A Randomized Double-Blind Sham-Controlled Trial for Evaluating Effectiveness and Tolerability of Ketamine Augmentation for Depression with Suicidal Ideation

Worldwide, there is a high prevalence of depressive disorder. Risk of suicide is high in depression and thus early response to treatment is warranted. Pharmacological treatment strategies to manage acute suicidal ideation in depression are limited by effectiveness as well as tolerability issues apart from the late onset of action. Ketamine has been envisaged as bringing about early response in depression particularly for suicidal ideation.

Methods that objectively map effect of current flow directly in the brain through functional neuroimaging signal changes after a series of ketamine sessions may help us understand how ketamine works, how it can be optimized, and if it can be used as an effective intervention for early reduction of depressive symptoms particularly for suicidal ideation.

Use of fNIRS/qEEG can depict the cortical activity associated with the changes in symptoms of depression. Levels of BDNF have been found to be low in depression that improves with response to treatment. These changes can also provide guidance towards the potential mechanism of action for ketamine

This study aim to assess the safety and effectiveness of adjuvant intravenous Ketamine infusion in individuals with depression having suicidal ideation using randomized double-blind comparison with intravenous normal saline infusion and to compare the change in serum BDNF levels, prefrontal hemodynamic activity (using fNIRS) and spectral/ERP changes (using qEEG) in individuals with depression after adjunctive treatment with normal saline or ketamine infusion

Consultants and Senior Residents in the outpatient department (OPD) and inpatient department (IPD) of Psychiatry, AIIMS, New Delhi shall be requested to refer all the patients with MDD having suicidal ideation. Out of the referred patients, those with HAMD score >17 (moderate or severe depression) will be chosen by a purposive method for participation in the study. Diagnosis of depression will be confirmed using DSM-5 criteria by clinical interview and subjects fulfilling the inclusion and exclusion criteria will be recruited. Subjects will be screened for psychiatric comorbidities using clinical interviews. Physical, neurological and substance use comorbidity as well as pregnancy/lactation will be ruled out by history and clinical examination. Written consent will be taken prior to participation in the study.

Those recruited in the study shall be randomized into two groups using block randomization into Active intervention group (IV Ketamine infusion) and Sham intervention group (IV Normal Saline infusion). Investigator and subject will be blind to group allocation. Investigator will allocate the subject to an alphanumeric id (A1/B2) and will refer the patient to mECT facility. Nursing staff will include the subject in one of the 2 groups of intervention based on a pre-defined chart (X/Y) prepared by the guide mentioning group allocation. Subjects would keep receiving the medications that they are taking and a record of it would be made. Pharmacological treatment will be decided by treating clinician.

Baseline assessments (at maximum of 2 days before beginning of intervention) would be done. Sociodemographic and Clinical data (Semi-structured datasheet) would be recorded. Questionnaires (HAMD, HAMA, KSET screening) would be applied and 2 ml blood would be drawn (for BDNF estimation). Cortical activation would be assessed (using fNIRS and qEEG) for resting as well as task related states.

All subjects will receive 6 sessions of saline or ketamine iv infusion (over 2 weeks) depending on their allocated groups. Post-intervention (after every IV session with ketamine or normal saline), evaluation with outcome parameters after 40 (+20) min of intervention (HAMD, HAMA, and KSET acute treatment) would be done. Thus, a total of six times post-intervention assessment would take place. Thereafter, further two more assessments (after 4 weeks and 8 weeks of recruitment (± 2-3 days)) would be done using the baseline questionnaires (HAMD, HAMA, KSET follow up), cortical activity (fNIRS and qEEG), and 2 ml blood would be drawn (for BDNF estimation). Any subject leaving the study prior to receiving complete intervention sessions, will be assessed on the leaving day if possible.