BRIEF REPORT

Oral Ketamine in Treatment-Resistant Depression

A Clinical Effectiveness Case Series
Maryam I. Al Shirawi, MD,*† Sidney H. Kennedy, MD, FRCPC,*†‡§|| Keith T. Ho, BSc,*¶
Roisin Byrne, MD,† and Jonathan Downar, MD, PhD, FRCPC*†‡§#
Downloaded from https://journals.lww.com/psychopharmacology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3I7ucIJ5GOrT3Wg+bH35glPxuGg6ajARZSwY7wFugnj9Yt83wbhGh7Q== on 10/10/2018

in TRD, distinguished from other agents in part via its putative

Abstract: mechanism of action as an N-methyl-D-aspartate receptor antago-
Purpose: The aim of the study was to assess the effectiveness, tolerability, nist and in part by reports of extremely rapid-onset of (<24 h) anti-
and safety of oral ketamine as an antidepressant treatment in adults with depressant action.3 Regarding pharmacology, ketamine has a
treatment-resistant depression. relatively short elimination half-life of 2 to 3 hours and may be
Methods: We reviewed retrospective data on 22 patients with treatment- dosed intravenously, subcutaneously, intranasally, or orally, with
resistant depression, who failed at least 3 adequate antidepressant treatment oral bioavailability of approximately 20% to 25% and intranasal
trials and 1 adequate trial of repetitive transcranial magnetic stimulation; subse- bioavailability of approximately 45%.4 Further details on the
quently, they received open-label treatment with oral ketamine, commenced at pharmacology, dosing, and adverse effects of ketamine are avail-
a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to able in a recent review.5
response and tolerability. The primary outcome measure was the Beck De- Rapid antidepressant effects of ketamine in MDD have been
pression Inventory II, which was used to rate subjective mood improvement recognized for more than 15 years; in 2000, Berman et al6
at baseline and then at each follow-up visit. Data about adverse effects conducted the first randomized, double-blind crossover study
related to ketamine and a self-harm risk assessment were also obtained. of intravenous ketamine (0.5 mg/kg) versus saline solution, in
Findings: Over the course of treatment, 18% of the patients showed unipolar or bipolar patients in a major depressive episode. All
greater than 50% reduction in the Beck Depression Inventory II scores, 8 patients who were treated with ketamine had significant
14% reported partial improvement in mood symptoms, while 45% had no improvement in depressive symptoms, and 1 patient maintained
response to ketamine and 23% showed a mild worsening in their depressive mood improvement for 2-week postinfusion.6
symptoms. The most frequent adverse effects were acute dissociation, In a subsequent double-blind crossover study in TRD, 12
dizziness, blurred vision, numbness and sedation. Neither serious adverse (71%) of the 17 participants receiving a single ketamine infusion
effects, nor any cases of abuse or dependence were observed. had a 50% or more reduction in 21-item Hamilton Depression
Conclusions: Although this case series found oral ketamine to be safe Rating Scale scores on the first day, compared with none (0%)
and well tolerated, the findings also showed rather modest effectiveness of the 14 participants treated with placebo. Six (35%) individuals
of oral ketamine in treatment-resistant depression, with only approximately continued to exhibit improved scores for at least 1 week.7 The next
30% reporting some benefit and approximately 70% reporting no change landmark study involving 73 TRD patients across 2 sites demon-
or worsening of mood. However, bearing in mind the limitations of this strated rapid antidepressant effects of ketamine compared with
small, open-label case series, further exploration of the effectiveness of oral midazolam as an active control. The treatment response rate at
ketamine is warranted. 24 hours was 64% for the ketamine group, compared with 28%
Key Words: depression, ketamine, case series, safety, tolerability in the midazolam group, with a significant difference of 8 points
on Montgomery-Åsberg Depression Rating Scale (MADRS)
(J Clin Psychopharmacol 2017;37: 464–467)
scores at end point between ketamine and midazolam groups.
The ketamine group continued to show a significant reduction
T reatment-resistant depression (TRD) is a serious, disabling ill-
ness with a significant impact on social and occupational out-
comes.1 Given that at least one third of patients with major
on MADRS score for a 1-week period postinfusion compared
with midazolam, with gradual loss of benefit after day 7.8
A subsequent meta-analysis of 9 randomized controlled trials
depressive disorder (MDD) do not achieve remission with con-
of intravenous ketamine (192 subjects with MDD and 34 with
ventional, monoaminergic antidepressant medications,2 new treat-
BD) reported significant improvement on depression scores for
ment strategies are urgently needed. The dissociative anesthetic,
ketamine compared with placebo. Two of the 9 trials evaluated
ketamine, has received increasing attention as a novel intervention
the duration of ketamine's effect, which seemed to last 2 to 3 days
From the *Department of Psychiatry, University Health Network; †Department
for a single dose.9 Serafini et al10 also carried out a systematic
of Psychiatry, ‡Institute of Medical Science, Faculty of Medicine, University of review of 24 studies involving 416 subjects with TRD and reported
Toronto; §Krembil Research Institute, Toronto Western Hospital; ||Li Ka Shing that ketamine has rapid antidepressant and antisuicidal effects.
Knowledge Institute, St. Michael's Hospital; ¶Ontario Brain Institute; and There have been relatively few studies concerning the crucial
#MRI-Guided repetitive transcranial magnetic stimulation Clinic, Centre
for Mental Health, University Health Network, Toronto, Canada.
question of whether repeated doses of ketamine are capable of
Received November 23, 2016; accepted after revision March 23, 2017. exerting a sustained antidepressant effect over time. Singh et al11
Reprints: Jonathan Downar, MD, PhD, FRCPC, University Health Network, conducted a multicenter, double-blind study to assess the efficacy
399 Bathurst St, Room 7M-415, Toronto, ON Canada M5T 2S8 of intravenous ketamine administered twice versus thrice weekly
(e‐mail: jonathan.downar@uhn.ca).
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
in TRD patients. A total of 68 subjects were randomized into 1
This is an open-access article distributed under the terms of the Creative of 4 arms in a double-blind trial; they received either intravenous
Commons Attribution-Non Commercial-No Derivatives License 4.0 ketamine or placebo either 2 or 3 times weekly for up to 4 weeks.
(CCBY-NC-ND), where it is permissible to download and share the work Both dosing regimens of ketamine were comparable in efficacy,
provided it is properly cited. The work cannot be changed in any way or
used commercially without permission from the journal.
which persisted for 15 days.11
ISSN: 0271-0749 There is also a paucity of information about other routes of
DOI: 10.1097/JCP.0000000000000717 administration for ketamine: can it reliably exert antidepressant

