Personalized use of ketamine and esketamine for treatment-resistant depression

Summary & key facts

Researchers reviewed studies of intravenous ketamine and nasal esketamine for people whose major depression did not get better with usual treatments. They found these drugs can work quickly for treatment-resistant depression, but not everyone benefits. Some personal or brain measures may help predict who will improve. The best clues so far are a family history of alcohol problems, a history of serious childhood trauma, and a specific change in fast brain waves after treatment. Blood tests show only very small changes. Most predictors are weak on their own, so combining several measures and using consistent methods will be needed to make dependable, usable tests for doctors.

Key facts:

• Intravenous ketamine and intranasal esketamine can act quickly and can help people with treatment-resistant depression, but individual responses vary.
• Having a family history of alcohol use disorder before treatment was linked to stronger improvement after ketamine in some studies.
• A history of significant childhood trauma before treatment was also linked to a better response to ketamine in some studies.
• In brain-wave tests, an increase after treatment in fast "gamma" waves across front and side brain regions is a promising sign that someone will respond to ketamine. EEG means measuring electrical activity from the scalp.
• Blood tests have not been very useful so far. The most consistent blood finding is a very small rise in brain-derived neurotrophic factor, or BDNF, but the effect is small.
• How strong a person’s dissociative symptoms (feelings of disconnection or odd perceptions) get during treatment usually does not predict whether they will feel less depressed afterward.
• The research on esketamine (the nasal form) is smaller than the research on intravenous ketamine, so we know less about predictors for esketamine.
• Most single predictors have only modest power to forecast who will get better, so researchers say we will likely need models that combine many clinical and biological measures and use the same methods across studies.

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 Lack of energy or motivation Sadness or low mood