Ketamine and Behavioural Activation Therapy study

INTERVENTION: Participants will be randomised to receive oral ketamine plus Behavioural Activation Therapy (BAT) (the intervention) or oral ketamine plus Treatment As Usual (TAU) (the comparator). Ketamine will commence at a dose of 0.5mg/kg diluted with 50 ml orange juice and sipped over 30‐60 minutes. Initial dosing will be twice weekly (with gaps of 3 and 4 days between doses). If tolerated and if the Montgomery Asperg Depression Rating Scale (MADRS)>6 on follow‐up (indicating mild depression or greater), dose can be increased to 1.5 mg/kg and then 2 mg/kg. If the MADRS is <6 on follow‐up, dosing can be reduced to weekly intervals at participant request. Dosing will be individualised through discussion with nursing staff. All participants will receive nursing contact and oversight on Ketamine dosing days and by telephone as needed over the study period. BAT consists of 12 sessions provided at twice‐weekly intervals for 4 weeks, then weekly intervals for 4 weeks. Sessions will be timed to occur within 24 hours of Ketamine treatments. BAT will be based on the manual by Lejuez et al. and be adapted by Assoc. Prof Jordan, Dr Katie Douglas, and Prof Greg Murray to work synergistically with the Ketamine treatment. BAT has already been adapted using He Puna Whakaata principles for use with Maori participants. BAT will provide an individual formulation for the participant and be a holistic treatment package alongside Ketamine therapy. BAT content includes psychoeducation about depression and the BAT model, values, goal setting, scheduling pleasant and mastery activities, negotiating support from others, dealing with rumination and worry, skills training as needed (e.g. problem solving, assertive communication) and managing early signs of relapse. BAT will include an CONDITION: Mental Health ‐ Depression Treatment Resistant Depression; ; Treatment Resistant Depression PRIMARY OUTCOME: Montgomery Asperg Depression Rating Scale (MADRS)[The MADRS will be measured weekly during the 8 weeks of active treatment and fortnightly between weeks 8 and 20 post‐baseline. ] Study feasibility will be assessed by tracking weekly attendance with Ketamine and BAT, retention to the study follow‐up protocol, and acceptability of treatment measures.[Weekly attendance with Ketamine and BAT will be assessed through recording attendance weekly. ; Retention to the study follow‐up protocol will be assessed by monitoring responses to the study phone calls occuring every two weeks from weeks 8‐20.; Acceptability of treatment will be assessed by the Behavioural Activation for Depression Scale ‐ Short Form (BADS‐SF) at baseline, week 8, and week 20.] SECONDARY OUTCOME: Bladder Pain Interstitial Cystitis (BPIC) questionnaire[Weekly for first 8 weeks, then week 20 post‐baseline] DASS‐21: Anxiety Subscale[Baseline, week 8, week 20 post‐baseline] DASS‐21: stress subscale[Baseline, week 8, week 20 post‐baseline] Depression Anxiety and Stress Scale (DASS‐21 ): Depression subscale[Baseline, week 8, week 20 post‐baseline] Functional impairment assessed using the Work and Social Adjustment Scale (WSAS)[Baseline, week 8, week 20 post‐baseline] GENEActiv actigraphs (a small wrist‐worn device) on the non‐dominant wrist. The primary actigraphic outcome measure will be total waking activity count per waking day (averaged across 7 days of data collection). [Actigraphs will be worn for si Xweeks in total; ; a) 1 week prior to and for 2 weeks after first ketamine treatment to test the acute impacts of ketamine ; b) 1 week prior to and 1 week after completion of ketamine treatment to test the impact of ketamine withdrawal (weeks 8 and 9) ; c) 1 week prior to week 20 to investigate maintenance of psychomotor benefits. ; ; ] Participant adherence to BAT will be assessed by the Behavioral Activation for Depression Scale – Short Form (BADS‐SF). [Baseline, week 8, week 20 post‐baseline] The MATRICS Consensus Cognitive Battery. This is a series of memory, attention, and learning tests that take about one hour to complete. [This will be administered at baseline and 7 days following end of Ketamine treatment. ] INCLUSION CRITERIA: Participants aged between 18 and 65 years with treatment‐resistant, DSM 5, Major Depressive Disorder (TR‐MDD) are eligible for entry to the study. A standard definition for treatment resistance will be used: having trialled, and not responded to, at least two antidepressant medications at adequate doses for more than 6 weeks. At screening, patients will have a Hamilton Depression Rating Scale‐17 (HAMD) greater than 16, reflecting depression of at least moderate severity. Participants will be required to be on stable medication treatment (or no treatment) for at least 1 month prior to screening for the study and commit to remaining on the same medication during active treatment to ensure treatment withdrawal or dose changes do not confound study effects. Proficient in spoken English