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New treatments for treatment resistant depression: exercise, healthy diet, and ketamine.

Major depressive disorder, or MDD, affects 10-15% of people over their lifetime. The current standard of care includes cognitive behavioral therapy and several classes of medications, mainly Selective Serotonin Reuptake Inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs). The combination of cognitive behavioral therapy and medical treatment has proven to be more effective than any other treatment on its own. As well, it is estimated that over 50% of patients do not respond to antidepressants and develop resistance to these drugs. In many cases treatment failure can be attributed to the way a person metabolizes these medications. Fortunately, pharmacogenetic testing can provide insights in to antidepressant intolerance. Test results can be used to adjust medications for people who do not metabolize antidepressants normally. People who metabolize these drugs normally and who fail to respond them require supplementary treatment. Research shows that exercise, weight control, improved nutrition, and supplements, can help in major depressive disorder treatment. More recently, the drug ketamine has been shown to be an effective treatment as well.

Physical Exercise

Exercise is important for both prevention and depression treatment. Resistance training and other forms of physical exercise induce a variety of substances called neurotransmitters in the brain. This includes endorphins, the feel-good hormones, and the Brain-Derived Neurotrophic Factor, which plays an important protective role in the brain. These neurotransmitters reduce the risk of depression and cognitive decline. An analysis of a number of studies showed that resistance training was associated with a significant reduction in depressive symptoms. The effect of physical activity has moderate response rate: it is estimated that one of the 4 people in the study achieved remission (Number Needed to Treat=4). For comparison, the Number Needed to Treat for an antidepressant is around 7.

Physical activity has a moderate effect reducing the symptoms of depression. It is estimated that for every 4 people who undergo treatment that focuses on exercise, one will achieve remission. For comparison, you would need to treat 7 people with medication for one person to achieve remission.

Of all the factors considered in the studies, the most important factor was the commitment and adherence to regular training sessions- 15 minutes of strenuous activity or 1 hour of moderate exercise was needed to reduce the risk of developing depression by 26%. The adherence to a regular exercise program was quite difficult for majority of healthy people and can be much more challenging for people with depression if they’re suffering from low energy levels. Healthcare providers and family members should encourage people with depression to undertake regular exercise to improve mental and cardiovascular health.

Nutrition and weight management

Obesity and poor nutrition are known risk factors for developing depression. The Mediterranean diet has been found to be one of most effective nutritional approaches to help reduce the risk of cardiovascular disease and diabetes. The SMILES trial investigated the effect of the Mediterranean diet on major depression. Study participants received dietary advice focused on motivational interviewing, goal setting, and mindful eating have shown greater improvement of depression compared with social support for patients with depression. The dietary counseling had greater effect on depression patients who also had type 2 diabetes.
The RAINBOW trial confirmed that weight loss treatment and problem-solving therapy improved depression symptoms for overweight people. The treatment lead to significant reduction in both mean body mass index and depression scores after 12 months of treatment. The therapy effect was significant but led to only to modest reductions in symptoms suggesting that lifestyle interventions should be used to augment drug and psychological treatment but not alone to treat depression. Similarly, specific supplements can help to improve depression management, but do not have sufficient impact to treat depression alone.


Ketamine is an anesthetic drug that has shown remarkable impact on treatment-resistant depression. The Food and Drug Administration in the US has recently approved nasal esketamine (Spravato), for treatment-resistant depression. A low dose of ketamine produced rapid and lasting effects on depressive scores and suicidal thoughts in treatment-resistant depression patients. Because ketamine induces confusion and dissociation, close monitoring is required during and after the drug is administered. Ketamine has the potential to be abused potential and abuse can lead to drug tolerance. Ketamine can help to treat major depression but it is very costly and is not covered by some insurance plans. Ketamine treatment weekly or twice a week administration can cost between $4,720 to $6,785 for the first month of treatment.

NSAIDs and Brexanolone

Non steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen, naproxen, celecoxib and other drugs can play important role in depression treatment. An analysis of 36 studies with over 9,400 patients shows that these drugs can have a medium to large effect when used to treat depression when they’re combined with antidepressant drug treatment.

Brexanolone, a synthetic form of steroid hormone allopregnanolone, high levels of which are present in the blood during pregnancy, was recently approved for postpartum depression. It is not yet approved in Canada and might cost up to $34,000 per patient for a course of treatment. Other new approaches such as psilocybin, and transcranial magnetic stimulation are being investigated for the treatment of depression but there is still not enough evidence on their effectiveness.

In summary, there is recent evidence to support new approaches for depression treatment. And if If you are suffering from treatment resistant depression, you can help yourself by starting regular physical exercise. If you also carry extra weight, nutrition and weight management counseling may help with your symptoms. Pillcheck can help as well: your genes impact how your body processes and responds to antidepressants and other medications. Personalized medication optimization with Pillcheck can help you and your doctor find which antidepressant is the safest for you, and which ones could cause side effects or be less effective including SSRIs and ketamine.


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