464 www.psychopharmacology.com Journal of Clinical Psychopharmacology • Volume 37, Number 4, August 2017
Journal of Clinical Psychopharmacology • Volume 37, Number 4, August 2017 Oral Ketamine in Depression

effects when administered by nonintravenous routes, such as oral Toronto, Canada, between July 2013 and November 2015. Access
or intranasal? This issue is of translational importance, given the to retrospective data on these patients was approved by the
high prevalence of TRD and the short duration of effect of individ- Research Ethics Board, University Health Network, Toronto,
ual ketamine doses. If the treatment requires patients to attend Ontario, Canada. The objectives of this review are (1) to assess
clinics twice weekly for intravenous sessions for extended periods acute and sustained effectiveness of oral ketamine and (2) to eval-
of time, then cost, resources, and inconvenience may limit the uate safety and tolerability of oral ketamine.
practical utility of ketamine in real-world settings.
Subsequently, some investigators have examined the antide- Patient Characteristics
pressant efficacy of ketamine via intranasal or oral routes. In
The patients (13 females, 9 males) had a mean age of
1 study, intranasal ketamine (50 mg) was compared with intravenous
39 years. All participants met Diagnostic and Statistical Manual
saline in a randomized, double-blind crossover design involving 20
of Mental Disorders, Fourth Edition, criteria for MDD, currently
unipolar TRD patients. Eight (44%) of 18 completers in the keta-
in a major depressive episode without psychotic features (based
mine group met response criteria after 24 hours, compared with 1
on the Mini-International Neuropsychiatric Interview screening
(6%) of 18 in the placebo group; effects persisted for 48-hour
tool).22 Fifteen participants (68%) had a comorbid psychiatric di-
posttreatment, in line with the durability of intravenous adminis-
agnosis, most frequently generalized anxiety disorder (27%), and
tration.12 So far, there have been no reports regarding sustained
10 (46%) had a medical comorbidity. Patients were either referred
efficacy for repeated doses of intranasal ketamine.
by their outpatient psychiatrist or primary care physician and were
Regarding oral ketamine, 0.5 mg/kg was administered to hos-
offered ketamine under the rationale of having exhausted or de-
pice patients receiving palliative care, who also had co-occurring
clined alternative interventions in TRD; all had failed to respond
depressive and anxiety symptoms based on Hospital Anxiety and
to at least 3 pharmacological interventions and at least 1 adequate
Depression Scale. Eight of the 14 patients completed the 28-day
trial of repetitive transcranial magnetic stimulation at our clinic,
trial, whereas 6 patients dropped out at different time points, 4 of
16 patients (73%) had refused electroconvulsive therapy, and
them withdrew because of no response to ketamine after day 14,
6 patients (27%) had previously failed to respond to electrocon-
and 2 withdrew because of different reasons, which were unrelated
vulsive therapy. Thirteen (59%) had not benefited from cogni-
to ketamine treatment. All 8 subjects who completed this open-label
tive behavioral therapy or mindfulness-based cognitive therapy.
trial reported significant improvement in mood and anxiety symp-
Twelve patients (55%) had previously failed to respond to lithium,
toms. In addition, no serious adverse events were observed.13 In
13 patients (59%) had previously failed to respond to an mono-
another report, oral ketamine was administered as an augmenta-
amine oxidase inhibitor, and 17 patients (77%) had previously
tion strategy in 2 patients with chronic suicidal ideation and at
failed to respond to an atypical (dopaminergic antagonist) agent.
least 2 significant past suicide attempts. Within 24 hours of the
Clinical ratings were performed weekly at each clinic visit, and
first treatment, both patients showed significant reduction on the
