Treatment-resistant major depressive disorder (TRD) is burdensome for individuals, families and society.Reference Mrazek, Hornberger, Altar and Degtiar1 Existing treatments for TRD have limitations, including side-effects and limited effectiveness of psychotherapy and medication treatments.Reference Rush2 It is therefore desirable that newly established treatments become available for patients in a timely manner. The N-methyl-D-aspartate receptor antagonist ketamine has emerged as a new treatment for major depressive disorder (MDD). Although the efficacy of ketamine treatment for TRD in the short term is now well established,Reference McIntyre, Rosenblat, Nemeroff, Sanacora, Murrough and Berk3 there are a number of challenges for the translation of ketamine treatment to routine care. These include the following: high rates of relapse that occur following cessation of regular dosing,Reference aan het Rot, Collins, Murrough, Perez, Reich and Charney4,Reference Kraus, Rabl, Vanicek, Carlberg, Popovic and Spies5 marked dissociative effects during parenteral dosing,Reference McIntyre, Rosenblat, Nemeroff, Sanacora, Murrough and Berk3 concern about the potential for dependence and misuse,Reference Swainson, Klassen, Brennan, Chokka, Katzman and Tanguay6 and concern about other side-effects such as interstitial cystitisReference Misra, Chetwood, Coker and Thomas7,Reference Nikayin, Murphy, Krystal and Wilkinson8 and memory impairment.Reference Zhornitsky, Tourjman, Pelletier, Assaf, Li and Potvin9,Reference Zhang, Tang, Liang, Ungvari and Lin10
An obvious challenge for mental health services is the matching of clinical resource to clinical need, and the rollout of new treatments in the most equitable way. In New Zealand, esketamine (the S-enantiomer of ketamine) is available for TRD in combination with a conventional antidepressant, and is delivered via nasal spray. Esketamine is not funded by Pharmac (the government agency that decides which medications are funded in New Zealand), and is very costly for consumers. Royal Australian and New Zealand College of Psychiatry (RANZCP) clinical guidelines also report caveats that esketamine has not been compared directly with ketamine, the majority of esketamine data stems from industry-sponsored trials and longer-term outcomes with this formulation are still a matter for debate.Reference Malhi, Bell, Bassett, Boyce, Bryant and Hazell11 Racemic ketamine (combined esketamine and arketamine) does not have regulatory approval for the treatment of MDD in New Zealand. Despite this, limited off-label ketamine use occurs in clinical and research settings, and demand from patients and clinicians for ketamine treatment is increasing. However, the routine use of ketamine in publicly funded specialist mental health services (SMHS) is largely absent. In large part, this relates to the challenges outlined earlier, accompanied by lack of expertise in ketamine treatment in clinicians.
Response to the challenges outlined above
We created treatment guidelines for ketamine use in publicly funded mental health services in response to the challenge of translating ketamine use to clinical practise. A primary goal was to provide a pathway for consumers with TRD to receive ketamine treatment. A secondary aim was to provide a framework for other services to follow and establish ketamine treatment in their treatment settings. This paper describes the process undertaken in creating the ketamine treatment guidelines. At the time of submitting this paper for review, the protocol remained in draft form. Although consultation was complete and there was general agreement with internal stakeholders on the content of the protocol, systemic changes affecting New Zealand health services nationally (the transition from District Health Boards to a single national healthcare entity, Te Whatu Ora) meant that new healthcare initiatives were not being progressed locally. Despite remaining in draft form, we believe there is merit in reporting the process undertaken and the protocol, to allow for broader dissemination and review.
Method
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. There were no procedures involving human patients.
Setting
Our SMHS provides government-funded health services to a predominantly urban catchment area. It is responsible for the health of approximately 600 000 people (comprising approximately 81.1% New Zealand European, 9.5% Māori, 12.4% Asian and 3.3% Pacifika). Comprehensive mental health services are available, including specialist child and adolescent, adult and old-age services, in in-patient and out-patient settings. Private psychiatry is minimal and without in-patient facilities.
Leadership
Before commencing the development of the ketamine treatment guidelines, we consulted with the Chief of Psychiatry at the SMHS, to ensure there would be service support for ketamine use. Following the endorsement by the Chief of Psychiatry, the Clinical Director of one of the adult community psychiatric teams was nominated as a key figure and member of the steering group.
Process and consultation
The first draft of the protocol was largely written by author B.B., drawing upon ketamine protocols used in research settings with P.G. This is unpublished work to date that utilises intramuscular and oral ketamine treatment. Following completion of the first draft an iterative process was undertaken. This involved circulating draft protocols before meetings with consultation groups. These groups included leadership and community psychiatrists, the SMHS pharmacy department, the electroconvulsive therapy (ECT) service, nursing representatives, Te Korowai Atawhai (the local Māori mental health service) and patient representatives. After each meeting, feedback received was used to revise and improve the protocol. We anticipate that there may be further versions of the protocol in response to the audit and further developments in the evidence base.
Steering group
When finalised, we anticipate a steering group to oversee ketamine use until it becomes an established intervention. Representatives from SMHS leadership (Clinical Director of community team), academic psychiatry, pharmacy, the ECT service, nursing representatives, patient representatives and Te Korowai Atawhai (the Māori mental health service) will constitute the steering group. We anticipate 3-monthly meetings to review ketamine audits, address issues as they arise and oversee ketamine treatment. Potential issues that may arise for the steering group include training issues in intramuscular administration, resourcing for intramuscular administration, patient selection and questions about management of relapse following treatment.
