USING KETAMINE

Ketamine infusion to treat mental illnesses

KETAMINE

Why is ketamine used for Augmented Psychotherapy?

Ketamine was developed as an anesthetic and pain reliever and has been used worldwise for over 50 years. It is a particularly safe medication with few side effects. In low doses, it can evoke a rapid antidepressant effect.

KETAMINE IN PSYCHIATRY

Ketamine infusions to treat depression, anxiety disorder and OCD

After the first studies on the treatment of depression in 2000, the (at least scientific) interest in ketamine for the treatment of severe depression was moderate. This has changed over the last decade. There has been a surge of interest in ketamine for the treatment of psychiatric disorders. Can ketamine be described as a “new therapy” for depression and other disorders? There is good evidence for the fast antidepressive effects of ketamine. We have compiled a short overview of studies for you.

The use of ketamine in the treatment of depression has been scientifically supported in many studies (Memon et al. 2020). In contrast to common antidepressants, rapid antidepressant effects are seen after the first administration. The positive effects on depressive symptoms often occur within one day after administration (Berman et al. 2000, Memon et al. 2020). In contrast, many common antidepressants (for example, SSRIs) take several days to a few weeks to have an effect. Notably, ketamine has also been studied in specifically severe depression (so-called treatment-resistant depression). For example, in a study by Zarate et al., rapid positive effects were achieved within 2 hours, but the antidepressant effect also flattened out sharply after a week (Zarate et al. 2006). Ketamine has also been studied for the treatment of obsessive-compulsive disorder. In a small study, a symptom-relieving effect was also achieved very quickly. Nevertheless, the positive effects on obsessive-compulsive symptoms subsided again relatively quickly (Rodriguez et al. 2013).

Therefore, it is important to solidify the short-term positive effects of ketamine so that they last long-term. We want to do so in Augmented Psychotherapy. More concretely, we work with the therapeutically valuable altered states of consciousness that ketamine induces. You can read more about this in the next section.

SOLIFY THE EFFECT OF KETAMINE

Our treatment with ketamine

A relevant effect of ketamine infusions is a significant change in one’s state of consciousness, which lasts for about an hour. We use this change therapeutically with you in our clinic as part of ketamine-augmented psychotherapy. By using a perfusor (a syringe pump) and specialist administration by an anesthesiologist, an optimal dose range for inducing therapeutically valuable altered states of consciousness can be found. The next day, a psychotherapy session is held to integrate the experience from the ketamine session. In this way, we aim to solidify the short-term positive effects of ketamine so that they last long-term.

The rapid reduction of depressive symptoms facilitates therapeutic work and opens a window for change in attitudes and behavior. The therapeutically accompanied and anesthesiologically monitored ketamine infusions are carried out once a week over a period of about 5 weeks. Clinical studies show a good success rate with low side effects in the combination of ketamine and psychotherapy (Dore et al. 2019).

SIDE EFFECTS

Ketamine has side effects

Ketamine has a mind-altering effect. During a ketamine infusion, patients experience a change in their perceptions, feelings and thoughts. The intensity of this change and experience can vary. We integrate the ketamine infusion into a specifically designed therapeutic concept.

Other physical side effects include a moderate increase in blood pressure and heart rate. Nausea, vomiting and blurred vision may also occur. Allergic reactions are very rare. In our practice, we explain the side effects of ketamine and any risks to patients in detail during medical education sessions.

KETAMINE SERIES

Ketamine in psychiatry

Our team has created a lecture series on ketamine. In the recording of an online lecture on ketamine, our MDs Sergio Pérez Rosal and Prof. Dr. med. Gerhard Gründer present the use of ketamine in psychiatry. Questions from the audience are addressed.

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DEVELOPMENT AS A DRUG

From lab to psychiatry

Research on ketamine began in 1926 with the development of phencyclidine (PCP). This substance was not marketed until 30 years later, in 1956, by the company Parke-Davis (today Pfizer) as the drug “Sernyl”. Two years later, the first animal trials with the substance as an anesthetic began.

One of the observations was a severe delirium in dogs. The first human trials tested PCP as an anesthetic or analgesic. An important observation was that protective reflexes and spontaneous breathing were preserved, an advantage compared to other anesthetics. Three years later, however, in 1959, PCP was classified as “not for human use” because it causes for example agitation, hallucinations and delirious states. Another three years later, Prof. Calvin Stevens researched variations (so-called derivatives) of PCP and discovered ketamine. Clinical trials were conducted, and in 1966 the first effects of ketamine on humans were described as “dissociative anesthesia.” However, the subjects of the studies also described the effects as “dream-like”, feeling like they were “floating in space” or “separated from the body”. In 1970, ketamine was approved as an anesthetic by the FDA (Food and Drug Administration) in the USA. As early as 1975, experiments in an animal model for depression in mice suggested that ketamine had antidepressant effects. This initially received little attention, and over time, the substance was increasingly abused. In 1999, regulations around ketamine were tightened and it became classified as an illegal substance in the United States. One year later, in 2000, a small study by Robert Bergmann showed the antidepressant effect of ketamine in depressed patients for the first time.

ABOUT SPRAVATO ®

Esketamine nose spray SPRAVATO ®

Ketamine is a so-called racemate, a mixture of two forms. One of the forms, esketamine, was developed by the U.S. company Johnson & Johnson into a medicine administered as a nasal spray. It was approved by both the U.S. FDA and the European EMA in 2019. The approval (as Spravato®) is for treatment-resistant depression, meaning depression which has not responded to at least two different therapies with antidepressants. For this purpose, esketamine is supposed to be given in addition to an SSRI or an SNRI. Spravato® has not yet been launched in Germany, but the market launch is imminent.

