Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults

Abstract

Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine's psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.We did not find conclusive evidence on adverse events with ketamine. To draw more robust conclusions, further RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine and to study different methods of sustaining antidepressant response, such as repeated administrations. There was not enough evidence to draw meaningful conclusions for the remaining two glutamate receptor modulators (memantine and cytidine). This review is limited not only by completeness of evidence, but also by the low to very low quality of the available evidence.

Critical Appraisal of Existing Ketamine Trials: Existing Limitations and Limited Applicability for Treatment

“…However, the authors cautioned against using ketamine as a novel antidepressant for treatment-resistant depression because they claimed that ketamine's underlying mechanisms of action are not entirely understood. The authors' findings and recommendations are in line with the reexamination by the Cochrane collaboration into the utility of ketamine as a rapid antidepressant for treatment of depression and of depression in bipolar disorder (2,3). The authors' findings and recommendations are in line with the reexamination by the Cochrane collaboration into the utility of ketamine as a rapid antidepressant for treatment of depression and of depression in bipolar disorder (2,3).…”

Ketamine: 50 Years of Modulating the Mind

“…The current evidence is limited by bias, small sample sizes, and limited data on important cofounding variables. In fact, a recent Cochrane Review determined that the efficacy of ketamine as an antidepressant may be limited beyond 1 week (McCloud et al, 2015). …”

Glutamatergic regulation of cognition and functional brain connectivity: insights from pharmacological, genetic and translational schizophrenia research

“…The synaptic concentration of glutamate is also regulated by glutamate uptake, into both neurons and glial cells, mediated by a range of glutamate transporters (for review, see Vandenberg and Ryan, ) and the cystine/glutamate antiporter (System Xc, Bridges et al, ). Much research has been dedicated to elucidate the roles of these molecular components in the regulation of cognitive and brain function, in part due to the proposed central involvement of glutamate system dysfunction in a broad range of brain disorders with prominent cognitive deficits including schizophrenia (SZ) (Coyle, 2006), bipolar disorder (McCloud et al, ), major depressive disorder (deWilde et al, ), autism spectrum disorders (Volk et al, ) and Alzheimer's disease (Lin et al, ).…”