Title: Ketamine and other glutamate receptor modulators for severe depression
Funder: Department of Health (England)

Abstract: Research Question: What is the effectiveness of ketamine and other glutamate receptor modulators for treating severe unipolar or bipolar depression?1.Intervention: Ketamine and other glutamate receptor modulators. 2.Patient group: Adults with severe unipolar or bipolar depression – exact inclusion criteria to be defined and justified by applicants.3.Setting: Hospital.4.Control: Placebo or another appropriate control or comparator. 5.Study design: Evidence synthesis by systematic review of the best available evidence. Applicants should consider and justify the inclusion of non-randomised studies. Subgroup analysis by type of depressive disorder and any other relevant groups should be carried out if data allow. 6.Outcomes: ‘Rapid’ improvement in depression scores reduction in suicidal ideation; adverse effects; neuropsychological effects; blood pressure; research recommendations. NHS decision problem to be addressed by this research: Severe depression is a leading cause of disability and is responsible for huge healthcare and workplace costs. Currently available antidepressant treatments all have a delayed action ranging up to several weeks. Shortening this delay is a major unmet challenge in the treatment of severe depression. Evidence is mounting that glutamate receptor modulators such as ketamine may be suitable as rapid action antidepressants. Ketamine has been used for decades as a sedative and anaesthetic but studies suggest that a single intravenous low dose can bring about substantial improvement in depression within hours even in patients that have not improved with other antidepressant treatments. However ketamine is associated with an array of adverse effects although other related drugs may be available that produce fewer side effects. Published systematic reviews of ketamine have included only small studies very few of which were controlled. Recently however many more studies have been published that have not been subject to systematic review. An up to date evidence synthesis is needed that builds on and broadens previous reviews to include unipolar and bipolar depression and a variety of glutamate receptor modulators not just ketamine and that identifies where future primary research might be needed.Source of topic A topic investigating the use of ketamine for severe depression was independently suggested by three MPOH panel members: the Panel Chair Professor Scott Weich Professor Paul Willner and Dr David Christmas.NICE and other guidanceNothing relevant found regarding the use of glutamate receptor modulators such as ketamine for depression either in the existing NICE clinical guidelines or their planned updates.Published researchEvidence Synthesis:•aan het Rot M Zarate CA Charney DS Mathew SJ. Ketamine for depression: where do we go from here? Biological Psychiatry 2012; 72(7): 537-547. Abstracted in DARE 2013:Centre for Reviews and Dissemination summary: The review concluded that ketamine seemed a reasonable treatment option for most patients with treatment resistant depression when administered by trained clinicians in appropriate settings. This was a poorly reported review that was at risk of various forms of bias. The synthesis was limited which suggests that definitive conclusions cannot be drawn and the authors’ conclusions cannot be considered reliable.•Sienaert P Lambrichts L Dols A De Fruyt J. Evidence-based treatment strategies for treatment-resistant bipolar depression: a systematic review. Bipolar Disord. 2013; 15: 61-9.Primary Research – including randomised and non-randomised studies•Murrough JW Iosifescu DV Chang LC Al Jurdi RK Green CE Perez AM Iqbal S Pillemer S Foulkes A Shah A Charney DS Mathew SJ. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013; 170: 1134-42. •Zarate C. A.; Mathews D.; Ibrahim L.; Chaves J. F.; Marquardt C.; Ukoh I.; Jolkovsky L.; Brutsche N. E.; Smith M. A.; Luckenbaugh D. A. A Randomized Trial of a Low-Trapping Nonselective N-Methyl-D-Aspartate Channel Blocker in Major Depression. 2012 Biological Psychiatry 74: 257–264.•Anand A Gunn AD Barkay G Karne HS Nurnberger JI Mathew SJ Ghosh S. Early antidepressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind randomized placebo-controlled trial. 2012; Bipolar disorders 2012; 14: 64-70. •Heresco-Levy U Gelfin G Bloch B Levin R Edelman S Javitt DC Kremer I. A randomized add-on trial of high-dose D-cycloserine for treatment-resistant depression. Int J Neuropsychopharmacol. 2013; 16: 501-6.•Sos P Klirova M Novak T Kohutova B Horacek J Palenicek T. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuro Endocrinol Lett. 2013; 34: 287-93.•Thakurta RG Ray P Kanji D Das R Bisui B Singh OP. Rapid antidepressant response with ketamine: is it the solution to resistant depression? Indian J Psychol Med 2012; 34: 56–60•Luckenbaugh DA Ibrahim L Brutsche N Franco-Chaves J Mathews D Marquardt CA Cassarly C Zarate CA Jr. Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression. Bipolar Disord. 2012; 14: 880-7. •Shiroma PR Johns B Kuskowski M Wels J Thuras P Albott CS Lim KO. Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression. J Affect Disord. 2013 Oct 29. S0165-0327(13)00778-7. [Epub ahead of print].•Zarate CA Singh JB Quiroz JA De Jesus G Denicoff KK Luckenbaugh DA Manji HK Charney DS. A double-blind placebo-controlled study of memantine in the treatment of major depression. The American journal of psychiatry 2006 163: 153-5.•Rasmussen KG Lineberry TW Galardy CW Kung S Lapid MI Palmer BA Ritter MJ Schak KM Sola CL Hanson AJ Frye MA. Serial infusions of low-dose ketamine for major depression. 2013; Journal of Psychopharmacology 2013 27: 444–450.•Murrough JW Perez AM Pillemer S Stern J Parides MK aan het Rot M Collins KA Mathew SJ Charney DS Iosifescu DV. Rapid and longer-term antidepressant effects of repeated ketamine infusions in treatment-resistant major depression. Biol Psychiatry. 2013; 74: 250-6.•Brennan BP Hudson JI Jensen JE McCarthy J Roberts JL Prescot AP Cohen BM Pope HG Jr Renshaw PF Ongür D. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology. 2010; 35: 834-46.NETS researchThere is an ongoing EME trial involving ketamine. NOTE however it is fundamentally different from the research question addressed by this topic because it is only examining the effects of ketamine given DURING electroconvulsive therapy (ECT): EME Project 10/90/04: To determine the size of clinical benefit of adjunctive ketamine given during anaesthesia for each ECT in preventing cognitive deficits and in speeding clinical response and whether ketamine protects against ECT’s deleterious effects on frontal cortex function and its disruption of fronto-hippocampal connectivity using functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI). Sample = 180 (01/04/2012 - 31/05/2015). Search terms used: (ketamine OR NMDA OR gluta*) AND depressionDate of searches/overlap checks: February 2014AuthorshipPanel Researcher: Dr Jemma KwintConsultant Advisor: Dr Bob Coates


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH