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An adult with acute depression not yet responding to an antidepressant drug has a 1 in 5 chance of substantial symptom reduction between 5 and 8 weeks if they continue taking it. In those unresponsive after eight weeks, 1 in 10 will respond between 9 and 12 weeks.

Changing treatment plans too early can mean needlessly discarding first choice anti-depressants. This is the first systematic review to calculate the proportions of people with a delayed but positive response at different time points.

The study combined results from nine double-blind randomised controlled trials of nearly 3,500 people. The selective serotonin reuptake inhibitors tested are the category of drug that NICE recommends alone or in combination with psychological treatments for moderate or severe depression.

These findings broadly support clinical guidance to wait for 3 to 8 weeks for antidepressants to work. This includes increasing support in the interim rather than switching to a less preferred antidepressant.

Why was this study needed?

Depression affects between 4 and 10% of adults at least once during their lives. A King’s Fund study in 2006 estimated that, between 2007 and 2026, total UK service costs resulting from depression would be £3 billion, and over £12 billion taking into account lost employment. Untreated depression greatly increases suicide risk.

Primary and secondary health services prescribe antidepressants alongside cognitive behavioural therapy and other psychological treatments. After three months of treatment, a half to two-thirds of people will be much improved, compared with around a third taking placebo tablets.

Deciding for how long to wait when an antidepressant does not work quickly can be difficult. Delayed therapeutic effects may lead to people withdrawing from treatment, especially if experiencing side effects. This systematic review aimed to estimate the probability that a person will gain benefit in comparison to placebo if treatment is continued beyond four weeks up to 24 weeks.

What did this study do?

This systematic review included nine trials of 3,466 adults with clinically diagnosed depression receiving either a single antidepressant or placebo. These studies recorded depression symptoms every four weeks from four weeks until at least 12 weeks after the start of treatment.

Trials covered different decades (the 1990s to 2010s), diagnostic criteria, measurement scales and antidepressants. Participants may have received the antidepressant as ‘first-line’ treatment, or been previously treated with an alternative drug or intervention. The sample included adults with additional psychiatric disorders and medical conditions.

The review was well conducted, using Cochrane Collaboration guidelines. Six trials were of good methodological quality, and publication bias was not likely, meaning we can have confidence in the findings.

What did it find?

  • Between 5 and 8 weeks after the start of antidepressant treatment, just over a fifth of unresponsive people had at least a 50% drop in depressive symptoms compared with just over an eighth receiving placebo tablets (22% vs 13%; 5 trials, 1,671 people). Symptoms were measured on clinician-administered rating scales such as the Hamilton Depression Rating Scale.
  • Between 9 and 12 weeks, one-tenth of people who had not responded by the end of eight weeks had this clinically significant level of response compared with very few on placebo (10% versus 2%; 5 trials, 1,671 people).
  • The overall response rates for people on antidepressants were 42% after four weeks, 55% after eight weeks and 59% after 12 weeks. These were all higher than the rates for people on placebo; 29% after four weeks, 38% after eight weeks and 39% after 12 weeks. According to two studies, few people began to respond to antidepressants after taking them for 12 weeks.

What does current guidance say on this issue?

NICE’s 2011 quality standard on depression states that treatment should be reviewed if people have not responded adequately within 6 to 8 weeks.

The NICE 2009 depression guideline gives details for antidepressants. With no or minimal response after 3 to 4 weeks of a therapeutic dose, frequency of support should be increased, and consideration given to dose increase or switching to a different drug, taking side effects into account. If there is partial improvement by four weeks, treatment should be continued for another two to four weeks. If there is no further response, side effects or the person prefers, then switching antidepressants should be considered.

The quality standard is under review.

What are the implications?

Shared individualised decisions are key. The probability of a delayed response may differ according to the specific drug and (if also used) psychological therapy, individual characteristics, clinical features, or concurrent conditions.

Useful improvement can occur in a fifth of people even if they haven’t improved by a month. This might encourage some patients to stick with their first anti-depressant for longer than implied in the NICE guideline. This research did not compare continuation of the same antidepressant with alternatives such as a dose increase, switching to or combining with a different drug, or continuing solely with psychological treatments.

Citation and Funding

Henssler J, Kurschus M, Franklin J, et al. Trajectories of acute antidepressant efficacy: How long to wait for response? A systematic review and meta-analysis of long-term, placebo-controlled acute treatment trials. J Clin Psychiatry. 2018;79(3).



Haddad P, Talbot P, Anderson J, McAllister-Williams H. Managing inadequate antidepressant response in depressive illness. British Medical Bulletin. 2015;115(1):183-201.

NHS. Antidepressants. London: Department of Health and Social Care; updated 2018.

NICE. Depression in adults: recognition and management. CG90. London: National Institute for Health and Care Excellence; 2009, updated 2018.

NICE. Depression in adults. QS8. London: National Institute for Health and Care Excellence; 2011.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


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Selective serotonin reuptake inhibitors are the newer type of antidepressant drug commonly used in clinical practice. They have a lower overdose risk, and generally fewer side effects than other anti-depressants.

Clinical depression rating scales such as the Hamilton Depression Rating Scale measure the severity of symptoms at a specific point in time. They do not give information on long-term recovery, quality of life, or functional outcomes.


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