Antidepressants – Efficacy and Risk?

Antidepressants are often prescribed for people complaining of symptoms of depression. But what is the real cause of depression and do antidepressants help or hinder someone’s overall health?

According to the CDC, between 2015-2018, 13.2% of people aged 18 and older used an antidepressant in the past 30 days. Between 2013-2019, 7.8% of children and adolescents aged 3-17 had taken medication for a mental health problem in the past year. During the COVID pandemic, antidepressant use increased around the world.

There was an estimated 21% increase in the number of antidepressant prescriptions in the United States in February and March of 2020, the highest noted since the start of the pandemic. Such an increase in antidepressant use worldwide raises concerns about the efficacy, safety and impact of long-term use. Globally, the total cost of depression and anxiety disorders is approximately 1 trillion dollars annually, but is there a cost to the health of those taking antidepressants?

Conventional medicine explains the cause of depression as a chemical imbalance in the brain justifying the prescribing of antidepressants. However, there are many treatable underlying causes of depression not sought out or diagnosed by physicians. Most notably, these include hormone deficiencies induced by trauma, environmental toxins, infections and/or aging.

Hormones have a powerful influence on mental health and well-being. Common hormonal imbalances causing symptoms of depression include thyroid, estrogen, progesterone, testosterone and growth hormone. As described in last week’s blog post, depression is a common symptom of low testosterone in men.

What is the basis for treating depression with antidepressants and are they hurting us rather than helping us? This blog post will review the use of antidepressants, the risks and theory behind their use.

Chemical Imbalance in the Brain Not the Cause of Depression After All?

Serotonin is a neurotransmitter or chemical messenger in the brain known for mood regulation. There are various classes of antidepressants. The most prescribed class is SSRIs, selective serotonin reuptake inhibitors, targeting an increase in serotonin in the brain.

The big push for antidepressants in the treatment of depression comes from a theory spanning decades called “the chemical imbalance theory”. This theory hypothesizes decreased neurotransmitter activity in the brain, such as serotonin, is responsible for depression. Pharmaceutical industries and conventional medicine providers promoted this theory when antidepressants came to market. However, in the medical community the theory has recently been debated as research has been done showing contradictory evidence against the use of antidepressants and their efficacy.

There is much unknown about SSRIs’ exact pharmacokinetics and pharmacodynamics, meaning the mechanism of action and how they work in the body. Only a hypothesis explains what they are doing to the brain. Justification for the use of antidepressants was analyzed in a recent 2022 systematic review of decades of research on the topic, calling into question what antidepressants actually do. The authors concluded:

“The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.”

This research is important as the general public was led to believe depression is the result of chemical abnormalities in the brain such as serotonin and other neurotransmitters. The authors state, “The idea depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.” In other words, a fair number of people are taught and encouraged to never come off antidepressants because of the chemical imbalance theory. When people try coming off antidepressants by themselves, 40-50% will have symptoms of withdrawal.

Antidepressants and Quality of Life

Many people placed on antidepressants are told by their doctors antidepressants will improve their quality of life. Is there evidence to support this?

A 2022 study investigated the effect of antidepressants on patient-reported health-related quality of life in adults with depression. Data was analyzed over a period of approximately 11 years in which 17.5 million adults were diagnosed with a depression disorder. During that time period 58% of those diagnosed started antidepressant therapy.

The researchers found there was no significant difference between patients who used antidepressants and those who did not. They conclude antidepressants do not continue to improve patients’ quality of life over time.

Evidence for Antidepressant Use?

A 2018 study assessing 21 different antidepressant drugs concluded all antidepressants were more efficacious compared to placebo in adults with major depressive disorder. This 2018 study was later reviewed and refuted in a 2019 study analyzing all publications assessing benefits and harms of antidepressant drugs compared to placebo from three scientific literature databanks from 1990-2019. They conclude the 2018 study has no clinical relevance, only short-term results were followed, and neither serious nor non-serious adverse effects were assessed.

