Discussion

This paper describes the process undertaken to develop ketamine treatment guidelines for use in a publicly funded mental healthcare setting. The ketamine clinic guidelines that resulted are provided to inform wider ketamine use by psychiatrists in other settings. In undertaking this work, we respond to the increasing evidence base for ketamine treatment of TRD and the gap that exists in translating evidence from clinical trials into use by clinicians. We believe the guidelines are a pragmatic reflection of the evidence base for ketamine treatment that provide a useful resource for services and clinicians, particularly in jurisdictions where resources for mental health treatment are significantly limited.

A further impetus for this work was the increasing awareness of new treatments for TRD in public domains. We were aware of increasing demand and pressure on individual clinicians to respond to requests for ketamine treatment. In this context, a SMHS-endorsed treatment pathway appeared desirable compared with ad hoc individual clinician-led solutions. Therefore, a critical feature in developing this guideline was the early involvement of SMHS leadership, wide consultation and planned ongoing review and audit of ketamine treatment.

The majority of treatment studies evaluating ketamine treatment for TRD use parenteral administration of ketamine, but ketamine is active in TRD irrespective of how it is administered.^{Reference McIntyre, Rosenblat, Nemeroff, Sanacora, Murrough and Berk3} The pharmacology of ketamine relating to its antidepressant activity has been linked to several of its metabolites, including norketamine and the hydroxynorketamines.^{Reference Highland, Zanos, Riggs, Georgiou, Clark and Morris15,Reference Paul, Singh, Khadeer, Moaddel, Sanghvi and Green16} After oral dosing, pharmacokinetic exposure to norketamine and the hydroxynorketamines is considerably more prolonged than exposure to ketamine.^{Reference Hasan, Modess, Roustom, Dokter, Grube and Link17} Furthermore, ketamine is still active as an antidepressant even when dosed by routes where bioavailability of parent ketamine is low.^{Reference Domany, Bleich-Cohen, Tarrasch, Meidan, Litvak-Lazar and Stoppleman18} A synthesis of these observations suggests that ketamine may be acting as a prodrug, where its antidepressant activity is substantially attributable to its metabolites. A meta-analysis of ketamine formulations identified that formulations that maximise first-pass metabolism of ketamine and delay time to maximum concentrations were better tolerated (less dissociation) and safer (less blood pressure change) than formulations that lack those characteristics.^{Reference Glue, Russell and Medlicott19} Our treatment guidelines allow for intramuscular ketamine as a test of ketamine responsiveness if desired by the clinical team and patient. We chose the dose of 1 mg/kg because of recent clinical trial and ‘real-world’ evidence that 0.5 mg/kg is an ineffective dose for some, and to optimise the likelihood of response.^{Reference Loo, Glozier, Barton, Baune, Mills and Fitzgerald20,Reference Ahuja, Brendle, Smart, Moore, Thielking and Robison21} Alternative routes include intravenous and subcutaneous administration. These have been shown to produce similar antidepressant effects in a small ascending dose study, although plasma ketamine levels are higher when given intravenously.^{Reference Loo, Galvez, O'Keefe, Mitchell, Hadzi-Pavlovic and Leyden22} This may prompt the need for dose adjustment if this route is preferred. In the study by Loo et al,^{Reference Loo, Galvez, O'Keefe, Mitchell, Hadzi-Pavlovic and Leyden22} the subcutaneous route of administration was better tolerated than other forms of administration, but we recommended intramuscular administration because of greatest familiarity with this route of administration locally, and because subcutaneous administration is not endorsed by Medsafe, the regulatory body overseeing medication use in New Zealand.

Following the intramuscular test and as an alternative pathway, ketamine treatment is provided orally. We chose this to allow more widespread use of ketamine, but recognise that there may be situations when repeated doses of intramuscular ketamine are preferred (particularly severe suicidality). The evidence base for oral treatment is less extensive than for parenteral administration, but oral ketamine administration is better tolerated, with minimal dissociative symptoms at the time of ingestion.^{Reference Rosenblat, Carvalho, Li, Lee, Subramanieapillai and McIntyre23,Reference Meshkat, Haikazian, Di Vincenzo, Fancy, Johnson and Chen-Li24} Oral ketamine is also associated with medium-to-large effect size improvements in depression severity after 2–6 weeks of treatment.^{Reference Rosenblat, Carvalho, Li, Lee, Subramanieapillai and McIntyre23,Reference Meshkat, Haikazian, Di Vincenzo, Fancy, Johnson and Chen-Li24} The decision to recommend oral ketamine is not without controversy because the majority of studies have still been with parenteral administration. The tolerability and ease of administration of oral ketamine was a key factor in our decision to prefer oral treatment. We recognised that delivering parenteral ketamine in busy psychiatric settings was an obstacle to ketamine use in our SMHS, and this is likely to be similar in other publicly funded SMHS. We were also concerned about issues of equity and access. Currently, esketamine and ketamine treatment is available for consumers who are able to seek treatment in private settings at considerable expense. We wished to increase access to other consumers, and the likelihood of parental administration of ketamine or esketamine becoming prevalent in public services seemed low. Also contributing to this decision was the established use of oral ketamine in research settings in Dunedin and Christchurch, New Zealand.