LITERATURE

STUDIES ABOUT KETAMINE

Publication by Berman et al., Biol Psychiatry 2000; 47: 351-354

Background: A growing body of preclinical research suggest that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression.

Methods: Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions.

Results: Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment).

Conclusions: These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

You find the article here.

Publication by Zarate et al., Arch Gen Psychiatry 2006; 63: 856-864

Context: Existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders.

Objective: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression.

Design: A randomized, placebo-controlled, double-blind crossover study from November 2004 to September 2005.

Setting: Mood Disorders Research Unit at the National Institute of Mental Health. Patients Eighteen subjects with DSM-IV major depression (treatment resistant).

Interventions: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. Subjects were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days postinfusion. Main Outcome Measure Changes in scores on the primary efficacy measure, the 21-item Hamilton Depression Rating Scale.

Results: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week.

Conclusions: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.

You find the article here.

Publication by Diazgranados et al., Arch Gen Psychiatry 2010; 67: 793-802

Context: Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health.

Objective: To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression.

Design: A randomized, placebo-controlled, double-blind, crossover, add-on study conducted from October 2006 to June 2009.

Setting: Mood Disorders Research Unit at the National Institute of Mental Health, Bethesda, Maryland. Patients Eighteen subjects with DSM-IV bipolar depression (treatment-resistant).

Interventions: Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. The Montgomery-Asberg Depression Rating Scale was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 postinfusion.

Main outcome measures: Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores.

Results: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52, 95% confidence interval [CI], 0.28-0.76); this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80, 95% CI, 0.55-1.04). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. One subject receiving ketamine and 1 receiving placebo developed manic symptoms. Ketamine was generally well tolerated; the most common adverse effect was dissociative symptoms, only at the 40-minute point.

Conclusion: In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist.

You find the article here.

Publication by Rodriguez et al., Neuropsychopharmacology 2013; 38: 2475-2483

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (≥35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

You find the article here.

Publication by Phillips, Norris, Talbot et al., Neuropsychopharmacology 2020; 45: 606–612

Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen’s d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

You find the article here.

Publication by Dakwar et al., Am J Psychiatry 2020; 177: 125-133

Objective: Pharmacotherapy and behavioral treatments for alcohol use disorder are limited in their effectiveness, and new treatments with innovative mechanisms would be valuable. In this pilot study, the authors tested whether a single subanesthetic infusion of ketamine administered to adults with alcohol dependence and engaged in motivational enhancement therapy affects drinking outcomes.

Methods: Participants were randomly assigned to a 52-minute intravenous administration of ketamine (0.71 mg/kg, N=17) or the active control midazolam (0.025 mg/kg, N=23), provided during the second week of a 5-week outpatient regimen of motivational enhancement therapy. Alcohol use following the infusion was assessed with timeline followback method, with abstinence confirmed by urine ethyl glucuronide testing. A longitudinal logistic mixed-effects model was used to model daily abstinence from alcohol over the 21 days after ketamine infusion.

Results: Participants (N=40) were mostly middle-aged (mean age=53 years [SD=9.8]), predominantly white (70.3%), and largely employed (71.8%) and consumed an average of five drinks per day prior to entering the study. Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days compared with midazolam. Infusions were well tolerated, with no participants removed from the study as a result of adverse events.

Conclusions: A single ketamine infusion was found to improve measures of drinking in persons with alcohol dependence engaged in motivational enhancement therapy. These preliminary data suggest new directions in integrated pharmacotherapy-behavioral treatments for alcohol use disorder. Further research is needed to replicate these promising results in a larger sample.

You find the article here.

Publication by Lipsitz, McIntyre, Rodrigues et al., Prog Neuropsychopharmacol Biol Psychiatry 2021; Mar 8: 105:110126

Background: Early symptomatic improvement with monoamine-based antidepressants is predictive of treatment response. The objective of this study was to determine if early symptomatic improvements with intravenous (IV) ketamine predicted treatment response to an acute course of four infusions.

Method: 134 adults with treatment resistant depression (TRD) received four ketamine infusions over one to two weeks. Depressive symptoms were measured using the Quick Inventory for Depressive Symptomatology Self-Report16 (QIDS-SR16) at baseline and post-infusions 1, 2, 3, and 4. Early improvement was defined as ≥20% reduction in QIDS-SR16 scores after the first or second infusion. Linear models were used to determine whether early improvement was associated with post-infusion 4 QIDS-SR16 scores after controlling for baseline characteristics.

Results: Early improvement post-infusion 1 (β = −3.52, 95% BCa CI [−5.40, −1.78]) and 2 (β = −3.16, 95% BCa CI [−5.75, −1.59]) both significantly predicted QIDS-SR16 scores post-infusion 4. Early improvers had significantly lower QIDS-SR16 scores at post-infusion 4 (post-infusion 1 improvers: M = 9.8, SD = 4.5; post-infusion 2 improvers: M = 10.6, SD = 5.7) compared to non-early improvers (post-infusion 1 non-improvers: M = 13.7, SD = 5.8; post-infusion 2 non-improvers: M = 14.1, SD = 5.3) when controlling for baseline characteristics. The majority (58%) of individuals who did not improve post-infusions 1 or 2 still experienced an antidepressant response or partial response (≥20% reduction in QIDS-SR16) post-infusion 4.

Limitations: This is a post-hoc analysis of an open-label study.

Conclusion: Early improvement was associated with greater antidepressant effects following a course of four ketamine infusions. However, individuals who did not show early improvements still had a high likelihood of experiencing clinically significant symptom reduction after the fourth infusion, suggesting that completing four infusions, regardless of early symptom changes, is appropriate and merited.

You find the article here.

Publication by Feder, Costi, Rutter et al., The American Journal of Psychiatry 2021; 178: 193-202

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.

Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.

Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.

Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.

You find the article here.