Establishing an esketamine clinic in Australia: Practical recommendations and clinical guidance from an expert panel

Major depressive disorder (MDD) can have severe impacts on function and quality of life. Up to one third of patients will have an inadequate response to their first line of treatment, with subsequent lines of therapy associated with lower remission rates and higher relapse rates. Recently esketamine has become available for Australian patients, and this agent provides an additional treatment option for those with MDD who have had an inadequate response to two or more antidepressant therapies during the current moderate to severe depressive episode. This paper provides an expert panel's practical recommendations and clinical guidance for establishing esketamine clinics in Australia.

Major depressive disorder (MDD) is a debilitating, recurrent disorder, with severe impacts on function and quality of life.The 12-month prevalence in Australia of MDD is 6% (Malhi et al., 2021).The initial goal of treatment is symptom relief, with a return to normal functioning, development of resilience and support for personal recovery and quality of life (Malhi et al., 2021).In addition to lifestyle measures and psychological support, most patients will require pharmacological treatment (Malhi et al., 2021).First-line pharmacological treatment typically involves a monoaminergic modulator, although treatment is tailored to patients to maximize efficacy and tolerability (Malhi et al., 2021).If the initial antidepressant is ineffective (<20% improvement of symptoms), an alternative agent may be selected, or augmentation with a second agent may be considered (Malhi et al., 2021).
However, each additional course of therapy is associated with lower remission-and higher relapse rates (Rush et al., 2006).
Esketamine nasal spray is a novel third-line treatment option for patients who fail to respond to treatment.The efficacy and tolerability of esketamine in this indication has been shown in three short-term studies (the TRANSFORM series), and two long-term studies (the SUSTAIN series) (Daly et al., 2019;Dold et al., 2020;Fedgchin et al., 2019;Ochs-Ross et al., 2020;Popova et al., 2019;Wajs et al., 2020).In a short-term study, esketamine co-initiated with a new oral antidepressant (OAD) significantly reduced depression scores (as measured by the Montgomery-Åsberg Depression Rating Scale [MADRS]) from baseline to week 4 by 4.0 points more than in patients treated with a placebo co-initiated with a new OAD.A post hoc analysis showed 69.3% of patients in the esketamine arm were responders and 52.5% of patients were in remission at day 28, compared to 52.0% and 31.0% in the placebo arm, respectively (Popova et al., 2019).In the longer-term SUSTAIN studies, esketamine plus an OAD significantly reduced the risk of relapse, and delayed the time to relapse in patients who achieved stable remission or who achieved stable response compared to placebo co-administered with a newly initiated OAD (Daly et al., 2019).
Based on these studies, the Therapeutic Goods Administration (TGA) approved esketamine in 2021.In Australia, esketamine hydrochloride (Spravato ® , Janssen-Cilag Pty Ltd.) is indicated for the treatment of major depressive disorder in adults who have not responded adequately to at least two different antidepressants of adequate dose and duration in the current moderate to severe depressive episode, and is to be commenced alongside a new OAD (Janssen-Cilag Pty Ltd, 2022).
The most recent clinical guidelines on the treatment of depression were developed prior to the registration of esketamine in Australia, and therefore lack detailed guidance regarding the use of esketamine (Malhi et al., 2021).Some recommendations have been published internationally (Kasper et al., 2021).While it is anticipated that esketamine will be included in future Australian treatment guidelines, this expert commentary was developed to serve as a guide for clinicians wishing to set up an esketamine clinic in Australia.

| METHODS
An expert panel (n = 11) comprising psychiatrists (n = 4), mental health care nurses (n = 4), pharmacists (n = 2), and others with experience establishing esketamine clinics (n = 1) was convened in Sydney to discuss the practical aspects of establishing esketamine clinics in Australia.Collectively, this expert panel has had 11 years' of experience treating patients with esketamine, including treatment of more than 300 individual patients.
The panel focused on developing a set of practical and clinical guidelines to assist with the implementation of esketamine clinics in Australia.
The panel was supported by industry representatives who were available to answer panelists' questions but did not participate in the panel discussions.The presence of representatives from Janssen at the panel discussions, even though they did not participate, does present a potential conflict of interest since Janssen is the manufacturer of esketamine.
Panel discussions were chaired by an independent professional facilitator.
An initial draft was developed based on the transcript of the panel discussion.Feedback on the initial draft was requested from all members of the panel.Changes were implemented accordingly, and this process was repeated with an additional two drafts prior to finalizing the recommendations.All authors endorsed the final recommendations.This work was developed in accordance with Good Publications Practice (DeTora et al., 2022).

