The role of ketamine in treatment-resistant depression: a systematic review

This review (24 studies; n=416) found that ketamine is a reliable fast-acting anti-depressant for patients suffering from treatment-resistant depression (TRD). Long-term effects, however, remain to be studied.

Abstract

“Background: At least 10-20% of the patients suffering from depression meet criteria for treatment-resistant depression (TRD). In the last decades, an important role of glutamate in mood modulation has been hypothesized and ketamine, a non noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptors, has been demonstrated to be effective in both MDD and TRD. However, concerns emerged about the optimal dosage, and frequency of administration of this treatment.

Methods: aiming to systematically review the current literature focusing on the main pharmacological properties and impact of ketamine in TRD, a detailed literature search in PubMed/Medline and ScienceDirect databases was conducted. Twenty-four manuscripts including a total of 416 patients fulfilled inclusion criteria.

Results: Most studies demonstrated that the NMDA antagonist ketamine has rapid antidepressant effects in TRD patients, confirming the active role of glutamate in the pathophysiology of this complex condition. Ketamine has been demonstrated to be rapidly effective and was associated with a significant clinical improvement in depressive symptoms within hours after administration. Also, ketamine was also found to be effective in reducing suicidality in TRD samples.

Limitations: The long-term efficacy of ketamine has not been investigated by most studies. The psychotomimetic properties may complicate the application of this pharmacological agent.

Conclusions: Ketamine may be considered a valid and intriguing antidepressant option for the treatment of TRD. Further studies are needed to evaluate its long-term antidepressant efficacy in patients with TRD.”

Authors: Gianluca Serafini, Robert H. Howland, Fabiana Rovedi, Paolo Girardi & Mario Amore

Summary

INTRODUCTION

Major depressive disorder (MDD) is a disabling illness associated with frequent relapses, incomplete recovery between episodes, and persistent psychosocial and functional impairment. Treatment-resistant depression (TRD) affects more than 1% of individuals in the United States and approximately 30% of all depressed patients may be classified as affected by refractory depression.

According to the monoamine hypothesis, depressive symptoms are mainly related to a deficit in the synaptic availability of monoamines. However, most antidepressant drugs take 4-12 weeks to show their effect.

Glutamate, a major excitatory amino acid in the central nervous system, plays important roles in many normal and abnormal physiological processes, including neurodevelopmental and neurotrophic effects, neurocognitive functions, and neurodegeneration.

Glutamate receptors are complex, and are divided into two main classes: ionotropic and metabotropic. Ionotropic glutamate receptors are divided into three groups: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), and kainate.

The first use of a glutamate-modulating drug therapy for mental disorders was reported more than 50 years ago with the use of cycloserine, an antibiotic drug originally developed for treating tuberculosis. Ketamine, a high-affinity NMDA receptor antagonist, has been associated with antidepressant effects in animal models of depression.

In this paper, we performed a systematic search of PubMed/Medline, Scopus, and Science Direct to identify all studies on the role of ketamine in patients with TRD.

A search was conducted using the following terms: Ketamine, treatment-resistant depression, NMDA receptor antagonist Ketamine, and treatment-resistant major depressive disorder. Two blinded, independent researchers conducted a two-step literature search.

Study Design and Eligibility Criteria

We followed the PRISMA guidelines for systematic reviews and meta-analyses when selecting studies to include in the present review.

Number of Selected Studies

A search strategy yielded 278 articles, of which 38 full-text articles were screened and 240 excluded. Of the 28 eligible articles, 4 were also excluded due to their low relevance for the main theme.

Case Reports and Case Series

Eight case reports and case series including a total of seventeen patients reported data regarding the efficacy of ketamine in patients with TRD. Some patients showed significant improvement in depressive symptoms in both the short and longer term, whereas no significant side effects were reported.

Subjects experienced significant improvement of depressive symptoms on the second day post ketamine infusion based on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores. The antidepressant effect of ketamine was observed throughout the subsequent 7 days.

SINGLE- OR MULTIPLE-DOSE OPEN-LABEL STUDIES

Five open-label studies evaluated the efficacy of ketamine in patients with TRD. 65% of patients met response criterion after 24 hours of ketamine infusion.

Ibrahim et al. [32] found that ECT-resistant TRD patients had a moderate effect size improvement in depressive symptoms after 230 minutes compared to non-ECT-resistant TRD patients.

In another study, 42 patients with TRD improved after a single intravenous infusion of ketamine with initially large and throughout the 28-day study moderate effect sizes of improvement.

Shiroma et al. [34] reported that 91.6% of subjects achieved response criterion and 66.6% remitted after TRD intravenous ketamine (.5 mg/kg) over 40 minutes during a 12-day period.

Murrough and colleagues [35] conducted a prospective open-label study in 24 TRD individuals who underwent a washout of antidepressant medications followed by up to six infusions of ketamine three times weekly over a 12-day period.

RANDOMIZED DOUBLE-BLIND PLACEBO- OR ACTIVE-CONTROLLED STUDIES

In a double-blind placebo-controlled study, 18 depressed subjects responded to ketamine after 110 minutes of administration, and 35% continued to respond for at least 1 week.

Ibrahim et al. [33] conducted a double-blind, randomized, parallel, placebo-controlled, flexible-dose inpatient study to evaluate the effects of ketamine on depression.

Niciu et al. [37] evaluated 22 patients with TRD and found that 18.1% scored greater than 12 on the Young Mania Rating Scale after receiving ketamine.

In a randomized double-blind active-control study, patients treated with ketamine had a greater improvement in the Montgomery-Asberg Depression Rating Scale (MADRS) score than those treated with midazolam.

