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Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response.

ABSTRACT: The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain.Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocognitive effects of ketamine in depressed patients. Therefore, the aims of the current study were to characterize the relationship between baseline neurocognition and antidepressant response to ketamine, measure the acute impact of ketamine on neurocognition, and investigate the relationship between acute neurocognitive effects of ketamine and antidepressant response.Neurocognitive functioning was assessed in 25 patients with TRD using a comprehensive battery: estimated premorbid intelligence quotient (IQ), current IQ, and tests from the MATRICS Consensus Cognitive Battery (MCCB). A subset of the MCCB was repeated immediately following a 40-min intravenous infusion of ketamine (0.5 mg/kg).Patients who responded to ketamine 24 h following treatment had poorer baseline neurocognitive performance relative to nonresponders and, in particular, slower processing speed (F?=?8.42; df?=?23; p?=?0.008). Ketamine was associated with selective impairments in memory recall, and the degree of cognitive change carried negative prognostic significance (e.g., negative cognitive effects immediately after ketamine predicted lower response rate at 24 h; Fisher's exact test two-sided p?=?0.027).Taken together, our findings suggest a potential baseline neurocognitive predictor of ketamine response and an inverse relationship between the cognitive effects of ketamine and antidepressant efficacy.

SUBMITTER: Murrough JW

PROVIDER: S-EPMC3952038 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response.

Murrough James W JW Wan Le-Ben LB Iacoviello Brian B Collins Katherine A KA Solon Carly C Glicksberg Benjamin B Perez Andrew M AM Mathew Sanjay J SJ Charney Dennis S DS Iosifescu Dan V DV Burdick Katherine E KE

Psychopharmacology 20130911

<h4>Rationale</h4>The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD). Despite the promise of a novel and urgently needed treatment for refractory depression, concerns regarding potential adverse neurocognitive effects of ketamine remain.<h4>Objectives</h4>Although extensive research has been conducted in healthy volunteers, there is a paucity of studies examining the neurocogni ...[more]

PMID: 24022236

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Project description:BackgroundClinical evidence that ketamine, a nonselective N-methyl-D-aspartate receptor (NMDAR) antagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating glutamatergic neurotransmission is a fundamental step in alleviating the debilitating symptoms of mood disorders. Acutely, ketamine increases extracellular glutamate levels, neuronal excitability, and spontaneous γ oscillations, but it is unknown whether these effects are key to the mechanism of antidepressant action of ketamine.MethodsTwenty drug-free major depressive disorder patients received a single, open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg). Magnetoencephalographic recordings were made approximately 3 days before and approximately 6.5 hours after the infusion, whereas patients passively received tactile stimulation to the right and left index fingers and also while they rested (eyes-closed). Antidepressant response was assessed by percentage change in Montgomery-Åsberg Depression Rating Scale scores.ResultsPatients with robust improvements in depressive symptoms 230 min after infusion (responders) exhibited increased cortical excitability within this antidepressant response window. Specifically, we found that stimulus-evoked somatosensory cortical responses increase after infusion, relative to pretreatment responses in responders but not in treatment nonresponders. Spontaneous somatosensory cortical γ-band activity during rest did not change within the same timeframe after ketamine in either responders or nonresponders.ConclusionsThese findings suggest NMDAR antagonism does not lead directly to increased cortical excitability hours later and thus might not be sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depressive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central to the antidepressant effect of ketamine.

Project description:ObjectiveThe 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.MethodData were analyzed from 4 studies of treatment-resistant inpatients with DSM-IV-TR-diagnosed MDD or bipolar I or II depression. Patients who were currently experiencing a moderate-to-severe major depressive episode were enrolled between November 2004 and March 2013. All subjects received a single subanesthetic (0.5 mg/kg) ketamine infusion over 40 minutes. Patients were analyzed at the 230-minute postinfusion time point (n = 108), at day 1 (n = 82), and at day 7 (n = 71). Univariate Pearson correlations were performed for each variable with percent change from baseline in the 17-item Hamilton Depression Rating Scale (HDRS). Multivariate linear regression was then conducted for statistically significant predictors (P ≤ .05, 2-tailed).ResultsHigher body mass index correlated with greater HDRS improvement at 230 minutes (standardized β = -0.30, P = .004) and at day 1 (standardized β = -0.37, P = .001), but not at day 7 (standardized β = -0.18, P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater HDRS improvement at day 1 (standardized β = -0.27, P = .014) and day 7 (standardized β = -0.41, P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized β = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of HDRS percent change variance at 230 minutes, day 1, and day 7, respectively.ConclusionsDespite its post hoc nature, this 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.

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Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response.

Publications

Neurocognitive effects of ketamine in treatment-resistant major depression: association with antidepressant response.

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