Psychosomatics 2013:]:]]]–]]] & 2013 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

Case Reports

Beneficial Pre-ECT Ketamine Infusion in a Patient withTreatment-Resistant Depression

Ryan Sultan, M.D., Patricio Riva-Posse, M.D., Steven J. Garlow, M.D., Ph.D.,Ann C. Schwartz, M.D.

We present a case of a 52-year-old white manwith treatment-resistant depression, who

received a single ketamine infusion before electro-convulsive therapy (ECT) and demonstrated markedand rapid improvement in his depressive symptoms.

Received November 1, 2013; revised November 27, 2013; acceptedNovember 29, 2013. From Department of Psychiatry and BehavioralSciences, Emory University School of Medicine, Atlanta, Georgia.Send correspondence and reprint requests to Ann Schwartz, 80 Jesse HillJr Dr, P.O. Box 26238, Atlanta, Georgia 30303; e-mail: aschwa2@emory.edu

& 2013TheAcademy of PsychosomaticMedicine. Published byElsevier Inc. All rights reserved.

Case Report

Mr. S, a 52-year-old white man, presented to a largeacademic center for inpatient psychiatric admissionbecause of intolerable insomnia and anxiety. In the 2weeks before hospital admission, his family had notedprogressive slowing of his speech and motor activity,to the point of remaining motionless for prolongedperiods. He was sleeping very little and had endorsed aplan to overdose on his medications.

Mr. S was accompanied by his wife and daughter,who reported that he had not been at his baselinefunctioning for approximately 4 years. The indexpresentation was 6 months after a hospitalization inour Medical Psychiatry Unit when he presented withdepressed mood, anhedonia, poor appetite withweight loss, and suicidal ideation. During this firstadmission, Mr. S received 12 ECT treatments, afterwhich he and his wife reported subjective improve-ment in his symptoms.Hewas discharged home after a1-month stay, and his medication regimen was 20 mgof escitalopram daily, 30 mg of mirtazapine nightly,20 mg of olanzapine nightly, and 0.5 mg of clonaze-pam nightly as needed for insomnia. Following dis-charge, Mr. S continued his treatment with hisoutpatient psychiatrist. As per his wife, Mr. S had asustained antidepressant effect from the ECT for

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approximately 1 month; however, his previous depres-sive symptoms returned after that period.

Regarding his past psychiatric condition,Mr. S hada long history of depression dating back over 25 years.The current episode started 4 years ago, when he beganexperiencing depressive symptoms including low mood,psychomotor retardation, and anhedonia with noknown precipitating event. A review of his recordsindicated that over the past 4 years, Mr. S hadinadequate responses to therapeutic doses of multiplemedications. Mr. S had no prior suicide attempts andhad never had symptoms ofmania.He did not use illegalsubstances or alcohol. Mr. S and his family reported nomedical conditions other than hyperlipidemia treatedwith atorvastatin. Family history was significant fordepression in his father and a completed suicide byshooting in his paternal grandfather.

Because of the severity of his depressive symptomsand suicidal ideation, Mr. S was admitted to theinpatient unit with the plan of pursuing ECT as atreatment modality. On admission, a medical workupwas completed. A baseline chemistry panel andcomplete blood count were essentially within normallimits. His total cholesterol level was 139 mg/dL, levelsof triglycerides were 47 mg/dL, high-density lipopro-tein level was 47 mg/dL, and low-density lipoprotein

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Case Reports

level was 83 mg/dL. His urine drug screen testedpositive for benzodiazepines, and his electrocardio-gram findings were normal. A computed tomographyscan of the head was unremarkable.

The inpatient team offered ECT; however, Mr. Swas reluctant to pursue the treatment given his limitedduration of response 6 months before. He was thenoffered a trial of a ketamine infusion based on positivereports in the literature for the treatment of severedepression. He agreed to the ketamine infusion as aninterim measure to provide immediate relief of theintense depressive symptomswith the plan to reconsiderECT after the infusion. The clonazepam was decreasedwith the plan to discontinue the medication, admin-istration of trazodone nightly was begun for insomnia.

The score on a 17-item Hamilton DepressionRating Scale1 was 34 points 1 hour before the infusion.Under the supervision of an anesthesiologist, Mr. Sreceived a ketamine infusion of 39.5 mg (0.5 mg/kg)over the course of 40 minutes. The ketamine was welltolerated, except for mild subjective anxiety, whichresolved within 1 hour after the infusion. The infusionwas followed by a clinical assessment of depression bythe 17-item Hamilton Depression Rating Scale, whichwas performed at 1, 3, 24, 48, and 72 hours, as well as1 and 4 weeks after treatment (Figure), and adminis-tered by the same psychiatrist.

Mr. S's depressive symptoms rapidly improvedfollowing the ketamine infusion, with the Hamiltonscore decreasing from 34 to 22 at 24 hours. Despite thisdecrease, he remained significantly depressed with sig-nificant psychomotor slowing. Mr. S agreed to ECT,

FIGURE. Change in depression severity after ketamine infusion

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which was initiated on day 5 after the ketamine infusion.Mr. S received 2 treatments of bitemporal ECT as aninpatient using methohexital for induction in combina-tion with succinylcholine. Alongwith the ECT, 25 mg ofnortriptyline was initiated for Mr. S, given his history ofpoor response with selective serotonin re-uptake inhib-itors (SSRIs), and olanzapine 10 mgas augmentation fordepression and to aid with his prominent insomnia. Hisinitial symptoms of depression as measured by the17-item Hamilton Depression Rating Scale decreasedsignificantly after 2 ECT treatments and his suicidalideation subsided entirely. He was given a titration of75 mg of nortriptyline and 20 mg of olanzapine, and thetrazodone was discontinued. He was discharged onhospital day 7 and received additional 6 ECT treatments(twice weekly) as an outpatient.

