REDUCED PSYCHEDELIC EFFECTS OF KETAMINE INFUSION AFTER ELECTROCONVULSIVE THERAPY:

A REPORT ON THREE CASES.

Author: Emmanuel Kiiza Mwesiga1,2,3; Racheal Alinaitwe2,3; Janet Nakigudde2; Seggane Musisi2,3.

Author Affiliations:

1. Department of Psychiatry and Mental Health; University of Cape Town.

2. Department of Psychiatry, College of Health Sciences; Makerere University.

3. Adult Psychiatric Unit, Nakasero Hospital Limited; Uganda.

Email address of authors:

1. Prof. Seggane Musisi; segganemusisi@yahoo.ca

2. Dr. Janet Nakigudde; janetnakigudde@gmail.com

3. Dr. Racheal Alinaitwe; rarukiri@gmail.com

Corresponding Author
Dr. Emmanuel Kiiza Mwesiga,
Psychiatrist,
Nakasero Hospital Limited,
plot 14A Akii Bua Rd,
Kampala, Uganda.
Email: emwesiga@chs.mak.ac.ug
Abstract

Background

Psychedelic side effects of ketamine limit its use for treatment of suicide ideations. Psychedelic
effects after ketamine infusion were assessed in two patients received prior electroconvulsive
therapy (ECT) and one who had not. Patients who received ECT prior to the infusion had lower mean
scores on all domains of the hallucinogen rating scale compared to the patient who did not receive
prior ECT. Confirming and understanding this association is needed through more rigorous research
methods.

Key words: Case report, Ketamine, electro convulsive therapy, Depression

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Background.

Infusion of sub anesthetic doses of ketamine is an off label treatment of suicidal ideations . It is
particularly preferred were rapid reduction of suicidal ideations is required . Ketamine was initially
indicated for use of induction of anesthesia but has been shown to induce rapid antidepressant
effects in both animal and human studies . The exact mechanism for the antidepressant effects of
Ketamine are not well understood but it is thought to exert its therapeutic effect through its
antagonism of the N- methyl D- aspartate receptors . The clinical use of ketamine is increasing and
intranasal (S)-ketamine has recently been approved for depression by the Food and Drug
Administration .

Despite its benefits, the use of ketamine infusion is limited by its ability to cause profound
psychedelic effects . Between 5 to 30% of patients experience perceptual difficulties that include
dissociative events, dream, auditory and musical hallucinations after subanesthetic doses of
ketamine . These side effects though often intense are transient and relieved after stopping the
medication. To improve the use of ketamine infusion, there is need to develop mechanisms to
reduce its psychedelic side effects.

In three case reports we highlight how two patients who had electroconvulsive therapy (ECT) prior
to ketamine infusion had better fewer perceptual side effects than one patient who had no prior
ECT. Also, patients who had prior ECT had faster remission of their suicidal risk compared to the one
who did not have prior ECT. Long term clinical outcomes after ketamine infusion are also highlighted.

Study site.

Patients were reviewed at Nakasero Hospital Limited in Kampala, Uganda (Figure 1). It is the only
private facility in the country that has a specialized psychiatric unit that offers both inpatient and
outpatient psychiatric services. The inpatient facility has six beds and inpatients are looked after by a
comprehensive mental health team comprised of three psychiatrists, one clinical psychologist, two
counsellors and psychiatric nurses. The outpatient clinic runs daily from Monday to Saturday and on
average reviews twenty patients a day. Currently it has specialty clinics for child and adolescent
mental health, addiction psychiatry, geriatric psychiatry, clinical psychology and adult psychiatry.

Procedure for sub anesthetic doses of ketamine (ketamine infusion)

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There are no clear guidelines for the use of ketamine infusion use. Usually three to six doses of
0.5mg /kg are given by bolus infusion over a 30 minute period with antidepressant effects
experienced over a period of 48 hours. These antidepressant effects may be sustained for a one
week period . At NHL, the procedure is supervised by a psychiatrist and an anesthesiologist.
Continuous monitoring of vitals like blood pressure, heart rate, oxygen saturation is provided for
during the procedure.

