Prediction of Prophylactic Response to Lithium in Bipolar Disorder Using Acute Antidepressant Non-Response to Ketamine: A Scoping Review

Lithium remains the first choice for long-term prophylaxis of mood episodes in bipolar disorder (BD), but only 30% of patients will respond, and there is no reliable method by which to predict treatment response. Ketamine is a rapid antidepressant therapy which ostensibly yields greater results in patients with clinical phenotypes that are classically associated with lithium non-response. Thus, we hypothesized an inverse relationship between acute ketamine response and efficacy of long-term prophylactic lithium therapy in BD. We conducted a scoping review of clinical and preclinical studies that examine convergent and divergent predictors and mechanisms of acute response to ketamine and long-term response to lithium. Preclinical data show mechanistic convergence of ketamine and lithium on the GSK-3β/mTOR pathways, and enhancement of synaptic plasticity. Furthermore, lithium appears to consistently limit ketamine-related oxidative stress and hyperlocomotion. However, clinical predictors diverge, with ketamine response associated with metabolic risk factors, anxiety/mixed features, and non-melancholic presentations, which are generally predictors of poorer prophylactic lithium response. No study directly tested ketamine response as a predictor of prophylactic lithium response. An important limitation is that clinical studies of ketamine are enriched for lithium-refractory populations and have often included mixed unipolar and bipolar cases. Overall, existing data support mechanistic overlap but clinical divergence between ketamine and lithium responders, which is only partially consistent with our hypothesized inverse relationship. We must therefore undertake longitudinal studies of prophylactic lithium therapy among patients with BD who received ketamine for acute antidepressant treatment. If this inverse relationship is validated, ketamine non-response could be used to rapidly identify lithium-responsive BD, thereby establishing control over this disease earlier in the course of illness.