| Eligibility |
Inclusion Criteria:
1. 25 to 65 years of age
2. Diagnosis of major depressive disorder (single and recurrent episodes) of moderate to
severe degree (HAM-D score = 17) according to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5) without psychotic features. Included ICD-10 diagnoses are
ICD-10: F32.1, F32.2, F33.1, F33.2.
a. If single episode, duration must be = 3 months.
3. Patients must meet criteria for treatment-resistance, defined as
a. no adequate improvement despite two adequate courses of antidepressant treatment (6
weeks each, minimum) with drugs of different pharmacological classes in the current
depressive episode. Augmentation with an add-on treatment counts as a second
treatment.
4. Patients have discontinued any monoaminergic psychiatric medication (i.e. SRIs,
antipsychotic medication) for at least 2 weeks before the first dosing session.
1. Patients who are still on any monoaminergic psychiatric medication at screening
must agree to down-titrate over an individualized down-titration schedule
(minimum 2 weeks; if they have been taken Fluoxetine the down-titration phase
should be minimum 5 weeks) in close supervision by their out-patient psychiatrist
and the study team. The treating psychiatrist must agree to supervise and monitor
the down-titration and to collaborate with the study team by signing a "treatment
agreement form".
2. If the treating psychiatrist refuses to monitor the down-titration, the patient
has to agree to down-titrate under supervision of clinicians in the outpatient
clinics of the two study sites or trial physicians and to come in for weekly
monitoring visits.
5. The subjects are abstinent from alcohol (breathalyzer blood alcohol concentration
(BAC) level 0.00) and a negative urine drug screen at days of dosing
6. The subject must be medically stable based on clinical laboratory tests, medical
history, vital signs, and 12-lead ECG performed at screening. If the results of the
serum chemistry panel, hematology, or urinalysis are outside the normal reference
ranges, retesting of an abnormal lab value(s) that may lead to exclusion will be
allowed once during the screening phase. In 12-lead ECG, QTcF should be = 450 ms for
males or = 470 ms for females and PR-interval < 220 ms at screening. A retest of an
abnormal ECG value will be allowed once in the screening phase. Blood pressure will be
the average of 2 measurements. The subject may be included only if the investigator
judges the abnormalities or deviations from normal to be not clinically significant or
to be appropriate and reasonable for the population under study. This determination
must be recorded in the subject's source documents and initialed by the investigator.
7. The subject must be willing and able to adhere to the prohibitions and restrictions
specified in this protocol.
8. The subject must sign an informed consent form indicating that he/she understands the
purpose of and procedures required for the study including peripheral biomarker
monitoring (i.e. blood) and is willing to participate in the study.
Exclusion Criteria:
1. Currently comorbid or previously diagnosed DSM-5 diagnosis of a
1. major depressive episode with psychotic features/major depressive disorder with
psychotic features (ICD-10: F32.3)
2. schizophrenia spectrum and other psychotic disorders, including schizotypal
(personality) disorders, delusional disorder, brief psychotic disorder,
schizophreniform disorder, schizoaffective disorder, substance/medication-induced
psychotic disorder and psychotic disorder due to another medical condition
(ICD-10: F20 - F29)
3. bipolar and related disorders (ICD-10: F30/F31)
4. cluster A personality disorders (paranoid personality disorder, schizoid
personality disorder, schizotypal personality disorder) and/or borderline
personality disorder (Patients will be carefully screened for presence of those
personality disorders by using the SCID-5-PD)
5. Post-traumatic stress disorder (PTSD; ICD-10: F43.1)
2. A family history (first-degree relative) of psychosis and/or bipolar disorder
3. The subject has a current or recent history of clinically significant suicidal
ideation within the past 6 months, corresponding to a score of 4 (active suicidal
ideation with some intent to act, without specific plan) or 5 (active suicidal
ideation with specific plan and intent) for ideation on the C-SSRS, or a history of
suicidal behavior within the past 1 year, as validated by the C-SSRS at screening.
