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.”
“Pharmacotherapy of Bipolar Depression”
Roger McIntyre gave a talk on the “Pharmacotherapy of Bipolar Depression” at the International Society for Bipolar Disorders Conference in Chicago, June 22-25, 2023
He pointed out that, contrary to the many approved agents for mania, there were few FDA-approved drugs for depression in patients with Bipolar Disorders. These approved drugs included: cariprazine (Vraylar); lumateperone (Caplyta); lurasidone (Latuda); quetiapine (Seroquel); and the olanzapine-fluoxetine combination (Symbyax). Other non-approved agents include: lithium, lamotrigine, antidepressants, MAOIs, pramipexole, carbamazepine, ketamine, bupropion+dextromethorphan, amantadine, memantine, and possibly minocycline and celecoxib. Surprisingly, more than 3,000 bipolar depressed patients have been reported to be taking ketamine and that this was not associated with the induction of hypomania or mania.
McIntyre reported on the antidepressant (AD) effects of intra-nasal (i.n.) insulin. The insulin receptor sensitizer metformin had AD effects, but only in those who converted to insulin sensitivity.
McIntyre reported on the mixed effects of the GLP-1 agonists in the prevention of depression (Cooper et al J. Psychiatric Res, 2023). This is of interest in relationship to the bidirectional relationship of diabetes mellitus and depression.
Liraglutide appeared to have an anti-anhedonia effect. Semaglutide had AD and antianxiety effects in animal models of depression.
Recent studies have explored the antidepressant effect of psilocybin. Small studies have indicated that it has rapid onset of AD effects, and, in contrast to ketamine where rapid onset AD and anti-suicidal effects are short lived, the AD effect of psilocybin may be more prolonged.
Ketamine repairs structure and function of prefrontal cortical neurons via glutamate NMDA receptor blocking action, while psilocybin and other psychedelics act via stimulating 5HT2A receptors. One single case study suggested that blocking 5HT2A receptors with trazodone could achieve a rapid onset of AD effects of psilocybin without the psychedelic effects, a very interesting finding that requires replication.
Higher Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach
Highlights from Posters Presented at the Society of Biological Psychiatry Meeting, April 27-29, 2023 in San Diego
Ben Goldstein of the University of Toronto reported that “Brain temperature was significantly higher in BD (bipolar youth) compared to CG (control group) in the precuneus. Higher ratio of brain temperature-to-CBF [cerebral blood flow] was significantly associated with greater depression symptom severity in both the ACC [anterior cingulate cortex] and precuneus within BD.”
These finding are of particular interest in light of the Unspecified Bipolar Disorder subtype called Temperature and Sleep Dysregulation Disorder (TSDD), where patients are over heated and respond to clonidine and other cooling techniques along with lithium and repeated intranasal ketamine insufflations.
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.”
Baseline Levels of CRP Could Help Predict Clinical Response to Different Treatments
C-reactive protein (CRP)
C-reactive protein, or CRP, is a marker or inflammation that has been linked to depression and other illnesses. People with high levels of CRP respond differently to medications than people with lower CRP, so assessing CRP levels may help determine which medications are best to treat a given patient.
High baseline levels of CRP (3–5pg/ml) predict a poor response to selective serotonin reuptake inhibitor antidepressants (SSRIs) and to psychotherapy, and are associated with increased risk of recurrent depression, heart attack, and stroke.
However, high baseline CRP predicts a better response to the antidepressants nortriptyline and bupropion. High CRP is also associated with better antidepressant response to infliximab (a monoclonal antibody that inhibits the inflammatory cytokine TNF alpha), while low levels of CRP predict worsening depression upon taking infliximab.
High baseline CRP also predicts good antidepressant response to intravenous ketamine (which works rapidly to improve treatment-resistant depression), minocycline (an anti-inflammatory antibiotic that decreases microglial activation), L-methylfolate (a supplement that can treat folate deficiency), N-acetylcysteine (an antioxidant that can improve depression, pathological habits, and addictions), and omega-3 fatty acids (except in people with low levels of DHA).
