Mindfulness-based relapse prevention

Three of the 19 studies evaluated mindfulness-based relapse prevention (MBRP) and ketamine.^{Reference Azhari, Hu, O'Malley, Blocker, Levin and Dakwar21–Reference Grabski, McAndrew, Lawn, Marsh, Raymen and Stevens23} MBRP is a manualised treatment that combines components of cognitive–behavioural therapy (CBT), stress reduction and lessons to develop mindfulness skills.^{Reference Bowen, Chawla, Collins, Witkiewitz, Hsu and Grow24} MBRP aims to teach patients to recognise and address early warning signs of substance relapse.^{Reference Brewer, Sinha, Chen, Michalsen, Babuscio and Nich25}

Cognitive–behavioural therapy

Three studies evaluated CBT and ketamine.^{Reference Rodriguez, Wheaton, Zwerling, Steinman, Sonnenfeld and Galfalvy26–Reference Wilkinson, Wright, Fasula, Fenton, Griepp and Ostroff28} CBT combines psychoeducation, cognitive restructuring and behavioural activation to address symptoms of psychiatric disorders.^{Reference Fenn and Byrne29}

Ketamine psychedelic therapy

Three studies evaluated ketamine psychedelic therapy (KPT).^{Reference Krupitsky, Burakov, Dunaevsky, Romanova, Slavina and Grinenko30–Reference Krupitsky and Grinenko32} KPT is a three-stage ketamine and psychotherapy protocol developed to treat SUDs.^{Reference Krupitsky and Grinenko33} Stage 1 involves preliminary individual psychotherapy to prepare the patient for the ketamine treatment and explores factors relating to their substance misuse history. Stage 2 consists of ketamine dosing and psychotherapy while the patient is under the influence of ketamine. The psychotherapy in this stage revisits themes explored in stage 1 to integrate factors identified earlier and harness the potential for change. The final stage starts the day after the ketamine session and involves discussion, interpretation, and integration of the patient's experiences in stage 2.

Motivational enhancement therapy

Two studies evaluated motivational enhancement therapy (MET) and ketamine.^{Reference Azhari, Hu, O'Malley, Blocker, Levin and Dakwar21,Reference Dakwar, Levin, Hart, Basaraba, Choi and Pavlicova34} MET, also known as motivational interviewing, is a counselling technique used to enhance intrinsic motivation by addressing ambivalence towards behaviour change.^{Reference Smedslund, Berg, Hammerstrøm, Steiro, Leiknes and Dahl35}

Trauma interventions using mindfulness-based extinction and reconsolidation

Two RCTs evaluated trauma interventions using mindfulness-based extinction and reconsolidation (TIMBER) and ketamine.^{Reference Pradhan, Wainer, Moaddel, Torjman, Goldberg and Sabia36,Reference Pradhan, Mitrev, Moaddell and Wainer37} TIMBER therapy incorporates components of CBT, yoga and mindfulness-based graded exposure to treat PTSD.

The remaining psychotherapies were only used in single studies. These were a mix of manualised and non-manualised therapies (see Tables 1 and 2 for details of the therapy type).

Substance use disorders

Seven of the 19 studies evaluated treatment of SUDs. Three studies were for the treatment of alcohol use disorder (AUD), alcohol dependence or alcoholism.^{Reference Grabski, McAndrew, Lawn, Marsh, Raymen and Stevens23,Reference Krupitsky and Grinenko32,Reference Dakwar, Levin, Hart, Basaraba, Choi and Pavlicova34}

Dakwar et al^{Reference Dakwar, Levin, Hart, Basaraba, Choi and Pavlicova34} completed an RCT comparing MET and ketamine with MET and midazolam for patients with AUD (n = 40). Patients received six MET sessions within 5 weeks. At 12 days post-ketamine infusion, there was a significantly greater proportion of alcohol-abstinent patients in the ketamine group (52.9%) compared with the midazolam group (40.9%).

