Maintenance Ketamine Treatment Produces Long-term Recovery from Depression

There have been several articles in recent years that show a powerful anti-depression effect from a single dose of ketamine.

Here are a few of the studies:

Berman RM, Cappiello A, Anand A, et al. (2007). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry;47(4):351-354.

Maeng S, Zarate CA Jr. (2007). The role of glutamate in mood disorders: results from the ketamine in major depression study and the presumed cellular mechanism underlying its antidepressant effects. Current Psychiatry Reports; Dec;9(6):467-74.

Zarate, Jr, CA, Singh, JB, Carlson, PJ, Brutsche, NE, Ameli, R, et al. (2006). A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression. Archive of General Psychiatry;63:856-864.

The huge benefit of the approach is that the client enters into a slight anesthetic state lasting around 60-90 minutes after the infusion ends. The patient does not become unconscious, and while some studies have shown side effects, they tend to cease when the ketamine is fully metabolized by the body. Beck Depression Inventory (BDI) scores tend to drop dramatically.

The downside is that in serious cases, the remission of symptoms last only 2-4 weeks, at least in the patient described in the case study. But the maintenance regimen produces a stable remission of profound symptoms.

This case is discussed in Psychiatry Weekly, and shows that maintenance doses of ketamine, as intravenous infusion, over time, produces a long-term recovery for patients.

Maintenance Ketamine Treatment Produces Long-term Recovery from Depression

May 17, 2010

Michael M. Messer, MD
Physician of Behavioral Health, SMDC Medical Center, Duluth, Minnesota

Irina V. Haller, PhD, MS
Senior Research Scientist of Education and Research, SMDC Health System

First published in Psychiatry Weekly, Volume 5, Issue 12, on May 17, 2010

Introduction

A growing body of evidence indicates that N-methyl-d-aspartate (NMDA) receptor antagonists significantly and rapidly improve depressive symptoms in MDD patients. Two randomized controlled trials, one including treatment-refractory depression (TRD) patients, reported a rapid antidepressant response from a single infusion of ketamine in patients with MDD.^1,2 There are no available data or general guidelines, however, on optimal dose, frequency, or inter-dose interval for ketamine administration to sustain remission. This case delineates a dosing regimen and may provide guidance to achieving sustained remission in TRD patients.

Case Report

In January 2008, a 46-year old female with MDD was hospitalized for a course of ECT. Successive interventions over 15 years had included trials of 24 psychotropic medications and 273 ECT treatments, 251 of which were bilateral. No intervention had produced remission but only a short-lived response to treatment. She had no history of an Axis II diagnosis, chemical dependency, or other major medical illnesses.

ECT during this admission was administered with ketamine as the anesthetic at 2 mg/kg given over 60 seconds. Surgical anesthesia occurred ~30 seconds after the end of intravenous injection and lasted ~10 minutes. There was no significant change in depression symptoms with the ketamine used as an anesthetic during the ECT treatment.

Based on recent reports^1,2 of rapid antidepressant effect of single dose ketamine in MDD patients, we reviewed the information available with the patient and obtained her consent. We discussed potential side effects known to be associated with the anesthetic dose of ketamine, such as psychosis during or after the treatment, elevations in liver enzymes, hypertension, a harlequin-like skin change, and malignant hyperthermia. At lower doses used for antidepressant treatment² reported in the literature, side effects included perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido, as well as gastrointestinal distress, increased thirst, headache, metallic taste, and constipation. These side effects appeared to abate within 80 minutes after the infusion.

Ketamine was administered at 0.5 mg/kg of ideal body weight (IBW) over 40 minutes. The first ketamine treatment led to a dramatic remission of depressive symptoms: the Beck Depression Inventory (BDI) score decreased from 22 to 6. Three additional infusions administered every other day over 5 days produced remission lasting 17 days after the last infusion in this series. Three series of six ketamine infusions given every other day except weekends were repeated over the next 16 weeks whenever the patient relapsed into depression. Each infusion sequence produced remissions lasting 16, 28, and 16 days, respectively, followed by a relapse. After three remission/relapse cycles and before relapse could occur after the fourth infusion series, a maintenance ketamine regimen was established on August 27, 2008 using 0.5 mg/kg IBW at a 3-week inter-dose interval. We based our estimation for the maintenance dosing interval on the time frame between remission and relapse for this patient. Relapse to depression was prevented by treating prior to the onset of a relapse.

With maintenance infusions, the patient has been in remission for >15 months. No concurrent pharmacotherapeutic agents have been administered or required during this time period, no adverse events have emerged, and there has been no cognitive impairment as is typical with ECT, polypharmacy, or from MDD itself.

Generally, weight-based dosing (eg, mg/kg) is a sound pharmacologic strategy. However, data and experience with weight-based dosing in a previous patient who was substantially overweight resulted in perceptual distortion,³ though antidepressant benefit was evident. In consultation with our Anesthesia department, they selected IBW to establish the dosing regimen. The Metropolitan Life Insurance weight tables⁴ can be used to determine IBW based on sex, age, height, and body frame.

For this case, ketamine infusions were administered with nursing supervision as a day patient procedure and treatment was well tolerated. Vital signs were monitored during the infusion. No psychotic or dissociative symptoms were noted during or after the ketamine infusions and no other adverse events occurred. Ketamine was safe in an outpatient setting without cognitive or physical impairment once ketamine was metabolized (usually within 2 hours post infusion). Repeated administration did not produce tachyphylaxis or tolerance.

Conclusion

A growing body of evidence suggests that the glutamatergic system, known to play a role in neuronal plasticity and cellular resilience, is also involved in the pathophysiology and treatment of MDD. Ketamine, an NMDA receptor antagonist with rapid antidepressant effect, emerged as a potential agent for treatment of mood disorders.

Optimal ketamine regimens to sustain remission from depression have not been defined. Previously, the authors successfully treated two patients with TRD using a series of ketamine infusions over a 12-day period.³ The patient who received two ketamine treatments separated by 6 days was symptom-free for 18 days and the patient who received six ketamine treatments (every other day over 12-day period) was symptom-free for 29 days.³ As reported by others, remission was followed by relapse.

In the case described here, a maintenance ketamine treatment continues to sustain this patient’s recovery from depression and was more effective in preventing relapse of depression than repeated series of infusions. It may also have some economic and quality of life advantages compared to ECT. As NMDA receptor antagonist action on TRD is explored, a maintenance treatment protocol requires further investigation as a means to sustain recovery from depression.

References

1. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4):351-354.

2. Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.

3. Messer MM, Haller IV, Larson P, Pattison-Crisostomo J, Gessert CE. The use of a series of ketamine infusions in two patients with treatment resistant depression. J Neuropsychiatry Clin Neurosci. In press.

4. Metropolitan Life Insurance Company. Weight Charts. Available at: www.coping.org/weightmgt/strategies/Weight%20Charts.doc. Accessed February 23, 2010.

Disclosure: The authors report no affiliations with, or financial interests in, any organization that may pose a conflict of interest.

Tags: depression, medicine, therapy, Psychology, ketamine, Michael M. Messer, Irina V. Haller, Psychiatry Weekly, Maintenance Ketamine Treatment Produces Long-term Recovery from Depression, Beck Depression Inventory