Hallucinogen rating scale

The hallucinogen rating scale (HRS) is a self-report questionnaire that is used to evaluate the acute
effects of hallucinogenic drugs . Participants rate different symptoms on a Likert scale that ranges
from zero for no effect at all for a specific symptom to four for extremely bothered by a symptom.
These symptoms are then divided into six main domains that include somaesthesia, affect,
perception, cognition, volition and intensity . Somaesthesia is the sensory perception of bodily
feelings like interoceptive, visceral, and tactile effects. Affect refers to emotional responses.
Perception refers to visual, auditory, gustatory, and olfactory experiences. Cognition assesses the
alterations in thought processes. Volition includes the ability to interact with the environment and
intensity refers to the strength of the various aspects of the experience. This scale was filled in
retrospectively after the last Ketamine infusion

The cases:

AA was the first patient to ever be given sub anesthetic ketamine infusion doses at NHL. She was a
22-year-old female who presented to our care in April 2017 as a referral from a therapist. She had
lost her mother in the same year and presented with depressive symptoms of low mood, poor sleep
and increased appetite. She also had feelings of being worthless, poor concentration at her place of
work and thought she would be better off dead. History reported multiple suicide attempts
beginning in early adolescence but luckily none was successful. Initially she had been started on
antidepressants but frequent suicidal attempts using the tablets led to them being withdrawn. To
prevent further attempts, she was given 6 doses of ECT in April 2017. She improved and continued
cognitive behavioral therapy. She was re-admitted on three separate occasions for high suicide risk
with suicidal attempt. In January 2018, subanesthetic infusion of ketamine was recommended after
presenting again with high suicide risk and this was performed according to the protocol above. She
did not experience any perceptual difficulties during the procedure.

BB is a 21-year-old Ugandan male who was first reviewed in January 2014. He was transferred from
the intensive care unit after emergency management for a failed suicide attempt. At initial review, a
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diagnosis of severe depression with psychotic features and suicidal plans was made. He was given
twelve doses of electroconvulsive therapy as well as cognitive behavioral therapy. He was discharged
home on Fluoxetine and Aripiprazole. Over the next four years he would have two more suicidal
attempts and was admitted with clear suicidal plans on another two occasions. On all occasions he
was certified as unsafe and committed under the mental health safety act. He received ECT
treatments on two other occasions in addition to ongoing pharmacotherapy (addition of mood
stabilizer in 2015) and psychotherapy (primarily cognitive behavioral therapy). In May 2018 after a
suicidal attempt, a decision was made to give him sub anesthetic doses of ketamine. BB would only
get mild perceptual experiences at the end of the treatment and these would be over while he
waited in the recovery area.

CC is a 27-year-old patient who has been in the clinic since 2017. She presented initially as a referral
from a clinical psychologist with severe post-traumatic stress disorder and severe depression with
suicidal ideations. She had experienced repeated sexual violence as a child and again as an
adolescent. Initially she was treated for PTSD with antidepressant therapy and psychotherapy
(cognitive behavioral therapy and trauma specific therapy). She however did not improve and
started developing perceptual difficulties and trouble with everyday socio-occupational functioning.
She was having trouble relating with her fiancé who wanted a child, but she was against it. She also
could not stay with her daughter as she always felt that she was not good enough to look after her
daughter. She never had any documented attempt but would continuously report suicidal ideations
with a clear plan. She declined to receive ECT initially and sub anesthetic ketamine infusions were
thus recommended. These were received according to the standard protocol above. CC had
profound perceptual difficulties. She would clearly see her attacker in the procedure room leading
her to cry and wail. Her blood pressure and heart rate would rapidly increase during the procedure
and she would need both physical and chemical restraints to complete the infusion. On most
occasions she required an intravenous benzodiazepine at the end of the procedure to calm down.

A summary of the three cases is highlighted in table 1.

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Table 1: Summary of the three cases highlighting differences in ECT and ketamine infusion exposure.

