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High-dose ketamine infusion for the treatment of posttraumatic stress disorder in combat veterans

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Introduction: Combat veterans are at high risk for the development of posttraumatic stress disorder (PTSD) and substance use disorders. Ketamine has been shown to be an effective treatment for numerous mental health disorders, although research on its efficacy in combat-related PTSD in veterans is very limited. Methods: The study population consisted of 30 US military veterans with combat-related PTSD. Participants underwent a standard induction series of six 1-hour ketamine infusions with the goal of obtaining a transpersonal dissociative experience. Participants were given a series of self-report questionnaires to assess for changes in symptoms of depression, PTSD, and substance use prior to the first and sixth infusions. Results: Symptoms of depression as measured by change in score on the Patient Health Questionnaire decreased significantly from an average of 18.9 to 9.5 (P < .001). Similarly, symptoms of PTSD as measured by change in score on the PSTD Checklist for DSM-5 dropped significantly from an average of 56.2 to 31.3 (P < .001). Self-reported levels of substance use did not significantly decrease during the study period, although the level of use trended down. Conclusions: This observational study suggests that high-dose ketamine infusion therapy, which induced a transpersonal dissociative experience, could be a valuable tool in the treatment of combat-related PTSD. Further study is needed to better elucidate ketamine's mechanism of action with regards to the treatment of PTSD.
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ANNALS OF CLINICAL PSYCHIATRY
AACP.com Annals of Clinical Psychiatry | Vol. 31 No. 4 | November 2019 271
ANNALS OF CLINICAL PSYCHIATRY 2019;31(4):271-276 RESEARCH ARTICLE
INTRODUCTION: Combat veterans are at high risk for the development
of posttraumatic stress disorder (PTSD) and substance use disorders.
Ketamine has been shown to be an effective treatment for numerous men-
tal health disorders, although research on its efficacy in combat-related
PTSD in veterans is very limited.
METHODS: The study population consisted of 30 US military veterans with
combat-related PTSD. Participants underwent a standard induction series
of six 1-hour ketamine infusions with the goal of obtaining a transpersonal
dissociative experience. Participants were given a series of self-report
questionnaires to assess for changes in symptoms of depression, PTSD,
and substance use prior to the first and sixth infusions.
RESULTS: Symptoms of depression as measured by change in score on the
Patient Health Questionnaire decreased significantly from an average of
18.9 to 9.5 (P < .001). Similarly, symptoms of PTSD as measured by change
in score on the PSTD Checklist for DSM-5 dropped significantly from an
average of 56.2 to 31.3 (P < .001). Self-reported levels of substance use did
not significantly decrease during the study period, although the level of
use trended down.
CONCLUSIONS: This observational study suggests that high-dose ketamine
infusion therapy, which induced a transpersonal dissociative experience,
could be a valuable tool in the treatment of combat-related PTSD. Further
study is needed to better elucidate ketamine’s mechanism of action with
regards to the treatment of PTSD.
High-dose ketamine infusion for the treatment of
posttraumatic stress disorder in combat veterans
CORRESPONDENCE
Cassie Ross, PsyD
Department of Psychiatry
Boston Children’s Hospital
300 Longwood Avenue
Boston, MA 02115 USA
E-MAIL
cassienross@gmail.com
Cassie Ross, PsyD
Department of Psychiatry
Boston Children’s Hospital
Boston, Massachusetts, USA
Rakesh Jain, MD
Department of Psychiatry
Texas Tech Health Sciences Center
School of Medicine
Midland, Texas, USA
Carl J. Bonnett, MD
Klarisana
San Antonio, Texas, USA
Philip Wolfson, MD
The Center for Transformational
Psychotherapy
San Anselmo, California, USA
KETAMINE FOR COMBAT PTSD
November 2019 | Vol. 31 No. 4 | Annals of Clinical Psychiatry272
INTRODUCTION
Combat veterans are at high risk for the development of
posttraumatic stress disorder (PTSD) as well as comor-
bid mental health and substance use disorders that can
lead to significant functional impairment and morbid-
ity.1 The estimated prevalence of PTSD ranges from
27% to 37% in Vietnam armed forces veterans,2 10.1%
for Gulf War veterans,3 11.5% for veterans deployed to
Afghanistan,4 and 18% for those deployed to Iraq.4 It
is estimated that less than half of returning veterans
receive mental health treatment, and of those who do
seek treatment, only half receive quality care.5
Ketamine, a widely used anesthetic, recently has
been found to effectively treat mental health disorders,
including treatment-refractory major depressive disor-
der, bipolar depression, suicidality, and PTSD.6-17 This
study sought to better characterize the role that ket-
amine could play in the treatment of PTSD.
METHODS
Study participants
The study population consisted of 30 US military veter-
ans. Inclusion criteria included participants who previ-
ously served in a designated combat zone and who had
been diagnosed with combat-related PTSD by clini-
cians at the Department of Veterans Affairs. Participants
were men and women age 18 to 75 who passed medical
screening, were not receiving lamotrigine or any mono-
amine oxidase inhibitors, and did not have psychosis.
The Institutional Review Board at IntegReview (Austin,
Texas) approved the study (Protocol KRP001), and
written informed consent was obtained from all study
participants.
Procedures
Eligible participants were identified by the clinical staff.
After consenting to participate in the study, each partic-
ipant underwent a psychosocial evaluation by a trained
mental health professional. Medical records from the
Department of Veterans Affairs were reviewed. Military
service records from the Department of Defense were
also reviewed to ensure that the participants had served
in a combat zone.
Participants underwent a standard induction
series of six 1-hour ketamine infusions. The first infu-
sion began with a dose of 1 mg/kg of the participant’s
body weight, with a maximum of 60 mg on the first
1-hour infusion. There were no boluses given. After the
first infusion, the dose was adjusted up or down, with
the goal of attaining what the investigators referred to
as the psychotropic therapeutic response (PTR). The
treatment center defined the PTR as the dose at which
the patient experiences the optimum transpersonal
and transformative experience. The major assumption
that underlies this treatment strategy is that the expe-
riential (or “psychedelic”) aspect of ketamine infusion
therapy is not a “side effect” to be eliminated, but rather
an essential component of the treatment. The PTR is an
individualized dose specific to each patient.
