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In people with major depression who haven’t been treated before, there are several equally effective treatment options

Gartlehner G, Gaynes BN, Amick HR, et al. Comparative Benefits and Harms of Antidepressants, Psychological, Complementary, and Exercise Treatments for Major Depression: An Evidence Report for a Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;164:331-41.

Review question

In people with major depression who haven’t been treated before, are antidepressant drugs any better or worse than other therapies?


Depression is a common mood disorder that affects how you feel, think, and behave. It may be mild or more severe and persistent (major depression). Symptoms include feeling sad, losing interest in things you like to do, having trouble thinking or concentrating, or feeling anxious or restless.

Depression is more than just being sad and may get worse if not treated. There are many treatments for depression including drugs, psychotherapies, and other treatments (e.g., exercise, acupuncture, supplements).

The research

45 studies (randomized controlled trials) that were published up to September 2015.

The studies included outpatients who had a diagnosis of major depressive disorder. Most were women with an average age of about 35 to 45 years.

Studies compared antidepressant drugs (mostly fluoxetine, sertraline, paroxetine, venlafaxine, citalopram, or escitalopram) with other therapies, including psychotherapies (mainly cognitive-behavioural therapy [CBT] or interpersonal psychotherapy), St. John’s wort, acupuncture, exercise, omega-3 fatty acid supplements, or S-adenosyl-L-methionine (SAMe) supplements.

Therapies lasted for at least 6 weeks, and most studies treated people for 12 weeks or less.

What the researchers found

Compared with antidepressant drugs:

  • CBT and St. John’s wort reduced depression in about the same number of people at up to 16 weeks of therapy;
  • fewer people using St. John’s wort stopped therapy because of an adverse event; and
  • about the same number of people having CBT stopped therapy because of an adverse event.

We don’t have enough information about how well other therapies work compared with antidepressant drugs.


In people with major depression who haven’t been treated before, antidepressant drugs, cognitive-behavioural therapy, or St. John’s wort work about equally well.

Antidepressant drugs vs other therapies in people with major depression who haven’t been treated before



Number of trials and people

Outcome rate with antidepressant drugs

Outcome rate with other therapy

Absolute effect of antidepressant drugs

Antidepressant drugs vs CBT

Response rate

5 trials (660 people)



No difference in effect at 8 to 16 weeks*


Stopped treatment because of adverse events

3 trials (441 people)



No difference in effect*

Antidepressant drugs vs St. John’s wort

Response rate

9 trials (1,517 people)



No difference in effect at 6 to 12 weeks*


Stopped treatment because of adverse events

9 trials (1,651 people)



About 3 more people out of 100 stopped therapy because of an adverse event (from as few as 1 to as many 6 out of 100)

CBT = cognitive-behavioural therapy.

*Although the rates for the 2 groups look a little different, the differences were not statistically significant. This means that the differences could simply be due to chance rather than due to the different therapies.


Randomized controlled trials
Studies where people are assigned to one of the treatments purely by chance.

Related Evidence Summaries

Related Web Resources

  • Depression

    Informed Health Online
    Depression is a common mood disorder that can make it hard to cope with everyday life. Causes and risk factors for depression include genes, difficult experiences and life circumstances, chronic anxiety disorders, biochemical changes, medical problems, and lack of light. Psychological therapies (e.g., cognitive behavioral therapy) and medication, alone or combination, are treatment options.
  • Medicines for Treating Depression: A Review of the Research for Adults

    This patient decision aid helps adults diagnosed as being depressed decide on the type of medicine by comparing the benefits, risks and side effects of each antidepressant.
  • Patient education: Delirium (Beyond the Basics)

    UpToDate - patient information
    Delirium is the result of brain changes that lead to confusion, lack of focus and memory problems. There is no specific treatment for delirium - it is best to avoid risks, treat underlying illnesses and receive supportive care. Sedatives and physical restraints should be avoided.
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