Intravenous Arketamine As Adjunctive Treatment for Bipolar Depression
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
I.D. Bandeira of Stanford University reported on the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) in treating six patients with bipolar depression: “Subjects received two intravenous infusions of arketamine of 0.5mg/kg, followed by 1mg/kg one week later.” Patients improved after the first dose and after “1mg/kg dose, the mean MADRS [Montgomery–Åsberg Depression Rating Scale] total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p<0.001).” All individuals tolerated both doses, exhibiting no dissociative or manic symptoms.
Effectiveness of Repeated Ketamine Infusions for Treatment Resistant Bipolar Depression
Highlights from the International Society for Bipolar Disorders Conference Posters and Presentations, Chicago, June 22-25, 2023
Farhan Fancy, of the University of Toronto, gave 66 highly treatment resistant (unselected) bipolar I or II patients four sub-anesthetic doses of IV ketamine (0.5-0.75mg/kg) over a two-week period. They saw significant reductions in depression, anxiety, suicidality, and disability. Response rates were 35% and remission rate was 20%. “Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis.”
Childhood Physical Abuse Predicts Response to IV Ketamine
At a recent scientific meeting, researcher Alan Swann reported the results of a study of intravenous ketamine in people with treatment-resistant depression. The 385 participants, who received four infusions of IV ketamine at a dosage of 0.5 mg/kg, could be grouped into three based on their type of response to the treatment.
One group had moderate depression at baseline and showed little change. A second group with severe baseline depression also showed minimal improvement. A third group who also had severe baseline depression had a rapid and robust antidepressant response to the treatment. This group had high scores relating to physical abuse on the Childhood Trauma Questionnaire (CTQ), but did not differ on other clinical variables. Swann and colleagues concluded, “Our outcomes show that IV ketamine should be considered as a primary treatment option for adults presenting with severe, treatment resistant depression and a self-reported history of childhood physical abuse. IV ketamine may not be as effective for moderately depressed individuals irrespective of childhood maltreatment.”
Ketamine May Enhance the Effects of Cognitive Training Therapy
Woman receiving cognitive training
Rebecca B. Price, a professor of Psychiatry and Psychology at the University of Pittsburgh, and colleagues reported at a recent scientific meeting that the combination of intravenous ketamine treatment and four days of cognitive training to enhance positive self-representations improved depression better than either intervention alone (IV ketamine plus a sham training or a non-medicated saline drip plus 4 days of cognitive work).
Price and colleagues suggested that priming brain plasticity with ketamine could enhance cognitive training focused on increasing positive self-representations. Psychologists have theorized that self-representations (or assessments of one’s strengths and other qualities) can be a resource that helps people cope with life stress.
Pilot Study Finds Intravenous Ketamine Improves Tough-to-Treat Adolescent Depression
A 2018 open study by Kathryn R. Cullen and colleagues in the Journal of Child and Adolescent Psychopharmacology suggests that intravenous ketamine may improve depression in adolescents who have not responded to at least two antidepressants.
Thirteen patients ranging in age from 12 to 18 with treatment-resistant depression were given six ketamine infusions over a period of two weeks, at doses of 0.5 mg/kg of body weight. A 50% drop in scores on the Children’s Depression Rating Scale-Revised (CDRS-R) was considered a good response, and the average drop in participants’ scores was 42.5%. Five of the thirteen participants (38%) met the criteria for a good response. Three of these participants were still in remission at six weeks, while the other two relapsed within two weeks.
Ketamine was fairly well-tolerated by the young participants. Some had temporary dissociative symptoms or blood pressure changes. Higher absolute doses of ketamine were linked to better response.
The response rates in this group were not as good as in some studies of adults. More research using larger sample sizes and placebo controls is needed to optimize dosing and clarify the safety and efficacy of intravenous ketamine in adolescents with tough-to-treat depression, but this is a promising finding in a small number of adolescents.
Single Dose of Ketamine Reduces Suicidal Ideation
A systematic review and meta-analysis by Samuel T. Wilkinson and colleagues in the American Journal of Psychiatry analyzed individual patient data from 10 studies in which a single intravenous dose of ketamine was given to patients with suicidal ideation. The review included data from a total of 167 participants.
Wilkinson and colleagues found that ketamine reduced suicidal ideation within 24 hours, and these effects lasted for up to seven days. Mood also improved, but the reduction in suicidal ideation was independent of the degree of improvement in depression.
Among the participants, 54.9% were free of suicidal ideation at 24 hours after the infusion, 60.0% were free of suicidal ideation one week after the infusion, and 61.1% were free of suicidal ideation at two weeks.
Editor’s Note: The authors report that there is much to clarify about ketamine treatment before it can be used clinically to treat patients at risk for suicide. However, ketamine’s powerful and rapid effects offer an interesting alternative to other slow-acting treatment options, and could be an ideal acute treatment for patients arriving in an emergency room because of high suicide risk. A ketamine injection could be especially useful for those who are not admitted to the hospital, as it could produce anti-suicidal effects that could help carry a patient over until their next psychiatric appointment.
Mixed Findings for Intranasal Ketamine
The drug ketamine can rapidly and temporarily improve depression when delivered intravenously. Researchers have been working on extending ketamine’s effects and finding easier ways of delivering the medication. One new delivery method under investigation is nasal spray, which could be used repeatedly to extend ketamine’s effects.
Unfortunately, researcher Colleen Loo reported in the Journal of Psychopharmacology in 2018 that a pilot study of self-administered intranasal ketamine for severe depression was suspended when 5 of the 10 participants had side effects that included high blood pressure, psychotic symptoms, and motor incoordination that made them unable to keep using the spray. Early in the four-week study, dosage was adjusted to leave more time between sprays, but this was not enough to prevent the problems with side effects.
