Elsevier

Journal of Affective Disorders

Volume 155, February 2014, Pages 123-129
Journal of Affective Disorders

Research report
Augmentation of response and remission to serial intravenous subanesthetic ketamine in treatment resistant depression

https://doi.org/10.1016/j.jad.2013.10.036Get rights and content

Abstract

Background

Ketamine has been showing high efficacy and rapid antidepressant effect. However, studies of ketamine infusion wash subjects out from prior antidepressants, which may be impractical in routine practice. In this study, we determined antidepressant response and remission to six consecutive ketamine infusions while maintaining stable doses of antidepressant regimen. We also examined the trajectory of response and remission, and the time to relapse among responders.

Methods

TRD subjects had at least 2-month period of stable dose of antidepressants. Subjects completed six IV infusions of 0.5 mg/kg ketamine over 40 min on a Monday–Wednesday–Friday schedule during a 12-day period participants meeting response criteria were monitored for relapse for 4 weeks.

Results

Fourteen subjects were enrolled. Out of twelve subjects who completed all six infusions, eleven (91.6%) achieved response criterion while eight (66.6%) remitted. After the first infusion, only three and one out of twelve subjects responded and remitted, respectively. Four achieved response and six remitted after 3 or more infusions. Five out of eleven subjects remain in response status throughout the 4 weeks of follow-up. The mean time for six subjects who relapsed was 16 days.

Limitations

Small sample and lack of a placebo group limits the interpretation of efficacy.

Conclusions

Safety and efficacy of repeated ketamine infusions were attained without medication-free state in patients with TRD. Repeated infusions achieved superior antidepressant outcomes as compared to a single infusion with different trajectories of response and remission. Future studies are needed to elucidate neural circuits involved in treatment response to ketamine.

Introduction

The efficacy of current pharmacological agents for depression is disappointing. The largest (4041 patients at 41 clinical sites) and longest (data collected over seven years) study ever done to evaluate depression treatment, the Sequenced Treatment Alternatives to Relieve Depression (STARD) study (Trivedi et al., 2006), showed that approximately only 30% of patients achieved remission after first-line antidepressant citalopram. A second large-scale study, the Combining Medications to Enhance Depression Outcomes (CO-MED) trial (Rush et al., 2011), compared two antidepressant combinations with serotonin selective reuptake inhibitor monotherapy at 12 weeks and 7 months. Similar to STARD, remission rates were modest (37.7–38.9%).

In addition to low response rate, the long delay of traditional antidepressants in the onset of therapeutic action (up to 12 weeks) increases the burden of illness, morbidity, and risk of suicidal behavior (Jick et al., 2004). Current antidepressants exert their primary biochemical effect by targeting monoamine substrates. The delay in the therapeutic actions of existing pharmacologic agents is due to the fact that they initially act on substrates that are considerably upstream of targets that are ultimately responsible for the antidepressant effects. Neurotrophic signaling cascades and the glutamatergic system are expected to be more closely related to adaptive changes in critical neuronal networks responsible for sustainable long-term therapeutic action of antidepressants. More recently, Ketamine, a noncompetitive, high-affinity antagonist of the N-methyl-d-aspartate (NMDA) type glutamate receptor used for induction and maintenance of anesthesia (Green and Li, 2000), has been investigated for its high efficacy and rapid antidepressant effect.

Since Berman and colleagues reported the first finding of a rapid antidepressant response to a single infusion of ketamine as compared to saline in nine depressed patients (Berman et al., 2000), multiple case reports, case series, and several clinical trials including placebo-controlled studies (Zarate et al., 2006, Diazgranados et al., 2010, Zarate et al., 2012) have supported the rapid antidepressant effect of a single ketamine infusion in unipolar or bipolar depression. However, follow-up periods have been variable with common return of depression within a day to a week and occasional patient showing several weeks of remission following the single infusion. The strategy of repeated ketamine infusion to maintain antidepressant response has recently been explored.

Murrough et al. (2013b) conducted series of six thrice weekly ketamine infusions (0.5 mg/kg over 40 min) found an overall response rate (as defined by an at least 50% reduction in depression scores by study end) of 70.8%, which was higher than 50–71% reported with single-infusion studies in unipolar depression (Berman et al., 2000, Zarate et al., 2006). Similarly, Rasmussen et al. (2013) had a response rate of 80% using multiple infusions although at a slower rate of administration (0.5 mg/kg over 100 min).

Most studies of ketamine infusion wash subjects out from prior antidepressants, which may be impractical in clinical settings and even unethical especially among patients with TRD. Other studies allow modification of concurrent antidepressant dosages during infusion confounding the effect of ketamine on depression. In this preliminary report, we aim to determine whether antidepressant response and remission can be increased by completing six consecutive infusions as compared to a single infusion. For this purpose, we maintain stable doses of antidepressant regimen including other psychotropic medications used as augmenting agents. By the administration of multiple infusions, the study also examined the trajectory of treatment response, particularly important for those subjects that do not respond after a single infusion. Finally, we also aimed to estimate time to relapse among responders after completion of the six infusions.

Section snippets

Participants

Adult subjects participated in an open-label study of repeat ketamine infusion conducted over 12 days at the Special Diagnostic and Treatment Unit (SDTU) of the Minneapolis VA Medical Center followed by a 4-week follow-up period. Subjects were recruited by direct referral from clinicians in the Mental Health and Primary Care Clinics. Medical records were reviewed prior to a brief phone interview with patients. Those who qualified were invited to a personal interview to determine final

Demographic and clinical characteristics

Fourteen subjects were enrolled in the study; one dropped out after the first infusion due to decreased energy and increased irritability. Another patient dropped out after two infusions due to dissatisfaction of expected therapeutic effect from ketamine. Demographics and baseline characteristics of the study sample are presented in Table 1. Among fourteen patients, all were males, 13 were Caucasians, 10 had at least one first degree relative with mood disorder, 3 had a past history of

Discussion

In this open label trial of ketamine for TRD, the major findings are that (1) repeated ketamine infusions increased antidepressant response and remission rates compared to a single infusion, (2) response and remission were achieved without wash out from previous antidepressants, (3) the trajectory of response and remission varied by subjects during ketamine infusions, and (4) durability of antidepressant response after completing six infusions was highly variable.

Using a six infusion protocol,

Role of funding source

This study was supported by the Mental Health Service Line at the Minneapolis VA Medical Center. Dr. Shiroma is supported by a Career Development Award from the Center for Epidemiological and Clinical Research (CECR)-VA Clinical Research Center of Excellence. The funding source had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Conflict of interest

I can affirm that all the authors do not have any conflict of interest whether it is actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations that could inappropriately influence, or be perceived to influence, their work.

Acknowledgments

We are extremely grateful to the staff from Special Diagnostic and Treatment Unit (SDTU) at the Minneapolis VAMC for their support during the conduction of the study.

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