| Practical considerations for esketamine clinic setup
The Australian Product Information stipulates that patients administered esketamine must undergo monitoring following administration of esketamine (Janssen-Cilag Pty Ltd, 2022).Clinicians are responsible for direct supervision of the patient while they self-administer the medication, and also for monitoring the patient for acute side effects such as hypertension, sedation, and dissociation until the patient is clinically stable; this can be up to a period of 2 h after administration (Janssen-Cilag Pty Ltd, 2022).In some rare cases, patients may require additional time for side effects to subside prior to discharge.This requires clinicians to have a suitable clinic space to administer and then monitor patients.These so-called Esketamine Clinics may be set up in hospital outpatient departments, private practices, or may be co-located within a general practice.Adequate governance structures, including contingency measures and sufficient trained staff to cover unexpected leave periods, should be in place, however, the expert panel acknowledged these would differ from setting to setting depending on multiple factors such as local clinical governance requirements.
Expert panel recommendations for esketamine clinic establishment 1. Adequately consider the cost, space and resourcing requirements prior to establishing the clinic.2. Provide a dedicated space for administration of esketamine and post-administration monitoring of patients.*Centers offering transcranial magnetic stimulation (TMS), or electroconvulsive therapy (ECT), may use the same treatment space.3. The treatment area should be in a low-stimulus environment, including low light and low noise, and include a comfortable place for the patient to relax, such as a reclining chair, bed, or a beanbag.4. Blood pressure monitoring equipment is required.5.It may be necessary to stagger appointments as infrequently patients may need to be monitored for more than 2 h (especially at the beginning of their treatment).6.A drug safe appropriate for the storage of Schedule 8 medications is required within the practice.Additional considerations 1. Patients' needs may be diverse and what works for one patient may not work for another.Other possible features to offer patients are (weighted) blankets, sweet flavored lollies (to help cope with dissociation and the unpleasant taste of the medication) and sensory deprivations including eye masks, and noise canceling headphones.Some patients may like to bring their own music or playlists.2. Space may need to be provided for a support person or companion pet if requested by the patient.
Individual care providers will need to ensure adequate resourcing, including employment of appropriately trained, engaged staff, who are willing to develop a therapeutic alliance with the patient.

| Practical considerations for prescribing and pharmacy
As For patients with elevated baseline blood pressure, consider lifestyle or pharmacologic therapies to stabilize blood pressure before commencing treatment with esketamine.Clinicians should ensure that uncontrolled hypertension is managed prior to the initiation of esketamine treatment.
However, the decision whether to delay esketamine should take into account the balance of benefit and risk in individual patients.
Expert panel recommendations for patient selection Clinical characteristics 1. Diagnosis of major depressive disorder 2. Inadequate response to two different antidepressants of adequate dose and duration in the current depressive episode 3. Aged 18 years or over 4. No comorbid substance use disorder 5. Are not at serious risk if there is an increase in blood pressure or intracranial pressure (that is, do not have a known aneurysmal vascular disease or a known history or intracerebral hemorrhage).6. Esketamine has been successfully delivered to patients with psychosis, however, this may be more challenging and additional precautions may be required for patients with co-morbid psychosis.Other considerations 7. Willing to commit to the esketamine treatment course (e.g.time off work to attend treatment sessions)

| Initiating treatment
Esketamine should be prescribed in conjunction with a newly initiated OAD (Janssen-Cilag Pty Ltd, 2022).However, this should be done with caution as withdrawal of a partially effective antidepressant may lead to an exacerbation of symptoms.Cross-titration and using an adequate dose of the new antidepressant should be considered.Specific patient factors need to be taken into account, such as medication history and potential interactions between the two OADs.To date, there is insufficient evidence to support initiating esketamine without a new OAD, although the expert panel hopes that there will be additional data to support this approach in the future.The ESCAPE-TRD study (NCT04338321) in Europe is currently evaluating the efficacy of esketamine in combination with a continuing antidepressant.It should be noted that for some patients it may not be appropriate to discontinue their current antidepressant treatment.In this case, the expert panel recommends continuing the current antidepressant medication and adding an additional appropriate OAD.It is not advised to cease an antidepressant medication and add esketamine and a new adjunctive medication simultaneously.

| Esketamine treatment sessions
It is important in the pre-administration consultation to discuss the The patient self-administers esketamine under direct supervision of their healthcare provider.Doses should be titrated based on the patient's response to treatment and tolerance of side effects.

