Does Ketamine Live Up to the Hype in Depression?

[David Baxter PhD]

Ketamine vs ECT for Depression: First Head-to-Head Results​

Stephen M. Strakowski, MD; Gerard Sanacora, MD, PhD; and Charles B. Nemeroff, MD, PhD, Medscape
August 17, 2022

Intravenous ketamine is effective for treating depression but is inferior to electroconvulsive therapy (ECT), new research suggests.

In the first head-to-head trial, ECT was more effective than IV ketamine in hospitalized patients with severe depression, with higher remission rates and a greater reduction in symptoms.

However, ketamine led to remission in nearly half of participants and is a "valuable" option for treating severe depression, particularly in younger patients, investigators note.

The high rate of remission for ketamine infusion "indicates that it definitely can be used in a clinical setting, but it is more probable that a patient will achieve remission with ECT compared to ketamine," principal investigator Pouya Movahed Rad, MD, PhD (Pharmacology), senior consultant and researcher in psychiatry, Lund University, Sweden, told Medscape Medical News.

Results of the KetECT study were recently published online in the International Journal of Neuropsychopharmacology.

Primary Focus on Remission​

The parallel, open-label, non-inferiority study included 186 patients aged 18-85 years who were hospitalized with severe unipolar depression and had a score of at least 20 on the Montgomery–Åsberg Depression Rating Scale (MADRS).
Participants were randomly allocated (1:1) to thrice-weekly infusions of racemic ketamine (0.5 mg/kg over 40 minutes) or ECT. All patients continued to take their antidepressant medication during the study. The primary outcome was remission, defined as a MADRS score of 10 or less.

Results showed the remission rate was significantly higher in the ECT group than in the ketamine group (63% vs 46%, respectively; P = .026). The 95% confidence interval of the difference in remission rates was estimated between 2% and 30%.

Both ketamine and ECT required a median of six treatment sessions to induce remission.

Age was a factor in the findings. In the ECT group, remission was significantly more likely in older patients (age 51-85 years) compared with younger patients (18-50 years), with remission rates of 77% and 50%, respectively.

But the opposite was true in the ketamine group, with significantly higher remission rates in younger vs older patients (61% vs 37%).

The study results also support the safety and efficacy of ketamine in patients with psychotic depression, which was present in 15% of patients in the ECT group and 18% of those in the ketamine group.

In this subgroup, half of patients with psychotic depression remitted after ketamine, with no indications of adverse reactions particular for these patients. The remission rate with ECT was 79%.

During the 12-month follow-up period, rate of relapse among remitters was similar at 64% in the ECT group and 70% in the ketamine group (log rank P = .44).

Let the Patient Decide​

As expected, ECT and ketamine had distinct side effect profiles. Prolonged amnesia was more common with ECT and reports of dissociative side effects, anxiety, blurred vision, euphoria, vertigo, and diplopia (double vision) were more common with ketamine.

"Dissociative symptoms were, as expected, observed during treatment with ketamine, but they were brief and in the majority of cases mild and tolerable," Movahed Rad said.

The investigators note that participating study sites all had long-time experience with ECT but no experience administering ketamine.

"Staff, and some patients, were familiar with side effects common to ECT but were less prepared for the adverse psychological effects of ketamine. This, and knowing ECT was available after the study, probably contributed to the higher dropout rate in the ketamine group," they write.

If both ECT and ketamine are available, "the patient's preference should, of course, be taken into account when choosing treatment," said Movahed Rad.

"Ketamine should be offered if ECT is not available, or cannot be given due to excessive risks with anesthesia or other somatic risk factor. Patients who have not responded to ECT or have had unacceptable side effects should be offered ketamine infusion and vice versa," he added.

A Good Alternative​

Commenting on the findings for Medscape Medical News, Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Canada, said the data confirm ECT is highly effective for treatment-resistant depression and show that "newcomer" IV ketamine also performs "exceptionally well."

"This is an extremely important study that really establishes the efficacy of ketamine in a very difficult to treat population," added McIntyre, who was not involved in the research.

McIntyre added that this "rigorous, well-designed study addresses a critical question" about the comparative efficacy of ECT and IV ketamine. It also makes "quite a strong statement about the efficacy of ketamine in younger people."

He cautioned, however, that this study represents the "first data point and, of course, is not the final word on the topic. There are other studies currently still ongoing that are also comparing ECT to IV ketamine and we'll look forward to seeing the results."

The fact that 15% to 20% of the study patients had psychotic depression is also noteworthy, said McIntyre.

