Why is this review important?

Depression is one of the most common mental disorders, estimated to affect 350 million people worldwide. Antidepressant medication tends to be given as a first treatment for people with major depression. Antidepressants are however only effective in about two out of three people. Effective alternative medications to treat depression are needed. A new group of medications is called ‘glutamate receptor modulators’. This group includes the medicine ketamine. In this review we examined the evidence for glutamate receptor modulators, including ketamine, as a treatment for depression.

Who will be interested in this review ?

- People with depression, their friends and families.

- General practitioners, psychiatrists, psychologists and pharmacists.

- Professionals working in adult mental health services.

What questions does this review aim to answer?

1. Is treatment with ketamine and other glutamate receptor modulators more effective than treatment with placebo (dummy pill) or other antidepressants?

2. Is treatment with ketamine and other glutamate receptor modulators more acceptable than placebo or other antidepressants?

Which studies were included in the review ?

We searched medical databases to find all relevant studies (specifically randomised controlled trials) completed up to 9 January 2015. To be included in the review , studies had to compare ketamine or other glutamate receptor modulators with placebo , other medicines or electroconvulsive therapy (ECT) for depression in adults (aged 18 and over). We included 25 studies in the review , involving a total of 1242 people. The studies investigated 11 different glutamate receptor modulator medications. The majority of participants had severe depression at the start of the studies. Nine of the studies included only people with 'treatment resistant' depression (people who had not responded to appropriate courses of at least two different antidepressants).

What does the evidence from the review tell us?

Among the 11 drugs included in this review , only ketamine was more effective than placebo at reducing symptoms of depression. These effects lasted no more than one week after treatment and clearly disappeared after two weeks. Ketamine did, however, cause more confusion and emotional blunting than placebo . These findings were based on low quality evidence.

In one study more people showed symptom reduction up to one week after treatment with ketamine compared to the antidepressant, midazolam. This evidence was of low quality.

Findings from one study also showed greater symptom reduction for ketamine compared to ECT up to 72 hours after treatment, but not after one or two weeks. This was based on very low quality evidence.

The glutamate receptor modulator sarcosine was more effective than the antidepressant citalopram at reducing symptoms at four weeks, but not at two weeks. This evidence was rated as low quality.

There was no evidence of a difference between the other nine glutamate receptor modulators included in this review and placebo or other medications. This was based on very low to moderate quality evidence.

What should happen next?

This review provides limited evidence that ketamine reduces symptoms of depression compared to placebo . This effect continues for up to one week after treatment, but there is less certainty about how long this lasts for. Evidence for the other glutamate receptor modulators is lacking. Ketamine appears to have promise as a treatment for depression, however it is important to note that in some trials attempts to prevent participants and investigators from knowing what medicine was being given were not successful. Very few trials were included in the statistical analyses and so we can only draw tentative conclusions about its effects at this stage. There is a clear need for further trials of glutamate receptor modulators so that clearer conclusions can be drawn.