Antidepressants, depression & supplements

Antidepressant use is rising at a considerable rate in the UK. In England, between April 2023 and March 2024, antidepressant prescriptions increased by 3.3% to 89 million prescriptions. A huge 8.7 million people are taking prescribed antidepressants, and more than a quarter have been taking them for 5 years or more (source: NHS England). At the same time, research shows that half of the people who have been prescribed antidepressants suffer from side effects.

Mental health is a serious subject. This article is for informational purposes, to help readers understand some of the potential mechanisms behind depression and encourage an exploration of health, diet and lifestyle improvements that have been shown to improve mental health.

Are antidepressants effective?

Unfortunately many people struggle with depression, even after trying a variety of antidepressants. In one study, a placebo-controlled trial found that 30% of people in the placebo group enjoyed an improvement in symptoms, compared to 50% of those in the antidepressant group that saw an improvement, meaning the antidepressants were only effective half of the time and only 20% more effective than the placebo.

The gut and depression

90% of serotonin (our happy hormone), which is in the brain, originates from the gut. Serotonin is made from the amino acid l-tryptophan and is converted into serotonin by probiotics in the gut microbiome. There have been several research studies into the effect that bacteria in the gut has on depression, and they show that disturbances and imbalances in gut bacteria may result in the onset of anxiety and depression. Other studies also show that the Lactobacillus and Bifidobacterium probiotic species can help reduce depression.

Blood sugar and depression

Another important factor in relation to gut health and mental health is our blood sugar levels. Once serotonin has been created in the gut, it travels into the brain on the back of insulin. If blood sugar levels are not stable, or if insulin resistant (prediabetes), the levels of available serotonin in the brain may not be adequate to support mood levels, which may lead to lower moods or depressive tendencies. As a result, managing blood sugar levels as well as maintaining a healthy gut is vital for mental health.

Tryptophan to serotonin pathway

There are several cofactors needed to aid the conversion of tryptophan into serotonin. The nervous system connection to the gut is through the hepatic and coeliac branches of the vagus nerve, a nerve with a huge role in mood regulation, anxiety, and depression. The nerves are stimulated by bacterial byproducts, gut hormones and neurotransmitters, most of which are created in the gut. A study looking at campylobacter jejuni and citrobacter amalonaticus found that these two bacteria induced anxiety. Conversely, research has found that supplementation with Lactobacillus rhamnosus and Bifidobacterium longum alleviated anxiety and depression. The gut microbiome also influences dopamine levels in the frontal cortex.

The 'kynurenine pathway' is another big factor in the link between gut health and neuropsychology. Kynurenine is produced from tryptophan by some pathogenic bacteria, preventing it from being converted into serotonin. Kynurenine is neuroinflammatory and implicated in neurodiversity. The conversion of tryptophan into kynurenine is associated with a reduced level of Lactobacillus reuteri. Inflammatory interleukins are elevated in those with depression. 

Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications.

Best supplements for depression

Omega 3

Omega 3 fats are needed for both the structure and function of the brain, and inadequate levels of these fats can impact our brain function. Studies show that Omega 3 fats help decrease the risk of depression. Another study has found that Omega 3 supplementation combined with antidepressant usage leads to a higher rate of improvement in people with depression when compared to those on antidepressants alone.

B Vitamins

B vitamins are essential for brain health and emotional wellbeing. Among the most studied in relation to mood and mental health are Vitamin B12, Folate (Vitamin B9), and Vitamin B6. These nutrients support the production and regulation of neurotransmitters such as serotonin, dopamine, and GABA, which directly influence mood, sleep, and stress response.

Vitamin B12

Vitamin B12 plays a central role in brain function, nerve health, and red blood cell formation. Research suggests that early Vitamin B12 supplementation in individuals at risk of depression may delay its onset and enhance the efficacy of antidepressants if taking them, and insufficient levels of B12 are associated with a higher risk of developing depression and a poorer response to treatment.