Mr. S received 8 ECT treatments in the short-termcourse. At a follow-up visit shortly after the eighthtreatment, Mr. S reported that he felt the best that hehad felt in more than 2 years. Given Mr. S's history ofrapid relapse as well as the severity of his depression,maintenance ECT was recommended every 3 weeks. Inaddition, he was maintained on a medication regimenof nortriptyline and olanzapine. Nortriptyline level wastested approximately 5 weeks after the medication wasinitiated andwas in the therapeutic range at 133 ng/mL.

Discussion

Ketamine, a noncompetitive N-methyl-D-aspartatereceptor antagonist, has emerged as a promising agent

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Sultan et al.

in the treatment of patients with depression.2,3 Ket-amine and related drugs target glutamate, the majorexcitatory neurotransmitter in the brain and one that iscurrently not directly affected by available antidepres-sants. Its action as primarily an antagonist of theN-methyl-D-aspartate receptor has presented an excit-ing new avenue for the treatment of depression asmostcontemporary antidepressants target the monoamineoxidase system. This potential new mechanism, whichis capable of mediating antidepressant action, is one ofthe most exciting developments in psychopharmacol-ogy in the last half of the century.4

There is emerging clinical data in support ofketamine's use as an antidepressant.3,5–7 Ketaminewas first reported to have therapeutic effects in apreliminary study of 8 patients with major depressivedisorder in 2000.8 Using a larger sample size (18patients) in a randomized controlled trail, Zarateet al.5 confirmed the findings from the preliminarystudy by Berman et al. and showed a robust and rapidantidepressant effect from a single intravenous dose ofketamine. In this randomized controlled trail, IVketamine had rapid, but transient, antidepressanteffects in individuals with treatment-resistant majordepressive disorder, including some patients who hadnot responded to ECT.5 Investigators sought toreplicate ketamine's antidepressant efficacy in bipolardepression and found that patients receiving a singleketamine infusion experienced a rapid and robustantidepressant response.6,7

Recently, Murrough et al.9 evaluated the rapidantidepressant efficacy of ketamine in a large group ofpatients with treatment-resistant major depression. Inthis 2-site, parallel-arm, randomized controlled trial, asingle infusion of ketamine was compared with anactive placebo-control condition with midazolam(n ¼ 73). The ketamine group had greater improve-ment in the Montgomery-Åsberg Depression RatingScale score than the midazolam group 24 hours aftertreatment, further supporting N-methyl-D-aspartatereceptor modulation as a novel mechanism for accel-erated improvement in severe and chronic forms ofdepression.

Ketamine's rapid onset in the improvement ofdepressive symptoms is in stark contrast to the severalweek duration needed for existing antidepressantmedications. However, ketamine lacks the mainte-nance and sustained effects of conventional treat-ments. ECT is a well-established, Food and Drug

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Administration–approved, and highly effective treat-ment for severe and treatment-resistant depression.10,11

ECT is the most rapid of the accepted treatmentsfor depression, yet there remains a delay in theantidepressant effect. Ketamine has been used as themain anesthetic agent in ECT, usually when it is notpossible to adequately induce seizures with barbitu-rates, given their inherent anticonvulsant properties.12

Two case studies report dramatic mood improvementsafter the use of ketamine anesthesia in ECT, suggest-ing synergistic antidepressant effects.13,14 Ostroffet al.15 reported a case of rapid response in depressivesymptoms in a patient receiving ketamine anesthesiafor ECT but not achieving an adequate seizure duringECT. Goforth et al.16 described a case with animmediate response to a treatment of bilateral ECTcombined with ketamine anesthesia in a patient withsevere major depressive disorder with psychotic fea-tures. Findings from an open-label trial suggestedthat ketamine anesthesia has an early antidepressanteffect during ECT that was superior to propofolanesthesia. This effect may come from the antidepres-sant effect of ketamine. A limitation of ketamine isthat its use at full anesthetic doses may lead to dose-related adverse psychotogenic effects such as halluci-nations. As these effects of ketamine are dose-related,subanesthetic doses of ketamine used in combinationwith alternate anesthetic agents may be an alternativeeffective augmentation strategy for patients withsevere depression.12

Although there is evidence supporting antidepres-sant effects of ketamine in its use as an anesthetic forECT, there are few data on the use of subanestheticdoses of ketamine as an augmentation strategy withECT to speed the response rate. Our case illustrates thenovel use of pretreatment of ketamine as an augmen-tation strategywithECT for treatment-resistant depres-sion in an individual with severe depressive andcatatonic symptoms. A potential confounding variableis that multiple treatment interventions were initiatedsimultaneously, including the addition of a tricyclicantidepressant (TCA) in combination with olanzapineand ECT. Therefore, it is possible that the observedresponse was not entirely attributable to ketamine.However, given the severity of the treatment resistanceand the chronicity ofMr. S's depression, ketamine likelyplayed a significant role in his treatment response.

The use a subanesthetic dose of ketamine as anadjunct before the electroconvulsive treatment, while

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Case Reports

still using barbiturate anesthesia, could be a promisingstrategy in patients with treatment-resistant depres-sion. Its use as a facilitating agent while transitioningto a more permanent treatment strategy, such as ECTor pharmacologic treatments, provides practitionersof psychosomatic medicine another relatively low-risk

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strategy to consider in the management of complextreatment-resistant cases.

Disclosure: The authors disclosed no proprietary orcommercial interest in any product mentioned or con-cept discussed in this article.

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