The Impact Of Testosterone Replacement Therapy On Depression: What The Science

Written by the UPGUYS Editorial Team

Published on June 24, 2025

Depression is one of the most common mental health challenges among men in Canada, often going underdiagnosed or undertreated. 

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At the same time, low testosterone—also known as hypogonadism—is gaining attention as a potential contributor to low mood, fatigue, and motivation loss. 

Testosterone replacement therapy (TRT) in Canada has become an increasingly discussed treatment, not only for restoring physical vitality but also for its possible effects on mental well-being. 

As awareness grows, so does the need for clear, evidence-based answers: Can TRT really help with depression, or is the hype ahead of the science? This article examines the latest research to explore whether TRT offers genuine relief for depressive symptoms in men—and if so, under what conditions. 

Topics covered in this article: 

How Low Testosterone Affects Mood and Brain 

Testosterone plays a vital role in brain function, particularly in areas that regulate mood, energy, and cognitive clarity. When testosterone levels drop—whether due to aging, medical conditions, or other factors—it can trigger a range of psychological symptoms that closely mimic or contribute to depression. Understanding this connection is key to evaluating the role of testosterone replacement therapy (TRT) in mental health care. 

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Research has shown that testosterone interacts with several brain systems involved in emotional regulation. These include: 

1. Serotonin and dopamine activity: Low testosterone is linked to reduced levels of these neurotransmitters, both of which are critical for stabilizing mood and motivation. 
2. Cortisol balance: Testosterone helps buffer the effects of cortisol, the body's primary stress hormone. Low testosterone can mean higher cortisol levels, increasing vulnerability to stress and anxiety. 
3. Neuroplasticity and brain volume: Some studies suggest that low testosterone may reduce hippocampal volume—an area of the brain associated with memory and emotional processing. 

These biochemical shifts can result in symptoms such as persistent sadness, irritability, low self-esteem, mental fatigue, and decreased interest in activities—hallmarks of depressive disorders. This overlap explains why many men with low testosterone are misdiagnosed or not fully treated for underlying mood issues. 

What the Research Shows: Key Studies on TRT and Depression Outcomes 

Multiple clinical trials and meta-analyses have investigated whether testosterone replacement therapy (TRT) can reduce depressive symptoms—especially in men with low testosterone levels. The evidence suggests that TRT may be effective in certain cases, but results vary based on the severity of depression, baseline hormone levels, and the type of study conducted. 

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A 2019 meta-analysis published in JAMA Psychiatry, which reviewed 27 randomized controlled trials involving over 1,800 men, found that TRT had a moderate but statistically significant antidepressant effect, particularly in men with low or borderline testosterone levels. Another key study from the European Urology Focus journal echoed this, noting that TRT improved mood in men with mild or subclinical depression, especially when hypogonadism was diagnosed. 

However, not all research is uniformly positive. A large-scale observational study published in 2022, based on over 70 million U.S. health records, found that men receiving TRT were more likely to be diagnosed with major depressive disorder or experience self-harm events. These findings suggest a potential risk in broader or long-term use, especially among men who do not have a clear medical indication for TRT. 

In summary, the most consistent positive outcomes occur in men who have both low testosterone and mild depressive symptoms. The evidence is weaker—and even contradictory—for men with major depressive disorder or those using TRT without clinical hypogonadism. 

TRT's Effect on Mild vs. Major Depression 

The impact of testosterone replacement therapy (TRT) on depression depends heavily on the type and severity of symptoms a patient experiences. Clinical research consistently shows that TRT is more effective for men with mild or subthreshold depression—especially when accompanied by confirmed low testosterone levels. In these cases, men often report improvements in mood, energy, and motivation within weeks of starting therapy. 

However, for men diagnosed with major depressive disorder (MDD), the evidence is far less convincing. Multiple randomized controlled trials, including those reviewed in European Urology Focus and JAMA Psychiatry, indicate that TRT alone does not reliably alleviate symptoms of MDD. These patients typically require standard psychiatric interventions such as antidepressants or psychotherapy, and TRT is not recommended as a standalone treatment. 

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Key differences in TRT response by depression type: 

1. Mild/Subthreshold Depression: Responds positively to TRT when testosterone is low; improvements seen in mood, fatigue, and motivation. 
2. Major Depressive Disorder (MDD): Little to no clinical benefit from TRT unless used alongside traditional depression treatments; not recommended as first-line therapy. 

This distinction is crucial for clinical decision-making. While TRT can be a useful adjunct in mild cases with hormonal deficiencies, it should not be viewed as a cure for major depression. 

Who Benefits Most from TRT for Mood Support 

Testosterone replacement therapy (TRT) is not a one-size-fits-all solution for mood disorders, but certain groups of men are more likely to experience real benefits when it comes to depressive symptoms. Identifying the right clinical profile is essential for safe and effective treatment. 

