The proposed study aims to examine the antidepressant efficacy of oral S-ketamine augmentation in patients with TRD treated with regular antidepressants in a double-blind randomised controlled trial. Secondary questions involve the effects of oral S…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this trial is to examine the antidepressant efficacy
of oral S-ketamine augmentation in patients with TRD. This will be measured by:
1) change in symptom severity, expressed as a change in total score on the
HDRS17;
2) response, defined as >= 50% decrease in total score on the HDRS17;
3) partial response, defined as 25-49% decrease in total score on the HDRS17.
Secondary outcome
1) To examine whether oral S-ketamine, compared to placebo, will:
- Have sustained effect on reducing the severity of depression after the
discontinuation of treatment, as measured with the HDRS17;
- Reduce self-reported severity of depression, as measured with the IDS-SR;
- Have a different effect in subgroups of patients, as measured with the HDRS17
and IDS-SR;
- Reduce the severity of symptom dimensions, as measured with the HDRS17 and
IDS-SR;
- Reduce the severity of suicidal ideation, as measured with the Beck Scale for
Suicide Ideation (BSS);
- Reduce the severity of anhedonia, as measures with the Snaith-Hamilton
Pleasure Scale (SHAPS) and the functional MRI (fMRI) Reward task;
- Improve general clinical impression, as measured with the Clinical Global
Impression (CGI);
- Reduce anxiety symptoms, as measured with the BAI;
- Reduce pain, as measured with the Graded Chronic Pain Scale (GCPS);
- Reduce nicotine dependence, as measured with the Fagerström Test for Nicotine
Dependence (FTND);
- Improve auto-biographical memory, as measured with the Autobiographical
Memory Test (AMT);
- Improve health-related quality of life, as measured with the EuroQol-5D 5
Level (EQ-5D-5L);
- Increase brain activation in the prefrontal cortex, investigated with fMRI
scanning;
- Reduce brain activation of limbic structures, insula, and the default mode
network in responders, investigated with fMRI scanning;
- Alter the volume of the prefrontal cortex and limbic structures, investigated
with MRI scanning;
- Alter glutamate and glutamine concentrations in the anterior cingulate
cortex, investigated with Magnetic Resonance Spectroscopy (MRS) scanning;
- Alter cerebral blood flow, investigated with Arterial Spin Labelling (ASL)
scanning;
- Change biomarkers patterns in blood and urine, pointing to changes in
underlying disease mechanisms;
- Change gene expression patterns in white blood cells, which could point at
changes in neuroplasticity;
- Induce side effects, as measured with the Systematic Assessment for Treatment
Emergent Events (SAFTEE), the Iowa Sleep Disturbance Inventory (ISDI), the
Questionnaire for Psychotic Experiences (QPE), the Dissociation Tension Scale
(DSS), and by the monitoring of body weight, blood pressure and liver enzyme
levels.
2) To conduct an economic evaluation that will assess cost-effectiveness and
cost-utility of oral S-ketamine as compared to placebo from a societal
perspective. Cost-effectiveness will be expressed as incremental cost per
additional percentage point of patients recovered from depression as measured
with the HDRS17. Cost-utility will be expressed as incremental cost per Quality
Adjusted Life Year (QALY) gained, with health related quality of life scores
assessed by means of the EQ-5D-5L and QALY*s calculated over the studies 10
weeks time horizon.
3) To conduct a Budget Impact Analysis (BIA) to inform decision-makers about
the financial consequences of the adoption and diffusion of oral S-ketamine for
TRD in the Dutch healthcare system.
4) To describe S-ketamine and norketamine pharmacokinetics after oral
administration.
5) To explore the relationship between S-ketamine and norketamine
pharmacokinetics and improvement on the HDRS17.
6) To determine the genotype of the CYP enzyme(s) involved in the metabolism of
S-ketamine.
