Treatment resistance depression – a solution finally?

Jan 2018, Dr Chee L Khoo

The mainstay for the treatment of major depression disorder (MDD) has been SSRIs since the 1980s. But up to a third of patients with MDD don’t respond to the usual treatment for depression. This is commonly referred to as treatment resistant depression (TRD). The NDMA glutamate receptor antagonist, ketamine is known to have an efficacious and rapid-onset anti-depressant effect in patients with TRD. The only problem is that it has to be given intravenously! Well, up until now.

Ketamine is one of many NDMA receptor antagonists which has many psychotropic effects including amnesia, analgesia and psychosis. It is a useful anaesthestic agent widely used in emergency situations whereby it induces a state called dissociative anaesthesia marked by catalepsy, amnesia and analgesia. At sub-anaesthestic doses, it has mild stimulant effect and at higher doses, hallucination and dissociation which unfortunately, also makes it a candidate as a recreational drug.

The first trial of intranasal esketamine ( a more potent S-isomer of ketamine) as an adjunctive treatment of TRD was recently presented by Daly et al in JAMA Psychiatry. It showed that compared with placebo, intranasal esketamine has a significant effect on depressive symptoms after one week of treatment (twice weekly dosage) with the duration sustained for at least 2 months. It was a randomised, double-blind study of only 67 participants with TRD who continued their existing anti-depressant medication for the duration of the trial. Only 5% discontinued treatment due to adverse side effects.

The novel route of administration allows ketamine to be more widely general use in TRD in the near future. This is the first trial involving intranasal use of a NDMA antagonist and the findings are encouraging and should lead to investigations in larger trials. Watch this space.

Access abstract here


Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80 (6):424-431.

Fond G, Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M, Micoulaud-Franchi JA, Richieri R, Courtet P, Abbar M, et al. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl). 2014 Sep; 231(18):3663-76. Epub 2014 Jul 20.

Michael E. Thase, MD; Andrew Winokur,MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC;Wayne C. Drevets, MD. Efficacy and Safety of Intranasal Esketamine Adjunctive

to Oral Antidepressant Therapy in Treatment-Resistant Depression A Randomized Clinical Trial. JAMA Psychiatry. Published online December 27, 2017