Table 2.

Characteristics of Published N-of-1 Trials for Depression^*

First Author, Year Published, Country	Number of Patients	Patient Characteristics	Rationale for N-of-1 Design	Treatments, Blinding	Treatment Sequence, Randomization, Washout, and Duration	Depressive Symptom and Other Outcome Measures	Analytic Approach
White32, 1992, US	1	Foster care residing depressed adult with HIV-associated encephalopathy, resistant to TCA treatment	Determine effectiveness in a patient with a comorbidity that would have made him ineligible for most conventional RCTs	Methylphenidate vs placebo, double- blinded	Counterbalanced, randomized block design: ABA or BAB; number of blocks: 1; treatment period duration: 2 weeks; washout- period: <1 day; trial duration: 6 weeks	Patient-reported mood VAS assessed twice per day and physician- reported HAM-D, digit span, symbol digit substitution test, side- effects, nurse assessed sleep and mood as per chart	Positive change in symptoms on outcomes scales, no statistical testing
Little29, 1993, US	18	Depressed inpatients, age 24-45 years, no antidepressant medication use within one week	Determine if there is clinically significant heterogeneity of treatment effects of d- amphetamine vs methylephenidate in depressed patients	d-Amphetamine vs methylphenidate, double-blinded	Counterbalanced, randomized block design: AB or BA; number of blocks: 1; treatment period: 1 day; washout: <1 day; trial duration: 2 days	Patient completed VAS appetite scale, suicidality scale, memory tests, psychiatrist-completed the HAM-D, psychiatrist and patient rated global drug effect VAS scale (worse, no change, better)	Positive change in symptoms on outcomes scales, no statistical testing
Maier31, 1994, Germany	10	Chronically depressed community-dwelling adults (>2 years duration), at least one 6-week trial with tricyclic without success within 3 months	Gain preliminary evidence for an untested treatment for chronic, treatment resistant depression, and to determine the extent of inter- individual differences in treatment effects	Sulpiride vs placebo, double-blinded	Counterbalanced, randomized block design (ABAB or BABA);number of blocks: 1; treatment period: 6 weeks; washout: 1 week; trial duration: 28 weeks	Daily evening patient ratings using Hopkins Checklist 90 (3 subscales: depression, anxiety, and somatization as a proxy for drug side- effects)	ARIMA method used to compare sulpiride versus placebo in each pair of treatment periods
Jansen28, 2001, Holland	3	Depressed geriatric patients residing in nursing homes	Guide treatment decisions regarding a controversial medication with uncertain individual-level harms and benefits in depressed geriatric patients	Methylphenidate vs placebo, double- blinded	Counterbalanced, randomized block design (AB or BA); number of blocks: 5; treatment period: 2 days; washout: 1-2 days; trial duration: 5 weeks	Geriatrician completed MADRS and the Barthel Activities of Daily Living scale after each 2 day treatment period; side effects were assessed though method unclear	Paired t-test with alpha 0.1 to denote significance
Loo30, 2016, Australia	15	Treatment refractory depressed adults >4 weeks duration, insufficient response to one or more antidepressant medications	To assess the feasibility, safety, and efficacy of a practical individual dose titration approach	Ketamine at 5 increasing doses vs active placebo (midazolam), administered via IV (N=5), intramuscular (N=5), or subcutaneous (N=5) route, subjects evaluated weekly at drug administration, no dose-specific repetitions	Ascending dose design block with random insertion of sham between the first 3 doses (A1-sham-A2A3A4A5); number of blocks: 1; treatment period: 1 week; washout period: <1 day; trial duration: 6 weeks	Observer-administered MADRS at 0,4,24,72, 144 hours after each treatment period; psychotomimetic, cognitive and physical side effects including HR, BP assessed before and after each treatment	Positive change in symptoms on outcomes scales, no statistical testing

Abbreviations: TCA, tricyclic antidepressant; RCT, randomized controlled trial; MADRS, Montgomery Asberg Depression Rating Scale; ARIMA, autoregressive integrated moving average; HAM-D, Hamilton Depression Ratings Scale

^*Period: The time during which a single treatment (A or B) is administered. The order of periods within a pair or treatment block may be randomized. Block: A repeated unit of a set number of periods in N-of-1 trials; the sequence of periods may be randomized (for example, three repeating blocks of four periods may look like “AABB BBAA ABAB”). Sequence: Multiple blocks comprise an entire sequence. The sequence is the consecutive set of periods, which may or may not indicate size of the repeated unit. Washout period: A period in which no intervention is administered. A washout may be administered between different treatment periods or may act as a period in itself, as in a “reversal” design (to “wash out” the effects of a treatment before it is re-administered).