To enroll in this clinical trial, prospective participants must meet stringent criteria. The participants need to fall within the age range of 18 to 64 and exhibit chronic depression at therapy resistance stage 2. This stage signifies that the participants have undergone unsuccessful treatment with at least two different antidepressants, despite adequate dosage and duration. Moreover, the participants should have engaged in at least 12 sessions of psychotherapy without experiencing significant relief from depressive symptoms. Additionally, participants must demonstrate the cognitive capacity to provide informed consent.

Upon expressing interest in the study and consenting to participate, individuals undergo a thorough screening process. This screening encompasses a comprehensive clinical interview to assess medical and psychiatric history, as well as various medical tests. These tests include physical examinations, blood draws (which may include pregnancy tests for female participants), and electrocardiograms (ECGs) to evaluate heart function. Following the screening, participants are randomly assigned to one of three different treatment groups (Ketamine +TAU; Ketamine+CBASP, Placebo+CBASP).

The study protocol involves a combination of psychotherapeutic treatment and either ketamine infusions or placebo. Throughout the study period, participants are subject to regular data collection, including psychological assessments, blood samples, and magnetic resonance imaging (MRI) scans. Participants' responses to treatment, as well as any changes in symptoms or side effects, are closely monitored.

After completing the study, participants are offered follow-up therapy as part of standard care. MRI scans are conducted to examine changes in brain activity associated with treatment response and depressive symptomatology, particularly focusing on alterations in neural circuitry and thought processes. Additionally, participants are encouraged to report any changes in medication regimen or other treatments received during the study period.

To participate in this clinical trial, one must have reached the age of 18 at the time of enrollment and not have exceeded the age of 64. Additionally, the pilot study is designed for patients with chronic depression who are in therapy resistance stage 2. Therapy resistance stage 2 means that one has taken at least 2 antidepressants from two different classes in sufficient dosage over a sufficient period of time without experiencing significant and sustainable improvement in depressive symptoms. Furthermore, one should have received at least 12 sessions of psychotherapy (psychoanalysis, psychodynamic psychotherapy, or cognitive behavioral therapy) without significant and sustainable improvement in depressive symptoms. Also, one must have the capacity to consent.

Those interested in participating in this study must have provided written consent to participate. A screening takes place to check the criteria for study participation using a clinical interview. The clinical interview collects information about current and previous physical and mental symptoms or diagnoses and treatments and lasts approximately 100 minutes. Additionally, a physical examination, a blood draw of approximately 20 ml, and an electrocardiogram (ECG) to determine heart activity are performed.

If one meets the inclusion criteria and no exclusion criteria are present, one can participate in the study and will be randomly assigned to one of the three treatment groups (Ketamine+TAU; Ketamine+CBASP, Placebo+CBASP). Participants are being told what type of psychotherapy the participant will receive. If one is assigned to one of the CBASP groups, neither the participant nor the treatment team will be informed whether the participant is receiving ketamine or placebo.

Once the group assignment is made, further data is collected in the first study week. In week 2, the psychotherapeutic treatment begins with a two-week introductory phase. Psychotherapy includes two individual sessions per week as well as group therapies. At the end of the introductory phase, further data collection takes place.

In week 3, additional data is collected, and a blood draw is performed to repeat the pregnancy test. Subsequently (weeks 4-6), one is treated with an infusion twice a week for three weeks (ketamine or placebo). The infusions within a week are spaced 2-3 days apart and each lasts approximately 40 minutes. Psychotherapy continues during these three weeks. After completing the combination treatment of study medication/placebo and psychotherapy, further data is collected, and psychotherapy continues for another 6 weeks (weeks 7-12). After that, the treatment as part of the study is completed.

To optimize treatment success and prevent relapses, an appropriate follow-up therapy is planned and initiated in consultation with the study therapist, depending on the individual development during the study therapy. Three months after completing the study therapy, the final data collection is carried out. Throughout the entire study, a total of 9 blood draws are performed.