"We've been hesitant to use ketamine in these patients, I think for obvious reasons, but we recently published a paper showing that it is safe and very effective in these patients," he said.

Having ketamine as a treatment option is important because the majority of patients who could benefit from ECT decline it, often because of the stigma associated with the procedure, which is often portrayed negatively in films and other media.

"I have been recommending ECT almost every day of my professional life and 98 times out of 100 people say, 'Thanks but no thanks.' That's a problem because ECT is so effective.

The study was funded by the Swedish Research Council, The Crafoord Foundation, Skåne Regional Council, The Königska Foundation, Lions forsknings foundation Skåne, and the OM Perssons donation foundation. Movhed Rad has received lecturer honoraria from Lundbeck. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and AbbVie. McIntyre is also CEO of AltMed.

Int J Neuropsychopharmacol. Published online December 4, 2021. Full text

 

[David Baxter PhD]

Single Infusion of Ketamine Rapidly Reduces Suicidal Thoughts​

Megan Brooks, Medscape
November 11, 2021

A single infusion of ketamine rapidly improves distorted thinking and reasoning to reduce suicidal thoughts, independent of the drug's effect on severe depression, new research shows.

Dr J. John Mann
"Previously it was shown that ketamine rapidly improved depression and that explained part of the rapid improvement in suicidal ideation," senior author J. John Mann, MD, with Columbia University in New York City, told Medscape Medical News.

"What was unclear was what else changed that could decrease suicidal ideation and the risk for suicidal behavior. This study identifies a second new domain of improvement — namely rapid improvement in several cognitive functions that can potentially reduce suicide risk," said Mann.

The study was published online November 2 in the Journal of Clinical Psychiatry.

Boosts Cognitive Function​

A total of 78 adults with major depressive disorder and clinically significant suicidal ideation underwent neuropsychological testing before, and 1 day after, double-blind treatment with a single intravenous infusion of ketamine or midazolam.

"Ketamine produced rapid improvement in suicidal ideation and mood" compared with midazolam, the authors report.

Ketamine was linked to specific improvement in reaction time and cognitive control/interference processing — a measure that has been associated with previous suicide attempt in depression.
A subgroup of patients whose suicidal ideation did not remit on midazolam were later treated with unblinded ketamine and retested. In these individuals, reaction time and cognitive control/interference processing also improved relative to pre-ketamine assessments.

Neurocognitive improvement, however, was not correlated with changes in depression, suicidal thinking, or general mood, the researchers note.

Nonetheless, they say ketamine had a "positive therapeutic effect" on neurocognition 1 day after treatment on at least one measure associated with suicidal behavior in the context of depression.

The results suggest "additional independent therapeutic effects for ketamine in the treatment of depressed patients at risk for suicidal behavior," they write.

"Ketamine modulates many neurotransmitter systems including glutamate transmission which is crucial for learning and memory. It increases the number of synapses or connections between neurons. These effects are fundamental to cognition and are logical explanations of the beneficial effects observed in this study," Mann told Medscape Medical News.

"Our study helped us gain a better understanding of how ketamine works in the brain and how quickly it can improve distorted thinking. Being able to think more clearly can make someone feel less suicidal," study investigator Ravi. N. Shah, MD, chief innovation officer, Columbia Psychiatry, said in a news release.

Important Research With Caveats ​

Reached for comment, James Murrough, MD, PhD, director, Depression and Anxiety Center for Discovery and Treatment at Mount Sinai in New York City, said the study is important and "adds to a growing understanding of how ketamine affects brain systems and thinking in the context of depression and suicide risk."

"One reason this study is significant is that prior studies have shown that ketamine can have harmful effects on cognitive functioning in the context of ketamine misuse and exposures to high doses for long periods of time," Murrough, who wasn't involved in the study, told Medscape Medical News.

"In contrast in this study, a single low-dose treatment of ketamine can have the opposite effects, actually boosting some markers of cognitive functioning, at least in the short-term," he noted.

Murrough said one caveat to the study is that it only examined the effect of ketamine on cognition once, 1 day after a single treatment.

"While this is an important initial observation, we don't yet have any understanding of how persistent this effect on cognition is, or how this observed change may be related to any benefit ketamine may have on depression or suicide risk," Murrough said.

"In fact, the researchers found that there was no association between change in cognitive functioning following ketamine and change in depression or suicidal thinking. The patients who showed improved cognitive function following ketamine did not differ in terms of mood or suicide risk compared to patients who did not show an improvement in cognition," Murrough noted.