Background summary
Major depressive disorder (MDD) is a common mental disorder with an impressive
disease burden, for which currently available treatments (medication,
psychotherapy and electroconvulsive therapy - ECT) unfortunately may be in
effective. Around 30% of patients have therapy-resistant depression (TRD),
defined as having no or only a partial response to a range of treatments. These
patients often spend years in chronic depression, and there is a strong need to
develop additional options to relieve this suffering.
A novel intervention that has shown rapid antidepressant effects is intravenous
(IV) ketamine infusion. Ketamine currently is a well-known anaesthetic.
Intravenous ketamine however has strong psychomimetic effects and is often
given only once, leading to rapid relapse of depression. Oral ketamine
administration is less invasive, may be provided for longer periods of time and
current evidence shows a more benign side effect profile. Despite these
potential benefits, the efficacy and tolerability of oral ketamine for TRD have
not been sufficiently investigated.
Study objective
The proposed study aims to examine the antidepressant efficacy of oral
S-ketamine augmentation in patients with TRD treated with regular
antidepressants in a double-blind randomised controlled trial. Secondary
questions involve the effects of oral S-ketamine on sleep, autobiographical
memory, pain, anxiety, anhedonia, suicidal ideation, nicotine dependence,
quality of life and consumption of medical care, as well as a detailed
assessment of possible side effects caused by the ketamine treatment. Brain
activation, brain blood flow and volume parameters, neuroplasticity, glutamate
and glutamine concentrations in the brain, biomarkers, and the genotype of the
CYP enzyme(s) involved in the metabolism of ketamine will be assessed, to
develop a better understanding of the mechanisms of action and metabolism of
S-ketamine. Furthermore, the study will also investigate the duration of
effects after discontinuation of S-ketamine add-on treatment.
Study design
This study comprises a double-blind randomised placebo-controlled trial.
Participants will be assigned double-blind to one of the two treatment groups,
and will receive either S-ketamine (50%) or placebo (50%). The effect of oral
S-ketamine add-on treatment is investigated during ongoing and unchanged
antidepressant therapy.
After inclusion (week 0), patients take medication 3 times per day for 6 weeks.
After completion of this part of the study, a follow-up will be done after one
(week 7), two (week 8) and four (week 10) weeks. Therefore, the total study
duration is 11 weeks.
In the first week of treatment, oral S-ketamine and placebo will be
administered at the study locations, in an inpatient setting. From week 2 on,
patients can be discharged and use the study medication at home, if their
treating psychiatrist decides it is clinically acceptable and convenient for
the patient.
The questionnaires will be applied at the study locations in Groningen,
Amsterdam, Rotterdam and Geldrop. The self-rating questionnaires can be filled
in at home. Urine and blood will be collected at the study locations;
neuroimaging scans will be performed in Groningen and Amsterdam.
Intervention
Subjects are randomly assigned to treatment with oral S-ketamine or placebo
during 6 weeks. The tapering-in process consists of gradually increase dosages
in the 4 first days of the treatment. The last day of the tapering-in process
is day 4, which consists of 3 doses of 30 mg, leading to a total of 90 mg of
S-ketamine. The tapering-off process consists of gradually decreasing dosages
in the 3 last days of the treatment.
Study burden and risks
Participants will answer several questionnaires at several moments during the
study. This is time consuming and it might be experienced as boring and/or
annoying. Answering these questionnaires constitutes a negligible to mild
burden.
In addition, venipunctures are involved in this study. Venipuncture to
determine variables other than screening factors is optional for participants
with needle phobia. Venipuncture is associated with negligible and known risks
(e.g. skin irritation and bruising).
Of the 128 participants, 50 will undergo two MRI scan sessions of approximately
one hour. During the scans, participants lie in a MR-scanner, which is a narrow
space, and are required to lie still and perform some tasks. With regard to the
MR-scanner noise, earplugs will be provided.
Participants will be hospitalized during the first week of the study, which is
time-consuming, can be burdensome, and might interfere with daily activities.