For each infusion, the patient sat in a recliner in a
private room with one staff member in attendance for
the entire 1-hour infusion and for at least 30 minutes
afterwards. The 6 infusions were performed over a 2-
to 3-week period depending on each patient’s avail-
ability. Patients had IV access established and were
monitored using continuous pulse oximetry and 3-lead
cardiac monitoring. Blood pressure was recorded prior
to infusion and at regular intervals during and after
each infusion. Most patients watched videos of nature
scenes with a relaxing soundtrack. Some patients chose
to listen to their own music with or without the video
playing. Each infusion room was decorated to create
a relaxing ambiance. Although historically used as an
anesthetic agent, the use of ketamine in this context
would be more appropriately referred to as ketamine for
non-anesthetic indications (KNAI).
Study design and outcome measures
This was an observational case series of US veterans
who received ketamine infusion therapy for the treat-
ment of PTSD. Each participant was given a series of
self-report questionnaires prior to the first and sixth
TABLE 1
Final ketamine dose calculation
and ketamine dosage
Mean SD Median Range
Dose calculation
(mg/kg)
1.94 0.73 1.80 0.83 to
4.13
Final dose (mg) 163.83 52.50 150.00 60.00 to
300.00
SD: standard deviation.
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ANNALS OF CLINICAL PSYCHIATRY
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ketamine infusions. The PTSD Checklist for DSM-5
(PCL-5), a 20-item self-report measure, was admin-
istered to monitor change in PTSD symptoms.18 The
Patient Health Questionnaire (PHQ-9) was used to
screen for symptoms of depression.19 Alcohol consump-
tion, behaviors associated with alcohol consumption,
and alcohol-related problems were screened for using
the Alcohol Use Disorders Identification Test (AUDIT).20
The Drug Abuse Screen Test (DAST-10) was admin-
istered to screen for drug abuse and negative conse-
quences of drug use.21 In addition, participants were
asked about current marijuana use and history of rec-
reational ketamine use. Participants were also asked to
describe their experience regarding the dissociative and
psychomimetic effect of the ketamine and their percep-
tions of the value of PTR as part of their therapy.
RESULTS
Although the ketamine doses administered in this study
were generally higher than those in previously reported
research, the participants were responsive to verbal
stimuli at all times during the infusion. The doses were
gradually increased on each infusion based on a given
participant’s response during the previous infusion.
Ketamine dose calculations and final doses are pre-
sented in TABLE 1. Other than some occasional nausea,
none of the participants experienced any significant
adverse events or significant vital sign abnormalities.
Comparisons of self-report questionnaires pre- and
post-infusion are demonstrated in TABLE 2. Individual
responses on the PHQ-9 and PCL-5 for pre- and post-
infusions are outlined in TABLE 3. No participants
endorsed increased symptoms on the PHQ-9, and 2
participants (7%) reported no change in symptoms.
On the PCL-5, 3 participants (10%) endorsed increased
symptoms. On measures of substance abuse (DAST-10
and AUDIT), 6 and 7 participants had missing data,
respectively. While self-reported levels of substance
abuse did not significantly decrease during the study
period, it appeared that ketamine infusion did not
predispose patients to increased substance use, and
the level of use trended down. Anecdotally, some par-
ticipants reported a decreased desire to drink alcohol
after receiving the ketamine infusions. On a measure of
depression (PHQ-9), symptoms of depression dropped
significantly, from an average score of 18.9 to 9.5, a 50%
reduction, with a Cohen’s d effect size of 1.38 (F = 90.0,
P < .001). Finally, symptoms of PTSD as measured by
PCL-5 also dropped significantly, from an average score
of 56.2 to 31.3, a 44% reduction, with a Cohen’s d effect
size of 1.42 (F = 55.6, P < .001).
DISCUSSION
This observational study suggests that ketamine infu-
sion therapy could be a valuable tool in the treatment
of combat-related PTSD. Case reports have indicated
that ketamine or ketamine analogues may be an effec-
tive treatment for veterans with PTSD.22 McGhee et al23
reported the somewhat serendipitous finding that
PTSD in Operation Iraqi Freedom/Operation Enduring
Freedom veterans who received ketamine during sur-
geries was 27% compared with 46% in those who did
not receive ketamine. In a recent study by Albott et al,24
veterans with comorbid treatment-resistant depression
(TRD) and PTSD were administered 6 ketamine infu-
sions of 0.5 mg/kg over a 12-day period. The research-
ers found a significant decrease and remission of both
symptoms of depression and PTSD over the study
TABLE 2
Pre- and post-infusion comparison of self-report measures
Instrument N
Pre-
infusion SD
Post-
infusion SD F P Chi-squared
PHQ-9 30 18.9 6.2 9.5 7.3 90.9 <.0001 37.0
PCL-5 30 56.2 14.5 31.3 20.0 55.6 <.0001 19.7
AUDIT 23 5.3 6.8 4.4 6.7 1.0 .3 37.6
DAST-10 24 1.7 1.3 1.6 1.4 0.7 .4 62.0
AUDIT: Alcohol Use Disorders Identification Test; DAST-10: Drug Abuse Screen Test; PCL-5: PTSD Checklist for DSM-5; PHQ-9: Patient Health Questionnaire;
SD: standard deviation.
KETAMINE FOR COMBAT PTSD
November 2019 | Vol. 31 No. 4 | Annals of Clinical Psychiatry274
period, with a median length of symptom relapse of 20
days for depression and 41 days for PTSD.24 As such, ket-
amine infusions appear to be a promising treatment for
veterans with TRD and/or PTSD, and further research is
needed to understand ketamine’s safety and efficacy in
this population. To our knowledge, this is the first study
to investigate the efficacy of high-dose ketamine infu-
sion treatment of PTSD in combat veterans.