"This raises the important question of what is the relevance of change in cognition to the potential benefits of ketamine. This is an important area and should be the focus of future research in order to improve outcomes for patients with depression and who are at risk for suicide," he added.

Also weighing in, Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Canada, said the study is "very interesting and in keeping" with some previous work that he and his colleagues have done showing that ketamine "seems to benefit aspects of cognition which is a core element in depression."

"It's a testable hypothesis that the improvement in cognition now being reported and replicated could play some role in the improved quality of life and functioning with this treatment and as well reduce reducing suicide," said McIntyre.


This study was supported by the National Institute of Mental Health. Mann receives royalties for commercial use of the Columbia-Suicide Severity Rating Scale, which was not used in this study. Murrough's institution (Mount Sinai) was involved in research involving esketamine (Spravato) for treatment-resistant depression and receives financial remuneration from the manufacturer of esketamine. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Eisai, Minerva, Intra-Cellular, and Abbvie. McIntyre is also CEO of AltMed.


J Clin Psychiatry. Published online November 2, 2021. Abstract

 

[David Baxter PhD]

Ketamine Fast, Effective for Suicidal Crises​

Megan Brooks, Medscape
February 10, 2022

Ketamine is a rapid and effective treatment for suicidal ideation and has a "major" moderating effect based on the primary mental health diagnosis, results of a large randomized controlled trial shows.

In addition, a strong effect of ketamine was observed in patients with bipolar disorder, "whereas the effect was moderate and did not quite reach significance in those with other psychiatric disorders and unexpectedly was non-significant in those with major depressive disorders," the researchers write.

"We assessed for the first time in the same study the effect of ketamine on three a-priori defined groups of nonpsychotic patients: those with a bipolar disorder, those with a depressive disorder, and those with other diagnoses," study investigator Fabrice Jollant, MD, PhD, professor of psychiatry, University of Paris, France, told Medscape Medical News.

"This allowed us to find that comorbid disorders are important modulators of the clinical effects of ketamine, and that the effect of ketamine is particularly marked among patients with a bipolar disorder," Jollant added.

The study was published online February 2 in The BMJ.

Swift, Full Remission​

The study included 156 adults admitted voluntarily to seven French teaching hospitals with severe suicidal ideation, including 52 with bipolar disorder, 56 with depressive disorder, and 48 with other psychiatric diagnoses.

They were randomly allocated to two 40-minute intravenous infusions of ketamine (0.5 mg/kg) or placebo (saline) administered at baseline and 24 hours, in addition to usual treatment.

The primary outcome was the rate of patients in full suicidal remission at day 3, confirmed by a score of 3 or less on a clinician-rated scale for suicidal ideation based on 19 items scored 0 to 2 (maximum score, 38).

"We investigated the full remission of suicidal ideas and not only the response, which is usually defined as a reduction of 50% of scores on a given scale. If people remain slightly suicidal, the suicidal risk persists. We want all suicidal ideas to disappear," said Jollant.

They found that more patients reached full remission of suicidal ideas at day 3 after two ketamine infusions than after placebo infusions (63% vs 32%; odds ratio [OR], 3.7; 95% CI, 1.9 - 7.3; P < .001).

This anti-suicidal effect of ketamine was rapid, with 44% remission only 2 hours after the first infusion, the authors report.

The effect of ketamine on suicidal remission was greatest in patients with bipolar disorder, with 85% achieving full remission at day 3 (OR, 14.1; 95% CI, 3.0 - 92.2; P < .001), compared with 42% of patients with depressive disorder (OR, 1.3; 95% CI, 0.3 - 5.2; P = .6) or 62% of those with other disorders (OR, 3.7; 95% CI, 0.9 - 17.3; P = .07).

At 6 weeks after treatment, remission in the ketamine group remained high, although nonsignificantly vs placebo (69.5% vs 56.3%; OR, 0.8; 95% CI, 0.3 - 2.5; P = .7).

The researchers note the beneficial effect of ketamine on suicidal ideation could be mediated by an effect on psychological pain.

"Although mental pain does not necessarily lead to suicidal ideas, recent studies suggest that individuals with severe suicidal ideas (notably those with a plan) also have high levels of mental pain. Ketamine might therefore exert its effects through analgesic mechanisms that reduce mental pain," they write.

Ketamine’s side effects were "limited" with no manic or psychotic symptoms seen. The main side effects, including sedation, denationalization/derealization, nausea, and dizziness, were of short duration and occurred in about 10% or fewer patients.

