TRT Therapy – Can Testosterone Replacement Make Depression Worse or Better?

The question really should be to what extent TRT therapy alleviates depression, and the factors that influence the positive outcomes. But let’s not scare you with long headings. ​

With the backdrop of a sweeping epidemic, debilitating lock downs, social distancing norms it is no surprise world mental health day is trending. Even return gift bags given with thoughtful notes being penned about understanding & empathy, coaxing to reach out if feeling down and depressed. ​

Low-T being the cause of mood issues, a certain lack of overall well being is well understood, as is the ability of testosterone to boost mood and bestow that spring in the step, feel good, win the world feeling. ​

So testosterone eminently qualifies as a therapy option. Although it can be nuanced and it might not be for everyone, but for a certain subset of people testosterone replacement is simply tailor-made to a T to deal with depressive symptoms. ​

It has long been debated among medical professionals about using TRT therapy for overcoming depression. An affliction millions suffer which has a debilitating effect on life and lifestyle. ​

Indisputable is the efficacy of testosterone in helping treat depression as per a huge analysis of existing studies, in fact the biggest one done involving thousands.​

27 relevant randomized placebo-controlled clinical trials encompassing almost 2000 subjects were selected whittling down from 7000+ records and 2622 studies excluded. ​

The paper published in JAMA (Journal of American Medical Association) titled Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men A Systematic Review and Meta-analysis. ​

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Study found Testosterone:​

• Has a moderate antidepressant effect compared to placebo
• The beneficial effect of testosterone was pronounced at higher doses
• First time ever a study suggested higher doses of testosterone for anti-depressant effect

While the authors are clear that more specific trials need to be conducted since testosterone trials were largely conducted with low-T symptom outcomes and not depression per se, and many other parameters need to be explicitly studied for definite answers. For example - the way testosterone was administered - transdermal via gels or intramuscularly.

Previous research provided evidence that testosterone treatment is effective in reducing depressive symptoms in hypogonadal or middle-aged men up to age 60 years.

This meta-analysis provides important new evidence that testosterone treatment may also be effective and efficacious for eugonadal (not suffering from low-T) and older men when higher testosterone dosages are administered.

How does depression, low-T and testosterone all connect?

Prevalence of depression in men increases with age, so does the prevalence of low-T or hypogonadism. Depression and anxiety are the most common psychopathological symptoms associated with male hypogonadism.

The question is whether the age-related gradual decline in testosterone levels contributes to the rising rate of depression in older men?

Improvement in depressive symptoms of men with low-T have been demonstrated in many studies while treated with testosterone. In fact, a subset of hypogonadal men seem to respond better while on testosterone replacement for depression.

Testosterone deficiency is associated with numerous non-specific symptoms including decline in libido, erectile dysfunction, increased fat deposition, decreased muscle mass, decreased energy and depression.

The relationship between increased depressive symptoms and declining testosterone levels is complex because many conditions are independently associated with depression and testosterone deficiency. These conditions include medical illnesses, such as HIV/AIDS, and obesity, stress, smoking, and alcohol abuse.

Most studies do suggest that testosterone deficiency is associated with depressive symptoms, although the literature does not support a consistent relationship between testosterone levels and depressive symptoms.

Why is TRT therapy so effective in improving depressive symptoms?

TRT has been shown to improve depressive symptoms in most men. This could be due to the fact that testosterone is a modulator of GABA A receptors and inhibits 5-HT3 receptors centrally.

GABA(GAMMA Amino Butyric Acid) is an inhibitory neurotransmitter in adults. It slows our breathing, heart rate, lowers blood pressure. It imparts a chillax effect so to speak.

40% of the synapses in the brain work with GABA, so not having enough GABA can lead to anxiety, depression, difficulty concentrating, insomnia among other symptoms. Low-T also presents with similar symptoms. See the connection?

GABA A & GABA B are the 2 types of receptors GABA interacts with.

Essentially GABA A receptors tells the neuron - “buddy take a chill pill”.

GABA A acts as an automatic gate when it binds to GABA and stops the neuron from activating:

GABA A receptors are ionotropic receptors. When GABA binds to the GABA A receptor, it opens up an associated ion channel that is permeable to the negatively charged ion chloride. When negative chloride ions flow into the neuron, they hyperpolarize the membrane potential of the neuron and make it less likely for the neuron to fire up.

5HT3 receptors are a type of Serotonin receptor, which is excitatory and testosterone has an inhibitory effect in the CNS (Central Nervous System).

However there appears to be a sub-population of depressed male patients that tend to respond best to TRT.

These patients include men who have more severe testosterone deficiency, HIV/AIDS, mild depression, use transdermal testosterone as opposed to IM testosterone, and those not responding to *SSRIs.​

What has testosterone got to do with Patients on SSRIs?

Patients taking *SSRIs also experience a significant improvement in depressive symptoms once treated with TRT.

A medical review emphatically declares that:

“Men with depressive symptoms and testosterone deficiency syndrome should be given a trial of testosterone replacement therapy for at least 3 months as TRT alone may improve clinical symptoms of depression. Furthermore, men already on SSRIs may also experience further improvement in depressive symptoms after initiating TRT.“

*Selective serotonin reuptake inhibitors (SSRIs) are a widely used type of antidepressant. They are mainly prescribed to treat depression, particularly persistent or severe cases, and are often used in combination with a talking therapy such as cognitive behavioral therapy (CBT).

Is TRT therapy the last word in treating depression?

Testosterone has its limitations, given that depression is a complex disorder, with many causes social, economic, even cultural included apart from the clinical & psychological manifestations. So while it has a beneficial effect on treating depressive symptoms there are exceptions like psychosis, severe lack of social skills, etc., which need other kinds of interventions to help. Sometimes people have to be taken off TRT therapy since it has undesirable outcomes.

Unfortunately depression does not have a cookie-cutter solution, but testosterone seems to help.

Certainly as more insights are gained from ongoing research, into the intricate interactions of neuroactive hormones including testosterone & neurotransmitters and their receptors, testosterone therapy will keep on pushing the envelope and treatment locus.