Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder

Abstract

Objectives: Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. Method: Electronic search engines PubMed/MEDLINE, , and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. Results: Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. Conclusions: A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.

Neurotrophic Factor BDNF, Physiological Functions and Therapeutic Potential in Depression, Neurodegeneration and Brain Cancer

“…The BDNF Val66Met polymorphism has been associated with cerebral cortex plasticity [ 117 , 118 ], with gray matter structures [ 119 , 120 ], or white matter integrities and structural networks [ 121 , 122 ]. More specifically, BDNF Val66Met polymorphism is associated with cognitive processes [ 112 , 123 , 124 , 125 , 126 , 127 ], and cognitive impairment in neurodegenerative disease, such as Parkinson’s disease (PD) [ 128 , 129 ] and AD [ 130 , 131 ], and even more with several brain disorders, including MDD and bipolar disorder [ 132 , 133 , 134 , 135 , 136 , 137 ], epilepsy [ 138 , 139 , 140 ], schizophrenia [ 125 , 141 , 142 , 143 , 144 ], aging and dementia [ 145 ] and stroke [ 117 , 146 , 147 ]. Met66, but not Val66, BDNF pro-domain can induce the growth cone retraction in young hippocampal neurons [ 148 ].…”

Ketamine – a prototype of rapidly acting antidepressant drugs

“…Wśród potencjalnych czynników, które mogą wskazywać na wydłużone w czasie przeciwdepresyjne działanie ketaminy wymienia się chorobę alkoholową u członków rodziny pierwszego stopnia, brak prób samobójczych, zaburzenia o charakterze dysocjacyjnym (głównie depersonalizacja) w trakcie wlewu leku i zanikające w krótkim czasie po jego zakończeniu, poprawa takich objawów depresji jak smutek i trudności w koncentracji dzień po wlewie, wysoki indeks BMI, niskie podstawowe poziomy adiponektyny, wysokie podstawowe stężenia witaminy B 12 , mutacja Val66Met genu kodującego czynnik neurotroficzny pochodzenia mózgowego (BDNF, ang. brain-derived neurotrophic factor) [32][33][34][35][36]. Kwestią sporną pozostaje wpływ płci na działanie przeciwdepresyjne ketaminy.…”

Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support

“…For instance, despite the range of pharmacological options, approximately half of patients remain treatment resistant even after months of use and continue to experience ongoing SI [ 8 ]. Further, selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, usually first-line antidepressant treatments, require 3–8 weeks to improve mood [ 8 , 9 ], leaving individuals at greater risk for SI [ 10 ]. This highlights the need for new approaches.…”

“…However, while ketamine is considered a promising treatment for patients with treatment-resistant depression and SI, individual patients vary in their response to ketamine [ 14 , 15 ], and some individuals do not respond sufficiently, even with serial, titrated treatments. The reasons for the heterogeneity of response to ketamine are unclear but may reflect differences in individuals’ underlying demographic attributes, pathophysiology, genetic makeup, and clinical features [ 10 ]. The ability to systematically estimate the likelihood of a positive response to ketamine on an individual basis would be beneficial to clinicians and researchers.…”

“…The ability to systematically estimate the likelihood of a positive response to ketamine on an individual basis would be beneficial to clinicians and researchers. Identification of pre-treatment predictors of response, such as clinical, phenotypic and biological variables, will provide significantly improved clinical outcomes for patients and represent an opportunity for personalised healthcare provision [ 10 ]. Prediction analyses have the potential to provide insights into treatment candidacy and personalised treatment selection for suicidal individuals.…”