Verified by 
Key points
- Matthew Perry’s death highlights the need for safety protocols and monitoring for ketamine treatment.
- Traditional antidepressants, like SSRIs, have advanced treatment but have limitations.
- Ketamine offers a novel approach, especially for treatment-resistant depression.
The tragic death of actor Matthew Perry in 2023, found with high levels of ketamine in his system, underscores the need for caution in the use of novel psychiatric treatments. Perry was undergoing ketamine infusion therapy, but his autopsy suggested he likely took ketamine on his own (Diaz, 2023). This week, criminal charges were brought against five people, including two physicians and Perry's assistant, who are accused of illegally providing the actor with ketamine. This incident serves as a reminder of ketamine’s addictive potential and the importance of careful monitoring, particularly for patients with a history of substance abuse.
Unmet Need for Depression Treatment
Depression is a pervasive and debilitating condition that impacts individuals across all demographics. The National Institutes of Health (NIH) estimated that in 2021, 21 million adults in the United States experienced a major depressive episode, representing 8.3 percent of the population (National Institute of Mental Health, 2023). Depression can severely impair one’s ability to function, affecting work, relationships, and overall well-being. In severe cases, it can lead to suicidal thoughts or behaviors.
Existing Treatments
Before the 1950s, depression treatments were limited. Electroconvulsive therapy (ECT) was used in severe cases but came with serious side effects and stigma. The 1950s saw the introduction of tricyclic antidepressants (TCAs) like imipramine, which, while effective, had side effects such as weight gain and cardiac issues. Also introduced in the 1950s were monoamine oxidase inhibitors (MAOIs), which, though effective, are limited due to a potentially fatal interaction if ingested with certain foods or other medications.
The landscape of depression treatment changed dramatically in 1988 with the FDA approval of Prozac, the first U.S.-approved selective serotonin reuptake inhibitor (SSRI). Prozac and subsequent SSRIs, like Zoloft and Lexapro, increase serotonin availability in the brain, offering effective treatment with more tolerable side effects. SSRIs, along with serotonin and norepinephrine reuptake inhibitors (SNRIs) like Effexor and Cymbalta and atypical antidepressants like Wellbutrin, have been the mainstay of depression treatment for decades. ECT has also seen a resurgence, and transcranial magnetic stimulation (TMS) was approved in 2008, providing another non-pharmacological treatment option.
Treatment-Resistant Depression
Despite these advances, approximately one-third of patients experience treatment-resistant depression (TRD), defined as an inadequate response to at least two adequate trials of first-line treatments. Ketamine, initially FDA-approved in 1970 as a combat anesthetic during the Vietnam War, has emerged as a promising treatment for TRD. Derived from the psychedelic club drug phencyclidine (PCP), ketamine works by blocking the NMDA receptor, increasing serotonin and dopamine levels (Alshammari, 2020).
Research revealed ketamine’s potential to alleviate depressive symptoms, leading to the 2019 approval of esketamine (Spravato), an intranasal form of ketamine, for TRD and severe depression with acute suicidal thoughts. Insurance plans often cover this FDA-approved treatment.
Dr. Ziv Cohen, a psychiatrist at Weill Cornell Medical College and founder of Principium Psychiatry, highlights ketamine’s unique mechanism: unlike traditional antidepressants that affect monoamines like serotonin, ketamine influences glutamate, a neurotransmitter crucial for mood regulation. This novel approach benefits patients unresponsive to conventional treatments like Prozac (Z. Cohen, personal communication, August 1, 2024).
Ketamine Infusion Therapy
In recent years, ketamine infusion centers have proliferated across the country. Although intravenous administration lacks FDA approval, off-label use has gained popularity. A 2023 Harvard Medical School study by Anand et al. found that 55 percent of patients treated with intravenous ketamine experienced at least a 50 percent improvement in depressive symptoms, with benefits lasting six months and minimal side effects (Anand et al., 2023). A 2019 study by Mandal et al. showed significant improvement in depression immediately after the first dose and lasted up to six weeks (Mandal et al., 2019).
Administration and Monitoring
Ketamine treatments are typically administered in outpatient centers where vital signs are monitored. Infusions last about 40 to 50 minutes, with a recovery period of approximately one hour. Patients may experience dissociation or sedation during infusions. A standard treatment involves six infusions over two to three weeks, with some patients responding rapidly and others requiring more time. Many centers offer therapy sessions post-infusion to help patients process their experiences. Maintenance treatments may be beneficial, often in conjunction with oral antidepressants.
Beyond Prozac
Ketamine represents a significant advancement in treating depression, especially for those with TRD. Dr. Cohen explains that while Prozac and similar medications remain effective for many patients, ketamine offers a "beyond Prozac" solution, providing hope for patients unresponsive to traditional treatments (Z. Cohen, personal communication, August 1, 2024). However, its use must be carefully monitored to prevent misuse and ensure patient safety. By enhancing our understanding of ketamine’s role in depression treatment, we can better address the needs of those suffering from this debilitating condition and continue our journey to discover novel and effective therapies.
To find a therapist near you, visit the Psychology Today Therapy Directory.
References
Alshammari, T. K. (2020). The Ketamine Antidepressant Story: New Insights. Molecules, 25(23), 5777. https://doi.org/10.3390/molecules25235777
Anand, A., Mathew, S. J., Sanacora, G., Murrough, J. W., Goes, F. S., Murat Altinay, Aloysi, A. S., Asghar-Ali, A. A., Barnett, B. S., Chang, L. C., Collins, K. A., Costi, S., Iqbal, S., Jha, M. K., Krishnan, K., Malone, D. A., Nikayin, S., Nissen, S. E., Ostroff, R. B., & Reti, I. M. (2023). Ketamine versus ECT for Nonpsychotic Treatment-Resistant Major Depression. The New England Journal of Medicine, 388(25). https://doi.org/10.1056/nejmoa2302399
Diaz, J. (2023, December 15). What is ketamine, the drug tied to actor Matthew Perry’s death? NPR. https://www.npr.org/2023/12/15/1219761972/what-is-ketamine-friends-matt…
Mandal, S., Sinha, V., & Goyal, N. (2019). Efficacy of ketamine therapy in the treatment of depression. Indian Journal of Psychiatry, 61(5), 480. https://doi.org/10.4103/psychiatry.indianjpsychiatry_484_18
National Institute of Mental Health. (2023). Major Depression. National Institute of Mental Health. https://www.nimh.nih.gov/health/statistics/major-depression
