Clinical Predictors of Ketamine Response in Treatment-Resistant Major Depression

Abstract

Objective The N-methyl-D-aspartate receptor antagonist ketamine has rapid antidepressant effects in treatment-resistant major depressive disorder (MDD) and bipolar depression. Clinical predictors may identify those more likely to benefit from ketamine within clinically-heterogeneous populations. Method Treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I/II depression currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute post-infusion time point (N=108), at Day 1 (N=82), and at Day 7 (N=71). Univariate Pearson correlations were performed for each variable with change-from-baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (p<0.05, two-tailed). Results Higher body mass index (BMI) correlated with greater HDRS improvement at 230 minutes and at Day 1 (standardized β=−0.30, p=0.004), but not at Day 7 (standardized β=−0.18, p=0.10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at Day 1 (standardized β=−0.37, p=0.001) and Day 7 (standardized β=−0.41, p<0.001). No prior history of suicide attempt(s) was associated with greater improvement only at Day 7 (standardized β=0.28, p=0.01). The overall statistical model explained 13, 23, and 36 percent of HDRS percent change variance at 230 minutes, Day 1, and Day 7, respectively. Conclusion Despite its post-hoc nature, the study identified several clinical correlates of ketamine's rapid and durable antidepressant effects. Further investigation of these relationships is critical for individualized treatment of depression.

Neurocognitive Effects of Ketamine and Association with Antidepressant Response in Individuals with Treatment-Resistant Depression: A Randomized Controlled Trial

“…Prior studies have found associations between clinical and demographic factors and therapeutic response to conventional antidepressants (Perlis, 2013), however, a quantitative laboratory-based behavioral or biological predictor of treatment response has remained elusive (Kapur et al, 2012;Simon and Perlis, 2010;Trivedi, 2013). Prior research involving ketamine for unipolar or bipolar depression has suggested candidate clinical or demographic variables associated with therapeutic response, including a family history of alcoholism and a higher body mass index (BMI) (Niciu et al, 2014). Candidate baseline biological predictors of antidepressant response to ketamine previously reported include a single-nucleotide polymorphism in the gene coding for BDNF (Laje et al, 2012), as well as differential responses to emotional faces within the anterior cingulate cortex during magnetoencephalography (Salvadore et al, 2009).…”

Ketamine and other N-methyl-D-aspartate receptor antagonists in the treatment of depression: a perspective review

“…This includes systematic study of enriched treatment subgroups, for example, patients with treatment-resistant depression and a family history of an alcohol use disorder [Phelps et al 2009;Niciu et al 2014b] [Clinical Trials identifier: NCT02122562] or dimensional anxious depression , to develop treatment response biomarkers and other surrogate endpoints for personalized antidepressant treatment selection.…”

“…Our group recently published a secondary data analysis of 108 patients with treatment-resistant major depression (both MDD and BDep) who received a single subanesthetic dose infusion of ketamine to study the relationship between improvements in depression/anxiety and suicidality; in this sample, improvements in suicidal thinking were partially related to improvements in neuropsychiatric symptoms, explaining up to 20% of the antisuicidal effect [Ballard et al 2014]. Interestingly, in another secondary analysis of the same sample, a lack of a lifetime history of suicide attempt predicted improved antidepressant response to ketamine at 1 week post infusion [Niciu et al 2014b]. Nevertheless, as these studies were not conducted in patients who were acutely suicidal and presenting for intervention, these studies are likely investigating chronic as opposed to acute suicidal ideation with greater potential for suicidal behaviors.…”

“…In a multivariate linear regression, increased body mass index (BMI) correlated with ketamine's antidepressant action at 230 minutes and 1 day post infusion, a family history of an alcohol use disorder correlated at 1 day and 1 week post infusion and no lifetime personal history of suicide attempt correlated at 1 week only [Niciu et al 2014b]. Permoda-Osip and colleagues performed a similar factor analysis in 42 patients with bipolar depression.…”

Is Depressive Rumination Rational?

“…On the psychological level this is manifest as extreme self-focus and hopelessness. It are these findings concerning glutamate-ergic excitation in MDD that might explain why GABA-ergic drugs like ketamine can act so quickly (within 24 h) to bring relief to depressed patients who are suicidal (Niciu et al, 2014). GABA-ergic drugs can help dampen the self-focus, thereby making it possible that externally introduced positive stimuli can effectively reduce negative affect.…”