NCT01179009.

Study name	A safe ketamine‐based therapy for treatment‐resistant depression
Methods	We will be test whether a 100‐hour ketamine infusion would be more effective than the standard 40‐minute ketamine infusion currently used in other TRD studies. We will randomise participants to one of 2 arms: (1) 100‐hour (+/‐ 4 hours) ketamine infusion plus clonidine for the entire infusion (2) 40‐minute ketamine infusion (plus clonidine) following a 100+/‐ hour saline infusion. All participants will receive clonidine, an alpha‐2 agonist, to minimise side effects of ketamine (namely, brief/mild psychotic and cognitive symptoms) A subset of 20 patients with TRD will receive a 100‐hour (+/‐ 4‐hours) ketamine infusion with head MRIs pre (2) and post (1) infusion. Little research has been done on the mechanism of ketamine's putative antidepressant action. There is now a consensus that, in early stages of the novel treatment development for depression, clinical studies should be paired with mechanistic studies (neuroimaging) to understand the underlying mechanism and validate this as a treatment target. Ketamine is thought to have an antidepressant effect by increasing synaptic connections and therefore increasing connectivity in critical cognitive/emotional circuits Allocation: randomised Endpoint classification: safety/efficacy study Intervention model: parallel assignment Masking: double‐blind (participant, outcomes assessor) Primary purpose: treatment
Participants	Inclusion criteria Males and females aged 18‐65 years Diagnostic and Statistical Manual (DSM) IV diagnosis of Major Depressive Disorder, recurrent, severe Depression must be considered treatment refractory as defined by Montgomery Asberg Depression Rating Scale (MADRS) score of 22 or above which is consistent with other studies On a stable dose of permitted antidepressant medication or no medication pre‐infusion Not currently psychotic and no history of psychosis within the previous 12 months; psychosis reported in the distant past may not be exclusionary if brief, per PI's judgement No history of significant clinical or intolerable side effects or complications from clonidine If a female of child‐bearing potential: not pregnant or breast feeding and agrees to use birth control during the time of pre‐dosing and infusions; and Able to give informed consent Exclusion criteria Confirmed bipolar disorder, schizophrenia, or schizoaffective disorder Current or recent substance abuse/dependence (or any lifetime recreational ketamine or PCP use) Any severe Axis II personality disorder or schizophrenia spectrum disorder that, in the PI's judgment, could confound diagnosis or adherence to treatment the presence of any abnormal laboratory findings or serious medical disorder or condition that may, in the judgment of the PI, confound the assessment of relevant biologic measures or diagnoses including: clinically significant organ system dysfunction; significant and uncontrolled endocrine disease, including diabetes mellitus; hypothyroidism; cardiovascular disease; coagulopathy; significant anaemia; significant acute infection; glaucoma; dehydration; epilepsy; any diagnosed cardiac condition causing documented haemodynamic compromise or dysfunction of the SA or AV node; any diagnosed respiratory condition causing documented or clinically recognised hypoxia (e.g. chronic obstructive or restrictive pulmonary disease); after evaluation, anyone determined to have a potentially compromised airway that could be difficult to intubate; fever; BMI less than 14.5; or any medical condition known to interfere with cognitive performance; medication‐related exclusions include memantine, or any medication that could be considered contraindicated ketamine Current treatment with any medication contraindicated with ketamine or clonidine Lifetime illegal use of PCP or ketamine; no clinical use of ketamine for past 3 months Meets DSM‐IV criteria for Mental Retardation Currently hospitalised Acutely suicidal or homicidal (i.e. in imminent danger with plan, urges and intent to harm oneself or others) including any prior serious attempts (e.g. those requiring hospitalisation) at the PI's discretion Is pregnant or breastfeeding; unwilling to use birth control if female of child bearing potential Unable to provide informed consent For participants in the neuroimaging subset: history of claustrophobia, serious head injuries, seizures disorder, developmental delays, pacemaker, metal implants, permanent metal piercings or anything else that would preclude having an MRI
Interventions	Ketamine 40 minutes versus 100 hour
Outcomes	Primary outcome measures: reduction in (1) Clinical Global Interview (CGI) scores and (2) Montgomery‐Asberg Depression Rating Scale (MADRS) scores. Time frame: approximately 5 years. [Designated as safety issue: yes]. Primary Aim 1: to evaluate the efficacy and tolerability of a single safener for the prevention of ketamine‐induced psychotomimetic effects in healthy humans. Primary Aim 2: to evaluate the effect of a standardised IV ketamine plus optimal safener combination treatment on change in the severity of depression in patients with TRD
Starting date	April 2012
Contact information	mailto:schweigj%40psychiatry.wustl.edu?subject=NCT01179009, 10‐0000, Treatment Resistant Depression (Pilot)
Notes	NCT01179009