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Orale ketamine als aanvullende behandeling bij patiŽnten met een therapieresistente depressie


- candidate number25445
- NTR NumberNTR6161
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR21-okt-2016
- Secondary IDsZonMW 80-83600-98-3074/EudraCT 2015-003957-16  ABR NL55069.042.15/METc 2015/471
- Public TitleOrale ketamine als aanvullende behandeling bij patiŽnten met een therapieresistente depressie
- Scientific TitleA randomised controlled trial of oral S-ketamine as add-on medication for patients with treatment-resistant major depressive disorder
- ACRONYMKetaminestudie
- hypothesis
- Healt Condition(s) or Problem(s) studiedDepression, Therapy resistent
- 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 MDD, first or recurrent episode, ascertained by the Mini International Neuropsychiatry Interview (MINI-plus);
- TRD, 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- 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°Įs 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.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingDouble
- controlPlacebo
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 1-okt-2016
- planned closingdate1-feb-2019
- Target number of participants128
- Interventionsoral S-ketamine or placebo during 6 weeks
- Primary outcomeThe 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 the following main study endpoints at the end of treatment: 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- HDRS17 changes in total sum score after the discontinuation of treatment;
- IDS-SR changes in total sum score during and after the discontinuation of treatment;
- HDRS17 changes and IDS-SR changes in symptom dimension scores during and after the discontinuation of treatment;
- BSS changes in total sum score during and after the discontinuation of treatment;
- SHAPS changes in total sum score during and after the discontinuation of treatment;
- fMRI reward task changes in total sum score during treatment; - CGI severity changes and CGI improvement scores during and after the discontinuation of treatment;
- BAI changes in total sum score during and after the discontinuation of treatment;
- GCPS changes in item scores during and after the discontinuation of treatment;
- FTND changes in total sum score during and after the discontinuation of treatment;
- AMT changes in total specific sum score during and after the discontinuation of treatment;
- EQ-5D-5L changes in total sum score (calculated using the Dutch tariff) and in VAS score, during and after the discontinuation of treatment;
- Changes of brain activation in the prefrontal cortex, limbic structures, insula and default mode network during treatment; - Changes of the prefrontal cortex and limbic structures volumes during treatment;
- Changes of glutamate and glutamine concentrations in the anterior cingulate cortex of the brain during treatment;
- Changes of blood flow in the brain during treatment;
- Changes of biomarker patterns in blood and urine during and after the discontinuation of treatment;
- Changes in gene expression patterns, measured by the use of RNA, during and after the discontinuation of treatment;
- SAFTEE changes in total sum score and item scores during and after the discontinuation of treatment;
- ISDI changes in symptom dimension scores during and after the discontinuation of treatment;
- QPE changes in total sum score and symptom dimensions scores during and after the discontinuation of treatment;
- DSS changes in total sum score during and after the discontinuation of treatment;
- Body weight changes during and after the discontinuation of treatment;
- Blood pressure changes during and after the discontinuation of treatment;
- Liver enzyme level changes during treatment;
- Incremental costs per additional percentage point of patients recovered from depression, with recovery assessed by the means of the HDRS17, and defined as a more than 50% decrease in score from week 1 to week 6 and 10;
- Incremental costs per QALY gained, with QALYs assessed by means of the EQ-5D-5L and calculated over the 10 week study period;
- Expected changes in the flows of expenditure in the Dutch health care system after the adoption of ketamine as a new intervention for treatment resistant depression;
- Report on new pharmacokinetics knowledge of S-ketamine and norketamine after oral administration;
- Report on associations between S-ketamine and norketamine pharmacokinetics and changes on the HDRS17;
- Report on new genotype knowledge of the CYP enzyme(s) involved in the metabolism of S-ketamine.
- TimepointsIntervention: week 1 up to and including week 6.
Folluw up: week 7 up to and including week 10.
HDRS17 measurement: week 2, 4, 6, 7, 8, 10
- Trial web site
- statusplanned
- CONTACT FOR PUBLIC QUERIES Ketaminestudie
- CONTACT for SCIENTIFIC QUERIES Ketaminestudie
- Sponsor/Initiator University Medical Center Groningen (UMCG)
- Funding
(Source(s) of Monetary or Material Support)
ZON-MW, The Netherlands Organization for Health Research and Development
- Publications
- Brief summaryRationale: 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.

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: A randomised controlled add-on trial with two arms of treatment, oral S-ketamine vs. placebo, administered for 6 weeks under double-blind conditions. Clinical interviews and self-report questionnaires are performed before treatment, repeatedly during treatment, shortly before the end of treatment and at follow-up. Neuroimaging is performed before and at the end of treatment. Collection of blood and urine takes place before and during treatment and at follow-up. During the trial, all participants continue the antidepressant medication they had before study start.

Study population: Subjects are 128 inpatients and outpatients diagnosed with at least a moderately severe MDD (Hamilton Depression Rating Scale 17 items (HDRS17) - score higher than 18), aged between 18 and 80 years, and not having responded to at least 3 different antidepressant medications.

Intervention: One group of participants receives oral S-ketamine 3 times per day with a tapered start and finish. The other group of participants receives placebo. Participants in both groups will continue their ongoing antidepressant medication.

Main study parameters/endpoints: The primary outcomes are: 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
- Main changes (audit trail)
- RECORD21-okt-2016 - 12-feb-2017


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