Subjects with a prior suicide attempt of any sort, or prior serious suicidal
ideation/plan > 6 months ago, should be carefully screened for current suicidal
ideation and only included at the discretion of the investigator.
4. Current comorbid psychiatric diagnosis except their major diagnosis (inclusion
criterion 3) in form of
a. Diagnoses mentioned under exclusion criterion 1) b. Substance use disorder (except
tobacco-related disorders/caffeine-related disorders) i. Alcohol consumption must be
limited to = 40 gram for men and = 20 gram for women per day, e.g. = two/one large
beer (0.5 l) for men/women.
5. Use of classical psychedelics (i.e. LSD, psilocybin, mescaline, dimethyltryptamine) in
the past year and or more than five life-time uses of classical psychedelics.
6. Failure to establish sufficient rapport with the two therapists as judged by them
after the first two preparation sessions
7. Lithium intake
8. The patient has any disorder for which the treatment takes priority over treatment of
depression or is likely to interfere with the study treatment or impair treatment
compliance. This includes current signs/symptoms of liver or renal insufficiency,
hypothyroidism or hyperthyroidism (subjects who are on stable treatment with thyroid
supplementation and show an euthyroid metabolism with normal thyroid-stimulating
hormone [TSH] may participate), significant cardiac disease (including current or past
history of atrial fibrillation/flutter), vascular, pulmonary, endocrine, neurologic
(including epilepsy), hematologic, inflammatory (e.g., rheumatoid arthritis,
inflammatory bowel disease, Crohn's disease) or metabolic diseases as long as these
diseases are not medically controlled or might significantly interfere with
participation in the study. Diabetes mellitus (DM) may be allowed when blood glucose
is stably controlled (HbA1c less than 7.5% or 58 mmol/mol).
a. To rule out the presence of any serious neurological condition that might be
underlying the depression (e.g. Parkinson's Disease, dementia), patients must provide
a recent (i.e. not older than 5 years) brain neuroimaging (MRI or CT). If the clinical
manifestation has changed qualitatively or in severity, a more recent neuroimaging is
required.
9. Women who are pregnant, nursing or refuse to use an effective method of contraception
(hormonal or barrier method of birth control; abstinence) throughout their study
participation. Women of childbearing potential must have a negative urine pregnancy
test at screening and the two dosing days.
10. Positive urine drug screen for any illicit drugs of abuse or alcohol at any of the two
dosing days. The regular drug screen includes cocaine, amphetamine, opiates, ecstasy,
EDDP, cannabinoids, benzodiazepines and barbiturates.
11. The subject has a QTc interval > 450 ms (for men) or > 470 ms (for women)
(Fridericia's correction) at screening or at baseline, as calculated by the ECG
equipment and evaluated by the investigator.
12. The subject has received an investigational drug or used an invasive investigational
medical device within 3 months before the first administration of the study drug or
anticipates participation in another clinical trial until the primary endpoint.
13. The subject is unwilling or unable to undergo multiple venipunctures because of poor
tolerability or lack of easy access.
14. The subject is unable to read and understand the patient information and the consent
form, complete study-related procedures, and/or communicate with the study staff.
Cognitive impairment that would render the informed consent invalid or limit the
ability of the subject to comply with the study requirements also excludes from
participation in the study.
15. The subject has any condition for which, in the opinion of the investigator,
participation would not be in the best interest of the subject (e.g., compromise the
well-being) or that could prevent, limit, or confound the protocol-specified
assessments.
16. Subject has had major surgery (e.g., requiring general anesthesia) within 12 weeks
before screening, or will not have fully recovered from surgery, or has surgery
planned during the time the subject is expected to participate in the study.
17. The subject has undergone electroconvulsive therapy (ECT) within twelve months prior
to screening or treatment with ketamine or esketamine within six months prior to
screening.
18. The subject has received any prior treatment with vagal nerve stimulation, or a deep
brain stimulation device.
19. Subject is an employee of the investigator or study site, with direct involvement in
the proposed study or other studies under the direction of that investigator or study
site, as well as family members of the employees or the investigator.
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