Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects

Tuyen T Le; Joshua D Di Vincenzo; Kayla M Teopiz; Yena Lee; Danielle S Cha; Leanna M W Lui; Nelson B Rodrigues; Roger C Ho; Bing Cao; Kangguang Lin; Flora Nasri; Hartej Gill; Orly Lipsitz; Mehala Subramaniapillai; Rodrigo B Mansur; Joshua D Rosenblat; Roger S McIntyre

doi:10.1016/j.psychres.2021.114231

Ketamine for psychotic depression: An overview of the glutamatergic system and ketamine's mechanisms associated with antidepressant and psychotomimetic effects

Psychiatry Res. 2021 Dec:306:114231. doi: 10.1016/j.psychres.2021.114231. Epub 2021 Oct 9.

Authors

Tuyen T Le¹, Joshua D Di Vincenzo², Kayla M Teopiz³, Yena Lee⁴, Danielle S Cha⁵, Leanna M W Lui³, Nelson B Rodrigues⁴, Roger C Ho⁶, Bing Cao⁷, Kangguang Lin⁸, Flora Nasri⁹, Hartej Gill¹⁰, Orly Lipsitz⁴, Mehala Subramaniapillai⁴, Rodrigo B Mansur¹¹, Joshua D Rosenblat¹², Roger S McIntyre¹³

Affiliations

¹ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
² Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada.
³ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada.
⁴ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada.
⁵ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁶ Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore 117599, Singapore; Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore. Electronic address: pcmrhcm@nus.edu.sg.
⁷ Key Laboratory of Cognition and Personality (SWU), Faculty of Psychology, Ministry of Education, Southwest University, Chongqing 400715, PR China.
⁸ Department of Affective Disorder, the Affiliated Brain Hospital of Guangzhou Medical University, (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China; Laboratory of Emotion and Cognition, the Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou Medical University, Guangzhou, China.
⁹ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada.
¹⁰ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada.
¹¹ Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹² Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
¹³ Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Mood Disorders Psychopharmacology Unit, Poul Hansen Family Centre for Depression, University Health Network, Toronto, ON, Canada; Brain and Cognition Discovery Foundation, Toronto, ON, Canada; Canadian Rapid Treatment Center of Excellence, Mississauga, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: roger.mcintyre@uhn.ca.

PMID: 34798487
DOI: 10.1016/j.psychres.2021.114231

Abstract

Approximately 0.35-1% of the general population is afflicted with psychotic depression at some time in their life. Psychotic depression is a subtype of major depressive disorder characterized by mood congruent hallucinations and/or delusions. Patients with psychotic depression often represent the most severe cases, with high relapse and mortality rate. Although treatment guidelines recommend a combination of antidepressants and antipsychotics or electroconvulsive therapy, most patients subsequently relapse due to treatment resistance. Furthermore, with the concern of antipsychotic drug's side effects (e.g., tardive dyskinesia), there is a need for an alternative pharmacotherapy for psychotic depression. Recently, several case studies demonstrated that treatment with ketamine not only ameliorated mood, but also improved psychotic symptoms in patients with treatment-resistant depression and psychotic features. However, the safety of ketamine in these patients is controversial since ketamine is known to induce psychotomimetic and dissociative effects. Additionally, the efficacy and safety of ketamine in patients with psychotic depression has not been established as most clinical trials have excluded these persons due to the theorized risk of aggravating psychotic symptoms. Notwithstanding, it is not established empirically that ketamine treatment in psychotic depression would predictably amplify psychotic symptoms and/or overall illness presentation. Future trials evaluating ketamine in depression should include patients with psychotic features to inform whether ketamine is safe and effective in this subpopulation.

Keywords: Bipolar disorder; Depression; Ketamine; Psychotic depression; Psychotic features; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Antidepressive Agents / adverse effects
Bipolar Disorder* / drug therapy
Depression / drug therapy
Depressive Disorder, Major* / drug therapy
Humans
Ketamine* / adverse effects

Substances

Antidepressive Agents
Ketamine