Did Ketamine Therapy Help Your Bipolar Disorder?

Cochrane

Why is this review important?

Bipolar disorder is one of the most serious psychiatric illnesses. It is characterized by a chronic pattern of relapses in mania (unnaturally elevated mood or irritability and related symptoms with severe functional impairments or psychotic symptoms, lasting seven days or longer), or in hypomania (comparable symptoms with decreased or increased function, four days persistent or longer) and severe depression. The depressive phase of the illness is associated with a greatly increased risk of self-harming behavior or suicide. Current treatments for the symptoms of depression are of limited effectiveness and are generally slow to take effect. One of the most promising alternatives with a different mechanism of action is a new class of drugs called glutamate receptor modulators. New compounds have been tested, especially in unipolar depression. However, recent studies focus on bipolar depression. Some recent reviews attempted to summarize the evidence on the effectiveness of glutamate receptor modulators, but they either focused only on ketamine or did not include relevant data from the very latest studies. For these reasons, a comprehensive and updated summary of all available studies is required.

Who is this review for?

- People with bipolar disorder, their friends and families.

- General practitioners, psychiatrists, psychologists and pharmacists.

- Professionals working in institutions for mentally ill adults.

Which questions does this review want to answer?

1. Is treatment with ketamine and other glutamate receptor modulators more effective than placebo or other antidepressants?
2. Is treatment with ketamine and other glutamate receptor modulators better accepted than placebo or other antidepressants?

Which studies were included in this review?

We searched medical databases to find all relevant studies (mainly randomized controlled trials) that were completed by January 9, 2015. To be included in this review, the studies had to compare ketamine or other glutamate receptor modulators with a placebo or other drugs used to treat adults. We included five placebo-controlled studies, with a total of 329 participants. The studies looked at three different glutamate receptor modulators: ketamine (two studies), memantine (two studies), and cytidine (one study). All studies in this review included participants who were also receiving other drugs (either lithium therapy, valproate, or lamotrigine). In the majority of the studies, the included participants were already receiving these treatments (with insufficient success). We rated the quality of the evidence across the various comparisons as “very low” to “low”.

What does the evidence summarized in this review tell us?

Mainly, effectiveness was measured as the number of patients who responded to treatment. A single intravenous dose of ketamine was found to be better than placebo, but this was based on very limited evidence (two studies with 33 participants) and its effects only lasted up to 24 hours. The evidence on which this result is based was of low quality. In terms of adverse events, there were no differences between ketamine and placebo, despite frequent reports of trance-like states or hallucinations. The very small sample examined in this review may have limited the ability to see real differences. No differences were found between memantine or cytidine and placebo in the number of people who responded to treatment or who experienced adverse effects.

What should happen next?

Ketamine could be an effective drug as add-on therapy to mood stabilizers in people with acute bipolar depression. However, due to the small amount of data available for analysis, we are unable to draw firm or reliable conclusions. The effects of ketamine can come on very quickly, but they are likely to last for less than three days. All studies examining the effectiveness of ketamine used intravenous administration only, which could potentially limit its applicability in a clinical context. Future research should focus on studies comparing long-term use of ketamine (including in combination with other active interventions) in order to be able to draw reliable conclusions about the effectiveness of different treatment modalities. Unfortunately, the present review did not find any reliable information on the tolerability of glutamate receptor modulators. However, adverse effects, especially with repeated treatment with ketamine, remain a major concern in this research area.