TCPR: Where do ketamine and esketamine fit in psychiatry?
Dr. Brody: I work with IV ketamine on inpatient units, so I’ll focus on that, but most of what I say in this interview applies to esketamine as well. These are not first-line treatments. Their main role is in depression, for acute suicidality and treatment resistance—patients who did not recover after two antidepressants and hopefully an evidence-based psychotherapy as well. At that point, ketamine therapies are good rapid-acting augmentation strategies and can be alternatives to lithium or an antipsychotic.

TCPR: Are they for short- or long-term use?
Dr. Brody: Preferably short term. That’s often how we use ketamine in patients who have had a few episodes of depression, spaced out over years with good recovery in between. Ketamine can get them out of depression, and we can use other therapies for maintenance. On the other hand, if someone has had a chronic course with more failed trials and shorter periods of recovery, they may need ketamine as a maintenance treatment. Most of the long-term maintenance data are with esketamine (Spravato), through the SUSTAIN 1–3 trials, which lasted up to 4.5 years. They found no new safety problems with continuation. That was reassuring.

TCPR: Are any of the long-term trials placebo controlled?
Dr. Brody: There are two. Both found preventive benefits with esketamine. In SUSTAIN-1, continuing esketamine after 16 weeks of acute treatment reduced the relapse risk by 50%–70% compared to switching to placebo (Daly EJ et al, JAMA Psychiatry 2019;76(9):893–903). That preventive effect was greater for patients who did not fully recover on esketamine, suggesting they are more likely to require maintenance. Another trial compared esketamine to quetiapine over eight months in treatment-resistant depression, though it wasn’t blinded. Patients on esketamine had higher remission rates in the short term (27% vs 18%), and over the long term they were 1.6 times more likely to remain euthymic (Reif A et al, N Engl J Med 2023;389(14):1298–1309).

TCPR: Are you more likely to continue it if they respond but don’t fully recover?
Dr. Brody: Yes. Maintenance treatment is reasonable then. At some point we start to think about tapering it off. That is usually a slow process, spacing out the treatments until they’ve stopped successfully. But other patients who have chronic depression may need ongoing maintenance therapy, not unlike some patients who need maintenance ECT. So some patients stay on ketamine long term, once or twice a month, and that’s probably safe as long as we’re talking about usual therapeutic doses.

“ECT is more effective than ketamine for psychotic and catatonic depression, features that are more common in severe depression. For outpatients with less treatment resistance, they’re probably near equivalent.” - Benjamin D. Brody, MD

TCPR: What are the risks with long-term use?
Dr. Brody: First is neurotoxicity. In terms of symptoms, that would present as problems with cognition and executive function. We see this with high doses in recreational use and animal studies, but not at the doses we use for depression (Li SW et al, Am J Psychiatry 2025;182(10):903–912). Next is bladder problems. Ketamine can cause severe bladder ulcers with long-term use of high doses. The third problem is misuse. This is rare when ketamine is delivered in the office, but it’s probably much more common when ketamine lozenges or other formulations are shipped directly to patients for home use. I also think that it’s important to exercise some discretion with other controlled substances, although ketamine is not contraindicated with stimulants, occasionally as-needed benzos, or opioids. Some clinicians use compounding pharmacies so patients can take it outside the clinic, but ketamine and esketamine are not intended for home use, and there have been deaths reported with home use. This is not a practice I support. Remember, it’s a general anesthetic.

TCPR: Are there withdrawal problems with ketamine?
Dr. Brody: There are reports of ketamine causing a withdrawal syndrome, but personally I’ve never seen it, and I would not expect to encounter it at therapeutic doses and frequencies. The bigger risk with stopping ketamine is relapse. When we use a rapid-acting treatment for severe depression or suicidality, there’s a substantial chance of relapse if it is stopped. Close monitoring, especially for suicidality, is needed during that period. So for example, we don’t want to give ketamine to suicidal patients, have them feel rapidly better, and then abruptly stop treatment. Of course, that’s true for any antidepressant, but it might be more pronounced with ketamine given its rapid therapeutic time frame and transient effects, which are typically a few weeks.