dose adjustments were performed on the basis of tolerability and
total MADRS score and on the suicide item. Remission was
clinical response. Participants were allowed to remain on ongoing
sustained with repeated treatment every 2 to 4 weeks, with no adverse
medications or psychological treatment, without dose adjustment
events reported.14
during the trial. Concomitant psychotropic medication classes in-
Still, less evidence is available regarding the real-world
cluded selective serotonin reuptake inhibitor (n = 3), serotonin/
incidence of adverse outcomes that could potentially ensue
norepinephrine reuptake inhibitor (n = 5), tricyclic antidepressant
during ketamine treatment outside the research setting. Based
(n = 2), bupropion (n = 2), trazodone (n = 3), and atypical (dopa-
on effects seen among recreational ketamine users, these adverse
minergic antagonist) agent (n = 6). Patients were not offered treat-
outcomes range from the potential for misuse, diversion, or de-
ment if an axis 1 diagnosis other than MDD was considered
pendence,15 to the possibility of emergent psychotic symptoms
primary or if there was a significant axis 2 diagnosis or a history
with repeated use,16 or urinary complications such as “ketamine
of substance dependence or psychotic illness.
bladder” with sustained use.17 Although reviews on safety in the
research setting have been encouraging,18 it is unclear whether
such findings translate to the clinical setting or to patients receiv- Treatment Approach
ing treatment at home. Oral ketamine has been prescribed fairly Before initiating ketamine, patients discussed with the pre-
commonly for home use in patients with chronic pain, following scriber the nature of ketamine as an anesthetic agent under inves-
guidelines for dosing,19 safety, and efficacy.20,21 However, such tigation for off-label use as an antidepressant, as well as discussing
data are not yet available in the setting of MDD. the potential risks, benefits, and alternatives to off-label use of ke-
In summary, despite 15 years or more of research on the tamine for depression. Ketamine was prescribed as compounded
antidepressant properties of ketamine, the treatment has not en- 25-mg capsules and obtained by the patients from a compounding
tered widespread use outside research settings, and a number of pharmacy in the Toronto area. The treatment approach was de-
important translational questions remain unresolved. First, does rived from a recommended oral ketamine strategy in chronic
oral ketamine reliably exert comparable effects to intravenous ad- pain.19 The initial dose of oral ketamine was taken under pre-
ministration? Second, do the antidepressant properties of ketamine scriber supervision at the clinic, and subsequent doses were taken
persist with repeated dosing over timescales of weeks to months? at home during nighttime, once every 3 days to minimize overall
Third, do adverse outcomes (eg, misuse, dependence, psychosis, dosage and to avoid tachyphylaxis associated with daily dosing.
or urinary complications) ensue when ketamine treatment is pro- The dose commenced at 50 mg and was titrated upward by
vided outside the research setting? To explore these questions, data 25 mg at each dose (ie, every 3 days), until reaching 1 of the fol-
from real-world effectiveness studies may be informative. lowing 3 end points: (1) improvement in depressed mood on the
day after the dose, (2) a lack of tolerability of the dose, without im-
provement in mood, or (3) no improvement in mood despite
CASE SERIES reaching a dose of 300 mg. If the latter 2 end points occurred, ke-
Here, we report on a case series of 22 patients with TRD who tamine treatment was discontinued and the patient considered a
received rescue open-label treatment with a course of oral keta- nonresponder. In the case of the former end point, the dose was
mine at Toronto Western Hospital, University Health Network, maintained or titrated upward by 1 or 2 increments to maximize