The men who benefit most from TRT as a mood-enhancing therapy typically fall into these categories: 

1. Men with diagnosed hypogonadism: Those with consistently low serum testosterone and related symptoms like low libido, fatigue, and irritability. 
2. Men with mild or subclinical depression: Especially if antidepressants haven't worked and there are physical signs of low testosterone. 
3. Older men with age-related testosterone decline: Some evidence suggests that mood improvements are more pronounced in men over 50 who experience natural testosterone drops. 
4. Men with chronic medical conditions: Individuals with conditions like HIV/AIDS or metabolic syndrome may see both hormonal and psychological benefits from TRT. 

In these use cases, TRT has been shown to improve emotional stability, motivation, and quality of life when prescribed appropriately. However, treatment should always begin with lab-confirmed low testosterone levels and a full clinical evaluation to rule out other causes of depression. 

Risks, Side Effects, and Ethical Questions 

While testosterone replacement therapy (TRT) may offer mood benefits for some men, it comes with medical risks and ethical limitations that must be taken seriously. TRT can cause a range of side effects, particularly when used without clear clinical need or adequate supervision. 

Reported risks and limitations include: 

1. Cardiovascular concerns: TRT has been linked in some studies to increased risks of blood clots, heart attack, and stroke, especially in older men or those with preexisting heart conditions. 
2. Hormonal imbalances: Overuse or inappropriate dosing can lead to suppressed natural testosterone production, infertility, or enlarged breast tissue. 
3. Mood instability: Although TRT may improve mood in some, others may experience increased irritability, aggression, or emotional volatility. 
4. Placebo effect: Some clinical trials show only marginal differences between TRT and placebo in mood outcomes, raising questions about the true psychological impact. 
5. Ethical concerns: Off-label or lifestyle-driven use of TRT, especially in men with normal testosterone levels, raises red flags around overtreatment and long-term safety. 

Because of these issues, most medical guidelines—including those in Canada—recommend that TRT be reserved for men with confirmed testosterone deficiency and closely monitored by a healthcare provider. The decision to start TRT should balance potential mood benefits against real physiological risks. 

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Best Practices for Safe and Effective TRT Use 

To ensure testosterone replacement therapy (TRT) is both safe and effective for managing depressive symptoms, it must be approached through proper medical channels. That starts with accurate diagnosis, regular monitoring, and a collaborative approach between endocrinology and mental health care. 

Best practices include: 

1. Confirming low testosterone through lab testing: At least two separate morning blood tests should show total testosterone levels below the clinical threshold (typically <300 ng/dL or ~10.4 nmol/L in Canada) before starting treatment. 
2. Evaluating symptoms holistically: Depression-like symptoms should be assessed in context—considering sleep, stress, diet, and underlying mental health disorders—to avoid misdiagnosis. 
3. Choosing appropriate TRT formulations: Options like gels, injections, or patches should be tailored to the patient's lifestyle, goals, and tolerance. 
4. Ongoing monitoring: Regular follow-ups are essential to track testosterone levels, red blood cell count, PSA levels, and mood changes. This helps manage risks and ensure therapeutic value. 
5. Co-managing with mental health professionals: For men with moderate to severe depressive symptoms, TRT should not replace psychiatric care. Instead, it may complement antidepressants or psychotherapy when used judiciously. 

In Canada and globally, the emphasis is shifting toward integrated care models where hormone therapy and mental health treatment work together. This reduces the risk of overtreatment and ensures that mood improvements are grounded in both medical and psychological support. 

Future Directions for TRT and Depression Research 

Despite growing interest in testosterone replacement therapy (TRT) as a potential mood treatment, important gaps remain in the clinical evidence. While current studies suggest benefits for certain men—particularly those with low testosterone and mild depression—the research is far from conclusive. 

Key areas that future studies need to address include: 

1. Long-term mental health outcomes: Most current trials are short-term. More data is needed on how TRT affects mood, cognition, and emotional stability over several years. 
2. Population diversity: Many studies underrepresent younger men, men with comorbid psychiatric conditions, and non-Western populations. Broader trials would clarify how results apply across different groups. 
3. Mechanisms of action: While testosterone's influence on neurotransmitters is acknowledged, the exact pathways linking hormone levels to depression are not fully understood. 
4. TRT as adjunct therapy: There's limited evidence on how TRT works in combination with antidepressants, cognitive behavioural therapy, or other psychiatric interventions. 
5. Clearer diagnostic criteria: More standardized definitions of "low testosterone" and "mild depression" would improve trial consistency and real-world treatment decisions. 

In Canada and beyond, there's a growing push for multidisciplinary studies that blend endocrinology, psychiatry, and personalized medicine. Until more definitive data emerges, TRT should be viewed as a targeted tool—not a general treatment—for mood disorders. 

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