Grabski et al^{Reference Grabski, McAndrew, Lawn, Marsh, Raymen and Stevens23} completed a four-arm RCT (n = 96) for AUD comparing combinations of ketamine or saline treatment with MBRP or alcohol education (an active therapy control). Patients allocated to receive MBRP received six sessions over 3–6 weeks. At 6 months after the end of treatment, higher rates of abstinence were reported for ketamine groups compared with saline groups when the results were pooled across therapy conditions (mean difference = 10.1, 95% CI 1.1–19.0). However, no significant difference in alcohol-abstinent days was present between the ketamine plus MBRP group and the ketamine plus alcohol education group.

Krupitsky and Grinenko^{Reference Krupitsky and Grinenko32} evaluated KPT for the treatment of alcoholism (n = 211). Patients received the KPT protocol at the end of a 3-month in-patient treatment plan that involved treatment of alcohol withdrawal syndrome and comorbid psychiatric and/or somatic disorders with individual and group psychotherapy. In this study, stage 3 of KPT was undertaken in groups with patients who had received ketamine the previous day. Outcomes were compared between those who had received KPT and a comparison group of in-patients that had not received KPT. At 1 year post-treatment, abstinence was reported in 65.8% of patients in the KPT group compared with 24.0% in the comparison group.

Two RCTs evaluated heroin dependence.^{Reference Krupitsky, Burakov, Dunaevsky, Romanova, Slavina and Grinenko30,Reference Krupitsky, Burakov, Romanova, Dunaevsky, Strassman and Grinenko31} In the study of Krupitsky et al,^{Reference Krupitsky, Burakov, Romanova, Dunaevsky, Strassman and Grinenko31} all patients (n = 70) received KPT, although stage 3 was provided individually. Patients were randomly assigned to receive high-dose ketamine or low-dose ketamine during stage 2 of KPT. The rate of heroin abstinence at 2 years post-intervention was approximately 17.5% in the high-dose ketamine group and approximately 2.5% in the low-dose ketamine group.

In a separate RCT, Krupitsky et al^{Reference Krupitsky, Burakov, Dunaevsky, Romanova, Slavina and Grinenko30} treated heroin-dependent patients (n = 59) with KPT, with the third stage provided individually. Patients were then randomly assigned to receive two further addiction counselling sessions at monthly intervals or two additional stage 2 ketamine doses and addiction counselling at monthly intervals. Patients in the multiple KPT group also received an additional two psychotherapy sessions after each ketamine dosing to integrate their experiences. At 1-year follow-up, 50.0% heroin abstinence rates were reported in the multiple session group compared with 22.2% in the single session group.

One RCT evaluated cocaine dependence.^{Reference Dakwar, Nunes, Hart, Foltin, Mathew and Carpenter22} In this study, patients (n = 55) received 12 MBRP sessions over 5 weeks. At the end of treatment, abstinence from cocaine was observed in 48.2% of patients receiving ketamine and MBRP compared with 10.7% of patients receiving midazolam and MBRP. After controlling for route of use, the odds of abstinence in the ketamine group were 5.7 times those of the midazolam group (95% CI 1.3–25.1). One single-arm study evaluated cannabis use disorder.^{Reference Azhari, Hu, O'Malley, Blocker, Levin and Dakwar21} Patients (n = 8) received ketamine treatment combined with two sessions of MET, followed by six sessions of MBRP. At 12 days post-infusion, there was a significantly greater proportion of cannabis-abstinent patients in the ketamine group compared with the midazolam group.

Post-traumatic stress disorder

Five studies evaluated patients with PTSD, one of which also included patients with generalised anxiety disorder and MDD.^{Reference Davis, Mangini and Xin38} Two very small RCTs (n = 10–20)^{Reference Pradhan, Wainer, Moaddel, Torjman, Goldberg and Sabia36,Reference Pradhan, Mitrev, Moaddell and Wainer37} evaluated TIMBER therapy and ketamine for the treatment of PTSD. Neither study reported a significant difference in PTSD symptoms between groups at 24 h after treatment.^{Reference Pradhan, Wainer, Moaddel, Torjman, Goldberg and Sabia36,Reference Pradhan, Mitrev, Moaddell and Wainer37} However, Pradhan et al^{Reference Pradhan, Mitrev, Moaddell and Wainer37} reported a longer treatment effect in the ketamine group (M = 34.44, s.d. = 19.12) compared with the comparator group (M = 16.50, s.d. = 11.39) following the intervention.

