A recent study published in the Journal of Affective Disorders sheds light on the long-term outcomes of using ketamine to treat mood disorders like major depressive disorder and bipolar disorder. The research examined whether individuals who participated in controlled ketamine clinical trials went on to use ketamine or its derivative, esketamine, after leaving the trial, and assessed their current mental health status.
Mood disorders, such as major depressive disorder and bipolar disorder, significantly impact daily functioning and overall well-being. While existing treatments—including medications, therapy, and neuromodulation—are effective, there is a pressing need for fast-acting solutions. Over the past twenty years, numerous studies have highlighted ketamine’s rapid antidepressant effects.
Given its long-standing use as an anesthetic, ketamine quickly gained traction for off-label use in treating depression, especially treatment-resistant depression, following the approval of esketamine in 2019. However, concerns about ketamine’s long-term side effects and potential for misuse remain. This study aimed to explore these aspects by following up with participants who had received ketamine in highly regulated clinical trials conducted by the National Institute of Mental Health (NIMH).
“Our group has studied the effects of ketamine on people with depression for almost two decades,” explained senior author Elizabeth D. Ballard, an associate scientist and the Director of Predoctoral Training in the Experimental Therapeutics and Pathophysiology Branch (ETPB) at the National Institute of Mental Health.
“Since this research started, there has been an explosion of interest in using ketamine to treat depression in community clinics. One question we are often asked is, ‘what happens to your patients after the ketamine trial?’ This study was designed to answer that question.”
The follow-up study reached out to 1,000 individuals who had previously participated in various NIMH studies between 2002 and 2022. These individuals had been part of clinical trials for experimental treatments for depression and bipolar disorder, including ketamine, or cross-sectional neurobiological studies. Researchers contacted participants through email, postal mail, and phone, using the latest available contact information.
Participants who agreed to partake in the follow-up study completed online self-report questionnaires and participated in telephone interviews with trained clinicians. The questionnaires covered topics such as psychiatric treatment history since leaving NIMH, current mental health symptoms, history of suicide attempts, and ketamine/esketamine use. Tools like the Beck Depression Inventory (BDI) and the Ketamine Side Effect Tool (KSET) were used to measure depressive symptoms and potential side effects related to ketamine, respectively.
Of the 1,000 individuals contacted, 203 (20%) completed the online questionnaires, and 159 of these (78%) also completed the telephone interviews. The study sample was 55% female, with an average age of 53 years. The primary diagnoses were major depressive disorder (77.3%) and bipolar disorder (22.2%).
The study found that participants who had received ketamine during their time at NIMH were more likely to use ketamine or esketamine post-discharge compared to those who had not received ketamine during their initial participation. Specifically, 42% of the ketamine group continued to use these treatments, compared to 16% of the non-ketamine group.
The study did not find a significant association between initial ketamine administration at NIMH and current symptoms of depression or anxiety, suicide attempts, or psychiatric hospitalization. Additionally, none of the participants reported seeking non-prescribed ketamine, and only three reported mild cravings, all of whom were still receiving ketamine/esketamine treatments.
“Overall, our data does not show any concerning ‘safety signals’ of increased substance misuse or dependence in former participants in our ketamine trials,” Ballard told PsyPost. “However, individuals who are administered ketamine as part of our studies are more likely to seek out ketamine in community settings after research.”
Interestingly, those who used ketamine/esketamine post-discharge reported higher levels of depression and anxiety at follow-up.
“We were surprised that individuals who go onto use ketamine in community settings were still reporting elevated depressive symptoms at follow-up assessment,” Ballard said. “This could be because individuals who are depressed are the ones seeking out ketamine treatment. Overall, this underscores the importance of better treatments for individuals experiencing depression.”
Despite its insights, the study has limitations. For instance, the response rate was relatively low at 20%, raising concerns about selection bias.
“This is just one relatively small sample of participants from one research site,” Ballard noted. “To truly understand the long-term impact of ketamine utilization, we need very large registry studies that can capture the thousands of individuals who receive ketamine each year.”
Future research should aim to include larger and more diverse samples to better understand the long-term impacts of ketamine on mood disorders. Stratifying analyses by specific diagnoses, such as major depressive disorder versus bipolar disorder, could reveal important differences. More comprehensive assessments of dissociative symptoms and substance use would also provide a fuller picture of ketamine’s long-term effects.
“We hope that publishing these results can inspire other researchers/clinicians to look into the long-term impact of ketamine on study participants,” Ballard said. “We are also interested in whether we can identify some characteristics of our participants that predict who will go on to receive ketamine in community settings.”
The study, “Long-term follow-up of participants in ketamine clinical trials for mood disorders,” was authored by Kelly T. Hurst, Abigail Vogeley, Deanna K. Greenstein, Lauren Durland, Stephanie Makel, Philip R. Wang, Mani Yavi, Carlos A. Zarate Jr., and Elizabeth D. Ballard.