Psychotherapy, administration of study medication/placebo, and data collection are carried out at the study site. Existing medication may continue to be taken during the study and will be optimized as needed. If medication with benzodiazepines is prescribed, it cannot be taken on the day before the infusion or on the day of the infusion.

The first blood draw and urine sample are used to get an impression of one's overall health status and thus assess whether participation in the study is possible or permissible according to the inclusion and exclusion criteria. In addition, a drug screening is performed on the urine sample to exclude acute substance abuse (alcohol, drugs), and a pregnancy test is performed based on the blood sample.

In the event of discontinuation of the study, follow-up treatment will be offered within the standard therapy for depressive disorders.

Additional medications (including over-the-counter ones) of which the investigator is not yet aware may only be taken in emergencies after consulting the investigator. If one is being treated by other doctors, the other doctors must be informed about participation in the clinical trial. The investigator must also be informed about any medical treatment received from another doctor during the clinical trial. One will receive a study ID card, which should always be carried for emergencies.

The fMRI examination in weeks 3 and 12 is performed to assess changes in brain activity during treatment and in relation to changes in depressive symptoms. Additionally, the relationship between mind wandering and brain activity in the presence of depressive illness is analyzed.

Inclusion Criteria:

• Age: 18 to 64 years at the time of study inclusion.
• Diagnosis of chronic depression: recurrent depressive disorder, severe or moderate episodes (no full remission between the episodes according to DSM-IV-TR (Falkai et al., 2015) [no distinct depressive symptoms for at least two months]) or acute depressive episode lasting two or more years
• Treatment resistance stage 2 according to (Thase and Rush, 1997): Patient's symptoms fulfil the criteria of chronic depression listed above even after at least two appropriate treatment attempts with two antidepressant medicaments from two different effect categories
• Patient's symptoms fulfil the criteria of chronic depression listed above even after executing at least 12 sessions of psychotherapeutic treatment (psychoanalysis, depth psychology-based psychotherapy or cognitive behaviour therapy)
• Understand and voluntarily sign an informed consent document prior to any study related assessments/ procedures.
• Able to adhere to the study visit schedule and other protocol requirements.
• Females of childbearing potential (FCBP) must agree to utilize two reliable forms of contraception simultaneously or practice complete abstinence from heterosexual contact from study start until 28 days after the last infusion.
• Males must agree to use a latex condom during any sexual contact with FCBP from the first infusion until 65 days after the last infusion, even if the person has undergone a successful vasectomy to refrain from donating semen or sperm from the first infusion until 65 days after the last infusion.
• All subjects must agree to refrain from donating blood from the first infusion until 28 days after last infusion.
• All subjects must agree not to share medication.

Exclusion Criteria:

• Acute substance misuse as primary diagnosis (assessed by the Structured Clinical Interview for DSM-V (SKID, Wittchen et al., 1997))
• Neurologic disorders: Stroke, cerebral ischemia, tumor, cerebral infection, autoimmune disease (according to clinical interview)
• Disorders with increase of intracranial pressure, e. g. due to head injury (according to clinical interview)
• Circulatory disturbance in the brain (according to clinical interview)
• Pregnant or lactating females
• Participation in any clinical study or having taken any investigational therapy, which would interfere with the study's primary end point
• Epilepsy (according to clinical interview)
• History of hypersensitivity to an investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product (according to clinical interview)
• Pre-treatment with ketamine hydrochloride (Ketamin Inresa 2 ml) and/ or - CBASP (according to clinical interview)
• Not or insufficiently treated hypertonia (subject will be excluded if repeated measures (3 times/ day) show values greater than 150 mmHg systolic or 100 mmHg diastolic blood pressure or if a lifetime diagnosis of hypertonia is reported)
• Not or insufficiently treated hyperthyroidism (according to clinical interview)
• Heartache due to insufficient blood circulation (unstable angina pectoris) or heart muscle infarct (myocardia infarct) during the last six months (according to clinical interview)
• Increased intraocular pressure (glaucoma) and perforating eye injury (according to clinical interview)
• Interventions in the area of the upper respiratory passages (according to clinical interview)