Abstract
The promise of ketamine treatment for depression has upended half a century of the monoamine theory of depression. As an N-methyl-D-aspartate (NMDA) receptor antagonist, it has a completely different mechanism of action compared to standard antidepressant (AD) medications. It has recently emerged as a potential effective therapy for treatment-resistant depression (TRD), with placebo-controlled trials showing greater efficacy than other AD medications, with a 50–70% response rate and a 30% remission rate – as well as a faster onset of action (hours versus weeks). Efficacy has also been observed in depression refractory to treatment with electroconvulsive therapy (ECT), to date the most effective treatment for severe depression. Worldwide, there is a rapidly increasing use of ketamine as a treatment for depression as evidence from clinical trials accumulates, with newer preparations developed, for example, an intranasal formulation of esketamine was recently approved by the US Food and Drug Administration for the treatment of depression. Yet, there remain important considerations. The effects of ketamine are generally short lived (typically days) – though a small number of patients may be ‘super-responders’ who remit after a single dose (Gálvez et al., 2014). Important knowledge gaps include potential side effects arising from long-term exposure to ketamine, risks of addiction, lack of consensus on dosing protocols and uncertainty over the role of ketamine in overall treatment algorithms for TRD.
These issues are exemplified in a recent New South Wales (NSW) Health Care Complaints Commission (HCCC) ruling (HCCC v Chen, 2018) which discusses important issues relevant to Australian clinicians considering ketamine treatment for depression. While the case details deficits in general clinical skills and standards (leading to findings of unsatisfactory professional conduct and professional misconduct), it also comments on issues related to appropriate informed consent for an emerging treatment with a limited evidence base and refers to regulatory issues of which many medical practitioners may be unaware.
As ketamine injection is only approved in Australia by the Therapeutic Goods Administration (TGA) as an anaesthetic or sedative agent, prescribing was ‘off-label’ – ketamine is not currently TGA approved or indicated in the product information for treatment of depression. The consent form was therefore judged to lack information about the material risks of the use of ketamine in circumstances where the nature of prescribing ketamine for depression is experimental; and further, there was a lack of a documented evidence-based treatment protocol. Regarding regulatory issues pertaining to Schedule 8 (S8) drugs of addiction, there was failure to obtain prior authority in cases where ketamine was prescribed for a period exceeding 2 months. This has important implications for practitioners in Australia and New Zealand, as rules governing the use of S8 drugs in both countries are complex and practitioners should refer to country, state and territory specific regulations (see Table 1).
State, territory and country-based regulations relevant to prescribing ketamine for depression.
NSW: New South Wales; VIC: Victoria; QLD: Queensland; ACT: Australian Capital Territory; NT: Northern Territory; SA: South Australia; TAS: Tasmania; WA: Western Australia; NZ: New Zealand.
Apart from measurements of blood pressure, heart rate and oxygen saturation, there were no structured assessments of safety or side effects, including lack of monitoring for cumulative effects of repeated treatments. A recent systematic review (Short et al., 2018) found that there is currently limited or poor-quality information on the safety of ketamine given in repeated doses. Research studies in depression have mostly assessed acute safety outcomes for 4 hours after a single treatment, and therefore, there are minimal data on cumulative or long-term effects. High or repeated doses of ketamine in patients with chronic pain or in recreational users have been associated with potentially serious and possibly persisting toxic effects including hepatic dysfunction, urological problems (e.g. cystitis), craving or dependence and cognitive changes (Short et al., 2018). Therefore, it is the responsibility of each clinician proposing to give a course of ketamine treatment to be familiar with the literature on adverse effects and to devise and implement an appropriate framework for monitoring safety. An international expert group is currently developing the Ketamine Side Effect Tool (KSET), based on findings of the aforementioned systematic review, for monitoring potential acute, cumulative and long-term side effects of ketamine.
The Royal Australian and New Zealand College of Psychiatrists (RANZCP) do not recommend use of ketamine for depression (citing further research needed) but nevertheless provide recommendations for psychiatrists considering prescribing ketamine outside of a research setting. These include that they should ensure the patient is willing and able to consent and they should discuss ketamine therapy with peers (and preferably including a second opinion) and/or seek institutional review by a medicines advisory committee and/or seek consideration by an institutional research ethics committee (RANZCP, 2017). Likewise, the American Psychiatric Association consensus statement on the use of ketamine in the treatment of mood disorders (Sanacora et al., 2017), while it warns of risks, provides guidance to shape clinical practice that is already occurring – a pragmatic approach based on a ‘harm minimisation’ model.
Given the emerging nature of ketamine treatment, with guidelines recommending against routine clinical use, any clinician considering the clinical use of ketamine would be expected to first familiarise themselves with the literature on efficacy, safety and required monitoring, in order to derive an appropriate clinical framework for the use of ketamine. Such a framework would need to include at least the following: robust screening processes with determination of suitability of patients to receive ketamine (e.g. unipolar vs bipolar depression, personality disorder or substance misuse problems); appropriate pathways for referral and care, during and after a course of treatment (e.g. whether to require a general practitioner or psychiatrist referral); comprehensive medical and psychiatric assessment including the use of structured scales; a detailed consenting process which includes details of the evidence base available at the time (including its current status as an ‘experimental’ treatment in depression and that safety and side effects in prolonged use have not been established); discussion of alternative available treatments; a framework for determining duration of treatment, especially given the jurisdiction-specific regulatory restrictions; dosing guidelines and a treatment protocol informed by the evidence base; appropriate safety monitoring and follow-up; as well as credentialing of staff administering ketamine who have up-to-date basic and advanced life support training.
Ketamine treatment for depression offers hope for a new mechanism of action AD that may have advantages over traditional ADs in terms of efficacy and speed of action. Its success in research trials mean that many practitioners are eager to prescribe the drug to patients in clinical settings. However, a number of important considerations remain for practitioners contemplating treating patients in the ‘real world’, including the typical transient nature of any AD effect, the potential for dependence as well as possible side effects with repeated dosing. Any clinical use of ketamine would require the practitioner to have a detailed knowledge of the evidence base, be able determine where ketamine fits in relation to existing treatment-resistant depression algorithms, adhere to jurisdiction-based regulatory controls, undertake appropriate consenting of patients with full disclosure that treatment remains ‘off-label’, formulate evidence-based treatment protocols and implement a rigorous safety monitoring framework.
Footnotes
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors are involved in a large multicentre clinical trial of ketamine treatment for depression, funded by the NHMRC.
Funding
The author(s) received no financial support for the research, authorship and/or publication of this article.