Two small (n = 10–11) open-label studies evaluated ketamine and psychotherapy for PTSD.^{Reference Keizer, Roache, Jones, Kalpinski, Porcerelli and Krystal39,Reference Shiroma, Thuras, Wels, Erbes, Kehle-Forbes and Polusny40} Both studies reported large effect size improvements in PTSD scores (d = 1.44, and d = 1.21) from pre-post treatment.^37,38 A retrospective analysis of clinical records of patients receiving body-centred therapy for PTSD reported moderate effect-size improvements in PTSD scores (d = −0.48) that failed to reach statistical significance.³⁶

Treatment-resistant depression

Three studies evaluated TRD.^{Reference Wilkinson, Rhee, Joormann, Webler, Ortiz Lopez and Kitay27,Reference Wilkinson, Wright, Fasula, Fenton, Griepp and Ostroff28,Reference Zydb and Hart41} . Wilkinson et al^{Reference Wilkinson, Wright, Fasula, Fenton, Griepp and Ostroff28} conducted an open-label study of TRD patients (n = 16) involving 12 sessions of CBT over a 10-week period following ketamine treatment. Fifty per cent of the study population responded to the intervention, and 43.8% achieved remission. Wilkinson et al^{Reference Wilkinson, Rhee, Joormann, Webler, Ortiz Lopez and Kitay27} then completed a follow-up RCT for patients with TRD (n = 28). Patients who responded to an initial ketamine dose were allocated to receive 15 sessions of CBT over 17 weeks or treatment as usual (TAU). TAU consisted of regular meetings with a study physician for concomitant medication management. Wilkinson et al^{Reference Wilkinson, Rhee, Joormann, Webler, Ortiz Lopez and Kitay27} did not report significant between-group differences favouring the addition of psychotherapy to ketamine when measured by a clinician-rated depression scale (Montgomery–Åsberg Depression Rating Scale, MADRS), although the effect size was moderate (d = 0.65, 95% CI −0.55 to 1.82). However, a significant difference in favour of ketamine and psychotherapy treatment was observed when the Quick Inventory of Depression Symptomatology self-report depression scale was used (d = 0.71, 95% CI −0.30 to 1.70).

The remaining TRD study was an open-label study (n = 10) that reported significant improvements in self-reported depression symptoms at the end of ketamine and psychotherapy treatment.^{Reference Zydb and Hart41}

Other diagnostic groups

The remaining four studies were single-arm studies that evaluated patients with eating disorders and comorbid generalised anxiety and depression symptoms,^{Reference Robison, Lafrance, Brendle, Smith, Moore and Ahuja42} obsessive–compulsive disorder (OCD)^{Reference Rodriguez, Wheaton, Zwerling, Steinman, Sonnenfeld and Galfalvy26} and mixed diagnostic samples.^{Reference Dames, Kryskow and Watler43,Reference Dore, Turnipseed, Dwyer, Turnipseed, Andries and Ascani44}

Dore et al^{Reference Dore, Turnipseed, Dwyer, Turnipseed, Andries and Ascani44} retrospectively analysed data from patients (n = 235) who had received ketamine and psychotherapy across three private psychiatric practices. Patients in this study had varying diagnoses including MDD, PTSD, complex PTSD, attention-deficit hyperactivity disorder, anxiety disorders and SUDs. The number of in-office ketamine and psychotherapy sessions ranged from 1–25. Some patients were also prescribed sublingual ketamine to take at home between in-office ketamine and psychotherapy sessions. Ketamine dose, route and frequency and psychotherapy frequency were individualised depending on the patients’ diagnosis and circumstances. Symptom rating scales were administered at intake and again at discharge from treatment. Significant decreases in the Beck Depression Inventory (M = 26.55 at baseline, M = 15.31 post treatment, P < 0.0001) and the Hamilton Rating Scale for Anxiety (M = 20.35 at baseline, M = 15.03 post treatment, P < 0.0001) were both reported at the end of treatment.

