Ketamine for Depression: an Old Drug with a New Indication

Major depressive disorder (MDD) is a severe and chronic condition affecting 350 million subjects worldwide with 1 million subjects committing suicide every year (World Health Organization 2008). MDD is prevailing in wealthy countries including Italy, where lifetime prevalence was estimated at 9.9% (Bromet et al. 2011). Diagnosis is defined by fulfilling at least five of the nine criteria described in the Diagnostic and statistical manual of mental disorders (DMS-5; American Psychiatric Association 2013). Symptoms should be present for at least 2 consecutive weeks and should “represent a change from previous functioning”. Moreover, the presence of “depressed mood” or “loss of interest or pleasure“ (criteria 1 and 2, respectively) is mandatory for the diagnosis of MDD (DSM-5; American Psychiatric Association 2013). A wide array of treatment options are currently available for MDD, spanning from pharmacotherapy and psychotherapy to their combination, as well as electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS). Despite all these therapeutic options, only a fraction of patients achieves remission (a period of at least 2 months without significant signs or symptoms of the disease) and chronicity of symptoms predisposes to treatment resistance. Treatment-resistant depression (TRD), defined as the failure of at least two antidepressant treatments from two different classes, is a major concern for public health (Souery et al 2006). A great deal of research has been addressed to develop new therapeutic strategies based on innovative psychopharmacological approaches. In this frame, glutamatergic system represents a promising target for an effective intervention as long as NMDA receptor antagonism has been found to produce fast acting antidepressant effects. Ketamine has been instrumental in developing this new concept. This drug is a non-selective NMDA antagonist with anaesthetic (Marland et al. 2013), analgesic (Persson 2013) and anticonvulsivant properties (Dorandeu 2013). Despite its promising clinical application, ketamine use in limited by potentially harmful psychotomimetic effects (Krystal et al. 1994, Lahti et al. 1995, Moore et al. 2011) which are responsible for its recreational use and abuse (Morgan et al. 2004, Muetzelfeldt et al. 2008). More recently, the potential clinical use of ketamine for the treatment of MDD and bipolar depression (BD) has been evaluated (Aan Het Rot et al. 2010, Messer et al. 2010, Blier et al. 2012, Cusin et al. 2012, Krystal et al. 2013, Murrough et al. 2013 a,c, Niciu et al. 2013). Hereafter we summarize the most recent findings on the antidepressant activity of ketamine, together with a brief update on the potential mechanism of action.