A key challenge to ketamine treatment is the short-term nature of beneficial effects, with high rates of relapse following single and repeated dosing.^{Reference aan het Rot, Collins, Murrough, Perez, Reich and Charney4,Reference Kraus, Rabl, Vanicek, Carlberg, Popovic and Spies5} This finding creates a dilemma for clinicians: determining the best duration of ketamine treatment, including whether to commit to long-term or maintenance treatment. Our guidelines specify that the duration of ketamine treatment should be up to 12 weeks. Twelve weeks was chosen to provide sufficient time for a robust clinical response. We also believe that a 12-week course provides opportunity for behavioural activation and the reinforcement of mood improvements by behavioural change. However, we were reluctant to recommend long-term or maintenance treatment of racemic ketamine because controlled trials supporting this approach are not yet published,^{Reference Smith-Apeldoorn, Veraart, Spijker, Kamphuis and Schoevers25} and we were concerned that the clinical resource for ketamine treatment could be overwhelmed. However, regular steering group meetings provide a mechanism for change to the ketamine guidelines if ongoing audit suggests that the time frame for treatment is unfeasible.

The extent and burden of TRD in the community is significant,^{Reference Mrazek, Hornberger, Altar and Degtiar1} but our guidelines limit access to ketamine treatment to those with severe TRD under SMHS care. This was a practical decision taken as the first step toward greater access to ketamine treatment in our local community. In doing so, we prioritise access to ketamine treatment for those with most severe TRD and ensure that treating psychiatrists are at the forefront of ketamine treatment. We did not wish to create a situation where psychiatrists were required to address issues with ketamine treatment provided in other settings that were not endorsed by SMHS. We recognise that this approach may not fully address the community need for ketamine treatment, but believe it is justified given the risks of ketamine treatment and longer-term side-effects.

Although a large part of the ketamine treatment evidence base addresses the management of TRD, there is growing evidence for the use of ketamine treatment for other psychiatric disorders, including anxiety and substance use disorders.^{Reference Walsh, Mollaahmetoglu, Rootman, Golsof, Keeler and Marsh26} We anticipate that the indication for ketamine treatment will broaden with time, but recommend restricting treatment to TRD initially as a pragmatic response, given the uncertain extent of demand following opening a new service.

There are studies that suggest additional benefits from combining psychotherapy and ketamine treatment for TRD.^{Reference Kew, Porter, Douglas, Glue, Mentzel and Beaglehole27} This evidence base is expanding, but given that moderate-to-large effect size improvements result from oral ketamine treatment for TRD alone,^{Reference Rosenblat, Carvalho, Li, Lee, Subramanieapillai and McIntyre23} specifying that psychotherapy be required did not appear justified. However, we do require patients receiving ketamine to be managed by SMHS. We regard the relationship with a case manager and psychiatrist to be an important adjunct to the ketamine treatment that will help embed behavioural change alongside any improvements in mood.

The RANZCP has released a clinical memorandum to provide information for psychiatrists about the potential utility of ketamine in psychiatric practice.¹² We internally bench-marked our guidelines against the key messages of this memorandum. Our guidelines were consistent with the key messages, with the exception of the requirement for the treating psychiatrist to have expertise in ketamine treatment. In our view, the use of oral ketamine and the oversight provided by these guidelines, alongside clinical support from psychiatrists with more ketamine treatment expertise, means that psychiatrists treating patients with TRD can initiate and supervise the use of oral ketamine treatment without extensive prior ketamine treatment experience, and will gain this in the process specified by this protocol.

The wide consultation we undertook allowed for refinement of the protocol in a number of areas. For example, the importance of a careful informed consent process balancing the risks and benefits was emphasised during patient and Te Korowai Atawhai consultation. Community psychiatrists were largely supportive, but not universally so, with concern about off-label use and the lack of translational evidence for ketamine. Clinical pharmacy expertise helped refine protocol and advice for patients considering ketamine treatment. Each of the groups consulted were supportive of a protocol to support ketamine use by SMHS.