Expert panel recommendations for esketamine administration
Prior to initiation of treatment 1. Perform a clinical consultation that includes a detailed medical history, physical examination, and medication review.2. Complete symptom and functional rating scales.There are a range of rating scales that are available (see examples in Table 1).*Clinicians should choose an objective rating scale to monitor the patient's treatment response (Malhi et al., 2021).*Consider the use of digital apps or other platforms to support the measurement of functional changes.3. Discuss esketamine including the mechanism of action, and the potential for side effects.Describe the differences between depersonalization, dissociation, and heightened sensory perception.4. Share the variability of patient experience. 5. Discuss the planned treatment process, the importance of adhering to suggested time intervals between treatments, and the importance of minimizing stressors in the hours prior to treatment sessions.6. Suggest items that the patient may wish to bring with them on the day (e.g., blanket, music); take into account that patients will differ on their preference for finding comfort during the session.7. Advise the patient: *Not to eat for at least 2 h prior to administration, and not to drink for 30 min prior to administration.*Not to use nasal corticosteroids or nasal decongestants for 1 h prior to administration.*To avoid concomitant use of alcohol.8. Discuss the consent process.9.After the consultation, follow up with an email including information about the treatment such as a patient guide, a link to a video on self-administration of treatment, and a consent form.10.Consider the opportunity for patients to hear from others with lived experience of esketamine treatment.On administration day 1.Assess blood pressure prior to administration.If blood pressure is elevated (>140 mmHg systolic, or >90 mmHg diastolic), then consider the risk of short term increases in blood pressure versus the benefit of esketamine treatment.Do not administer esketamine if an increase in blood pressure or intracranial pressure poses a serious risk.2. Advise the patient not to inhale too strongly (use a "whiff" not a "snort").This reduces the risk of post-nasal drip, and bad taste, and increases the chances the full effect of esketamine is experienced.*If the patient can taste the medication at the time of administration then this indicates that the patient should inhale less strongly.*Patients should administer the drug while reclined to 45 degrees, as per the drug administration recommendations.*The device should remain in the nose for 5 s following actuation to ensure the full dose is received.3. Directly supervise the patient self-administering esketamine.4. Ensure access to medication to treat side effects is available if required (e.g., antiemetics for nausea). 5.In the early stages of the treatment course, work with the patient to establish any preferences regarding room entry; for example, clinic staff using a bell to announce when they are entering the room, or the clinician touching the patient's shoulder to alert them that they are present.
T A B L E 1 Suggested rating scales.

| Adverse event management
It is important to prepare the patient for potential adverse events.
These may include psychotomimetic effects, sedation, and acute hypertension.Less frequent side effects include panic attacks and increased anxiety; though these are less likely to occur if the patient has been well-prepared ahead of treatment.Clinical studies have demonstrated that most adverse events for esketamine were transient, appeared shortly after dosing and were resolved by 2 h after dosing (Popova et al., 2019).Esketamine administration can also cause transient increases in systolic and/or diastolic blood pressure and blood pressure changes may last between 1 and 2 h (Popova et al., 2019).
Questionnaires such as the Ketamine Side Effect Tool (KSET) (Short et al., 2020) and the Clinician-Administered Dissociative States Scale (CADSS) (Bremner et al., 1998) can be useful for monitoring side effects during treatment sessions.
Expert panel recommendations for monitoring during treatment sessions 1.The patient should be checked regularly for blood pressure.
*Assess blood pressure 40 min post-esketamine administration, and subsequently as clinically warranted.*Patients with elevated blood pressure should be observed and remain in the clinic until their blood pressure has to baseline.2. Advise patients not to drive, operate heavy machinery, or make important decisions until the next day, after a restful sleep.3. Post-treatment monitoring can take between 1 and 2 hours depending on the individual patient.They can be discharged once assessed as clinically stable.4. Suggested scales for side effect monitoring can be found in Table 1.
Expert panel recommendations for management of adverse events 1. Discuss the potential for adverse events upfront.2. Rarely occurring panic attacks can be prevented using grounding techniques such as ice-packs in the hands, by using a stress ball to hold, weighted blankets, holding the patient's hands, deep breathing (e.g., box/square breathing, breath awareness), cognitive grounding (e.g., re-orientation, sensory challenge, naming categories).Reassure patients and maintain their orientation.3.In general, dissociation does not require medication as it is transient and should resolve within 2 h of treatment administration.*Patient reassurance and grounding techniques are key for patients experiencing significant levels of dissociation.*Cases of distress arising from dissociation and associated acute anxiety/panic can be resolved with lorazepam 1 to 2.5 mg or diazepam 5 to 10 mg. 4. The patient's level of consciousness should be monitored and crisis response enacted if there are signs of severe sedation or loss of consciousness.