TCPR: What about higher doses?
Dr. Brody: If a patient comes to us and says, “I’ve taken higher doses before” then asks for something higher than the 0.5 mg/kg we typically use, my stance would be similar to how I would see a patient coming in and asking for higher doses of a benzodiazepine: I’d consider it something of a red flag. I might refer that patient to ECT or transcranial magnetic stimulation if they want to pursue neuromodulation.

TCPR: Most psychotropics can cause psychiatric side effects. What about ketamine?
Dr. Brody: Very few patients get acutely worse during administration, but the good news is that if they do, it’s transient. Ketamine is a dissociative anesthetic. For most patients, it is a neutral experience, but few find it intoxicating or rewarding, and for another minority, it is intensely unpleasant—something we’ve labeled dysphoric dissociation. This might be akin to a “bad trip” with a psychedelic. I’ve seen patients have panic attacks or become acutely suicidal during ketamine treatment. One patient felt a warm and sleep-like sensation, then told us that she heard screaming, “and then I realized the person screaming was me.” Fortunately, it is transient and only lasts a few hours. This is one of the reasons I like the formulation of an IV infusion over 40 minutes. If it isn’t going well, we can simply turn the infusion off (Brody BD et al, J Clin Psychiatry 2025;86(3):25com15946).

TCPR: Some recent papers have raised concerns about ketamine’s efficacy.
Dr. Brody: Right, most notably the inpatient trial from the group in Ireland. I appreciate what those investigators were trying to accomplish, but there were a number of problems with that study. It was a negative trial of IV ketamine in 65 hospitalized patients. It was double blinded, with midazolam as the control, but many correctly guessed their treatment. This was a pragmatic study, so they looked at real-world outcomes and enrolled many types of depression, including bipolar. That might contribute to the negative results, but that’s a minor issue, as we do have trials showing ketamine is effective in bipolar depression. The bigger issue is that the trial only enrolled patients who were not suicidal. In the US, who do you think gets psychiatrically hospitalized for depression? The vast majority are suicidal. So that report isn’t really generalizable to our populations at all. It is a select group who are admitted to a hospital without suicidality, and they may not be the best responders, as suicidality is one of the indications for ketamine and esketamine. I don’t know if their IRB or other oversight body prevented them from enrolling suicidal patients, but it was an unfortunate missed opportunity (Jelovac A et al, JAMA Psychiatry 2025;82(12):1216–1224).

TCPR: Is it possible the structure and support of the hospital washed out any detectable benefit there?
Dr. Brody: I wouldn’t criticize the trial for that reason, because the idea was to test it in a real-world setting. I do applaud that group for taking this on. That’s what effectiveness research is about, as opposed to efficacy research where we test a treatment in more rarefied research settings. But it might mean that with 30-odd subjects in the treatment arms, the study may have also been underpowered.

TCPR: How do you use ketamine for suicidality?
Dr. Brody: This is what sparked my interest in ketamine. We often admit people for suicidality and change their antidepressant, but they stay only a few days, while the medication takes weeks to work. Ketamine can quickly reduce suicidality. Lithium is antisuicidal, but not immediately. One strategy for acutely suicidal patients is to give a few doses of ketamine while starting a long-term medication like lithium, then gradually switch to lithium as the longer-term maintenance treatment. This idea has not been adequately tested, but lithium has been successful for maintenance after ECT.

TCPR: How do patients with borderline personality respond to ketamine?
Dr. Brody: The limited research suggests they respond as well in terms of depression but may have a greater risk of dissociation (Scott E et al, Aust N Z J Psychiatry 2025;59(12):1046–1058). Ketamine may also increase empathy, which can be helpful for patients with borderline personality or a trauma history. Drugs that do this are called entactogens. They help with mentalization—understanding others’ thoughts and feelings (Hu H et al, Psychiatry Res 2025;349:116513). Potentially, this could lead to more stable therapeutic connections and better engagement in psychotherapy. This is an area my colleagues and I are interested in. The mainstay treatments for personality disorders are psychotherapies such as dialectical behavioral therapy. Ketamine may augment those, but won’t replace them.

