The investigators will compare 3 groups (ketamine + naltrexone vs ketamine alone vs placebo) in an 8-week randomised, double-blind, placebo-controlled trial (n=65) of repeated IV ketamine (0.5 mg/kg weekly x4) for comorbid MDD and AUD.
An open-label lead-in (n=5) will first test repeated IV ketamine (0.5 mg/kg weekly x4) for safety and preliminary efficacy with 4-week follow-up.
Following the lead-in, an 8-week randomised, double-blind, parallel-group trial (n=60 planned; total n=65 actual) will compare IV ketamine (0.5 mg/kg weekly x4) plus monthly IM naltrexone (380 mg, 2 injections) versus ketamine plus IM placebo versus IV psychoactive placebo (midazolam 0.045 mg/kg) plus IM placebo; primary outcomes assess depression and alcohol-use measures with 4-month follow-up.
IV ketamine once weekly x4 infusions plus IM naltrexone monthly x2 injections.
IV ketamine 0.5 mg/kg, once weekly for 4 infusions
Naltrexone 380 mg IM monthly, 2 injections
IV ketamine once weekly x4 infusions plus IM placebo monthly x2 injections.
IV ketamine 0.5 mg/kg, once weekly for 4 infusions
IM placebo monthly, 2 injections
IV psychoactive placebo midazolam once weekly x4 infusions plus IM placebo monthly x2 injections.
Psychoactive placebo midazolam 0.045 mg/kg IV, once weekly for 4 infusions
IM placebo monthly, 2 injections