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Tricyclic antidepressants, selective serotonin reuptake inhibitors, and St John’s wort reduce symptoms in the short term in depression treated in primary care

Linde K, Kriston L, Rucker G, et al. Efficacy and acceptability of pharmacological treatments for depressive disorders in primary care: systematic review and network meta-analysis. Ann Fam Med. 2015;13:69-79.

Review questions

In adults with unipolar depression (not bipolar or manic–depressive disorder) being treated in primary care (e.g., by family doctors or other health care workers providing general health care), do drugs reduce symptoms more than placebo? Which drug types work best?


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

Depression is more than just being sad and may get worse if not treated. There are many treatments for depression, including different types of drugs.

How the review was done

The researchers did a systematic review of drug treatments, searching for studies that were published up to December 2013.

They found 66 randomized controlled trials with 15,161 people (average age 37 to 78 years, 41% to 100% women).

The key features of the trials were:

  • people were treated in primary care settings;
  • most people had major depression, although some had other depressive disorders;
  • most trials evaluated tricyclic and tetracyclic antidepressants (TCAs) (e.g., amitriptyline, imipramine, dothiepin/dosulepin, clomipramine, desipramine, doxepin, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine , sertraline, citalopram, fluvoxamine, escitalopram), or St. John’s wort (Hypericum perforatum L. extracts);
  • other treatments included serotonin-noradrenaline reuptake inhibitors (venlafaxine), serotonin (5-HT2) antagonists and reuptake inhibitors (trazodone), and noradrenergic and specific serotonergic antidepressive agents (mirtazapine);
  • drugs were compared with one another or placebo; and
  • most people were treated for 6 to 12 weeks.

What the researchers found

For reducing depressive symptoms in the short-term:

  • TCAs, SSRIs, and St John’s wort were better than placebo;
  • other drug types were no better than placebo; and
  • TCAs, SSRIs, and St John’s wort were similar to each other.

For the proportion of patients who stopped taking drugs because of adverse effects in the short term:

  • TCAs and SSRIs were worse than placebo;
  • St John’s wort was similar to placebo; and
  • TCAs, SSRIs, and St John’s wort were similar to each other.

There was not enough information about the effects of drugs when taken for more than 12 weeks.


In adults with depression being treated in primary care, tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors, and St John’s wort* reduce depressive symptoms in the short term. The 3 types of drugs reduce symptoms to a similar extent.

*St John’s wort is available without prescription. If you take St John’s wort, you must inform your doctor as it can interact/interfere with other medications.

Drugs vs placebo for reducing symptoms† in people with depression treated in primary care

Drugs or drug types

Number of trials (people)

Rate of events with drugs

Rate of events with placebo

Absolute effect of drugs

Tricyclic or tetracyclic antidepressants

8 trials (1096 people)



Symptoms were reduced in about 13 more people out of 100 (from as few as 6 to as many as 20)

Selective serotonin reuptake inhibitors

7 trials (1946 people)



Symptoms were reduced in about 12 more people out of 100 (from as few as 8 to as many as 17)


1 trial (154 people)



No effect‡

St John’s wort§

9 trials (1084 people)



Symptoms were reduced in about 18 more people out of 100 (from as few as 9 to as many as 26)

†Score on a depression scale reduced by 50% or more.

‡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 treatments.

§St John’s wort is available without prescription. If you take St John’s wort, you must inform your doctor as it can interact/interfere with other medications.


A harmless, inactive, and simulated treatment.
Randomized controlled trials
Studies where people are assigned to one of the treatments purely by chance.
Systematic review
A comprehensive evaluation of the available research evidence on a particular topic.

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  • 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)

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