Ketamine infusions might improve cognitive function in depressed individuals

A study of individuals with treatment-resistant depression found that four infusions of the antidepressant ketamine led to enhanced cognitive functioning that persisted for five weeks. These improvements appeared to be independent of the antidepressant response. The study was published in the Journal of Affective Disorders.

Depression is a mental health disorder characterized by persistent feelings of sadness, hopelessness, and a lack of interest or pleasure in activities. It adversely affects various aspects of daily life, including sleep, appetite, and concentration. According to the World Health Organization, approximately 322 million people worldwide suffer from depression.

Typical treatments involve a combination of therapy, medication, and lifestyle changes. However, for about 30% of individuals, symptoms of depression persist even after two or three rounds of treatment. These individuals are considered to have treatment-resistant depression. Statistics indicate that their risk of disability and suicide is significantly higher than that of individuals with treatable forms of depression. Therefore, finding ways to address treatment-resistant depression is a topic of critical scientific interest.

One promising new treatment for treatment-resistant depression is ketamine. Ketamine is widely used in medicine as an anesthetic and an analgesic, but recent studies indicate that administering ketamine in specific doses that are below the dose needed for its anesthetic effect reduces the symptoms of depression in 60%-70% of individuals with treatment-resistant depression. Other studies have indicated that it might also have an effect on cognitive impairments, which are one of the core symptoms of depression.

Study author Artemis Zavaliangos-Petropulu and his colleagues wanted to examine whether infusions of ketamine in doses lower than those needed to produce anesthetic effects could positively impact cognitive functions of individuals with treatment-resistant depression. They were particularly interested in executive function, inhibitory control and attention, language processing, and episodic and working memory.

The study included 66 adult participants experiencing a depressive episode who had not responded to at least two antidepressant treatments. Eligible participants were aged between 20 and 64, diagnosed with unipolar or bipolar depression, and exhibited moderate or severe depressive symptoms at the study’s outset.

Participants received ketamine infusions of 0.5 mg/kg, diluted in 60 cm³ of saline, administered intravenously over 40 minutes. Each participant underwent four infusions across a 14-day period. They completed the NIHToolbox Cognition Battery neurocognitive assessment 24 hours after the first and fourth infusions, and again five weeks after the final infusion.

Results indicated that participants’ working memory, processing speed, episodic memory, and overall neurocognitive test performance improved following the four ketamine infusions. There were also modest improvements in language, attention, and inhibition. Notably, the enhancement in overall neurocognitive performance and specific functions persisted five weeks post-treatment.

Depression symptom severity was also reduced after the 4 ketamine treatments, but it started increasing again by 5 weeks after treatment.

“We demonstrated cognitive safety and procognitive effects of serial ketamine treatment that were sustained 5-weeks following the end of four serial infusion treatments,” the study authors concluded. “Additionally, we found that the brain processes leading to improvements in inhibition related to those leading to successful antidepressant response following ketamine treatment. In contrast, improvements in other neurocognitive functions including processing speed, episodic memory, working memory, and attention over the course of treatment occurred independently of change in depressive symptoms.”

The study makes a valuable contribution to the scientific understanding of antidepressant effects of ketamine. However, it also has limitations that need to be taken into account. Notably, the study did not include a control group and participants were aware of the characteristics of the treatment they were undergoing. Researchers note that participants were not told to expect changes in cognitive functioning, but in spite of this, the study design does not allow any definite cause-and-effect conclusions to be drawn from the results.

Additionally, participants completed the same test battery in multiple assessments and it is possible that (at least some of) the observed effects are consequences of practice instead of treatment. The lack of a control group makes it impossible to differentiate between these two possibilities.

The paper, “Neurocognitive effects of subanesthetic serial ketamine infusions in treatment resistant depression”, was authored by Artemis Zavaliangos-Petropulu, Shawn M. McClintock, Jacqueline Khalil, Shantanu H. Joshi, Brandon Taraku, Noor B. Al-Sharif, Randall T. Espinoza, and Katherine L. Narr.