| Long-term follow-up
Measurement-based care is recognized increasingly in mental health as a key driver for delivery of more personalized and high-quality clinical care (Hickie et al., 2019).As part of routine care, it is important to track long term patient outcomes using a robust, validated depression management tool as recommended by the Royal Australian and New Zealand College of Psychiatrists (RANZCP) guideline (Malhi et al., 2021).While data to date indicate esketamine is effective in the long-term with continued treatment (Capuzzi et al., 2021), continued follow-up of patients is important to assess long-term functional outcomes.This ensures the treating clinician can monitor for any future clinical challenges that require early intervention.
It is important that this includes multidimensional outcomes identified five key themes relating to the successful set up of esketamine clinics in Australia:1.Practical considerations for esketamine clinic set-up, including mul--term follow-up First and foremost, treatment of esketamine requires multidisciplinary team involvement.Depending on the clinical setting, this may include a general practitioner, nursing staff, and pharmacist in addition to the prescriber.
significant variability in treatment experience from patient to patient and also that there may be variability in what a patient experiences from one treatment to the next.It is important to summarize this information again immediately before treatment commencing.Encourage the patient to use positive suggestive techniques: that is, suggest the patient thinks of positive outcomes of the treatment prior to the treatment, as this can influence the patient's experience of side effects.If the patient has experienced recent distress (e.g., on the day of treatment a major argument at work or with their spouse) then consider postponing the treatment session.Generally, patients who are depressed and have associated memory and cognition deficits may not retain information well, and therefore repeated patient education and reassurance is important in this setting.
such as functional participation in employment or education, social roles, suicidal behavior, alcohol and other substance misuse and physical health status.It is now possible to combine the power of mobile, personal, and digital technology tools with individual selfreport and repeated frequent assessments, to describe the patterns of relevant outcomes in those receiving novel treatments in regular clinical service settings.This data is not only of benefit to the individual patient, but it can also be aggregated to assess the relative contributions of novel treatments, like esketamine, to enhance clinical practice and provide more effective mental health care.Collection of long-term functional outcome data is not only of value clinically, but is also of interest to potential payers for example Government, Department of Veteran Affairs, and Private Health Insurers.4| CONCLUSIONThis paper provides guidance on establishing esketamine clinics in Australia, including the treatment room setup, and practical considerations prior to, during, and after administration of esketamine.DD, WB and JSC have participated in Janssen-Cilag's SPRAVATO Early Access Program.EMS has received honoraria from Janssen for speaking engagements related to the Esketamine QoL Study.GJ and JK are employees of Janssen-Cilag Pty Ltd, Australia.
Esketamine Clinic is necessary to ensure clear records are maintained of medication dispensed, used and discarded, and that adequate supplies are on hand.The expert panel recommended that the pharmacy is notified which patients are scheduled for treatment prior to each treatment session, to allow for dispensing, documentation and, if applicable, delivery of medication to the clinic.
a Schedule 8 medication, state/territory-based prescribing restrictions apply to esketamine.Please refer to your local Ministry of Health for the specific requirements that apply in your jurisdiction.Clinics should have a drug safe to store the medication in accordance with Schedule 8 regulations.A good relationship with the local pharmacy is critical.They will require sufficient space to securely store stock of esketamine devices within their drug safe.Further, good communication with the (PTSD).Based on the clinical experience of the panel, patients with comorbid PTSD may demonstrate reductions in anxiety symptoms and subjectively report a reduction in hypervigilance.