There is a rapidly growing body of literature show-
ing that ketamine is a safe, effective, and novel therapy
for TRD.8,13-16,24 Given the alarming number of veteran
suicides in the United States, a more effective means
for treating PTSD and TRD is urgently needed. Many of
the current theories of how ketamine works to treat TRD
center around its action at the N-methyl--aspartate
receptor and the alpha-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid receptor.6 Anecdotally, many
of the patients treated at our center report that the abil-
ity to achieve a change in their cognitive paradigms and
the ability to “reset” their thought patterns helps them
to radically alter the way in which they contextualize
their traumatic experiences. As our results show, this
can lead to a significant decrease in symptomatology
in this population. While this study was not designed to
elucidate the exact role of the experiential component,
it does demonstrate successful outcomes with ketamine
doses that are higher than the traditional 0.5 mg/kg,
which is the dose administered in many previous stud-
ies. Some authors have suggested that ketamine therapy
may increase the symptoms of PTSD.25 In our study, 3 of
30 participants endorsed increased symptoms; however,
the 2 previous studies that showed an increase in symp-
toms looked at the administration of ketamine shortly
after a traumatic injury, which is a very different context
than the patients we were treating in this study.25,26 It is
not entirely clear why 3 veterans endorsed an increase in
their PTSD symptoms, especially in light of the fact that
2 of the 3 had a decline in their depressive symptoms.
Additionally, none of the participants reported subjec-
tively that the experience worsened their symptoms. We
have found that the appropriate “set and setting” makes
an enormous difference in how the ketamine experience
is perceived. The staff member in attendance plays a
very proactive role in helping to guide and ground the
patient through his/her ketamine journey. In this regard,
our treatment strategy diverges from a more traditional
“infusion center” model in that it incorporates elements
of shamanistic healing that have historically been absent
from Western medicine. Further studies are needed to
better characterize the role of the experiential compo-
nent of ketamine and PTSD symptomatology, as well as
if any individuals experience increased PTSD symptom-
atology from ketamine infusions.
TABLE 3
Individual responses on the PHQ-9
and PCL-5 pre- and post-infusion
Instrument PHQ-9 score PCL-5 score
Pre-
infusion
Post-
infusion
Pre-
infusion
Post-
infusion
Veteran 1 26 19 53 58
Veteran 2 27 14 80 42
Veteran 3 19 155 14
Veteran 4 11 137 5
Veteran 5 14 351 16
Veteran 6 18 11 50 32
Veteran 7 24 824 20
Veteran 8 15 960 19
Veteran 9 5 0 68 8
Veteran 10 7 2 29 11
Veteran 11 14 263 13
Veteran 12 25 12 60 21
Veteran 13 23 11 62 38
Veteran 14 26 18 75 62
Veteran 15 24 864 32
Veteran 16 19 260 10
Veteran 17 16 10 65 36
Veteran 18 15 559 26
Veteran 19 10 042 5
Veteran 20 24 21 64 77
Veteran 21 17 14 74 50
Veteran 22 25 13 65 44
Veteran 23 16 037 7
Veteran 24 23 23 79 64
Veteran 25 24 13 43 36
Veteran 26 11 149 13
Veteran 27 22 22 35 44
Veteran 28 17 16 51 48
Veteran 29 23 18 60 56
Veteran 30 27 772 32
PCL-5: PTSD Checklist for DSM-5; PHQ-9: Patient Health Questionnaire.
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Limitations
There are several limitations to this study. This was an
observational study and did not have a placebo arm.
Also, because the final set of survey instruments was
administered before the sixth infusion, the data demon-
strate the effect of ketamine after 5 infusions. We suspect
that the effect size would have been greater if the instru-
ments could have been administered several days after
the sixth infusion. In our clinical experience, however,
we have found that compliance with questionnaires
and psychological screening instruments in the veteran
population can be quite challenging to obtain after they
have finished their induction series of infusions. We felt
that it would be better to have a complete data set after 5
infusions rather than to risk losing patients to follow-up
after they completed their full series of 6.
Another limitation was the ability to assess the
effect of ketamine on veterans’ use of alcohol and illicit
drugs. A few of the veterans in this study did not fill out
the AUDIT and the DAST-10; thus, there was an incom-
plete data set with regards to those instruments. Several
veterans also admitted that they initially underreported
their use of alcohol and illicit substances because they
had not yet built a sense of trust with the treatment team.
Nonetheless, there was a trend towards a decrease in
alcohol use. Anecdotally, several participants reported
a significant decreased desire to drink alcohol. This ele-
ment of ketamine therapy deserves further study.
Finally, this study did not look at long-term out-
comes but rather the change in PTSD symptomatology
over the course of the 2- to 3-week induction series. In
our clinical experience, patients will need a “booster”
infusion at regular intervals in order to maintain the
improvement in symptomatology.
CONCLUSIONS
We feel that this study provides valuable evidence of
the role that ketamine can play in the treatment of
combat-related PTSD. Specifically, the success we had
with significantly higher doses than those used in other
studies suggests that the experiential or psychedelic
effect of ketamine may be a critical element of how it
works therapeutically, rather than an adverse effect to
be eliminated. Further study is clearly needed to better
elucidate ketamine’s mechanism of action with regards
to the treatment of PTSD.
DISCLOSURES: Dr. Bonnett is the medical director and
owner of Klarisana, the ketamine infusion center where
this study was conducted. To preserve objectivity, out-
come measures and statistical analyses were verified
by Cassie Ross, PsyD, who has no financial relationship
with Klarisana. Dr. Jain has received research support
from or served as a consultant to, speaker for, or on
the advisory board of Addrenex, Alkermes, Allergan,
Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics,
Neurocrine Biosciences, Osmotica, Otsuka, Pamlab,
Pfizer, Shire, Sunovion, Supernus, Takeda, Teva, and Tris
Pharmaceuticals. Drs. Ross and Wolfson have no finan-
cial relationships with any companies whose products
are mentioned in this article, or with manufacturers of
competing products.
