Personalized use of ketamine and esketamine for treatment-resistant depression

Summary & key facts

This paper reviewed research on using ketamine (given through a vein) and esketamine (given as a nasal spray) for people whose major depression has not improved with usual treatments. The authors found that these drugs can work quickly for hard-to-treat depression, but not everyone gets better. Some clinical clues and brain measurements may help predict who will respond, but the signs found so far are only modestly useful and more consistent, larger studies are still needed before doctors can reliably personalize treatment.

Key facts:

• Both intravenous ketamine and intranasal esketamine are rapid-acting treatments that can reduce symptoms in people with treatment-resistant depression.
• Not everyone responds to ketamine or esketamine; response varies a lot between people.
• A family history of alcohol use disorder before treatment and a personal history of serious childhood trauma before treatment have been linked to a stronger response to ketamine in some studies.
• A change in brain activity measured by EEG — specifically an increase in fast brain waves called gamma in front-and-side brain regions after treatment — looks like a promising sign that ketamine is working.
• Blood tests have so far been of limited help. The most consistent blood change is a small rise in a protein called BDNF, but that effect is weak.
• How much someone experiences dissociation (a feeling of being detached or unreal) during treatment usually does not predict whether they will get better from ketamine or esketamine.
• Most predictors found so far have only small effects. That means combining many pieces of information into a single prediction model will probably be needed to improve accuracy.
• The field needs studies that measure clinical signs and biomarkers the same way across different research groups so results can be compared and trusted more easily.

Abstract

A large and disproportionate portion of the burden associated with major depressive disorder (MDD) is due to treatment-resistant depression (TRD). Intravenous (R,S)-ketamine (ketamine) and intranasal (S)-ketamine (esketamine) are rapid-acting antidepressants that can effectively treat TRD. However, there is variability in response to ketamine/esketamine, and a personalized approach to their use will increase success rates in the treatment of TRD. There is a growing literature on the precision use of ketamine in TRD, and the body of evidence on esketamine is still relatively small. The identification of reliable predictors of response to ketamine/esketamine that are easily translatable to clinical practice is urgently needed. Potential clinical predictors of a robust response to ketamine include a pre-treatment positive family history of alcohol use disorder and a pre-treatment positive history of clinically significant childhood trauma. Pre-treatment versus post-treatment increases in gamma power in frontoparietal brain regions, observed in electroencephalogram (EEG) studies, is a promising brain-based biomarker of response to ketamine, given its time of onset and general applicability. Blood-based biomarkers have shown limited usefulness, with small-effect increases in brain-derived neurotrophic factor (BDNF) being the most consistent indicator of ketamine response. The severity of treatment-emergent dissociative symptoms is typically not associated with a response either to ketamine or esketamine. Future studies should ensure that biomarkers and clinical variables are obtained in a similar manner across studies to allow appropriate comparison across trials and to reduce the signal-to-noise ratio. Most predictors of response to ketamine/esketamine have modest effect sizes; therefore, the use of multivariate predictive models will be needed.

Topics

Functional Brain Connectivity Studies Treatment of Major Depression Tryptophan and brain disorders

Categories

Health Sciences Medicine Pharmacology

Tags

Anesthesia Cognition Depression (economics) Dissociative Economics Ketamine Macroeconomics Major depressive disorder Medicine Neurology Psychiatry Treatment-resistant depression

Substances

Ketamine

Conditions & symptoms

Addiction Depression Sadness or low mood