (PMDD), a more severe form of premenstrual syndrome (PMS);
Perinatal depression, occurring during pregnancy or after childbirth; and
Perimenopausal depression, occurring during the transition to menopause.

During depressive episodes, individuals may exhibit a variety of symptoms that occur persistently:[7],[8]

Emotional changes which could range from sadness, anger, guilt and anxiety;
Changes to engagement in daily activities, such as loss of interest and/or pleasure or problems concentrating, making decisions or completing even small tasks;
Fatigue or changes to sleeping patterns;
Changes to appetite and weight loss/gain;
Slowed thinking, speaking and/or body movements;
Frequent or recurrent thoughts of death, suicidal thoughts, suicide attempts or suicide; and
Unexplained physical problems, such as back pain or headaches.

Depression can significantly worsen existing health conditions such as chronic pain or diabetes and increase the risk of other chronic diseases including diabetes, cardiovascular disease, dementia.[9] Likewise, individuals with chronic health conditions can develop depression as a result. Individuals with depression are more prone to develop substance use problems and withdraw from social interactions, further contributing to poor health.[10],[11] These combined factors exacerbate the risk of suicide.

There are several pathways linking PCOS to increased risk for depression:[12],[13]

Allopregnalone (ALLO): PCOS is associated with increased levels of gonadal and neuroactive steroids (NASs), small molecules or metabolites formed when the body breaks down cholesterol.[14] In particular, ALLO, a metabolite produced when the body breaks down the progesterone hormone,[15] is believed to key play a role in the altered activity of gonadotropin-releasing hormone neurons (GnRH) neurons in individuals with PCOS.[16] These NASs also affect mood by altering the sensitivity of Gamma-aminobutyric acid-A (GABAA) receptors,[17] neurotransmitters or signaling molecules that reduce the level of neuronal activity by reducing the transmission of signals between neurons.[18],[19] Reduced GABA activity is linked to the development and maintenance of depression symptoms.[20]
Insulin resistance: PCOS is associated with insulin resistance, whereby the cells in your muscles, fat and liver don’t respond well to insulin and can’t easily take up glucose from your blood.[21] Insulin resistance alone doubles the risk of developing major depressive disorder.[22] Cells in the brain are also believed to develop insulin resistance, disrupting dopamine signaling, the hypothalamic-pituitary-adrenal (HPA) axis and linked to abnormal functioning of the Hippocampal and Anterior Cingulate Cortex (ACC).[23] Brain insulin resistance is believed to increase levels of lipid and protein oxidation (cell damage) in the striatum and nucleus accumbens (NAc),[24] areas of the brain involved in decision making and pleasure, reward and addiction respectively.[25],[26] It also leads to increased levels of monoamine oxidase A and B (MAO A and MAO B).[27] MAO A is a protein that oxidizes serotonin, a hormone influencing happiness and other body processes,[28] as well as norepinephrine and epinephrine,[29] hormones that control the “fight-or-flight” reflex by increasing blood flow in the body.[30],[31] MAO B is a protein that converts serotonin to ammonia (deaminates) serotonin.[32],[33]
Inflammation: PCOS is associated with increased inflammation linked to the reduced production of adiponectin.[34] Increased inflammation leads to increased permeability of the blood brain barrier, enabling inflammatory molecules to enter the central nervous system (CNS).[35] Increased inflammatory signals in the CNS leads to functional and structure changes, particularly in the hippocampus, the region of the brain involved in learning and memory.[36],[37]
Estrogen: PCOS is associated with slightly elevated levels of estrogen where there is an accumulation of follicles in the ovaries.[38] This stimulates the production of pro-inflammatory cytokines (signaling molecules released by immune cells that trigger and amplify inflammation) that are known to induce depressive-like symptoms when they reach the brain, including TNF-α, interleukin 4 (IL-4), IL-1, IL-6 and interferon γ (INF- γ).[39],[40]
Cortisol: PCOS is associated with significantly increased levels of cortisol, the “stress hormone”.[41] These elevated cortisol levels may be a combination of both disruption to the Hippocampus Pituitary Adrenal (HPA) axis[42] and an outcome of living with the burden of disease (see below). Elevated cortisol levels linked to a state of chronic stress is a risk factor for the development and severity of depression.[43]
Burden of disease: PCOS, its associated symptoms and health problems as well as poor experiences with the healthcare system can lead to withdrawal from social, professional and/or academic activities, a key risk factor for depression.[44]

Other risk factors for depression include:[45]

Certain personality traits such as low self-esteem;
Experience of traumatic or stressful events;
Family history of depression, bipolar disorder, alcoholism or suicide;
History of other mental health disorders;
Being lesbian, gay bisexual or transgender or being intersex in an unsupportive environment/context;
Abuse of alcohol or illegal drugs;
Experience of chronic or severe illness; and
Use of certain medications, including some blood pressure drugs and sleeping pills.

