Can antidepressants lead to depression?

A recent German epidemiological study (https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehy694/5195184) suggests that there may be no benefit to treating people with stage 1 hypertension (systolic blood pressure between 130-139 and diastolic blood pressure of 80-89) with antihypertensives for anyone apart from the drug companies who could almost double their patient populations by having almost 2 thirds of adults diagnosed with elevated blood pressure.

Not only is there no benefit, but there is a potential risk of great harm.

This German study, where more than 11 000 mostly middle aged men and women were followed up over a 10 year period, revealed that cardiovascular mortality rates were pretty much identical for people told they have normal blood pressure. The study was part of the MONICA trial, and was done from 1984-1995, so rather a long time ago now. Perhaps this explains the very high prevalence in cigarette smoking of 1 in 4 to 1 in 5 people. Also the rate of type 2 diabetes is probably higher now. Despite this, the results of this part of the study were only published in November 2018.

Apart from the interesting finding that people with stage 1 “hypertension” did not have elevated mortality rates, they also noticed that there was a greatly increased likelihood of people treated with antihypertensives to complain of depressed mood. People with stage 2 hypertension who were treated with antihypertensives had a prevalence for depressed mood of 47%. On the other hand people with stage 2 hypertension who were not on antihypertensives had a prevalence of 33% (P<0.0001).

The authors explained this difference by the stress and anxiety of being labeled with hypertension, which is possible. However, people with stage 2 hypertension were also more likely to be obese, suffer from type 2 diabetes, have high cholesterol and be less physically active, but to smoke slightly less, so we need to consider whether other factors may have contributed to their depression.

Now that we know that depression is another condition caused by increased inflammation and oxidative stress (just like obesity, hypertension, type 2 diabetes and heart disease, ie the metabolic syndrome) it is easy to see how depression would fit in with other metabolic diseases (and depression does track with diabetes, and obesity). However, I’d expect the rates of depression to be similar in all stage 2 hypertensives for this reason.

On the other hand lovastatin (the first statin) was first marketed by Merck in 1987. I do not know when it was first used in Germany, but I imagine it was probably fairly soon after this. Certainly statins were being used in Germany fairly regularly by the mid 1990s, although their use has continued to rise over the years. Use of a statin is believed to be causal in depression (statins are both antimicrobial agents acting as antibiotics to alter gut flora, and toxic to mitochondria, increasing oxidative stress). Antihypertensives may simply be a marker for medication use, particularly statins and glucose lowering medications.

However, there is another possibility, and that is that antihypertensives themselves can result in depressed mood. Older antidepressants, like calcium channel blockers, can cause insulin resistance (since calcium is necessary for the cell signaling that causes insulin to be released, and also for many of the cellular effects of insulin in promoting things like GLUT4 receptor transportation to the cell membrane, and in neurotransmitter function, release and in the synapse. Calcium channel blockers have in fact been associated with an increased risk in suicide in many previous studies. Diuretics result in depletion of many micronutrients, not just sodium and potassium. The water soluble B vitamins, vitamin C, zinc, calcium and magnesium are also depleted, which can easily impair mitochondrial function, immune cell function and cause oxidative stress and inflammation, as well as contribute to metabolic acidosis and dehydration, so depression as a side effect would be expected, if good quality studies on the matter had been performed. Reserpine, methyl dopa and beta blockers have also all been associated with depression. Beta blockers have been associated with increased suicide risk. Beta blockers deplete coenzyme Q10 and melatonin, two exceptionally important endogenous antioxidants, so this shouldn’t be much of a surprise. Some studies have also linked ACE inhibitors with depression.

Overall the evidence that the antihypertensives are causal in the development of depression is looking more likely to me. Also we know that similar dietary and lifestyle changes can help to manage weight, reverse type 2 diabetes, lower blood pressure, reduce inflammation, and even help with the symptoms of depression. These positive results have all been confirmed in clinical trials. The dietary changes involve eliminating sugar, refined carbohydrates, ultra-processed and highly processed foods, and replacing them with real foods, including meats and animal products. The lifestyle changes involve stress reduction techniques like meditation, yoga, walking, exercise, and stopping smoking. Even reducing time spent on social media may be helpful.

What do you think?

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