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

Effectiveness and Underlying Mechanisms of an Innovative Treatment Program for Persistent Mood and Anxiety Conditions

Ketamine-Assisted Psychotherapy (KAP) is an innovative treatment that combines intravenous ketamine with psychotherapy in a carefully monitored clinical setting. At Senz, this treatment is being evaluated in an open-label clinical trial for individuals with persistent depression who have not responded sufficiently to previous treatments. The combination of ketamine, psychological support, and integration sessions aims to promote emotional processing, psychological flexibility, and lasting therapeutic change.

Ketamine-Assisted Psychotherapy (KAP) combines the administration of intravenous ketamine with psychotherapy in a structured and medically supervised treatment programme. At Senz, KAP is currently being offered within the context of an open-label clinical trial for adults with persistent or treatment-resistant depression who have not experienced sufficient benefit from previous pharmacological and psychological treatments. The aim of the study is to evaluate both the clinical effectiveness and the subjective therapeutic impact of KAP in routine mental healthcare.

The treatment consists of several phases, including comprehensive psychological and psychiatric assessment, medical screening, preparation sessions, ketamine administration sessions, and post-session integration therapy. Prior to participation, clients undergo a detailed evaluation of psychiatric history, previous treatments, physical health, medication use, and relevant laboratory tests. During preparation sessions, participants receive psychoeducation, explore treatment intentions, learn techniques for emotional regulation, and develop a therapeutic framework for working with the experiences that may arise during ketamine sessions.

Safety is a central component of the protocol. Ketamine is administered intravenously in a controlled clinical environment under the supervision of a psychiatrist, psychologist, and trained nursing staff. Vital signs, including blood pressure, heart rate, and oxygen saturation, are monitored throughout treatment. Participants are screened for medical and psychiatric contraindications, and clear procedures are in place for managing adverse events or unexpected reactions. Following each treatment session, participants remain under observation until clinically stable and are required to arrange supported transport home.

The study includes a comprehensive assessment programme to evaluate both outcomes and therapeutic processes. Standardised measures of depressive symptoms are collected throughout treatment, alongside questionnaires assessing subjective experiences. Integration sessions following each ketamine administration help participants reflect on their experiences, consolidate insights, and translate these into meaningful behavioural changes in daily life. By combining rigorous clinical monitoring with psychotherapy and systematic outcome assessment, the trial aims to contribute to the growing evidence base for ketamine-assisted psychotherapy while providing high-quality care for participants.

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