REFERENCES
1. Hoge CW, Auchterlonie JL, Milliken CS. Mental
health problems, use of mental health services, and
attrition from military service after returning from
deployment to Iraq or Afghanistan. J Am Med Assoc.
2006;295:1023-1032.
2. Kulka RA, Schlenger WE, Fairbank JA, et al. Trauma
and the Vietnam War generation: report of findings from
the National Vietnam Veterans Readjustment Study. New
York, NY: Brunner/Mazel; 1990.
3. Kang HK, Natelson BH, Mahan CM, et al.
Post-traumatic stress disorder and chronic fatigue
syndrome-like illness among Gulf War Veterans: a
population-based survey of 30,000 veterans. Am J
Epidemiol. 2003;157:141-148.
4. Hoge CW, Castro CA, Messer SC, et al. Combat duty
in Iraq and Afghanistan, mental health problems, and
barriers to care. N Engl J Med. 2004;351:13-22.
5. Tanielian T, Jaycox L, Schell T, et al. Invisible wounds:
mental health and cognitive care needs of America’s
returning veterans. RAND Corporation. https://www.
rand.org/pubs/research_briefs/RB9336.html. Published
2008. Accessed September 16, 2019.
6. Abdallah CG, Averill LA, Krystal JH. Ketamine as a
promising prototype for a new generation of rapid-acting
antidepressants. Ann N Y Acad Sci. 2015;1344:66-77.
7. Albott C, Lim K, Forbes M, et al. Neurocognitive
effects of repeated ketamine infusions in co-occurring
posttraumatic stress disorder and treatment-resistant
depression. Biol Psychiatry. 2017;81:S405.
8. Vidal S, Gex-Fabry M, Bancila V, et al. Efficacy and
safety of a rapid intravenous injection of ketamine 0.5
mg/kg in treatment-resistant major depression. J Clin
Psychopharmacol. 2018;38:590-597.
9. Womble AL. Effects of ketamine on major depressive
disorder in a patient with posttraumatic stress disorder.
AANA J. 2013;81:118-119.
10. Diazgranados N, Ibrahim L, Brutsche NE, et al. A
randomized add-on trial of an N-methyl-D-aspartate
antagonist in treatment-resistant bipolar depression.
Arch Gen Psychiatry. 2010;67:793-802.
11. Feder A, Parides MK, Murrough JW, et al. Efficacy
of intravenous ketamine for treatment of chronic
posttraumatic stress disorder: a randomized clinical trial.
JAMA Psychiatry. 2014;71:681-688.
12. Grunebaum MF, Galfalvy HC, Choo TH, et al.
Ketamine for rapid reduction of suicidal thoughts
in major depression: a midazolam-controlled
randomized clinical trial. Am J Psychiatry. 2018;175:
327-335.
13. Hartberg J, Garrett-Walcott S, De Gioannis A. Impact
of oral ketamine augmentation on hospital admissions
in treatment-resistant depression and PTSD: a
retrospective study. Psychopharmacol. 2018;235:
393-398.
14. Murrough JW, Iosifescu DV, Chang LC, et al.
Antidepressant efficacy of ketamine in treatment-resistant
major depression: a two-site randomized controlled trial.
Am J Psychiatry. 2013;170:1134-1142.
15. Murrough JW, Perez AM, Pillemer S, et al. Rapid and
longer-term antidepressant effects of repeated ketamine
infusions in treatment-resistant major depression. Biol
Psychiatry. 2013;74:250-256.
16. Price RB, Iosifescu DV, Murrough JW, et al. Effects
of ketamine on explicit and implicit suicidal cognition:
a randomized controlled trial in treatment-resistant
depression. Depress Anxiety. 2014;31:335-343.
KETAMINE FOR COMBAT PTSD
November 2019 | Vol. 31 No. 4 | Annals of Clinical Psychiatry276
17. Sanacora G, Frye MA, McDonald W, et al;
American Psychiatric Association (APA) Council
of Research Task Force on Novel Biomarkers and
Treatments. A consensus statement on the use of
ketamine in the treatment of mood disorders. JAMA
Psychiatry. 2017;74:399-405.
18. US Department for Veterans Affairs. The PTSD
Checklist for DSM-5 (PCL-5). https://www.ptsd.va.gov/
professional/assessment/adult-sr/ptsd-checklist.asp.
Published 2013. Accessed September 16, 2019.
19. Kroenke K, Spitzer RL, Williams JB. The PHQ-9:
Validity of a brief depression severity measure. J Gen
Intern Med. 2001;16:606-613.
20. Saunders JB, Aasland OG, Babor TF, et al.
Development of the Alcohol Use Disorders Identification
Test (AUDIT): WHO collaborative project on early
detection of persons with harmful alcohol consumption—
II. Addiction. 1993;88:791-804.
21. Skinner H. The drug abuse screening test. Addict
Behav. 1982;7:363-371.
22. Striebel JM, Nelson EE, Kalapatapu RK. “Being with
a Buddha”: A case report of methoxetamine use in a
United States veteran with PTSD. Case Rep Psychiatry.
2017;2017:1-4.
23. McGhee LL, Maani CV, Garza TH, et al. The
correlation between ketamine and posttraumatic
stress disorder in burned service members. J Trauma.
2008;64(suppl 2):S195-S199.
24. Albott CS, Lim KO, Forbes MK, et al. Efficacy,
safety, and durability of repeated ketamine infusions for
comorbid posttraumatic stress disorder and treatment-
resistant depression. J Clin Psychiatry. 2018;79. doi:
10.4088/JCP.17m11634.
25. Schönenberg M, Reichwald U, Domes G, et
al. Ketamine aggravates symptoms of acute stress
disorder in a naturalistic sample of accident victims.
J Psychopharmacol. 2008;22:493-497.