We do not expect that absence from work will be a problem in most of the cases,
because we do not expect many participants to work on a regular basis, given
the severity of their mental illness.
The physical examination that is part of the screening session, can make feel
participants uncomfortable. This constitutes a negligible to mild burden.
The expected burden also consists of possible side effects of S-ketamine, such
as nausea, dissociation, light-headedness, drowsiness and an increased heart
rate. These side effects will be closely monitored during the treatment. The
safety and well-being monitoring will be performed by physicians in such a
frequency that actual risks will be identified swiftly and appropriately acted
upon. Because the use of ketamine can impair driving, for example due to
light-headedness, driving cars during the intervention period will be strongly
discouraged.
Participants are allowed to object any or part of the assessments or
investigations.
The study is intended to benefit one treatment group directly. Benefits to
subjects and other patients are very well possible because the treatment is
specifically tuned to reduce depression. However, they cannot be guaranteed.
Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
- Male or female, age range: 18 to 80 years;
- Signed informed consent;
- Good understanding of spoken and written Dutch;
- DSM-5 diagnosis of Major Depresive Disorder, first or recurrent episode, ascertained by the Mini International Neuropsychiatry Interview (MINI-plus);
- Treatment Resistant Depression, defined as nonresponse to at least 3 different classes of antidepressants during lifetime, all given in an adequate dose (i.e. defined daily dose) for at least 4 weeks;
- At least moderately severe depression, defined by a score higher than 18 on HDRS17;
- Current treatment with an officially approved antidepressant medicine.
Exclusion criteria
A potential subject who meets any of the following criteria will be excluded from participation:
- Bipolar depression or depression with psychotic features, according to the DSM-5;
- Previous or comorbid schizophrenia spectrum or other psychotic disorder according to the DSM-5, not including MDD with psychotic features;
- Comorbid severe personality disorder according to the DSM-5, that is the main reason for treatment;
- Previous or comorbid moderate or severe dependence of alcohol or drugs according to the DSM-5, not including tobacco-related and caffeine-related disorders;
- Recent (within the last 4 weeks) or current use of cannabis or any other non-prescribed psychoactive compounds, including Saint John*s wort;
- Relevant neurological disorder, such as dementia or epilepsy;
- Recent (within the last 4 weeks) change of antidepressant treatment;
- ECT sessions or any other antidepressant treatment change planned for the period of the study;
- Active suicidal intent, defined by scores higher than 2 on HDRS17 for suicidal ideation;
- (Suspected) pregnancy, insufficient contraception or lactation. If there is any doubt, a pregnancy test is performed;
- Recent (within the last 4 weeks) or current use of benzodiazepine and benzodiazepine-like agents (zolpidem, zopiclone) in excess of 2 mg lorazepam or an equivalent per day;
- Recent (within the last 4 weeks) or current use of somatic medication that commonly affects mood, like oral corticosteroids;
- Presence of any contra-indication for ketamine use, such as increased intracranial pressure, recent myocardial infarction or other relevant cardiac problems, severe hypertension, severe hyperthyroidism, severe liver problems, severe kidney problems, or the use of medication that ketamine interacts with on a major level, such as monoamine oxidase inhibitors;
- Vision or hearing problems that cannot be corrected and that interfere with the ability to comply with treatments and/or assessments;
- Mental incompetence to provide informed consent, based on the judgment of the general practitioner or treating psychiatrist of the participant;
- Inability to comply with treatments and/or assessments, based on the judgment of the general practitioner or treating psychiatrist of the participant.;For the MRI-scanning, there are additional exclusion criteria:
- MRI incompatible implants in the body, such as cochlear implants, insulin pumps or other metal implants;
- Any risk of having metal particles in the eye, for example due to manual work without proper eye protections;
- Tattoos containing red pigments;
- Claustrophobia;
- The refusal to be informed of structural brain abnormalities that could be detected during the experiment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-003957-16-NL |
| CCMO | NL55069.042.15 |