Depression is diagnosed by a healthcare professional through a combination of tests, which can include:[46]

Physical exam and/or questions about your physical health to identify any underlying health problem;
Laboratory tests: blood tests for blood count and thyroid function; and
Psychiatric evaluation: questions about your thoughts, feelings and behavior.

There are a number of clinically-validated assessments that can be used by a healthcare professional to define the type and severity of depression, including:[47]

Hamilton Depression Rating Scale (HDRS, HRSD or HAM-D): a questionnaire administered by a healthcare professional consisting of 21 items scored on a 3- or 5-point scale, often used before, during and after treatment to assess its effectiveness;
Montgomery-Åsberg Depression Rating Scale (MADRS): an adaptation of the HDRS scale where questions are rated on a 7-point scale with greater sensitivity to changes over time;
Social Problem-Solving Inventory-Revised (SPSI-RTM): self-reported measure of social problem-solving with both a long-form (52 questions) and short-form (25 questions);
Patient Health Questionnaire (PHQ): a questionnaire administered by a healthcare professional consisting of 9 items, used to establish a diagnosis and grade symptom severity;[48]
Beck Depression Inventory (BDI): a self-reported questionnaire consisting of 21 questions with multiple choice responses;
Center for Epidemiology Studies Depression Scale (CES-D): a self-reported questionnaire consisting of 20 questions scored on a 4-point scale, often used to screen for depression in primary care settings;
Diagnostic and Statistical Manual of Mental Disorders (DSM-5): a diagnostic tool for clinicians to measure maladaptive personality traits across negative effect, detachment, antagonism, disinhibition and psychoticism;[49]
Hospital Anxiety and Depression Score (HADS): a questionnaire comprising 14 questions, including 7 for the assessment of anxiety (HADS-A) and 7 for the assessment of depression (HADS-D);[50] and
EuroQoL (EQ-5D): standardized instrument for evaluating quality of life deficits across 5 dimensions.

Treatment for depression often includes a combination of psychotherapy, medication and lifestyle modifications, which can include:[51],[52]

Cognitive behavioral therapy (CBT): CBT provides tools for people to challenge and change unhelpful thoughts and behaviors and can include mindfulness principles and target specific symptoms;
Interpersonal therapy (IPT): IPT helps people improve communication skills, form social support networks and develop more realistic expectations to help deal with issues as they arise;
Selective serotonin reuptake inhibitors (SSRIs): Serotonin is a hormone involved in learning, memory, happiness, temperature regulation, sleep, sexual behavior and hunger and its deficit is linked to depression, anxiety, mania and other health conditions.[53] SSRIs block the process whereby serotonin is taken back into cells in the brain after it has carried a signal between cells (reuptake), thereby making more serotonin available to carry signals;[54]
Serotonin-norepinephrine reuptake inhibitors (SNRIs): Norepinephrine is a hormone involved in the body’s “fight-or-flight” response and its deficit is linked to anxiety, depression, ADHD, headaches, memory problems, sleeping problems, low blood sugar and low blood pressure.[55] SNRIs block reuptake of serotonin and norepinephrine;[56] and
Norepinephrine-dopamine reuptake inhibitors (NDRIs): Dopamine is a hormone involved in movement, memory, pleasure reward and motivation, behaviour and thinking, attention, sleep and arousal, mood, learning and lactation and its under or over-production is linked to many diseases.[57] NDRIs block reuptake of norepinephrine and dopamine.[58]

If depression is severe, endangering the life of the individual or doesn’t respond to other treatments, electrical or magnetic brain stimulation may be used.[59] Esketamine, a drug delivered via a nasal spray at a healthcare location, may also be used when an individuals’ symptoms do not improve after trying two or more antidepressants.[60]

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[17] https://www.researchgate.net/publication/275665591_Women_with_polycystic_ovary_syndrome_have_elevated_serum_concentrations_of_and_altered_GABA_A_receptor_sensitivity_to_allopregnanolone

Reviewed by Dr. S, one of Neuraura's friends and trusted advisors

Sources

PCOS and Depression