CLINICAL STUDIES INVESTIGATING NEUROBIOLOGICAL EFFECTS OF KETAMINE AND/OR ITS MECHANISM OF ACTION IN TRD

Ketamine treatment improved MADRS scores in 23 subjects, but BDNF levels did not change. Responders to ketamine showed increased cortical excitability but not spontaneous cortical -activity changes, and poorer baseline neurocognitive performance compared to nonresponders was predicted by negative cognitive effects early after ketamine.

Carlson et al. reported that regional cerebral glucose metabolism decreased significantly in the habenula, insula, ventrolateral and dorsolateral prefrontal cortices of the right hemisphere and increased in bilateral occipital, right sensorimotor, left parahippocampal, and left inferior parietal cortices in patients with TRD.

STUDIES ASSESSING THE EFFICACY OF KETAMINE ON SUICIDALITY IN TRD PATIENTS

Three studies reported that ketamine was effective in reducing suicidality in TRD patients. The efficacy of ketamine was sustained for 12 days by repeated-dose ketamine, and the acute improvements on suicidality were sustained even after repeated ketamine infusions.

Larkin and Beautrais examined the efficacy of a single IV dose of ketamine in 14 depressed emergency department subjects with suicide ideation.

Several studies reported on the safety and tolerability of ketamine in TRD samples. Side effects included drowsiness, confusion, elevations in blood pressure and pulse, dizziness, and increased libido, but all were resolved within 80 minutes after ketamine’s infusion.

Ketamine has not been reported to induce mania in patients with TRD, but rather mild positive psychotic symptoms. 88.9% of patients responded after the first and sixth ketamine infusions, and 88.9% relapsed, on average, 19 days after the sixth infusion.

Ketamine infusions were associated with feeling strange or unreal, abnormal sensations, blurred vision, and feeling drowsy or sleepy. Ketamine had minimal acute neurocognitive effects in TRD patients.

Ketamine has been associated with dizziness, blurred vision, headache, nausea or vomiting, dry mouth, poor coordination, poor concentration, and restlessness, and 17% of patients had significant dissociative symptoms.

DISCUSSION

Based on most studies, ketamine was found to exert a rapid and sustained antidepressant effect on samples of TRD patients. Ketamine may be considered a valid option for TRD based on its advantages in terms of rapid onset of action, on core depressive symptoms, and hopelessness.

Ketamine has been found to reduce suicidality in treatment-resistant depression patients. The effects of ketamine waned from days 7-10 and there was no significant difference compared to placebo.

A family history of alcohol dependence seems to predict a rapid initial antidepressant response to an NMDA receptor antagonist, suggesting that the altered sensitivity of the NMDA receptor complex may explain the greater response to ketamine in those with a family history of alcohol dependence.

Limited evidence investigated the antidepressant properties of the intramuscular formulation of ketamine. However, Chilukuri et al. reported that depressive symptoms fell by 58.86%, 60.29% and 57.36% in each group two hours after ketamine injection, and the improvement was observed for three days.

A female patient with metastatic ovarian cancer responded to intramuscular ketamine injections, and two patients with bipolar II disorder responded to intramuscular ketamine augmentation.

Ketamine is usually a racemic mixture consisting of two enantiomers: (R)- and (S)-. S-ketamine has been reported to be more active, have better pharmacokinetic properties, and induce less psychomimetic adverse effects than R-ketamine.

Ketamine has been suggested as safe and well tolerated in TRD patients, although its psychotomimetic and euphoric properties may preclude its utilization in treating depression in clinical practice. Ketamine has been associated with abuse liability, and cardiorespiratory monitoring should be a fundamental component of risk management when ketamine was administered.

Ketamine is safe and well-tolerated in nonpsychotic depressed patients when administered at a subanesthetic dose of 0.5 mg/kg over 40 minutes.

Ketamine acts by blocking the NMDA glutamate receptors, which may be an adequate target for developing new rapid-acting antidepressant therapeutic agents. NMDA receptor modulation may help to achieve clinical improvement in patients with severe and chronic forms of depression.

Ketamine is a rapid neuroplastic modulator drug able to induce enhanced dendritic branching and synaptic receptor number and density, and has been reported to strengthen appropriate emotional neural connections enhancing synaptogenesis in those brain areas affected by stress-related processes and associated with negative thinking in depressed individuals.

Ketamine may induce antidepressant-like behavioural effects through the inhibition of spontaneous miniature NMDA-receptor mediated currents leading to decreased eEF2 kinase activity and an increased BDNF translation.

Ketamine’s rapid initial antidepressant effects may not be mediated by BDNF. Similarly, AMPA-potentiators may not activate BDNF signaling although producing a characteristic antidepressant-like response.

LIMITATIONS

The present study should be interpreted in the light of the following limitations: ketamine is only effective when administered at a subanesthetic dose of 0.5 mg/kg over 40 minutes in short-term designs, and the long-lasting sustained antidepressant-like effects of ketamine need to be further investigated.

Although many limitations exist, rostral anterior cingulated cortex activation may be a reliable biomarker identifying a subgroup of patients who will favorably respond to ketamine’s antidepressant effects. Furthermore, repeated dose therapy with ketamine may lead to antidepressant tolerance or habituation.

All subjects with MDD examined in this systematic review were treatment-resistant, so the results may not be generalized to other samples of depressed subjects. In addition, the neurobiology underlying MDD is quite complex, and the possible mechanisms of action remain unclear.

Most studies included in the present review are open-label or case-reports/series in nature and did not allow to investigate the antidepressant effects of ketamine in the long-term period. Moreover, the small sample sizes and lack of a placebo group limited the generalization of the findings.

CONCLUSION

Ketamine has been shown to play a fundamental role in the treatment of TRD patients, elucidating new and intriguing insights into the neurobiology of this complex condition.