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Matthew J. Edlund M.D.


Are the Most Effective Antidepressants the Least Used?

Antidepressants do work—but the best you may never have heard of.

Source: Quentin Gellar at Pexels
Source: Quentin Gellar at Pexels

Do antidepressants really work to treat depression? A new, six-year meta-analysis amalgamating hundreds of the best-performed clinical trials has demonstrated that antidepressants are better than placebos.

The study, published in the Lancet, showed modest effects, positively affecting about 60 percent of people treated. The drugs varied in efficacy, ranging between about one-third to twice as effective as a placebo. What may be most surprising: Drugs that are rarely prescribed or not at all used to treat depression in the U.S. had the best profiles for efficacy and acceptability. What many have argued are the best overall anti-depressants, MAOIs, were not studied at all.

What Was Found

The study, performed by a group of international epidemiologists led by Dr. Andrea Cipriani of Cambridge, looked at literally thousands of trials, of which 522 were thought to be of sufficient quality to pool together. A total of 116,477 subjects were treated in those trials, many of which came from drug company projects that were never published.

The study was relatively exhaustive regarding issues of bias, a major problem in looking at antidepressants. The 289-page appendix is, in many ways, the heart of the study and shows how many confounding factors remain in understanding its results. But some of the main points can be summarized here:

1. All the 21 antidepressants with sufficient clinical data to be pooled were more effective than the placebo. That included atypical antidepressants, like trazodone and mirtazapine, the latter of which was ranked second for efficacy.

2. Those that were most efficacious, as defined by the highest odds ratio greater than the placebo, were not the same group as those most acceptable to patients, as defined by dropouts.

3. The study mainly looked at moderate depression researched for only two months, a standard trope used by governments to determine whether drugs can enter the market. It does not tell much about how useful antidepressants are for anxiety disorders, where they are perhaps most effective; how effective they are in the long-term remission of symptoms; how well they work in children; or how effective they are in the many other uses to which they are put, like treating OCD and panic disorder.

4. The overall effectiveness of these antidepressants appears to be like that of CBT (cognitive-behavioral therapy) over the short term.

Public Health Implications

Perhaps only about one in six people with depression in developed countries receive effective treatment for depression, and perhaps one in 27 in less developed nations. Many patients quit antidepressants within a month.

Depression is often listed as one of the top three causes of the global burden of disease, destroying the effectiveness of many workers in their prime productive years with major economic effects beyond the problems depression creates for suicide, communities, and families.

Treatment Implications

The most effective drug, as defined by odds ratio response, was amitryptiline. When used today in the U.S., amitryptiline is primarily tried as a drug for chronic pain, or in some cases, for its sedative effects. Despite its heavy anticholinergic side effects, amitryptiline was ranked sixth out of the 21 for overall acceptability.

The most acceptable drug to patients, agomelatine, is not available in the U.S. A unique atypical antidepressant, blocking melatonin and one of the main serotonin receptors, agomelatine helps resets biological clocks and is felt to be particularly useful in treating the sleep difficulties of depression. Due to the poor results of one study, its testing for U.S. approval stopped in 2011.

Amitryptiline is part of one of the first types of antidepressants devised, the tricyclics, first used in the 1950s. It and clomipramine, generally used only for OCD, were the only tricyclics to make the study list. Other drugs of the class that are generally considered easier to use, like desipramine and nortriptyline, were so understudied they did not make it into consideration.

Lack of research remains a big problem with antidepressants. Many drug companies have given up on the field, just as they have given up on antibiotics. Bacterial infections and depression are leading causes of the global burden of disease.

Perhaps most interesting, MAOIs, considered by many as more effective than tricyclics, are now virtually vestigial. The problems they create in terms of drug interactions and dietary restriction, plus the lack of recent marketing, cause many American internists to refuse to allow their patients to consider them. Many doctors have never heard of MAOIs.

Internists and GPs, who give more antidepressants to patients than psychiatrists due to the peculiarities of American health care, are far more comfortable with SSRIs. Serious overdoses are less problematic than with tricyclics. Escitalopram and paroxetine did fairly well among SSRIs in the Cambridge Study rankings for efficacy, ironic as paroxetine has often been pilloried for its sedation and supposed lack of effectiveness. Common drugs like Prozac (fluoxetine), which do worse than light therapy in clinical trials, did not come out so favorably.

Bottom Line

Antidepressants work. They work modestly well to treat garden-variety depression. They work better in conjunction with CBT and other psychotherapies, light therapy, and exercise. Combined treatment is best, as the overall efficacy and remission rates remain rather poor for any single treatment of depression.

But in an age where "new" treatments like hallucination-inducing ketamine are heralded as breakthroughs, the oldest drugs may work best. In a “natural experiment” in Germany, when the government decided it was being gouged by the makers of SSRIs, a clinical population shifted back to the old tricyclics demonstrated shorter hospital stays and better overall results. In previous trials, the MAOIs were often demonstrated to be the best drugs in elderly and Bipolar depressed patient groups, and are hardly even discussed today.

Given that many patients do not respond well to antidepressants, that’s a mistake.

Not uncommonly, as in the case of chlorthalidone, “old” drugs may prove superior to new ones in overall efficacy.

Those who forget the past may neglect the future.


About the Author

Matthew Edlund, M.D., researches rest, sleep, performance, and public health. He is the author of Healthy Without Health Insurance and The Power of Rest.