© 2017 Wolters Kluwer Health, Inc. All rights reserved. www.psychopharmacology.com 465
Al Shirawi et al Journal of Clinical Psychopharmacology • Volume 37, Number 4, August 2017

the antidepressant effect. Where ketamine was tolerated, the min- urges to use ketamine beyond the prescribed amount or more
imum duration of treatment was 4 weeks. During follow-up visits, frequently than prescribed. There were no pharmacy reports
information about subjective improvement, subjective mood of requests for early prescription refills, repeated reports of
ratings on the Beck Depression Inventory II (BDI-II), adverse “lost” supply, or other objective suggestions of overuse for any
effects related to ketamine and a self-harm risk assessment of the 22 patients.
were collected.
DISCUSSION
Mood Outcomes
Although ketamine has shown promising antidepressant
Patients reached a mean (SD) dose of 222(72) mg, with a
effects in the research literature for more than 15 years, so far
distribution as follows: 100 mg (2 patients), 150 mg (5 patients),
there has been much less literature on its potential to be used
175 mg (1 patient), 225 mg (4 patients), 250 mg (4 patients),
in real-world practice. Off-label regimens of oral ketamine (liquid
and 300 mg (6 patients). Over the course of dose titration as de-
or compounded capsules) for home use are fairly common in the
scribed previously, 4 of the 22 patients (18%) achieved more than
management of chronic pain, raising the question of whether
50% reduction in mood symptoms and 3 patients (14%) showed
similar regimens might be applicable in the management of
an improvement of 20% to 50% in mood symptoms. Ten (45%)
TRD. Although definitive answers to this question must await
of the 22 patients showed less than 20% improvement in mood,
the rigor of a formal randomized controlled trial, in the interim,
with a mean BDI-II score of 37.7 at baseline and 34.2 at the time
case reports and case series may be of interest.
of treatment discontinuation due to lack of effect. Five (23%) of
In the present case series, approximately 30% reported some
the 22 patients showed a slight worsening in mood over the course
clinical benefit, whereas approximately 70% had no benefit or felt
of the titration. The mean BDI-II scores at baseline and at last visit
worse. On the other hand, adverse effects were less severe than
for each group are summarized in Table 1. There was no signifi-
those reported in the research literature. In addition, none of the
cant correlation between baseline BDI-II score and percent
patients in this series showed evidence of overuse, abuse, or
improvement after treatment. We did not identify any relation-
dependence, nor were there any cases of urinary, hepatic, or
ship between ketamine response and concomitant psychotropic
ophthalmic adverse effects or evidence of psychosis or other
medication regimen. Among responders/partial responders, docu-
serious psychiatric sequelae.
mentation of continued efficacy ranged from 15 weeks to 2 years
There are a number of important limitations to the present
from the onset of treatment.
report that should inform future work. First, all of patients in this
series had highly resistant forms of depression, with failure of
Adverse Effects multiple treatment modalities (multiple antidepressant medica-
The most frequently reported adverse event was acute disso- tions, neuromodulation, and in most cases cognitive psychother-
ciation (a subjective report of feeling disconnected from one's apy). Second, adherence to the prescribed regimen could not be
thoughts or emotions, or a subjective sense of time passing more confirmed for at-home dosing regimens. Third, because this re-
slowly or quickly than normal, or out-of-body experiences) in port concerns a series of clinical cases rather than a randomized
the period from 30 to 120 minutes after taking the ketamine dose controlled trial, standardized clinician ratings of mood symptom
(41%). Although 1 subject reported acute visual hallucinations were not consistently obtained. Fourth, a series of 22 patients is
during the dissociative period, these were not accompanied by de- insufficiently large to assess the incidence of rare but serious ad-
lusions or thought disorder and did not persist beyond the period verse effects (medical or psychiatric) ensuing from the treatment.
of the acute dose. Other commonly reported adverse events were Notwithstanding these limitations, it would be premature to
dizziness (23%), blurred vision (18%), numbness (14%), sedation rule out the potential clinical usefulness of “chronic pain–like”
(4%), nausea (4%), and insomnia (4%). Two subjects reported at-home regimens of oral ketamine in the setting of depression.
transient suicidal ideation that was not associated with self-harm However, a reasonable conclusion from the present work is that
or suicidal attempt. One participant reported lower urinary tract while such regimens may not engender harmful effects in most
symptoms (mainly polyuria and dysuria), which occurred after TRD patients, they may not achieve marked improvement in most
6 months of ketamine treatment; this was investigated via urologi- TRD patients either.
cal consultation and determined to be unrelated to the ketamine. In light of the high prevalence and disability associated with
This patient subsequently reinitiated ketamine without a recur- TRD and the impracticality of providing in-hospital intravenous
rence of urological symptoms. Other adverse effects previously ketamine to most patients who might benefit, more formal studies
reported with ketamine (corneal edema, hepatic injury, changes of nonintravenous ketamine or comparable regimens should be
in blood pressure, or memory impairment) were not observed or considered a priority. This would include emerging agents that tar-
reported. Regarding propensity for ketamine abuse or dependence, get the N-methyl-D-aspartate receptor with antidepressant effect
no patient in this series reported developing ketamine cravings or but with fewer propensities for dissociation or dependence.23