An analysis of the 2019 study found all previous reviews generally show antidepressants have a statistically significant effect on depressive symptoms but the size of the effect on most patients is questionable, reviewed studies fell short of the threshold for clinical significance, and the risk of serious and non-serious adverse events were significantly increased with the use of antidepressants.

The authors of the study conclude, “The benefits of antidepressants seem to be minimal and possibly without any importance to the average patient with major depressive disorder. Antidepressants should not be used for adults with major depressive disorder before valid evidence has shown that the potential beneficial effects outweigh the harmful effects.”

What Are the Risks?

Many long-term effects of antidepressants remain unknown. The most serious effects of antidepressants are suicide, violent behavior and homicide. In 2007, the FDA advised all antidepressants update the black box warning to include increased suicidality, and patients taking antidepressants should be monitored daily for abrupt changes in behavior.

The risk of suicidality and aggression in children and adolescents treated with SSRIs doubled compared to placebo. A systematic review concludes antidepressants were shown to double the occurrence of suicidality and violence in adults and “the number needed to treat to harm one healthy person was 16.” Women treated with the antidepressant duloxetine for stress urinary incontinence had 4-5 times the risk of suicide and violence.

SSRIs were shown to increase both serious and non-serious adverse effects though non-serious effects are most common. With long term use, the 2019 study found the most troubling adverse effects experienced were sleep disturbances, sexual dysfunction and gastrointestinal problems. These effects may be persistent for some patients even after stopping treatment. Patients often do not have a good understanding of these side effects before starting antidepressants. In addition, withdrawal effects can last up to 4 years after stopping the medication. This withdrawal is akin to “hyper-reactivity closely resembling the neurological sensitization observed in alcohol, amphetamine, benzodiazepine, cocaine, and antipsychotic use.”

Can Antidepressants Affect Testosterone and Estrogen Levels?

There is evidence to show most antidepressants affects estrogen and testosterone levels. Six most common SSRIs were tested in an in vitro study to assess their effect on sex hormone production. “All six antidepressants were found to exert endocrine disrupting effects on hormone synthesis…All resulted in decreased testosterone levels….and increased estrogen/androgen production. Our study demonstrates the potential of SSRIs to interfere with steroid (hormone) production and should be investigated further to determine any hazards for the users.” The authors conclude careful use of these drugs is encouraged due to their endocrine disrupting potential.

A 2021 review showed antidepressants affect circulating levels of testosterone and estrogen. There were varying results for different classes of drugs however more than 50% of reviewed studies showed changes in testosterone and estrogen levels after the administration of SSRI antidepressants.

In small studies, SSRIs have been implicated in the impairment of growth hormone secretion and activity. This has been demonstrated in adolescents treated with SSRIs who experienced a decreased growth rate. Larger dedicated trials assessing the full effect of antidepressants on growth hormone secretion have not been conducted to date.

The conclusion is antidepressants can affect circulating hormone levels and the mechanism to which antidepressants cause this effect is not fully understood. Treating the “chemical imbalance” with antidepressants may lead to further imbalance in the body. Hormone levels should be assessed prior to initiating and during antidepressant therapy.

More Research Required to Understand the Effects of Antidepressants

The research on antidepressants is controversial as demonstrated by several meta-analyses analyzing decades of research. The “chemical imbalance theory” once used to support use of antidepressants for depression has been called into question as evidence to support the decades-long chemical imbalance theory is refuted.

Antidepressants might work for some people but determining who they may benefit and why are remaining questions. Antidepressants have been shown to disrupt the endocrine system.

At this point, the exact mechanism and long-term effects antidepressants have on the brain and endocrine system are unknown. If you are taking an antidepressant, do not abruptly stop it. Tapering off is critical and requires guidance by a medical professional.

If experiencing symptoms of depression, it is imperative to obtain a full work-up to find and treat underlying causes of depression rather than just treating the symptoms.

Have an awesome day! Dr. D