26. Schönenberg M, Reichwald U, Domes G, et al. Effects
of peritraumatic ketamine medication on early and
sustained posttraumatic stress symptoms in moderately
injured accident victims. Psychopharmacology (Berl).
2005;182:420-425.
... Eight publications that investigated the association between ketamine and post-traumatic stress disorder were identified. One RCT 93 and two open-label trials expressly focused on ketamine treatment for post-traumatic stress disorder symptoms, 94,95 whereas the other five retrospectively examined the effects of peri-Ketamine treatment for mental and health substance use disorders traumatic anaesthetic ketamine administration during treatment for physical injury. [96][97][98][99][100] The first retrospective study found that patients who were administered ketamine following trauma exposure demonstrated increased post-traumatic stress disorder symptoms at 1 year, 96 and a subsequent study by the same group identified increased symptoms of acute stress disorder, a precursor to post-traumatic stress disorder, 3 days subsequent to emergency treatment in people given ketamine compared with opioid and other analgesics. ...
... 94 Similarly, in another open-label study, 30 participants received six ketamine infusions beginning at 1 mg/kg; a significant reduction (44%) in post-traumatic stress disorder symptoms was observed from baseline to before the sixth infusion. 95 A cross-over RCT of a single intravenous subanaesthetic dose of ketamine (0.5 mg/kg) among 41 patients with chronic post-traumatic stress disorder reported that post-traumatic stress disorder symptom severity was improved compared with midazolam at 24 h, but not at 7 days. 93 ...
... Two studies explicitly reported no adverse effects 16,17 and 19 did not formally report presence or absence of adverse effects. 48,51,53,55,[61][62][63][64][65][66]76,84,88,[95][96][97][98][99][100] The remaining studies all reported adverse effects, with the most common being mild and transient increases in blood pressure that returned to baseline levels within 30-120 min. 40,72,83,87,102,106 Tachycardia and bradycardia were also reported, particularly at higher doses of ketamine, 6,86,89,90 and more severe cardiac effects. ...
Article
Full-text available
Background In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions. Aims In light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders. Method The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist. Results We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis. Conclusions Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.
... genetycznych i biologicznych, w oderwaniu od społecznych), tym samym wyłącznie w jednostce umiejscawiając de facto przyczynę i źródło (żeby nie powiedzieć: "odpowiedzialność za") zaburzenia. Do podobnych wniosków dochodzą Cosgrove i Karter 80 . Tymczasem wiele badań pokazuje, że status materialny i społeczny 81 , przynależność do mniejszości etnicznej 82 , czy bycie ofi arą znęcania się w dzieciństwie 83 mają związek z zapadalnością na poszczególne zaburzenia (a przynajmniej częstością ich diagnozowania!). ...
... 79 Moncrieff (2008b). 80 Cosgrove, Karter (2018). 81 Wicks, Hjern, Daman (2010). ...
... Examples of such an approach would be the current studies on the use of 3,4-methylenedioxymethamphetamine (MDMA) for the treatment of Posttraumatic Stress Disorder, where the psychoactive effects of MDMA are thought to allow for a specific therapeutic relationship to be established [75,76]. Other examples would be the use of psilocybin [77], LSD [78], ketamine [79,80] or ayahuasca and other substances for various disorders. It is important that the effects of such interventions are not reduced to the neurobiological level only. ...
Thesis
Full-text available
Prezentowana tutaj praca doktorska, pod tytułem „Model biomedyczny w psychopatologii i opozycja wobec niego. Perspektywa psychologiczna” jest projektem w istocie rzeczy interdyscyplinarnym, łączącym perspektywę historyczną i socjologiczną (socjologii wiedzy i socjologii zdrowia i medycyny) czy nawet filozoficzną, z namysłem nad współczesnymi zagadnieniami dotyczącymi psychopatologii i terapii zaburzeń psychicznych, które odwołują się do współczesnej wiedzy psychologicznej i psychiatrycznej. Takie podejście wydaje się konieczne, bowiem zdrowie psychiczne, czy też szeroko rozumiana psychopatologia, jest „obiektem granicznym” (w znaczeniu jakie nadaje temu terminowi Good (2000)) badanym przez różne dyscypliny naukowe; rzetelne przyjrzenie się tej problematyce wymaga więc uwzględnienia różnych perspektyw i ich integrację. Celem pracy jest próba naszkicowania rozwiązań, które mogłyby stanowić realną alternatywę wobec biomedycznego modelu zaburzeń psychicznych, tak w praktyce stricte klinicznej, jak i badawczej.
... Pour le LSD, on retrouve généralement un plus grand nombre de séances d'intégration post-administration, parfois jusqu'à trois, en grande partie en raison de l'intensité des effets psychodysleptiques provoqués par la molécule [39,46]. Par ailleurs, concernant la kétamine IV, certaines équipes titrent la posologie de manière à obtenir à chacune des administrations des effets psychodysleptiques d'intensité suffisante [74]. Une meilleure systématisation des techniques psychothérapeutiques (méthodologie, fréquence) serait bénéfique pour l'amélioration de ces prises en charge dans les troubles de l'humeur [38]. ...
... En parallèle de l'amélioration thymique dans les épisodes dépressifs comorbides, ces protocoles montrent généralement une diminution des symptômes spécifiques à l'ESPT (cauchemars, flash-back, anxiété anticipatoire). Pendant leur expérience psychodysleptique sous kétamine, les patients revivent parfois les événements traumatiques de manière moins violente, et avec une plus grande distance émotionnelle [74]. Ces études suggèrent que ces éléments traumatiques pourraient être spécifiquement retravaillés pendant l'administration aiguë, ou pendant les séances de débriefing, sans la présence de flash-back ou d'hyperactivation neurovégétative [76]. ...
