Is the ketamine story changing?

May 27, 2022

By Tom Insel, MD, and Matthew Hirschtritt, MD, MPH

Good morning, Research Roundup readers. A few weeks ago we reported on a chilling CDC study that found guns have surpassed cars as the leading cause of death among children and teens in the United States. The horrific news of the massacre of elementary school children in Uvalde, Texas, reinforces the urgent need to stop this rise in gun violence. As we said in our April 22 Research Roundup (“Guns now deadlier than crashes for kids“), we know how to do this. We just need the political will.

In today’s Research Roundup, we look at the real world of ketamine, an old drug recently hailed as new, fast-acting treatment for depression, and a new report on psychosis that incorporates the voices (and edits) of people with lived experiences of depression. We look forward to your thoughts. 

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Ketamine: Is the Luster Fading?

Ketamine has become an increasingly popular treatment for depression. Although it has been used for decades as an anesthetic, a new role for this old drug recently emerged in mental health with studies showing antidepressant effects in hours, compared to traditional antidepressants that require weeks of administration. In placebo-controlled studies, intravenous ketamine was effective even for forms of depression that had not responded to other antidepressants. In addition, many patients who responded within 24 hours continued to experience relief weeks later. In 2019, the FDA approved an intranasal form of ketamine called esketamine, in conjunction with an oral antidepressant, for the treatment of so-called treatment-refractory depression, or depression resistant to treatment. (This history is summarized in an excellent overview out this week in the Smithsonian magazine.)

Two new reports reveal some unexpected developments in the ketamine story. One issue is that intravenous ketamine continues to be used for treating depression, although only the intranasal form has been approved by the FDA. A report from the Yale Interventional Psychiatry Service compared intravenous and intranasal ketamine in patients with depression being seen in the same clinic with the same overall care except for the route of administration. There were few differences in the rates of response (37.8% for intravenous vs 36.0% for intranasal) or remission (29.6% for intravenous vs 24.0% for intranasal), but on some of the ratings of depression, people receiving intravenous ketamine did significantly better than those receiving the FDA-approved intranasal form.

Most people get ketamine at a bespoke clinic, not at an academic center. A letter in the American Journal of Psychiatry provides a surprising picture of 98 of these clinics across the country, all offering intravenous ketamine (more than half also offered intranasal or intramuscular administration of ketamine). While 68% of clinics reported having a physician as part of the treatment team, most of these were anesthesiologists. Most clinics – 73% – did not have a psychiatrist involved.  More than a quarter had a nurse anesthetist as the provider administering ketamine. Less than half of the clinics offered any form of counseling or psychological services. 

Ketamine provides an interesting case study in the implementation of a new treatment, particularly when a less expensive, older version is available. Based on the data from these two reports, this new treatment for depression is being administered mostly by anesthesiologists, not mental health professionals, and the non-approved version of the drug is more popular (and potentially more effective) than the FDA-approved formulation. In spite of the popularity of the treatment, from the Yale data it appears that less than half of people with severe depression respond and only about a quarter experience remission. Most people who improve report a relapse within a few weeks and therefore need multiple infusions. So, the original appeal of a rapid treatment is offset by the number of infusions required for a sustained response. In summary, this old anesthetic may be a new antidepressant, but its use in practice conforms to neither the regulatory approval nor the original clinical rationale.  

Evaluation of the Trajectory of Depression Severity With Ketamine and Esketamine Treatment in a Clinical Setting JAMA Psychiatry, May 11, 2022

An Update on Community Ketamine Practices  American Journal of Psychiatry, May 2022

– Tom Insel

Shining a Light Into The Lived Experience of Psychosis

Defining psychosis succinctly and accurately is challenging. The word describes a wide and diverse variety of experiences, including delusions, hallucinations, disorganized speech and behavior, along with depressive-like symptoms referred to as negative symptoms. But that list doesn’t even begin to do justice to the unique experiences of people with psychotic disorders.

Paolo Fusar-Poli of King’s College London and colleagues aimed to fill that gap in the literature with a collaborative report, leaning on the insights of people with lived experiences of psychosis. This report integrates findings from the published literature with contributions from co-authors who have or are experiencing psychosis. Fusar-Poli and team established a core writing group composed of academic experts in psychosis who evaluated all first-person accounts of psychosis published in Schizophrenia Bulletin between 1990 and 2021 and collected further personal narratives within and outside the medical field. The group then identified lived experiences of interest and assigned each of them to larger themes, which were grouped into illness stages of schizophrenia.  

Next came the most innovative part – the academics shared their tentative themes with people who had lived experience of psychosis (and their families) in two workshops and integrated their feedback. Finally, the study group fine-tuned the themes and selected representative quotes based on the current scientific understanding of psychosis.

The research group then examined the constellation of themes in the different stages of illness: premorbid (an individual’s functioning before the onset of psychotic symptoms),  prodomal (changes or deterioration prior to the onset of psychotic symptoms), first episode, relapses, and chronic illness. Among the findings:

• The premorbid phase was characterized by feelings of loneliness and isolation. Additional themes during this phase included interpersonal sensitivity or social anxiety, recurring anxieties and fears, and being considered “weird” or odd.

• The prodromal phase included feelings that “something important is about to happen,” a growing belief that innocuous inner feelings and external experiences have profound meaning, a disruption of a sense of self, a sense of alienation and remove from the world, an increasingly tenuous grasp of reality, and a need to “keep it secret.”

• In the first episode phase, emergent themes included a feeling of relief and resolution when full-blown delusions take over (and thereby give meaning and validity to the odd sensations from the prodromal phase), a feeling that everything relates to oneself, a blurring of lines between the inner and outer worlds, a complete dissolution of the sense of self, a noisy and chaotic inner monologue, and withdrawal from the world.

• Following the first episode, many patients go on to experience a relapsing phase, characterized by grief at personal losses, feeling split between realities, and an uncertain future. 

• Finally, in the chronic phase, patients come to terms with accepting a new internal or “self-world” and are often able to hide their inner chaotic thoughts and loneliness.

The report ends on a more positive note, describing themes relevant to seeking and receiving treatment, including the prevalent view that recovery is a journey. As a report we summarized last week suggests, as many as 50% of patients with early psychosis recover in the decades after their first episode.

This is a truly remarkable resource. The authors – traditional academics and people with lived experiences – manage to cohesively and vividly describe the often terrifying and isolating descent into psychosis, which will hopefully lead to a recognition of the chronic nature of this illness and navigating multiple treatment options. People with psychosis are routinely stigmatized, socially excluded, mocked, and misunderstood. This document testifies to their rich, diverse, and profound experiences.

The lived experience of psychosis: a bottom-up review co-written by experts by experience and academics. World Psychiatry, May 7, 2022.

– Matthew Hirschtritt

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If you or anyone you know is considering suicide, call the National Suicide Prevention Lifeline at 1-800-273-8255. And if you’re a veteran, press 1.

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Tom Insel, MD, is a psychiatrist, neuroscientist, and former director of the National Institute of Mental Health (NIMH). He is a donor to MindSite News and chair of its Editorial Advisory Board. Dr. Insel’s financial conflict of interest statement, which includes equity and advisory roles in several early-stage mental health technology companies, can be found here.

Matthew Hirschtritt, MD, MPH, is a clinical psychiatrist with the Permanente Medical Group, Inc., a mental health services researcher with the Division of Research, Kaiser Permanente Northern California, and assistant program director of the Kaiser Permanente Oakland Adult Psychiatry Training Program. His current research focuses on identification and treatment of patients with first-episode psychosis, as well as implementation of a telehealth-based mental health evaluation and referral program.

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