Working Mechanisms and Effectiveness of IV Ketamine-assisted Psychotherapy on Depression in TRD Clients

Inclusion Criteria:

* Adults (18 years and older)
* TRD
* A MADRS score above the established clinical cut-off, indicating clinically significant depressive symptoms
* Insufficient response to at least two adequate antidepressant treatment trials and one evidence-based psychotherapy, or failure to achieve adequate improvement following at least three consecutive treatment steps in accordance with the Dutch Multidisciplinary Guideline for Depression

Exclusion Criteria:

* Current substance use disorder or recent illicit drug use
* Substance use disorder not in remission for at least 3 months
* Inability to abstain from alcohol for 24 hours before and after treatment
* Acute suicidality
* Current or past psychotic disorder
* Significant neurological disorders (e.g., epilepsy, elevated intracranial pressure)
* Uncontrolled hypertension or medical conditions associated with increased cardiovascular or cerebrovascular risk (e.g., aneurysms, recent myocardial infarction or intracerebral hemorrhage)
* Significant bladder disease (e.g., cystitis)
* Severe hepatic impairment
* Pregnancy, breastfeeding, or ongoing IVF treatment
* Extreme underweight or obesity where treatment is deemed medically unsafe Inability to arrange an accompanying adult for transport and support after treatment