Article
Résumé La kétamine, un antagoniste non compétitif du récepteur NMDA, est utilisée aujourd’hui comme traitement antidépresseur d’action rapide dans les troubles dépressifs. Ce traitement provoque des effets psychodysleptiques dissociatifs associant une déréalisation et une dépersonnalisation, et déclenche des modifications synaptogéniques favorisant la plasticité cérébrale. Malgré plusieurs études préliminaires suggérant l’utilité de son association avec la psychothérapie, l’administration de kétamine n’est généralement pas combinée à des protocoles de psychothérapie per- et postperfusion dans le cadre de son utilisation clinique à visée antidépressive. Pourtant, la phénoménologie des expériences psychodysleptiques et l’effet synaptogénique pourraient potentialiser l’effet des psychothérapies cognitives et comportementales. Dans cet article, nous proposons un guide pratique de psychothérapie augmentée sous kétamine (KAP) synthétisant les données contemporaines de la littérature et notre expérience clinique. Nous détaillons des propositions de bonne pratique clinique et proposons quatre étapes importantes pour l’utilisation d’une molécule psychodysleptique à visée antidépressive : la préparation, l’administration, l’intégration, et la prolongation. Enfin, nous discutons les limites et les perspectives de cette combinaison dans la prise en charge des troubles de l’humeur.
... Pour le LSD, on retrouve généralement un plus grand nombre de séances d'intégration post-administration, parfois jusqu'à trois, en grande partie en raison de l'intensité des effets psychodysleptiques provoqués par la molécule [39,46]. Par ailleurs, concernant la kétamine IV, certaines équipes titrent la posologie de manière à obtenir à chacune des administrations des effets psychodysleptiques d'intensité suffisante [74]. Une meilleure systématisation des techniques psychothérapeutiques (méthodologie, fréquence) serait bénéfique pour l'amélioration de ces prises en charge dans les troubles de l'humeur [38]. ...
... En parallèle de l'amélioration thymique dans les épisodes dépressifs comorbides, ces protocoles montrent généralement une diminution des symptômes spécifiques à l'ESPT (cauchemars, flash-back, anxiété anticipatoire). Pendant leur expérience psychodysleptique sous kétamine, les patients revivent parfois les événements traumatiques de manière moins violente, et avec une plus grande distance émotionnelle [74]. Ces études suggèrent que ces éléments traumatiques pourraient être spécifiquement retravaillés pendant l'administration aiguë, ou pendant les séances de débriefing, sans la présence de flash-back ou d'hyperactivation neurovégétative [76]. ...
Article
Ketamine, a non-competitive NMDA receptor antagonist, is used as a fast-acting antidepressant therapy in depressive disorders. This treatment provokes dissociative effects associating derealization and depersonalization, and a synaptogenic signaling cascade promoting brain plasticity. Despite several preliminary studies suggesting the usefulness of its combination with psychotherapy, administration of ketamine isn’t generally combined with per- and post-infusion psychotherapy protocols in its clinical antidepressant use. However, the phenomenology of psychodysleptic experiences, and the synaptogenic effect associated with ketamine, could potentiate the effect of cognitive and behavioral therapies. In this article, we purpose a practical guide to augmented psychotherapy with ketamine (KAP) synthesizing contemporary data from the literature and our clinical experience. We detail four important steps for the use of a psychodysleptic molecule for antidepressant purposes: preparation, administration, integration and prolongation. Finally we discuss the limits and prospects of this combination in the management of mood disorders.
... In two different rodent models of PTSD, only the chronic administration of ketamine (i.p.) showed an anxiolytic effect (Zhang et al., 2015). In addition, an observational study of 30 U.S. military veterans with PTSD receiving six 1-h infusions of ketamine demonstrated that high-dose infusion therapy could be an effective tool in treating PTSD (Ross et al., 2019). However, future studies should investigate alternative routes of administration suitable for outpatient clinical settings (Feder et al., 2020). ...
Article
Post-traumatic stress disorder (PTSD) is a disabling psychiatric condition with a critical familiar, personal, and social impact. Patients diagnosed with PTSD show various symptoms, including anxiety, depression, psychotic episodes, and sleep disturbances, complicating their therapeutic management. Only sertraline and paroxetine, two selective serotonin reuptake inhibitors, are approved by different international agencies to treat PTSD. In addition, these drugs are generally combined with psychotherapy to achieve positive results. However, these pharmacological strategies present limited efficacy. Nearly half of the PTSD patients do not experience remission of symptoms, possibly due to the high prevalence of psychiatric comorbidities. Therefore, in clinical practice, other off-label medications are common, even though the effectiveness of these drugs needs to be further investigated. In this line, antipsychotics, antiepileptics, adrenergic blockers, benzodiazepines, and other emerging pharmacological agents have aroused interest as potential therapeutic tools to improve some specific symptoms of PTSD. Thus, this review is focused on the most widely used drugs for the pharmacological treatment of PTSD with a translational approach, including clinical and preclinical studies, to emphasize the need to develop safer and more effective medications.
... Examples of such an approach would be the current studies on the use of 3,4-methylenedioxymethamphetamine (MDMA) for the treatment of Posttraumatic Stress Disorder, where the psychoactive effects of MDMA are thought to allow for a specific therapeutic relationship to be established [75,76]. Other examples would be the use of psilocybin [77], LSD [78], ketamine [79,80] or ayahuasca and other substances for various disorders. It is important that the effects of such interventions are not reduced to the neurobiological level only. ...
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The article proposes a rough outline of an alternative systemic approach to mental health issues and of a more humane mental health care system. It suggests focusing on understanding mental distress as stemming from problems in living, using medications as agents facilitating psychotherapy, or as a last resort and short-term help, according to the principles of harm reduction. It argues that understanding drugs as psychoactive substances and studying the subjective effects they produce could lead to better utilization of medications and improvements in terms of conceptualizing and assessing treatment effects. Qualitative research could be particularly useful in that regard. It also advocates a radical departure from current diagnostic systems and proposes a synthesis of already existing alternatives to be used for both research and clinical purposes. Accordingly, a general idea for an alternative mental health care system, based on a combination of Open Dialogue Approach, Soteria houses, individual and group psychotherapy, cautious prescribing, services helping with drug discontinuation, peer-led services and social support is presented. The proposition could be seen as a first step towards developing a systemic alternative that could replace the currently dominating approach instead of focusing on implementing partial solutions that can be co-opted by the current one.