Training
Author B.B. presented the protocol to community psychiatrists and provides consultation and clinical back-up to SMHS clinicians who have commenced ketamine treatment using the draft protocol. Author P.G. provides additional ketamine experience, expertise and support. Author M.C. completed training in ketamine treatment during a recent sabbatical. It is intended that psychiatrists will observe three intramuscular treatments to ensure familiarity with the dissociative ketamine experience before overseeing intramuscular ketamine administration for future patients. Oral ketamine can be provided using the protocol for guidance, given the limited dissociation that occurs with oral dosing. National workshops for psychiatrists in other regions seeking to familiarise themselves with ketamine treatment and the setting up of ketamine clinics are planned.
Internal benchmarking with RANZCP clinical memorandum on use of ketamine in psychiatric practice
The RANZCP released a clinical memorandum for psychiatrists considering ketamine use in clinical practice.12 This guideline contains key messages. In devising this guideline, we aimed to be aligned with these messages. After completion of the guideline, we undertook an internal benchmarking process. This entailed comparing the key messages of the RANZCP clinical memorandum with our guideline. There was broad agreement with all key messages apart from partial agreement with the requirement that a psychiatrist with appropriate expertise in ketamine treatment should prescribe ketamine and take responsibility for its use. Appropriate expertise is not well defined. In our view, the predominant use of oral ketamine and other layers of oversight provided by our guideline ensure sound ketamine practice.
Audit
Our clinical research unit agreed to collate data on ketamine treatments. Sociodemographic details and specifics relating to ketamine treatment, including rating scale scores (e.g. for the Depression, Anxiety and Stress Scale; DASS-21Reference Lovibond and Lovibond13) and any adverse effects, will be reported to the 3-monthly steering group meeting. The data will be collated by the case manager. We considered using the Ketamine Side Effect Tool (KSET)Reference Short, Dong, Galvez, Vulovic, Martin and Bayes14 to monitor side-effects, but chose not to do so because of the complexity of this tool. Supplementary File 1 available at https://doi.org/10.1192/bjo.2023.577 is our suggested form to document ketamine treatment and side-effects.
Results
The draft ketamine treatment guidelines for adults aged 18–65 years are provided in Supplementary File 2. Table 1 provides key elements of the guidelines that relate to treatment provision for ease of reader review. Table 2 contains the patient information leaflet to assist informed decision-making. Table 3 provides the consent for ketamine treatment form to be used before treatment commencement for each patient.
Key elements of the ketamine clinic treatment guidelines
Suggested patient information leaflet: ketamine treatment for treatment-resistant depression
Suggested consent form for off-label ketamine treatment of depression
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.
Limitations
This protocol is intended to provide a useful ketamine pathway for the treatment of patients with TRD. The definition of TRD used is failure to respond to adequate trials of two antidepressants and evidence-based psychotherapy (if available), and of a sufficient severity to require management by SMHS. The concept of TRD can be challenged on multiple fronts, including unrecognised bipolarity, heterogeneity of presentation and inadequate treatments (as opposed to treatment resistance residing within the patient).Reference Malhi, Das, Mannie and Irwin28 We accept these criticisms of TRD, but suggest that some criteria are desirable for pragmatic reasons. We developed this guideline to provide a useful protocol for general adult services. Consequently, the use of ketamine in subspecialty areas such as child and adolescent psychiatry and maternal and infant health is not addressed, and should prompt the use of clinical pharmacy and psychiatric second opinions if considered.
This ketamine protocol is a local solution responding to the increasing evidence base for ketamine treatment and demand from clinicians and patients for greater availability of ketamine treatment for TRD. It remains in draft form because of an inability to progress the protocol to a finalised status in the context of recent structural changes to the provision of healthcare in New Zealand. Although designed with our local SMHS in mind, we believe that our local service characteristics can be generalised to other publicly funded SMHS, such as in Australia and the National Health Service in the UK. Our guideline specifies the use of oral ketamine despite a larger portion of the literature investigating parenteral ketamine. This was a pragmatic decision, and better-resourced services may choose to prioritise parenteral administration as a first choice despite obvious tolerability and resource advantages to oral treatment.
In conclusion, we have reported the process and protocol that arose from the development of a ketamine treatment pathway for TRD. We believe this protocol is of interest to services and psychiatrists wishing to respond increasing demand for ketamine treatment. We believe the protocol provides a practical pathway that could be replicated in other services, and lead to greater availability of ketamine for patients with TRD.
Supplementary material
Supplementary material is available online at https://doi.org/10.1192/bjo.2023.577
Data availability
Data availability is not applicable to this article as no new data were created or analysed in this study.
Acknowledgements
We thank the wider consultation group for their time and feedback, including representatives from our clinical leadership group and other psychiatrists, clinical pharmacology, nursing representatives, the ECT service, Te Korowai Atawhai and patient representatives.
Author contributions
B.B. drafted the report and completed consultation with stakeholders. M.C., P.G. and R.P. helped shape the report, provided feedback on drafts and agreed to the final version.
Funding
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Declaration of interest
B.B. is actively researching ketamine treatment for mood and anxiety disorders. P.G. has a research contract with Douglas Pharmaceuticals to develop novel oral ketamine formulations. He has also attended advisory boards for Janssen Pharmaceuticals. M.C. has no conflicts of interest to declare. R.P. has made use of computer software at no cost for research – provided by SBT-pro; received support for travel to educational meetings from Servier and Lundbeck; and is a Deputy Editor for BJPsych Open but did not take part in the review or decision-making process for this paper.
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