Administration of ketamine for unipolar and bipolar depression

This review (2017) examined clinical trials that investigated the antidepressant efficacy of ketamine for unipolar (MDD) and bipolar depression (BD). Results indicate that intravenous and intranasal ketamine produces strong reductions of depressive symptoms within a short period and with response rates up to 88%, however, depressive relapse occurs in up to 90% of patients within 2 weeks after treatment.

Abstract

“Objective: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile.

Methods: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science.

Results: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included.

Conclusions: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine’s efficacy.”

Authors: Christoph Kraus, Ulrich Rabl, Thomas Vanicek, Laura Carlberg, Ana Popovic, Marie Spies, Lucie Bartova, Gregor Gryglewski, Konstantinos Papageorgiou, Rupert Lanzenberger, Matthäus Willeit, Dietmar Winkler, Janusz K. Rybakowski & Siegfried Kasper

Summary

Ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages.

Introduction

Treatment-resistant depression (TRD) occurs in 10-30% of all major depressive disorder patients, is associated with higher risk of suicide, high relapse rates and large socioeconomic burden, and is often misdiagnosed and under- or even untreated.

Ketamine, an NMDA receptor antagonist, was tested for the first time in depressed patients fifteen years ago. Its antidepressant effects were confirmed in a placebo-controlled trial and it has been used as an anaesthetic for over 40 years at dosages two to five times higher than those applied in antidepressant treatment regimes.

While multiple small clinical trials confirmed ketamine’s antidepressant activity, usage in clinical psychiatry has not yet been approved by regulatory agencies. This results in off-label usage and insecurity in doctors not trained in anaesthesia.

We reviewed the results of clinical trials investigating the efficacy and tolerability of ketamine in depressive disorder and provided guidance for practical treatment including information on potential adverse events.

Literature review

We performed a literature search in medline, scopus and web of science and excluded studies that did not use depression scores as primary outcomes. We found 12 clinical trials on acute antidepressant effects of ketamine in unipolar MDD and seven trials on bipolar depression.

Pharmacology of ketamine

Ketamine is an arylcyclohexylamine derivative first synthesized in 1962 by Calvin Stevens at Park-Davis, and used as dissociative anaesthetic from the 1970s onwards. It has a short half-life and less side-effects than phencyclidine (PCP), and is also an agonist at r receptors 1 and 2. Ketamine is used for anaesthesia, analgesia and amnesia, and has been used for recreational drug abuse. It has several side effects, including dissociative symptoms, cardiac arrhythmia, tachycardia, hypertension, skin rash, bronchodilation, double vision and nausea.

Outcome measures

The primary outcome measures in the identified trials comprised standardized and frequently applied rating scales in depression, and self-rater assessments of depressive symptoms were performed in two trials. Seven trials indicated response and remission rates, and two trials used the clinical global impression scale.

Statistics

Six studies used ANOVA/ANCOVA, five used a general linear mixed model, and one used a Wilcoxon signed-rank test to assess depression. The studies reported 24-h post-treatment effects and response, remission and relapse rates.

Ketamine in unipolar depression

In 12 clinical trials, 226 major depressive patients (119 females) were treated with ketamine. Four studies applied a double-blind, placebo controlled, crossover setting, five were open label (longitudinal or single infusion), and two studies delivered an active control as the control group.

Antidepressant efficacy

All reviewed studies identified a rapid and robust antidepressant effect of ketamine, with average response rates of 59% after 24 h on primary outcome measures. Ketamine was always statistically significant superior to placebo, as well as statistically significant superior to a single control infusion of midazolam.

Relapse rates

In the first two published trials, 92% of patients receiving ketamine relapsed within 2 weeks post-treatment. Eight out of nine patients who received repeated infusions relapsed within an estimated mean 30 days.

Safety and tolerability

Five studies measured acute psychotic symptoms during and shortly after ketamine infusion, and two studies applied a VAS-scale on the feeling of being ‘high’. All studies reported entirely reversible positive symptoms only detectable at 40-min post-infusion, and no patient reported any distressing psychotic symptoms.