The investigators acknowledge that the nonsignificant effect of ketamine in the patients with major depressive disorders in this study is "challenging to interpret."

They point out the study may have lacked power to detect an effect in these patients. In addition, this group might be particularly heterogeneous, with more patients sensitive to a placebo effect and more patients requiring repeated ketamine infusions.

A New Perspective on Ketamine​

In an accompanying editorial, Riccardo De Giorgi, Wellcome Trust doctoral training fellow, Department of Psychiatry, University of Oxford, United Kingdom, said the study challenges current thinking about ketamine.

The "unexpected" outcome (no benefit) in the depressive group "perhaps defies the prevailing notion that patients with major depression would benefit most from ketamine," De Giorgi writes.

"In fact, both usual care and ketamine given with usual care led to low, comparable remission rates of 35.7% and 42.3% for suicidal ideation, respectively, in patients with depressive disorder," De Giorgi points out.

"While this study therefore confirms that many patients with depressive disorder and suicidal ideation remain poorly served by available treatments, it shows that another important group of patients with acute suicidal ideation, those with bipolar disorder, could benefit from ketamine," De Giorgi writes.

"Once again, here is evidence that careful clinical evaluation must precede any consideration of ketamine use, which must be reserved for specific clinical presentations and not given indiscriminately to anyone presenting with suicidal thoughts," he concludes.

Funding for the study was provided by Programme Hospitalier de Recherche Clinique National. Jollant and De Giorgi have disclosed no relevant financial relationships.


BMJ. Published online February 2, 2022. Full text, Editorial

 

[Daniel E.]

"Ketamine-assisted psychotherapy" seems interesting if one is eligible for ketamine:

Journey Clinical

www.journeyclinical.com

Similarly:

Frontiers | Psychedelic Harm Reduction and Integration: A Transtheoretical Model for Clinical Practice

Psychedelic Harm Reduction and Integration (PHRI) is a transtheoretical and transdiagnostic clinical approach to working with patients who are using or consi...

www.frontiersin.org

But speaking of ECT, which I tried at age 19 (during the late 1990s), it led to one of the most spiritual/memorable experiences I have had. There is a novel that discusses such "memories of amnesia."

While waking up from the anesthesia, I had no memory of who I was. I had that experience before at times when waking up normally, but not to that degree. There is the sense of self without the weight of the self. More curiosity than confusion.

As in the old days of psychoanalysis, even a dream journal can provide an alternative to one's everyday neurotic thinking. The new breed of daily planners are another way of seeing things in a more holistic way (with room for potentially beneficial magical thinking like the "law of attraction.")

 

[Daniel E.]

For the short-term, even a vacation or other source of novelty or "social novelty" can help -- and can be cheaper than ketamine. And that is how Gandhi marketed mindfulness or meditation -- as a daily vacation.

 

[Daniel E.]

I'm reminded again of the idea of therapy (or anything therapeutic) as being helpful by providing new or healing experiences -- though a much slower process maybe than using psychedelics to reset one's default mode(s).

 

[Daniel E.]

Ketamine Linked to Reduced Suicidal Thoughts, Depression, Anxiety

Ketamine infusions can help reduce symptoms of suicidal ideation, depression, and anxiety in patients with treatment-resistant depression, a new "real world" study suggests.

www.medscape.com

Concerns and Questions​

Commenting for Medscape Medical News, Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund University, Sweden, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.

He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.

Movahed Rad was not involved with the current research but was principal investigator for a recent study that compared intravenous ketamine to ECT.

He questioned whether the patient population in the new study really was "real world." Well-designed randomized controlled trials have been carried out in a "naturalistic setting, [which] get closer to real life patients," he said.

He also noted that the median dose after clinician titration (0.93 mg/kg/40 m) "may be considered very high."

With regard to doses being titrated to achieve symptoms of partial dissociation, "there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect," said Movahed Rad.

Finally, he noted that the finding that 28% of the participants were using illegal drugs "is worrying" and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.

 

[Daniel E.]

Reading Linehan in the Age of Critical Psychiatry

To read Linehan’s memoir is to realize that she underwent a crucifixion and resurrection of her own, and that the Pontius Pilate in her story is psychiatry itself.

www.psychiatrictimes.com

We insist on conceptualizing suicide as a neurobiological problem. We look for “miracle drugs” such as ketamine for a potential solution. We think the solution is more of the same thinking. We have focused on safety and control at the expense of dignity and autonomy to the point where even psychiatrists have begun to protest that hospitals feel more like prisons.