Folate (Vitamin B6)

Folate deficiency is strongly associated with depression, particularly in depression that is resistant to treatment, where patients don’t respond adequately to standard antidepressant therapy. Folate is involved in the methylation cycle, a biochemical process which is crucial for producing neurotransmitters including serotonin and dopamine. A deficiency in Folate can impair this process, leading to lower levels of mood-regulating chemicals in the brain.

There are two forms of Folate - folic acid (synthetic version) and L-methylfolate (the better, active form) - and both have been studied for their impact on mental health. L-methylfolate, in particular, crosses the blood-brain barrier more efficiently and is considered more effective in improving depressive symptoms. In fact, in the United States, L-methylfolate is approved as a medical food supplement for the adjunctive treatment of depression, highlighting the strength of evidence behind its use.

Vitamin B6

Vitamin B6 is essential for neurotransmitters including GABA, serotonin, and dopamine. These neurotransmitters are vital for regulating mood, calming the nervous system, and reducing symptoms of anxiety and depression. Research shows that Vitamin B6 supplementation can significantly reduce symptoms of depression, especially in individuals with low baseline levels or increased need due to stress or inflammation. One study found that participants who took a Vitamin B6 supplement experienced measurable improvements in mood, largely attributed to enhanced GABA activity in the brain — a neurotransmitter known for its calming effects.

Homocysteine and depression

An important biochemical marker that ties Vitamin B12, Folate, and Vitamin B6 together is homocysteine. Homocysteine is an amino acid that, when elevated, is associated with an increased risk of depression, cognitive decline, and cardiovascular issues. High homocysteine levels are often the result of deficiencies in Vitamin B12, B6, and Folate, because these vitamins are necessary to efficiently break down homocysteine. Supplementation of these B vitamins has been shown to lower homocysteine levels and may improve depressive symptoms in individuals with elevated levels.

Vitamin D3 and depression

Low levels of Vitamin D are consistently associated with a higher risk of depression. Vitamin D receptors are present in brain regions involved in mood regulation, and deficiency has been linked to both seasonal affective disorder (SAD) and major depressive disorder.

A 2020 meta-analysis concluded that Vitamin D supplementation had a significant moderate effect on depressive symptoms, particularly in people who were deficient in Vitamin D.

Magnesium

Magnesium is involved in hundreds of biochemical reactions in the body, including those related to the nervous system and neurotransmitter activity. Low magnesium levels are frequently observed in people with depression. In one randomised controlled trial, magnesium supplementation was shown to improve mood within two weeks, particularly in people with mild-to-moderate depression. Magnesium may also help reduce anxiety and improve sleep, which can indirectly support mood.

Zinc and depression symptoms

Zinc plays a key role in synaptic plasticity and neurotransmitter function. Low zinc levels have been linked with depression, and supplementation may enhance the effectiveness of antidepressant medication. One study found that people with major depression had significantly lower serum zinc levels. Zinc supplementation has been shown to improve mood and reduce depressive symptoms, especially when combined with conventional treatment.

Lifestyle changes and depression

Changes in lifestyle are also important for managing one's mood and combatting depression. Exercise has a wealth of research for mood enhancement and depression. A systematic review and network meta-analysis of randomised controlled trials concluded that exercise is an effective treatment for depression. It concluded that walking, jogging, yoga, and strength training are the most effective compared to other exercises.

Community and belonging

Community and belonging are essential components of human connection. It is vital for overall health and wellbeing. Research has found that people with a neutral sense of community were 2.2 times more likely, and those with a negative sense were 5 times more likely, to have moderate to severe depression symptoms compared to those with a positive sense of community.

Summary

While these supplements and lifestyle factors have good supportive evidence, it's important to remember that they work best as part of a holistic approach including diet, movement, sleep, and emotional support. Always consult a healthcare professional before starting a new supplement, especially if you're taking medications.