Dames et al^{Reference Dames, Kryskow and Watler43} administered ketamine in a group setting at weekly intervals for 3 weeks to patients (n = 94) with treatment-resistant psychiatric disorders. Processing took place within the group after the effects of the drug had subsided (approximately 90 min after dosing). Processing included conversation about the patients’ respective ketamine experiences. This was in addition to psychotherapy leading up to and following the ketamine sessions. By treatment end, improvements were reported in 91% of patients with generalised anxiety disorder symptoms, and 76% of patients with depression symptoms. Eighty-six per cent of patients with a baseline PTSD diagnosis were reported to no longer meet diagnostic criteria.

One small (n = 10) open-label study examined the treatment of OCD.^{Reference Rodriguez, Wheaton, Zwerling, Steinman, Sonnenfeld and Galfalvy26} This study provided a single intravenous (i.v.) ketamine infusion followed by exposure-based CBT. The mean estimated Yale–Brown Obsessive Compulsive Scale score was significantly lower at week 2 (difference = −10.75 points, s.e. = 1.44, P < 0.0001) and at week 4 (difference = −6.88, s.e. = 2.61, P = 0.01). A wide variation in response among individuals was reported in this study. An eating disorders study (n = 5)^{Reference Robison, Lafrance, Brendle, Smith, Moore and Ahuja42} evaluated a course of ketamine alongside routine group and individual therapy. This study reported significant improvements in depression scores for four participants and significant improvements in anxiety scores for two participants following treatment with ketamine and psychotherapy.

Intravenous

Eleven of the 19 studies examined psychotherapy and ketamine administered via i.v. infusion.^{Reference Azhari, Hu, O'Malley, Blocker, Levin and Dakwar21–Reference Grabski, McAndrew, Lawn, Marsh, Raymen and Stevens23,Reference Rodriguez, Wheaton, Zwerling, Steinman, Sonnenfeld and Galfalvy26–Reference Wilkinson, Wright, Fasula, Fenton, Griepp and Ostroff28,Reference Dakwar, Levin, Hart, Basaraba, Choi and Pavlicova34,Reference Pradhan, Wainer, Moaddel, Torjman, Goldberg and Sabia36,Reference Pradhan, Mitrev, Moaddell and Wainer37,Reference Keizer, Roache, Jones, Kalpinski, Porcerelli and Krystal39,Reference Shiroma, Thuras, Wels, Erbes, Kehle-Forbes and Polusny40} Doses ranged from 0.50 mg/kg to 1.41 mg/kg in the case of non-response. Treatment regimes include single and repeated infusions in combination with therapy.

Intramuscular

Six studies evaluated psychotherapy plus intramuscular (i.m.) ketamine injections.^{Reference Krupitsky, Burakov, Dunaevsky, Romanova, Slavina and Grinenko30–Reference Krupitsky and Grinenko32,Reference Robison, Lafrance, Brendle, Smith, Moore and Ahuja42–Reference Dore, Turnipseed, Dwyer, Turnipseed, Andries and Ascani44} . Treatment doses started at 25 mg in the ED population^{Reference Robison, Lafrance, Brendle, Smith, Moore and Ahuja42} and were typically in the 1–2 mg/kg range. Dosing frequency ranged from single ketamine dose protocols^{Reference Krupitsky and Grinenko32} to the case series reported by Dore et al^{Reference Dore, Turnipseed, Dwyer, Turnipseed, Andries and Ascani44} with up to 25 ketamine treatment sessions.

Oral/sublingual

Two single-arm studies evaluated psychotherapy and sublingual ketamine^{Reference Davis, Mangini and Xin38} or oral ketamine.^{Reference Zydb and Hart41} Zydb and Hart^{Reference Zydb and Hart41} examined oral doses of 75 mg administered once a week for 6 weeks. Davis et al^{Reference Davis, Mangini and Xin38} examined sublingual doses between 100 and 200 mg administered three times over 6 weeks.