Key point AA BB CC

Gender Female Male Female

Age (Years) 22 21 27

Year first reviewed April 2017 January 2014 October 2017

Year(s) received ECT April 2017 February 2014 October 2018

July 2016

December 2017

Total ECT doses 06 12, 06 and 06 on three 12

received different occasions

Year received January 2018. May 2018 July 2017

Ketamine infusion

Psychedelic side effects of Ketamine

The mean scores for each domain that are reported in the table 2.

Table 2: Comparing the scores of the three patients by HRS domain.

HRS DOMAIN BB mean scores AA mean scores CC mean scores

SOMAESTHESIA 2.00 1.62 2.77

AFFECT 1.82 1.35 1.88

PERCEPTION 1.47 1.82 3.06

COGNITION 2.00 1.45 2.73

VOLITION 1.12 2.50 2.38

INTENSITY 2.25 2.50 0

When we compared the combined mean scores for participants who received ECT to the one who
did not receive ECT prior to ketamine infusion we found the participant who declined ECT had higher
mean scores in all domains. Results are shown in table 3.
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Table 3: Comparing HRS scores of participants with prior ECT to the one who did not get ECT.

HRS No prior ECT HRS mean Prior ECT HRS mean

DOMAIN domain scores domain scores

SOMAESTH 2.77 1.81

ESIA

AFFECT 1.88 1.59

PERCEPTIO 3.06 1.65

N

COGNITION 2.73 1.73

VOLITION 2.37 1.81

INTENSITY 0.00 2.38

Discussion and conclusions.

To our knowledge, this is the first documented use of subanaesthetic doses of Ketamine infusion in
Uganda for the treatment high suicide risk. Psychedelic effects following ketamine infusion differed
among participants ranging from no disturbances to severe disturbances. Perceptual difficulties were
the most bothersome to the three patients while affect symptoms were the least bothersome. This
is in keeping with published literature of varying rates, symptom profile and intensity of psychedelic
effects of ketamine . Our observation of reduced perceptual difficulties in patients with prior ECT,
notwithstanding the study design and sample size limitations; needs further review.

Limitations

The severity of the suicidal risk and the clinical diagnosis were not confirmed using standardised
instruments. The three psychiatrists however have varying experience ranging from three to forty
years and used clinical interviews to determine the suicide risk and clinical diagnoses. The
administration of the HRS was done retrospectively which may be prone to recall bias. The duration
between receiving ECT and ketamine infusion also differs which may introduce bias and confounding
to the observed outcomes. Finally, the three different patients had three different diagnoses and for
different durations and this may be the reason for the difference in psychedelic side effect profiles.
Specifically, for CC the worsening effects may also be due to her reliving her traumatic experiences
as is common in PTSD.

List of Abbreviations

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APU: Adult Psychiatry Unit; ECT: electroconvulsive therapy; HRS: Hallucinogen Rating Scale; NHL:
Nakasero Hospital Limited.

Declarations

Ethics approval and consent to participate: Participants signed consent forms prior to receiving
ketamine infusion and/or electroconvulsive therapy as per APU standard operating procedures.
Institutional approval to write up the cases was obtained from the head of clinical services of the
hospital.

Consent for publication: Individual consent to publish this case report was received from each of the
three patients.

Availability of data and material: The scores of the HRS are shared as supplementary files. Data
sharing of patient case notes is not possible.

Competing interests: The authors declare no competing interests.

Funding: There was no funding for this publication. As Nakasero Hospital Limited is a private facility,
the participants paid for both the electroconvulsive therapy and ketamine infusion.

Authors' contributions:

EKM; Participated in the psychiatric management of the patients and writing of the case report

RA; Participated in the psychiatric management of the patients and writing of the case report

JN; Participated in the psychological management of the patients and writing of the case report

SM; Participated in the psychiatric management of the patients and writing of the case report

Acknowledgements: We acknowledge the patients who allowed us to write this report. We also
acknowledge the nursing staff of Nakasero Hospital Limited. Charles Twinomujuni helped design the
figures in this case report.

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