High baseline CRP also predicts a good response to the antipsychotic drug lurasidone (marketed under the trade name Latuda) in bipolar depression. In people with high baseline CRP, lurasidone’s positive results have a huge effect size of 0.85, while in people with low CRP (<3pg/ml) the improvement on lurasidone has a smaller effect size (0.35).
In personal communications with this editor (Robert M. Post) in 2018, experts in the field (Charles L. Raison and Vladimir Maletic) agreed that assessing baseline CRP levels in a given patient could help determine optimal strategies to treat their depression and predict the patient’s responsiveness to different treatment approaches.
At a 2018 scientific meeting, researchers Cynthia Shannon, Thomas Weickert, and colleagues reported that high baseline levels of CRP were associated with symptom improvement in patients with schizophrenia when they were treated with the drug canakinumab (marketed under the trade name Ilaris). Canakinumab is a human monoclonal antibody that targets the inflammatory cytokine interleukin-1 beta (Il-1b). Il-1b is elevated in a subgroup of patients with depression, bipolar disorder, or schizophrenia, and CRP levels are an indication of the associated inflammation.
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.
Scientific Mechanisms of Rapid-Acting Antidepressants
A pyramidal cell (Photo by Bob Jacobs, Laboratory of Quantitative Neuromorphology Department of Psychology Colorado College)
At a recent symposium, researcher Francis McMahon provided electrophysiological evidence that several different types of rapid-acting antidepressants—low-dose ketamine, scopolamine, and rapastinel (a partial agonist of the neurotransmitter NMDA)—act by decreasing the inhibitory effects of GABAergic interneurons on excitatory neurons called pyramidal cells, thus increasing synaptic firing.
Researcher Ronald Duman further dissected these effects, showing that ketamine and its active metabolite norketamine reduce the steady firing rate of GABA interneurons by blocking NMDA receptors, while the partial agonist rapastinel acts on the glutamate neurons directly, and both increase the effects of a type of glutamate receptors known as AMPA. These effects were demonstrated using a virus to selectively knock out GluN2B glutamate receptor subunits in either GABA interneurons or glutamate neurons.
Increasing AMPA activity increases synapse number and function and also increases network connectivity, which can reverse the effects of stress. Duman and colleagues further showed that when light is used to modulate pyramidal cells (a process called optogenetic stimulation) in the medial prefrontal cortex, different effects could be produced. Stimulating medial prefrontal cortex cells that contained dopamine D1 receptors, but not D2 receptors, produced rapid and sustained antidepressant effects. Conversely, inhibiting these neurons blocked the antidepressant effects of ketamine. Stimulating the terminals of these D1-containing neurons in the basolateral nucleus of the amygdala was sufficient to reproduce the antidepressant effects. These data suggest that stimulation of glutamate D1 pyramidal neurons from the medial prefrontal cortex to the basolateral nucleus of the amygdala is both necessary and sufficient to produce the antidepressant effects seen with ketamine treatment.
Researcher Hailan Hu reported that NMDA glutamate receptors drive the burst firing of lateral habenula (LHb) neurons, which make up the depressogenic or “anti-reward center” of the brain and appear to mediate anhedonic behavior (loss of interest or enjoyment) in animal models of depression. Ketamine blocks the burst firing of the LHb neurons, which disinhibits monoamine reward centers, enabling ketamine’s rapid-onset antidepressant effects. This may occur because inhibitory metabotropic glutamate receptors (mGluR-2) are activated, decreasing the release of glutamate.
MGluR-2 may also help explain the antidepressant effects of acetyl-L-carnitine supplements. L-carnitine is an amino acid that is low in the blood of depressed patients. The supplement acetyl-L-carnitine (ACL) activates the DNA promoter for mGluR-2, increasing its production and thus decreasing excess glutamate release. The acetyl group of the ACL binds to the DNA promoter for mGluR-2, thus this process seems to be epigenetic. Epigenetic mechanisms affect the structure of DNA and can be passed on to offspring even though they are not encoded in the DNA’s genetic sequence.
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.