... The study also concluded that ketamine reduced comorbid depressive symptoms and was generally well-tolerated (Feder et al., 2014). Another study done in 30 combat veterans suffering from PTSD found that repeated high-dose ketamine infusions significantly reduced both depressive and PTSD symptoms, and also reported an insignificant downward trend in substance use (Ross et al., 2019). An intriguing study from Glue et al. (2018) concluded that ketamine has even broader ability to ameliorate negative emotional states, showing efficacy against refractory anxiety disorders such as generalized anxiety disorder and social anxiety disorder. ...
Article
Excessive alcohol consumption is involved in 1/10 of deaths of U.S. working-age adults and costs the country around $250,000,000 yearly. While Alcohol Use Disorder (AUD) pathology is complex and involves multiple neurotransmitter systems, changes in synaptic plasticity, hippocampal neurogenesis, and neural connectivity have been implicated in the behavioral characteristics of AUD. Depressed mood and stress are major determinants of relapse in AUD, and there is significant comorbidity between AUD, depression, and stress disorders, suggesting potential for overlap in their treatments. Disulfiram, naltrexone, and acamprosate are current pharmacotherapies for AUD, but these treatments have limitations, highlighting the need for novel therapeutics. Ketamine is a N-methyl-D-Aspartate receptor antagonist, historically used in anesthesia, but also affects other neurotransmitters systems, synaptic plasticity, neurogenesis, and neural connectivity. Currently under investigation for treating AUDs and other Substance Use Disorders (SUDs), ketamine has strong support for efficacy in treating clinical depression, recently receiving FDA approval. Ketamine’s effect in treating depression and stress disorders, such as PTSD, and preliminary evidence for treating SUDs further suggests a role for treating AUDs. This review explores the behavioral and neural evidence for treating AUDs with ketamine and clinical data on ketamine therapy for AUDs and SUDs.
... However, ketamine has also been employed in a PAP-like model to facilitate therapeutic changes. Indeed, ketamine-assisted psychotherapy has been successfully used in the treatment of depression/anxiety [181], PTSD [229], as well as alcohol [230], heroin [231], and cocaine addiction [232]. These latter results are somewhat surprising given that ketamine is a substance of abuse [222], with significantly more harm and potential for physiological dependence than the psychedelics [233]. ...
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RationalePosttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual’s health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD.Objectives To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD.Methods Participants received two to three active doses of MDMA (75–125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire.ResultsThere was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = − 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = − 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.ConclusionsPTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.Trial registrationclinicaltrials.gov Identifier: NCT00090064, NCT00353938, NCT01958593, NCT01211405, NCT01689740, NCT01793610
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Background Post-traumatic stress disorder (PTSD) is a serious stress-related disorder caused by traumatic experiences. However, identifying a key therapy that can be used for PTSD treatment remains difficult. Ketamine, a well-known dissociative anesthetic, is considered safe to be used in anesthesia, pain management, and antidepressant actions since 1970. At present, it is still controversial whether PTSD can be treated with ketamine. The authors performed a meta-analysis to determine whether the use of perioperative ketamine lowers the incidence of PTSD. Methods Cochrane Central Register of Controlled Trials, Embase, PubMed, and Web of Science were searched to examine the use of ketamine for the treatment of PTSD among soldiers with combating experience. Studies were included if they were randomized placebo-controlled, case-control, and cohort studies. The primary outcome was the incidence of PTSD in the later stage of the wounded or burn soldiers. The secondary outcome was the influence of ketamine on PTSD-scale scores for early and chronic PTSD, respectively. Results Our search yielded a total of three studies ( n = 503 patients) comparing the use of ketamine ( n = 349) to control ( n = 154). The available evidence showed no significant difference in the incidence of PTSD between combatant soldiers on the battlefield with or without ketamine treatment (risk ratio = 0.81, 95% CI, 0.63–1.04; P = 0.10). In 65 patients from three trials, ketamine was not only ineffective in treating early PTSD but also lead to exacerbation of the disease (risk ratio = 2.45, 95% CI, 1.33–3.58; P < 0.001). However, in 91 patients from the other three trials, ketamine is effective in treating chronic PTSD (risk ratio = −3.66, 95% CI, −7.05 to −0.27; P = 0.03). Conclusion Ketamine was not effective on lower the PTSD incidence for soldiers on the battlefield, nor on the PTSD-scale scores in early PTSD patients. However, it may improve the PTSD-scale scores for chronic conditions. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021255516 , PROSPERO, identifier: CRD42021255516.
Article
Posttraumatic stress disorder (PTSD) is a devastating medical illness, for which currently available pharmacotherapies have poor efficacy. Accumulating evidence from clinical and preclinical animal investigations supports that ketamine exhibits a rapid and persistent effect against PTSD, though the underlying molecular mechanism remains to be clarified. In this literature review, we recapitulate the achievements from early ketamine studies to the most up-to-date discoveries, with an effort to discuss an inclusive therapeutic role of ketamine for PTSD treatment and its possible therapeutic mechanism. Ketamine seems to have an inimitable mechanism of action entailing glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity.