TCPR: What is the role of ketamine-assisted psychotherapy?
Dr. Brody: Psychotherapy (eg, cognitive behavioral therapy) might prevent depression after ketamine treatment, but that’s just from a small trial, so we don’t know much about whether therapy improves outcomes (Wilkinson ST et al, Psychother Psychosom 2021;90(5):318–327). There are several dozen trials of this underway, but very few of them involve mood disorders. Most are testing ketamine-assisted psychotherapy for substance use disorders or for end-of-life anxiety in conditions like terminal cancer. On its own, ketamine has a large effect size, which makes it hard to prove that add-on therapies improve anything beyond that. In a similar vein, ECT has a large effect size, and we haven’t been able to show that ketamine adds anything to ECT when it is used as the anesthetic agent. What is largely unknown is the role that ketamine-assisted psychotherapy may play in promoting behavioral or affective changes during ketamine treatment for treatment-resistant depression, and whether there is a relationship between these changes and longer-term remission following cessation of ketamine treatment.

TCPR: Does ketamine shift people’s perspective?
Dr. Brody: Yes, and that’s the opportunity for psychotherapy engagement. A core symptom of depression is negative affective valence. These patients are very pessimistic about life. Ketamine usually has a rapid and dramatic effect, so that patients can easily compare their condition to how it was a week ago. I’ll ask, “Do you think it’s possible that some of the views you had last week were symptoms of depression?” It directly challenges their cognitive distortions. They see the difference, and their families see it as well.

TCPR: What do you do if ketamine doesn’t work?
Dr. Brody: If there’s no improvement after four to six ketamine sessions, it’s unlikely they are going to respond later (Brody BD et al, J Affect Disord 2024;351:293–298). At that point, we may move on to ECT.

TCPR: Do some patients respond better to ECT than ketamine?
Dr. Brody: Yes. ECT is more effective than ketamine for psychotic and catatonic depression, features that are more common in severe depression. For outpatients with less treatment resistance, they’re probably near equivalent. For more severe depressions, the sorts of patients who are commonly hospitalized, ECT probably still has the edge as the gold standard (Anand A et al, N Engl J Med 2023;388(25):2315–2325; Rhee TG et al, JAMA Psychiatry 2022;79(12):1162–1172).

TCPR: What do you tell patients to expect with ketamine?
Dr. Brody: Ketamine can be an intense experience. Regarding dissociation, I’ll explain that they may feel disconnected from their body: unreal, like they are in a movie, or floating above the room observing themselves. The experience is temporary. Most people feel neutral about it, some feel euphoric, and a few find it uncomfortable or frightening. Patients may also feel drowsy but will remain conscious and should stay awake during the treatment.

TCPR: What should we look for when referring to a ketamine center?
Dr. Brody: I would only use IV ketamine or intranasal esketamine. Some places give ketamine orally, intranasally, or intramuscularly, but these methods are unreliable because ketamine is not well absorbed. They also carry a risk of misuse when used at home. Unmonitored or at-home use is a red flag, even with telehealth monitoring. Problems can happen when you don’t know how much the patient is taking, such as unconsciousness, bladder injury, or even death, as we saw with Matthew Perry. The center should perform a full diagnostic assessment. They should observe the patient during administration, watching for hypertension, sedation, and altered consciousness.

TCPR: Are there any medications we should stop before ketamine?
Dr. Brody: Yes, benzodiazepines and naltrexone. Ketamine acts on the glutamatergic system, which is modulated by GABAergic neurons, and there’s some evidence that ketamines are less effective when combined with benzodiazepines, so they should be minimized. Ketamine may treat benzodiazepine withdrawal, which eases the transition (Garel N et al, Neuropsychopharmacology 2023;48(12):1769–1777). Ketamine affects mu-opioid receptors, and its antidepressant effects can be blocked by opioid antagonists like naltrexone (Williams NR et al, Mol Psychiatry 2019;24(12):1779–1786).

TCPR: Thank you for your time, Dr. Brody.