dose of ketamine, a glutamate receptor modulator, rapidly decreases symptoms in unmedicated patients with obsessivecompulsive disorder (OCD), [1][2][3][4] we explored whether an intranasal delivery system is a practical alternative (eg, lower cost and easier administration) to IV infusion. Lapidus et al 5 reported that intranasal ketamine was tolerable and effective in major depression. Thus, we hypothesized that intranasal ketamine administration in OCD patients would be similarly tolerated and yield a greater proportion of treatment responders than midazolam at 1 week post-administration.Methods. OCD outpatients (aged 18-55) were recruited (September 2014 to May 2015) with institutional review board approval. Eligible patients met criteria for OCD (both DSM-IV and DSM-5), were at least moderately symptomatic (Yale-Brown Obsessive Compulsive Scale [YBOCS 6,7 ] score ≥ 16), and were on stable psychotropic medication doses for at least 6 weeks prior to enrollment. Exclusion criteria included severe depression (Hamilton Depression Rating Scale 17-item [HDRS] 8 score > 25) or comorbid psychiatric or medical conditions that made participation unsafe.Patients were randomized 1:1 to receive intranasal ketamine 50 mg or intranasal midazolam 4 mg. Ketamine was delivered using the administration protocol of a prior intranasal ketamine study in depression. 5 An independent evaluator, blind to treatment, evaluated OCD and depression symptoms at baseline and 1 week after drug administration. 6-8 Treatment response was defined a priori as ≥ 35% YBOCS score reduction. 9 Patients randomized to midazolam were offered open-label intranasal ketamine 50 mg after study completion.Results. Of the 23 adults with OCD who contacted the clinic to participate in pharmacologic studies, 20 (87%) were screened and determined eligible for study participation. Of those 20 adults, 15 (75%) refused study participation due to not wanting intranasal medication, 6 (40%) of whom endorsed fear of contamination from the nasal applicator. After 2 participants completed the study, we discontinued it due to low enrollment rate and poor tolerability as detailed below.Subject 1 was a 36-year-old African-American man who had moderate OCD without depression (YBOCS = 21; HDRS = 1) and was taking no medications at baseline. He was randomized to 50 mg intranasal ketamine. Upon administration, he showed visible signs of discomfort (eg, wrinkled nose, upper lip retraction, recoiling); he stated, "This is very unpleasant in my nose-isn't there another way for me to get this?" but wanted to continue the study. Side effects included dissociation (eg, body feeling unusually large, colors seemed brighter than expected, and time slowed) that lasted for 45 minutes after administration. One week after administration, he did not meet treatment response criteria (YBOCS score = 19; HDRS score = 0).Subject 2 was a 20-year-old white woman (on stable dose of sertraline 125 mg daily for OCD and divalproate 250 mg daily for migraines) with severe OCD and moderate depression (...

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