Ketamine, Esketamine (Spravato) in Treatment Resistant Depression

Can We Predict Who will Respond to Ketamine/Esketamine in TRD?

Treatment resistant depression

The heterogeneity of treatment response in MDD has provided a compelling rationale for identifying predictors of response/tolerability (and non-response/intolerability) amongst individuals assigned to a given treatment. The need to identify predictors of response is even greater when the treatment options being considered are more costly, require more resources for administration (e.g. specialized clinics), and/or may be associated with greater safety/tolerability concerns.

The recent approval in March 2019 by the U.S. FDA of intranasal esketamine (spravato)has raised many questions notably who is the appropriate candidate (and who isn’t!)? Towards answering this critical question that every clinician who sees persons with mood disorders is beginning to ask themselves is do we have any predictors today for predicting treatments to any antidepressants in MDD? The answer is no. Admittedly in academic circles, there are an assortment of “associations” and variables that look promising, but none have been so replicated robust and compelling that they can be recommended as routine in clinical practice (this also includes combinatorial gene testing!).

As a consequence, clinicians in the clinical ecosystem continue to rely on trial and error. For persons who are potential candidates for ketamine/esketamine (spravato) therapy, the notion of trial and error becomes even more of a concern in light of the factors mentioned above. What does the research currently tell us? Available scientific results suggest that there are some factors amongst people with mood disorders both phenotypic and biochemical (i.e. a pheno-biotype) that may be more likely to benefit from ketamine treatment. For example, there are some suggestions that individuals who have a higher body mass index (BMI) might be more likely to benefit from ketamine treatment acutely for MDD. An additional observation that has been associated with acute ketamine responses is a positive family history of alcohol use disorder in a first degree relative. This foregoing observation leads one to speculate that maybe opioidergic mechanisms may be altered as a “trait” across families wherein in one person it manifests as a mood response to ketamine while in another individual in the family it manifests as a substance misuse disorder.

Other biological factors that have been reported to be associated with ketamine response is a low baseline adiponectin level. Adiponectin is a protein not commonly known in psychiatry but well-known in the world of metabolism. Adiponectin is an adipokine that has anti-inflammatory and insulin sensitising properties. When adiponectin levels are low that implies that the body is in a state of pro-inflammatory balance. This is interesting because a pro-inflammatory balance is associated with region specific increases of glutamate (a key target of ketamine) in the central nervous system. Other suggested biomarkers that may associate with ketamine response is low baseline delta sleep ratio, increased anterior cingulate activity, as well as polymorphisms for the BDNF gene (Val66Met). Interestingly, and seemingly in contradiction with anti-cognitive effects of recreational use of ketamine, it appears that individuals with prior baseline cognitive disturbances may have differential responses to ketamine that are favourable in some cases.

Unfortunately, none of the factors above can be considered definitive or the final word. The inevitable phrase in medicine is “more research is needed” and this is certainly the case for predictors of response to ketamine. For now, the pheno-biotype that’s most likely the benefit from ketamine needs to be empirically established and for now that decision is a clinical decision in collaboration with the patient. Notwithstanding what does emerge from the extant literature is a suggestion that patients with disturbances in physiology implicated in inflammation, metabolism, opioidergic systems, neurotrophism, and glutamate signalling may be more likely to benefit. Not only is more research needed but research attempting to address these questions will be very exciting as we attempt to offer patients more personalized precision-based treatment options.