Footnotes Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The authors have no conflicts of interest to declare. Contributor Information Judith Bosman, Department of Clinical Pharmacy, Isala Clinics, Dr. van Heesweg 2, Zwolle, The Netherlands. Peter G.J. ter Horst, Department of Clinical Chemistry, Isala Clinics, Zwolle, The Netherlands. Jan Pieter Smit, Department of Psychiatry, Isala Clinics, Zwolle, The Netherlands. Jeroen R. Dijkstra, Department of Gynaecology and Obstetrics, Isala Clinics, Zwolle, The Netherlands. Hans R. Beekhuis, Department of Gynaecology Inhibitors,research,lifescience,medical and Obstetrics, Isala Clinics, Zwolle, The Netherlands. Robbert J. Slingersland, Department Inhibitors,research,lifescience,medical of Clinical Chemistry, Isala Clinics, Zwolle, The Netherlands. Wobbe Hospes, Department of Clinical Pharmacy, Isala Clinics, Zwolle, The Netherlands.
Major depressive disorders (MDDs) and bipolar affective disorders (BPADs) are frequently persistent, disabling psychiatric illnesses [Baune et al. 2007; Kessler et al. 2006]. Lifetime prevalence

of MDDs stands at approximately 16% [Kessler et al. 2003], and BPADs at 1–4% [Grant et al. 2005; Merikangas et al. 2007]: although diagnosed by the presence of pathological highs, depressive episodes (so-called bipolar depression) constitute the majority of illness in Inhibitors,research,lifescience,medical BPADs [Lloyd et al. 2011]. Our recent review [Penn and Tracy, 2012] highlighted the limited efficacy of traditional antidepressants and the lack of a robust evidence base to guide the management Inhibitors,research,lifescience,medical of patients with treatment-resistant depression (TRD). There is a considerable need to develop novel and efficacious antidepressants. Hallucinogenic drugs produce alterations in consciousness,

perception, thought and emotion and have been used recreationally and entheogenically for millennia. So-called ‘classical’ psychedelic drugs such as lysergic acid diethylamide (LSD), psilocybin, dimethyltryptamine Inhibitors,research,lifescience,medical (DMT) and mescaline are thought to exert their effects through agonism at the 5-HT2A receptors [Nichols, 2004]. Dissociative hallucinogens including ketamine, phencyclidine (PCP) and dextromethorphan (DXM) act primarily as N-methyl-D-aspartate Astemizole (NMDA) glutamate (Glu) receptor antagonists [Krystal et al. 1994]. There has been growing interest in the observation that ketamine has a rapid positive effect on depressive symptoms. Ketamine is used in medicine for inducing and maintaining anaesthesia, and illicitly for its hallucinogenic and dissociative effects. The fact that ketamine does not work through the ‘conventional’ antidepressant monoaminergic targets of serotonin and PD98059 mouse noradrenaline has provoked excitement: understanding its effects could provide novel insights into the pathophysiology of depression and open up a new class of medications.