The incidence of serious advents was very low. Only one study reported serious adverse events (hypotension/bradycardia, suicide attempt), and the other studies did not report any serious events.

General adverse events were reported by Murrough et al. (2013), aan het Rot et al. (2010) and Zarate et al. (2006). Intranasal ketamine was associated with small increases in systolic blood pressure and generally less side effects.

Ketamine in bipolar depression

The first study on bipolar depression used ketamine as adjunct to mood stabilizers and demonstrated improvement in 71% of patients.

A series of studies investigated ketamine in bipolar patients with TRD. Serum levels of brain-derived neurotrophin factor, nerve growth factor, neurotrophin-3, neurotrophin-4 and glial-derived neurotrophic factor were related to ketamine efficacy, but not to baseline levels of homocysteine, folic acid and vitamin B12.

In 18 bipolar depressed patients with concomitant mood-stabilizing drugs, neurocognitive performance improved on the third day after ketamine infusion, which positively correlated with baseline intensity of neuropsychological impairment.

A recent study investigated response criteria after a single infusion in 53 bipolar patients. The study found that the score decreased as early as after 24 h, to 14.2 7.2 points on the third day, to 12.5 7.7 points on the seventh day.

Previous findings indicate that ketamine has a substantial antidepressant effect in bipolar depressed patients receiving lithium or valproate. The effect of ketamine was evident on the first day after infusion.

Discussion

Ketamine is a highly effective and rapid acting antidepressant in patients suffering from unipolar and bipolar depression, and may be used in acute suicidal crises as well as treatment in highly resistant forms of depression.

Ketamine’s rapid antidepressant action with large effect sizes at 4 h, 24 h lasting to 7 – 14 d after treatment was recently emphasized by a meta-analysis. Higher body mass index, family history of alcohol abuse in first-degree relatives and no prior history of suicide attempts were predictors of better antidepressant response.

S-ketamine exhibited comparable efficacy with racemic ketamine, yet was found to be more efficacious in a lower dosage of 0.2 mg/kg.

Ketamine has a rapid anti-suicidal effect, as shown by the results of Price et al. (2009) and Murrough et al. (2015), who show rapid reduction of acute suicidality in post-traumatic stress disorder, bipolar disorder, borderline personality disorder and MDD. A recent Cochrane review demonstrated that ketamine has antidepressant and anti-suicidal effects, and that D-cycloserine, a partial agonist at the glycine-binding site on the NMDA receptor, reduces HAM-D values to a significantly larger degree than placebo.

The glutamatergic neurotransmitter system gained a lot of attention by the ‘ketamine revolution’, and non-NMDA glutamate receptor activation was found to be necessary for ketamine’s antidepressant action in an animal model.

Neuroimaging studies have shown that the perigenual anterior cingulate cortex (pgACC) is important for depression and that ketamine affects connectivity between the anterior cingulate and the amygdala. Furthermore, ketamine decreased FDG-metabolism in the habenula, insula, and ventrolateral and dorsolateral prefrontal cortices in treatment resistant MDD patients.

Safety and side effects

Ketamine is less invasive than ECT or DBS and can be performed in a controlled outpatient setting in stable patients without severe comorbid medical disorders. Side effects are common but reversible and include drowsiness, dizziness, poor coordination, blurred vision and feeling strange and unreal.

Although ketamine might inhibit serotonin reuptake, it is safe to use with monoaminergic antidepressants and irreversible MAO-inhibitors, and benzodiazepines might reduce ketamine metabolites. No increased substance use was detected after long-term follow-up.

Ketamine’s neurotoxic properties, repetitive dosages, and potential long-term side effects make it unsafe to use as antidepressant. It might be safer to limit repetitive ketamine dosages to a maximum lifetime amount and not to perform excessive repetitive dosing to achieve response.

Conclusion and future perspective

Ketamine treatment offers safe and rapid relief of depression in unipolar and bipolar depressive disorder, with high response rates and pronounced antisuicidal effects. It can be used without discontinuation of currently stable antidepressants, and there are patient-friendly and cost-effective candidate strategies to prolong ketamine’s antidepressant effects.