TABLE 1. Mood Outcomes for Oral Ketamine

Percentage of Subjects BDI-II Score BDI-II Score % Improvement

(n = 22), n (%) at Baseline Visit* at Last Visit* in BDI Scores*
Responder 4 (18.2) 33.0 (10.7) 11.7 (1.89) 62.7 (7.31)
Partial responder 3 (13.6) 47.3 (11.1) 37.0 (10.0) 22.3 (4.08)
Nonresponder 10 (45.5) 37.7 (7.90) 34.2 (7.3) 9.34 (6.4)
Negative responder 5 (22.7) 39.0 (12.6) 43.2 (11.7) −12.6 (8.79)
*Data are presented as mean(SD).

466 www.psychopharmacology.com © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Journal of Clinical Psychopharmacology • Volume 37, Number 4, August 2017 Oral Ketamine in Depression

The practical importance of devising safe and effective at-home 8. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of
treatment regimens bears further emphasis in the field. Such work ketamine in treatment-resistant major depression: a two-site randomized
will be essential to determine whether the promising research controlled trial. Am J Psychiatry. 2013;170:1134–1142.
literature on glutamatergic antidepressants can be translated into 9. Fond G, Loundou A, Rabu C, et al. Ketamine administration in
meaningful advances in the clinical setting. depressive disorders: a systematic review and meta-analysis.
Psychopharmacology (Berl). 2014;231:3663–3676.
ACKNOWLEDGMENT 10. Serafini G, Howland RH, Rovedi F, et al. The role of ketamine in
The authors acknowledge continuing research support from treatment-resistant depression: a systematic review. Curr Neuropharmacol.
the Ontario Brain Institute to the Canadian Biomarker Integration 2014;12:444–461.
Network in Depression.
11. Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized,
placebo-controlled, dose-frequency study of intravenous ketamine in
AUTHOR DISCLOSURE INFORMATION
patients with treatment-resistant depression. Am J Psychiatry. 2016;173:
Dr Al Shirawi receives fellowship funding from the Ministry 816–826.
of Health, Sultanate of Oman. Dr Kennedy has received research
funding or honoraria from the following sources: Allergan, 12. Lapidus KA, Levitch CF, Perez AM, et al. A randomized controlled trial
AstraZeneca, BMS, Brain Cells Inc, Brain Canada, Clera, CIHR, of intranasal ketamine in major depressive disorder. Biol Psychiatry.
Eli Lilly, Janssen, Lundbeck, Lundbeck Institute, OMHF, Ontario 2014;76:970–976.
Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion, and 13. Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of
Xian-Janssen. Dr Downar has received research support from depression and anxiety in patients receiving hospice care. J Palliat Med.
CIHR, Brain Canada, the Canadian Biomarker Integration 2010;13:903–908.
Network in Depression, the Ontario Brain Institute, the Klarman 14. De Gioannis A, De Leo D. Oral ketamine augmentation for chronic
Family Foundation, the Edgstone Foundation, a travel stipend suicidality in treatment-resistant depression. Aust N Z J Psychiatry. 2014;
from Lundbeck and from ANT Neuro, and in-kind equipment 48:686.
support for an investigator-initiated trial from MagVenture. 15. Morgan CJ, Curran HV, Independent Scientific Committee on Drugs.
No pharmaceutical or industry support was received for any Ketamine use: a review. Addiction. 2012;107:27–38.
part of this work. The opinions, results and conclusions are
those of the authors, and no endorsement by the Ontario Brain 16. Zuccoli ML, Muscella A, Fucile C, et al. Paliperidone for the treatment
Institute is intended or should be inferred. The authors declare of ketamine-induced psychosis: a case report. Int J Psychiatry Med.
2014;48:103–108.
no conflicts of interest.
17. Wu P, Wang Q, Huang Z, et al. Clinical staging of ketamine-associated
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