A review of potential neuropathological changes associated with ketamine

ABSTRACT

Introduction

Ketamine is an established intervention for treatment-resistant depression (TRD). However, long-term adverse effects with repeated doses remain insufficiently characterized. Although several animal models have shown N-methyl-D-aspartate glutamate receptor antagonists to produce various neuropathological reactions, attention surrounding the risk of brain lesions has been minimal.

Areas covered

The current review focuses on potential neuropathological changes associated with ketamine. Search terms included variations of ketamine, Olney lesions, tau hyperphosphorylation, and parvalbumin interneurons.

Expert opinion

Daily high-dose ketamine use in substance use disorder (SUD) populations was associated with clear neurotoxic effects, while no studies specifically evaluated effects of ketamine protocols used for TRD. It is difficult to discern effects directly attributable to ketamine due to methodological factors, such as comorbidities and dramatic differences in dose in SUD populations versus infrequent sub-anesthetic doses typically prescribed for TRD. Taken together, animal models and human ketamine SUD populations suggest potential neuropathology with chronic high-dose ketamine exposure exceeding those recommended for adults with TRD. It is unknown whether repeat sub-anesthetic dosing of ketamine in adults with TRD is associated with Olney lesions or other neuropathologies. In the interim, practitioners should be vigilant for this possibility recognizing that the condition itself is associated with neurodegenerative processes.

KEYWORDS:

• Ketamine
• esketamine
• neurotoxic
• depression
• treatment resistant depression
• bipolar disorder
• olney lesions
• parvalbumin interneurons
• tau phosphorylation
• dementia

Article highlights

• Long-term adverse effects of chronic ketamine use in TRD remain insufficiently characterized

• Animal models have shown reduction in parvalbumin-containing interneurons, increased tau hyperphosphorylation and Olney’s lesions with ketamine

• Ketamine use disorder populations suggest potential neuropathological effects with chronic high-dose ketamine exposure

• Neuropathological changes with TRD ketamine protocols (e.g. infrequent, sub-anesthetic doses) have yet to be evaluated

• Clinicians are cautioned to be familiar with the theoretical possibility of neurotoxicity with high dose chronic ketamine use

Declaration of interest

R McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation; and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and Abbvie. R McIntyre is a CEO of Braxia Scientific Corp. JD Rosenblat has received research grant support from the Canadian Cancer Society, Canadian Psychiatric Association, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from Janssen, Allergan, Lundbeck, Sunovion and COMPASS. JD Rosenblat is the medical director of a private clinic (Braxia Health) providing intravenous ketamine infusions and intranasal esketamine for depression. KM Teopiz has received personal fees from Braxia Scientific Corp. LMW Lui has received personal fees from Braxia Scientific Corp. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A peer reviewer on this manuscript has disclosed that their institution has a share of patents that were licensed to Janssen Pharmaceuticals related to the use of ketamine for TRD and suicide. They are also a co-founder of a company testing ways to optimize ketamine treatment. A separate peer reviewer declared that they have received grant support from the Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota. The remaining peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.