Studies of the use of ketamine for patients with depression have not adequately assessed side effects, particularly when the drug is administered in repeated doses, according to the first systematic review of the safety of ketamine in the treatment of depression.
“Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users,” investigators led by Colleen Loo, MD, University of New South Wales, Sydney, Australia, write.
The study was published online July 27 in Lancet Psychiatry.
An Afterthought?
“Studies over the last 15 years have reported truly remarkable antidepressant effects for ketamine. However, much less has been written about the safety of its use, an equally important aspect,” Dr Loo told Medscape Medical News.
In particular, she said, most studies have focused on side effects that occur within 2 to 4 hours of administration. There is far less information on safety beyond this timeframe, as well as on safety of repeated doses of ketamine.
“The latter is important,” said Dr Loo, “because the antidepressant effects of a single dose often wear off after a few days, and researchers and some clinicians are now giving a treatment course, where repeated treatments of ketamine are given, spaced a few days apart. However, there is limited evidence in the published literature about the safety of this approach.”
To review side effects associated with ketamine use in depression, the team searched MEDLINE, PubMed, PsycINFO, and Cochrane databases. They identified 288 articles, of which 60 were included in their review.
They found that acute side effects associated with a single dose of ketamine in depression are common, although they are generally transient and resolve spontaneously.
Psychiatric, psychotomimetic, cardiovascular, neurologic, and other side effects were more commonly reported after acute ketamine administration than after placebo. The most commonly reported side effects were headache, dizziness, dissociation, elevated blood pressure, and blurred vision. Anxiety was the most common psychiatric side effect.
However, said Dr Loo, “a different set of side effects may occur after repeated and cumulative use. These include effects on the liver, bladder, and possibly memory and thinking. It is important that these are thoroughly examined before the widespread clinical use of ketamine.”
Most of the reported side effects were associated with intravenous administration, the authors note.
They write that, on the basis of their review, “active assessment, surveillance, and reporting of side effects during trials of ketamine for patients with depression are inadequate.”
No Assessment of Long-term Risks
In the trials they reviewed, many side effects were assessed through passive monitoring only. If an assessment of side effects was completed, it was predominantly reported in ad hoc form, they write.
From this analysis, the investigators could only draw conclusions regarding single dosing and acute side effects, because “insufficient data were available regarding the side effects of repeated dosing and possible cumulative and long-term risks.”
“The absence of information does not mean we can assume it is safe,” said Dr Loo.
“We need more information about this, and also to know what monitoring is required over weeks to months when ketamine is given repeatedly. I think it is likely that we can give repeated doses of ketamine safely, with careful and adequate medical supervision and monitoring. We are examining this carefully in our current research trial at the University of New South Wales and Black Dog Institute.
“Ketamine is a drug with amazing potential for the treatment of depression. It is important that we develop its use carefully and responsibly so that we have the best chance of developing it as a truly useful treatment. In order to do this, we need to carefully evaluate safety as well as efficacy,” she added.
Dr Loo and colleagues are developing and validating the Ketamine Side Effect Tool and the Ketamine Safety Screening Tool for these purposes.
For now, she said, “anyone giving ketamine, either single or repeated doses, should thoroughly familiarize themselves with the existing literature and put in place detailed safety monitoring so that patients are not placed at risk. In our current trial, we are doing extensive safety monitoring, as what monitoring is required is currently not known. From this study, we will then be able to distill what level of monitoring is subsequently recommended for clinical practice.”
Good and Fair Review
Reached for comment, Roger Ho, MD, MRCPsych, associate professor and consultant psychiatrist, National University of Singapore, said, “This paper is a good and fair review.”
Prof Loo is a “renowned researcher who has been using ketamine to treat depressive disorder. This is one of the few articles which ketamine researchers admit potential risks of ketamine and study the side effects by systematic review. It is important to highlight the serious side effects when patients use ketamine on a long-term basis to treat chronic medical or psychiatric condition,” said Dr Ho.
Echoing the authors, Dr Ho said, “We definitely need more data on the safety of ketamine. So far, researchers are not able to confirm the acute mood elevation effect of ketamine is a real antidepressant effect and not due to ‘drug high’ effect. If ketamine is used to treat depressive disorder, there is high risk of diversion and misuse.
“Clinicians should not idealize ketamine and offer unrealistic promises to patients. I have seen cases when psychiatrists were overconfident with ketamine and stopped conventional antidepressants. Conventional antidepressants work well, and we should not devalue existing treatment. If a psychiatrist is good at augmentation with different antidepressants and other psychotropic medication, patients do not need ketamine treatment,” he added.
The study had no commercial funding. Dr Loo has received fees for attending a Janssen advisory board meeting. Dr Ho has disclosed no relevant financial relationships.
Lancet Psychiatry. Published online July 26, 2017. Abstract
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