Testosterone And Mental Health: What’s The Connection?

Take-home points

• Despite lower overall depression rates compared to women, men are at a higher risk for severe outcomes like suicide and substance-related deaths, particularly among those over 75 and in blue-collar professions such as mining, construction, and agriculture.
• Men often face underdiagnosis or misdiagnosis of depression, partly due to societal norms and traditional diagnostic frameworks that don't adequately address men's mental health. This can lead to them receiving inappropriate or insufficient treatment.
• Low testosterone levels can contribute to or exacerbate depressive symptoms in men. It’s important for healthcare providers to consider hormone levels, especially in men whose depression does not improve with standard treatments.
• Antidepressants, especially SSRIs, can have significant side effects, including sexual dysfunction, which may worsen depression. While Testosterone Replacement Therapy (TRT) has shown potential benefits in some cases, it is not widely recommended for treating depression due to inconsistent research findings and potential side effects.
  

Depression affects nearly twice as many women as men, but men are more likely to die by suicide, drug overdose, and alcohol-related deaths—often referred to as deaths of despair.¹ Men over 75 and those in blue-collar jobs like mining, construction, and agriculture have the highest rates.² Despite their higher risk, men are less likely to seek help, with only 15 percent receiving psychotropic medications or therapy in 2020 compared to 26 percent of women.³

Society is becoming more attuned to mental health nuances, but frameworks are traditionally built around women, leading to potential misdiagnoses in men.⁴ Physicians may diagnose depression and prescribe treatments without considering biochemical factors like testosterone deficiency (TD), which can mimic or worsen depressive symptoms, highlighting a broader issue in healthcare—a tendency to treat symptoms rather than underlying causes, especially in men’s health.

Increasing diagnoses of depression

As awareness about men’s mental health grows, so do conversations around mental health and diversity. Men are increasingly open to discussing their mental health, leading to more GP visits and depression diagnoses. However, the accuracy of these diagnoses can vary.⁵ Depression has multifactorial causes, some of which can't be addressed with antipsychotics alone.⁵

GP judgements about depression often result in false negatives and false positives.⁵ While some degree of inaccuracy is inevitable, high rates of false positives or negatives have significant implications. Misdiagnosis can prevent individuals from receiving appropriate treatment, leading to increased morbidity, impaired cognitive focus, and adverse effects on social, work, and home life.⁵

Depression is largely treatable with evidence-based pharmacological and non-pharmacological treatments. However, under-detection and under-treatment burden healthcare services, as untreated individuals are more likely to seek medical treatment for both mental and physical issues. It is concerning that patients presenting with depression may only have a 50% chance of being correctly diagnosed by their GP, risking untreated depression and continued suffering.⁵

One significant consequence is the overprescription of antidepressants in men with low testosterone levels. Many antidepressants affect testosterone and estrogen levels, which can impact sexual function, behaviour, and depressive symptoms.⁶ Men whose depression does not respond to medication should have their testosterone levels checked, ensuring a more accurate diagnosis and effective treatment.

Link between testosterone and depression

Anxiety, irritability, depression, and other mood changes are common in people with low testosterone. However, the exact cause of this correlation remains unclear.

Testosterone plays a critical role in enhancing our mood by increasing the release of dopamine, the brain’s neurotransmitter responsible for feelings of pleasure.⁷ There is also a potential link between testosterone levels and serotonin function.⁸ Reduced serotonin activity in the brain is often associated with depression, and testosterone may enhance serotonin activity, improving overall mood.

Lower testosterone levels are an important biomarker for depression risk. In men, lower testosterone is linked to a higher risk of depression, with bioactive "free testosterone" being a specific measure associated with this risk.⁹ Interestingly, both low and high testosterone levels might elevate depression risk, though this area requires further study.¹⁰

Testosterone therapy has shown promising results, reducing depressive symptoms in men. However, most studies assess depression as a single continuum, without considering differences between specific symptoms.¹¹ For instance, lower testosterone levels are associated with atypical depression, characterised by increased appetite, excessive sleeping, and mood reactivity.¹¹

Atypical depression is distinct from melancholic depression, which involves chronic sadness and anhedonia (the inability to feel pleasure). While testosterone levels have been linked to atypical depression, the connection to melancholic depression is less clear. This distinction suggests that testosterone might influence specific depression symptoms differently.¹¹

Research has also indicated that testosterone may be associated with anxiety disorders and social and specific phobias among men, but not necessarily depression itself.¹¹ For example, a study of older men found that the testosterone-regulating gene CAG-repeat length was linked to suicidal thoughts, anxiety, and a general deterioration of well-being, rather than directly to depressive mood.¹¹

Implications of wrong treatment

Treating depression linked to low testosterone with antidepressants can have serious drawbacks. Antidepressants may not be effective if they don’t address the root cause—low testosterone. Men with untreated low testosterone may not experience significant improvements in their depressive symptoms.

Moreover, antidepressants, particularly SSRIs, can negatively impact sexual health.¹² In a 2003 survey, 41.7% of men and 15.4% of women discontinued psychiatric medications due to sexual side effects.¹² SSRIs can cause sexual dysfunction in 40% to 65% of individuals, potentially worsening depression and hindering medication adherence.¹² Combined with the other harmful side effects of antidepressants, it may actually be doing more harm than good if these medicines are prescribed without further evaluation of the potential root causes of a man’s depressive symptoms.

TRT for TD-related depression

Testosterone Replacement Therapy (TRT) has emerged as a potent treatment for various disorders in hypogonadal men. However, randomised placebo-controlled trials examining TRT's impact on depressive symptoms have produced inconsistent results.¹³ Some studies suggest that TRT is not universally effective as an antidepressant, especially in men with Major Depressive Disorder.¹³

Positive outcomes have been reported in specific subpopulations, such as men with dysthymic disorder, HIV, treatment-resistant depression, or low testosterone levels.¹³ These findings indicate that TRT can be beneficial in certain contexts but is not broadly recommended for depression treatment. Clinical guidelines from the National Institute for Health and Care Excellence and the Endocrine Society do not endorse TRT for depression due to uncertainties about its efficacy, appropriate dosage, duration, and application methods.¹³

While rodent models show that testosterone can reduce depressive symptoms, some human studies find no significant difference between TRT and placebo.¹⁴ As with the improper use of antidepressants, over-administration of testosterone can also lead to adverse effects. More research is needed to determine if declining testosterone levels directly influence depression development in adult men.¹⁴

The way forward

Depression can be linked to testosterone deficiency, not just neurotransmitter dysregulation. While studies show promise for TRT in treating depression, it isn't yet approved by NICE for this purpose. Therefore, TRT should be considered on a case-by-case basis, ensuring all biochemical tests are conducted within guidelines. This approach allows for a tailored treatment plan, addressing the unique needs of each patient. With continued research, we hope to better understand TRT's role in managing depression and improve treatment options in the future.

References

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3. Centers for Disease Control and Prevention (CDC). Products - data briefs - number 419 - October 2021. Available from: https://www.cdc.gov/nchs/products/databriefs/db419.htm.‍
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