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Rationale: Depressive episodes are the leading cause of mental health-related hospital admissions in Australia, and 44% of those admitted have a previous history of hospitalisations for depression (Admitted patient mental health-related care: (Australian Institute of Health and Welfare Aust Hospital Stat 2011-12, 2013). Despite numerous available antidepressant treatments, many patients do not respond to conventional therapy, having what is called 'treatment resistance' (Fava Biol Psychiatry 53:649-659, 2003). In recent years, ketamine has risen to prominence as an effective, rapidly acting antidepressant (Ketamine: a light in the darkness: Paleos and Ross 28-33, 2013). However, customary intravenous (IV) and intramuscular (IM) routes of administration and relapse rates after cessation remain barriers to more widely adopted usage. Objectives: This study represents the largest retrospective review of patients receiving long-term oral ketamine for treatment-resistant depression and post-traumatic stress disorder (PTSD). Our purpose was to examine the safety and efficacy of oral ketamine therapy in an outpatient setting as measured by changes in hospitalisation for psychiatric episodes. Methods: Hospital records of 37 patients who received oral ketamine treatment were reviewed to compare the number and duration of psychiatric hospital admissions before and after treatment. Records were also screened for adverse medical events and changes in ketamine dosage over time. Results: Following treatment, inpatient hospital days were reduced by 70%, and hospital admissions were reduced by 65%. The dose of ketamine patients required was stable over time with no evidence of tolerance building. There were no serious adverse events and no long-term negative effects associated with ketamine. Conclusions: Oral ketamine offers a promising pharmacologic adjunct to depression treatment. It may offer a more approachable alternative to IV or IM ketamine. The results warrant further investigation into the safety and efficacy of oral ketamine for psychiatric treatment.
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Methoxetamine (MXE) is a ketamine analogue with a high affinity for the N-methyl-D-aspartate (NMDA) receptor. MXE is a newly emerging designer drug of abuse and is widely available through on-line sources and is not detected by routine urine drug screens. In this report, we describe a United States (US) veteran with posttraumatic stress disorder (PTSD) and heavy polysubstance use, who injected high dose MXE for its calming effect. Given MXE’s structural similarities to ketamine and recent work showing that ketamine reduces PTSD symptoms, we hypothesize that MXE alleviated this veteran’s PTSD symptoms through action at the NMDA receptor and via influences on brain-derived neurotrophic factor (BDNF). To our knowledge, this is the first case report of self-reported use of MXE in the US veteran population. More awareness of designer drugs, such as MXE, is an important first step in engaging patients in the treatment of designer drug addiction in both military/veteran settings and civilian settings.
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The discovery of ketamine's rapid and robust antidepressant effects opened a window into a new generation of antidepressants. Multiple controlled trials and open-label studies have demonstrated these effects across a variety of patient populations known to often achieve little to no response from traditional antidepressants. Ketamine has been generally well tolerated across patient groups, with transient mild-to-moderate adverse effects during infusion. However, the optimal dosing and route of administration and the safety of chronic treatment are not fully known. This review summarizes the clinical effects of ketamine and its neurobiological underpinnings and mechanisms of action, which may provide insight into the neurobiology of depression, relevant biomarkers, and treatment targets. Moreover, we offer suggestions for future research that may continue to advance the field forward and ultimately improve the psychopharmacologic interventions available for those individuals struggling with depressive and trauma-related disorders. Published 2015. This article is U.S. Government work and is in the public domain in the USA.
Article
Background: Ketamine has been documented for its rapid antidepressant effects. However, optimal dose and delivery route have not yet been thoroughly investigated. The objectives of this study were to document the safety and test the antidepressant and antisuicidal effects of a single rapid 1-minute injection of ketamine 0.5 mg/kg in treatment-resistant depression (TRD). Methods: Ten patients with TRD were included in an open, noncontrolled 4-week study and received a rapid intravenous dose of ketamine 0.5 mg/kg. Main outcome measure was the Montgomery-Åsberg Depression Rating Scale and suicidality was assessed using the Scale for Suicide Ideation. Results: Rapid injection of ketamine elicited transient increase of blood pressure and altered states of consciousness in all patients and mild psychotomimetic effects in 4 patients, which all resolved without any intervention. Decrease of depression severity was observed from 40-minute postinjection until day 15. Eight patients became responders within 1 day and all were nonresponders after 4 weeks. The decrease of suicidal ideation was significant until day 7. Analysis indicated that higher severity of depression and anxiety at baseline predicted a larger Montgomery-Åsberg Depression Rating Scale decrease after 4 weeks. Conclusions: This study suggests that in well-controlled medical settings with adequate monitoring, a single rapid 1-minute injection of ketamine 0.5 mg/kg can be well tolerated and is efficacious in rapidly reducing depression symptoms and suicidal thoughts in outpatients with TRD. These findings are relevant to the practice of general clinical psychiatry and emergency departments were ketamine can have a place in acute management of TRD. Larger studies are necessary to confirm these results.
Article
Objective: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans. Methods: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion. Results: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d'] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d' = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration. Conclusions: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD. Trial registration: ClinicalTrials.gov identifier: NCT02577250.
Article
Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder. Method: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1). Results: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction ≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up. Conclusions: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.
Article
Objective: While considerable attention has focused on improving the detection of depression, assessment of severity is also important in guiding treatment decisions. Therefore, we examined the validity of a brief, new measure of depression severity. Measurements: The Patient Health Questionnaire (PHQ) is a self-administered version of the PRIME-MD diagnostic instrument for common mental disorders. The PHQ-9 is the depression module, which scores each of the 9 DSM-IV criteria as "0" (not at all) to "3" (nearly every day). The PHQ-9 was completed by 6,000 patients in 8 primary care clinics and 7 obstetrics-gynecology clinics. Construct validity was assessed using the 20-item Short-Form General Health Survey, self-reported sick days and clinic visits, and symptom-related difficulty. Criterion validity was assessed against an independent structured mental health professional (MHP) interview in a sample of 580 patients. Results: As PHQ-9 depression severity increased, there was a substantial decrease in functional status on all 6 SF-20 subscales. Also, symptom-related difficulty, sick days, and health care utilization increased. Using the MHP reinterview as the criterion standard, a PHQ-9 score > or =10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. Results were similar in the primary care and obstetrics-gynecology samples. Conclusion: In addition to making criteria-based diagnoses of depressive disorders, the PHQ-9 is also a reliable and valid measure of depression severity. These characteristics plus its brevity make the PHQ-9 a useful clinical and research tool.