Loo said that the nasal spray version of ketamine has complications including variations in absorption among different people and on different days, depending on factors like mucus in the nose and exact application techniques. Its rapid absorption into the bloodstream could lead to high peak levels in certain people.
Loo and colleagues had previously found that elderly patients receiving injections of ketamine under the skin required highly individualized dosing to avoid side effects. This may also be the case with nasal spray.
While Loo’s study found intranasal ketamine infeasible for the moment, Janssen Research and Development, a pharmaceutical company owned by Johnson & Johnson, reported positive results in phase 3 clinical trials of intranasal esketamine (a component of ketamine) at the annual meeting of the American Psychiatric Association in May. Researchers for Janssen reported that intranasal esketamine was highly effective for depression and well-tolerated both in acute treatment and over a year-long period. Janssen is now pursing approval for the drug from the US Food and Drug Administration.
Repeated Ketamine Reduces PTSD and Depression in the Short Term
In a 2018 open study by C. Sophia Albott and colleagues in the Journal of Clinical Psychiatry, veterans with post-traumatic stress disorder (PTSD) and a simultaneous diagnosis of major depression were treated with six infusions of intravenous ketamine over a 12-day period (Mondays, Wednesdays, and Fridays for two weeks).
Ketamine produced large improvements in both conditions. The remission rate was 80.0% for PTSD and 93.3% for depression. The median time to first relapse after the treatment was 41 days for PTSD and 20 days for depression.
One side effect of ketamine was that dissociative symptoms increased temporarily with repeated infusions. PTSD symptoms did not worsen among those participants taking ketamine.
The study was intended to evaluate the efficacy, safety, and durability of repeated ketamine infusions. Ketamine has been used in emergency rooms to rapidly treat depression and suicidality, but the effects of a single infusion fade within days. Albott and colleagues reported that this treatment scenario with multiple ketamine infusions produced rapid results that lasted longer than single ketamine infusions.
Editor’s Note: While this study found that repeated ketamine infusions were safe, it is possible that long-term use may lead to addiction. Researcher Nolan R. Williams and colleagues reported in a 2018 article in the American Journal of Psychiatry that ketamine works via activation of the opiate receptor. The drug naloxone, which rapidly reverses opiate overdose, completely blocked ketamine’s antidepressant effects.
Intranasal Ketamine for Bipolar Disorder
An in-press article due out in January 2018 by Demitri F. Papolos and colleagues in the Journal of Affective Disorders reports that intranasal ketamine delivered every three to four days reduced symptoms of bipolar disorder in 45 teens (aged 16 years on average). The teens treated in one private practice had the ‘fear-of-harm’ subtype, which in addition to bipolar symptoms is characterized by treatment resistance, separation anxiety, aggressive obsessions, disordered sleep, and poor temperature regulation.
The repeated administration of ketamine produced long-lasting positive results, improving bipolar symptoms as well as social function and academic performance. Many participants reported via survey that they were much or very much improved after being treated for durations ranging from 3 months to 6.5 years. Side effects were minimal and included sensory problems, urination problems, torso acne, dizziness, and wobbly gait.
The ketamine was delivered to alternating nostrils via 0.1 ml sprays that included 50–200 mg/ml of ketamine in 0.01% benzalkonium chloride. Patients were instructed to increase the dosage just up until it became intolerable and then repeat the last tolerable dose every three to four days. Final doses ranged from 20–360 mg. The mean dose was 165 mg (plus or minus 75 mg) delivered every 3 days.
Papolos and colleagues called for placebo-controlled clinical trials based on the positive results from this open study.
An Overview of Ketamine for Treatment-Resistant Depression
A 2017 series of articles by researcher Chittaranjan Andrade in the Journal of Clinical Psychiatry reviews the last 10 years of research on ketamine, the anesthetic drug that in smaller doses (0.5 mg/kg of body weight) can bring about rapid antidepressant effects. Ketamine is typically delivered intravenously (though it can also be delivered via inhaler, injected under the skin or into muscles, and least effectively by mouth). Ketamine can improve depression in less than an hour, but its effects usually fade within 3 to 5 days. Repeating infusions every few days can extend ketamine’s efficacy for weeks or months.
Andrade cited a 2016 meta-analysis of nine ketamine studies by T. Kishimoto and colleagues in the journal Psychological Research. The meta-analysis found that compared to placebo, ketamine improved depression beginning 40 minutes after IV administration. Its effects peaked at day 1 and were gone 10–12 days later. Remission rates were better than placebo starting after 80 minutes and lasting 3–5 days.
Several studies have found that ketamine also reduces suicidality.
Andrade reported that both effectiveness and side effects seem to be dose-dependent within a range from 0.1 mg/kg to 0.75 mg/kg.
Side effects of ketamine are typically mild and transient. A 2015 study by Le-Ben Wan and colleagues (also in the Journal of Clinical Psychiatry) that Andrade cited reported that in 205 sessions of ketamine administration, the most common side effects were drowsiness, dizziness, poor coordination, blurred vision, and feelings of strangeness or unreality. The feelings of unreality (dissociative effects) diminish with repeated infusions. Heart and blood pressure may also temporarily increase as a result of ketamine administration.
One study found that ketamine could speed up and add to the effects of the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram (Lexapro). A meta-analysis of 10 randomized controlled trials found that ketamine did not improve the effects of electroconvulsive therapy.
Ketamine has some history as a recreational club drug (sometimes known as ‘K’ or ‘special K’), and can be misused or abused.
While there have been many studies of ketamine’s antidepressant effects, Andrade concludes that none is of a standard to justify US Food and Drug Administration approval for the drug. It is hoped that larger, more rigorous trials will be completed in the next few years. However, ketamine is already being used widely to treat treatment-resistant unipolar and bipolar depression.
