Each year brings another increase in the prevalence of antidepressant use and the rise is unlikely to abate any time soon. Between the years 1999 and 2014, there was a 64 percent increase in the number of people taking antidepressants, and as of 2017, 12.7 percent of the U.S. population over the age of 12 are taking antidepressants. Even more concerning is the increased use of antidepressants in children. Despite the black box warnings that were mandated in 2004, data from regional or national databases of five main developed countries (Denmark, Germany, the Netherlands, the United Kingdom, and the United States) found a substantial increase in antidepressant use among children and adolescents.

The most commonly prescribed antidepressants fall into three groups: Tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and selective serotonin noradrenaline reuptake inhibitors (SSNRIs). Being on the market longer than any other type of antidepressant, TCAs are considered first generation antidepressants. They are rapidly absorbed in the gastrointestinal tract and exert their therapeutic effects by inhibiting presynaptic reuptake of norepinephrine and serotonin, which increases the levels of these neurotransmitters. They also block numerous receptors such as peripheral alpha-adrenergic, histaminic, muscarinic and central serotonin receptors. As a result, undesirable side effects are most commonly experienced among those taking TCAs. Examples of TCAs include:

• Amitriptyline
• Amoxapine
• Desipramine (Norpramin)
• Doxepin
• Imipramine (Tofranil)
• Nortriptyline (Pamelor)
• Protriptyline (Vivactil)
• Trimipramine (Surmontil)

Micronutrient depletion is a common outcome of antidepressant use, but one which is rarely recognized or listed among the plethora of side effects. It is especially concerning for long-term users which classify most antidepressant users, according to an analysis reported in 2018 in the New York Times.

Niacin (Vitamin B3)

Individuals taking antidepressants may be at risk for developing a niacin deficiency. Many antidepressants inhibit the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), which is required for the de novo synthesis of niacin. Since niacin is involved in more than 500 intracellular reactions, a deficiency often contributes to neuropsychiatric and neurodegenerative disorders, for which antidepressants are often prescribed. The niacin deficiency may make it difficult to assess the efficacy of antidepressants, causing the practitioner to increases dosing unnecessarily.

Folate

Folate may be another micronutrient at risk for being depleted by antidepressants and contributing to depressive symptoms. Various studies including randomized controlled trials have noted a clear link between low serum folate levels and depression; however, many subjects resistant or non-respondent to antidepressant therapy showed significant improvement and much greater drug efficacy when given folate alongside traditional therapy.

Coenzyme Q10

Tricyclic antidepressants have been shown to inhibit coenzyme Q10-dependent enzymes, impair mitochondrial function and increase oxidative stress in in vitro assays. When mice were treated with Anitriptyline for two weeks, coenzyme Q10 was strongly decreased in liver and lung tissue, and lipid peroxidation was increased in a dose-dependent manner in liver, lung, kidney, brain, heart, and skeletal muscle tissues, further implying a deficiency of coenzyme Q10. As a major player in energy, fatigue, and oxidative stress, mitochondrial function is important for various psychiatric conditions. Mitochondrial dysfunction has been implied as an element in the pathology of depression.

Calcium and Vitamin D

Antidepressants may not only cause specific micronutrient depletion, but may increase the need for micronutrient supplementation to combat side effects linked to antidepressant use. For example, a systematic review and meta-analysis published in 2018 found an association between risk of fracture and the use of SSRIs which was not accounted for by age since it affected all age groups and the risk increased with greater antidepressant use. This association was also reported in an earlier systematic review and meta-analysis which encouraged clinicians to consider bone mineral density screening before prescribing SSRIs, specifically. While the exact mechanism behind this link is not fully understood, there is an association between depression and a lack of vitamin D. It is also known that osteoblasts, osteoclasts, and osteocytes possess serotonin receptors. Therefore, supplementing with calcium and vitamin D is important for combatting the decrease in bone mineral density among antidepressant users.

Many drugs have been found to deplete the body of vital micronutrients and antidepressants are not excluded from this list. Also, depression has been linked to numerous micronutrient deficiencies, further supporting the fact that the brain requires these critical nutrients to help maintain healthy neurotransmitter balance. As antidepressant therapy continues to rise, so must the requirement for additional micronutrients to help support neurotransmitter balance, energy production, and a positive outlook on life.