Ketamine for treatment-resistant depression: what the evidence shows

Treatment-resistant depression (TRD) is commonly defined as depression that has not responded adequately to at least two appropriate antidepressant trials. It can involve years of illness, repeated absences from work, strained relationships and substantial costs to the healthcare system. Ketamine has attracted attention because some people report a marked reduction in depressive symptoms within hours, instead of waiting several weeks for a conventional antidepressant to take effect. For community pharmacists, separating a promising signal from evidence that supports sustained, routine prescribing is therefore a daily professional responsibility.

This article examines intravenous ketamine and intranasal esketamine, the evidence behind their antidepressant effects, and the implications for medicines information, referral and follow-up in Australia. The focus is not simply on whether someone feels better after one infusion; it is on what can reasonably be expected, how benefits and harms should be discussed, and how these treatments fit with psychological care and other evidence-based options. That distinction is essential when patients are weighing hope, expense and uncertainty.

Defining the treatment-resistant depression context

TRD is not simply a label for “has not tried enough”. Before it is diagnosed, clinicians should check whether earlier antidepressant doses were adequate, whether treatment lasted long enough, whether adherence and side effects were addressed, and whether a bipolar-spectrum or psychotic illness has been overlooked. Depression can also be maintained by alcohol, cannabis, sleep disorders, untreated pain, social isolation or financial stress. A thorough assessment establishes whether the episode remains depressive and identifies goals that matter to the patient, such as returning to work or caring for family, rather than treating a questionnaire score as the only outcome.

Australian guidance does not position ketamine as a routine first-line antidepressant. It is generally considered within specialist assessment for people whose depression has persisted despite adequate treatment. Depending on severity and preference, options may include switching or augmenting antidepressants, psychological therapy, structured exercise and social support, repetitive transcranial magnetic stimulation, and electroconvulsive therapy. ECT remains particularly relevant when depression is severe, psychotic, catatonic or accompanied by significant suicide risk, although access and acceptability vary.

None of these approaches is automatically best for every patient. A person may value the speed of ketamine while another prefers a treatment available through a GP and Medicare-subsidised psychology under a Mental Health Treatment Plan. Pharmacists can clarify these pathways without presenting one service as a cure. They can also support early help-seeking by signposting reputable mental health resources alongside local primary care and crisis contacts, particularly when a patient feels unable to navigate waitlists alone.

Weighing the strength of clinical evidence

Ketamine is a dissociative anaesthetic with antagonism at the N-methyl-D-aspartate receptor, though its antidepressant action probably involves downstream changes in glutamate signalling, synaptic plasticity and cortical networks rather than one simple receptor effect. Esketamine is the S-enantiomer used in the approved nasal product. Depression itself is heterogeneous, so a mechanism cannot predict who will respond. Evidence for intravenous ketamine must also be distinguished from evidence for the licensed esketamine spray; oral lozenges, intramuscular products and compounded formulations cannot simply inherit the findings from another route.

Placebo-controlled trials and systematic reviews suggest that ketamine and esketamine can produce larger short-term reductions in depressive symptoms than placebo in selected adults with TRD. Improvements often emerge during the first week of an intensive treatment phase. The evidence is more convincing for a short-term group benefit than for a precise individual response rate, because studies differ in diagnosis, baseline severity, dosing schedule, outcome measures and follow-up. Network meta-analyses have also found ketamine-related options promising among treatments for TRD, while finding important uncertainty around longer-term effectiveness and tolerability.

Durability is the central weakness in the evidence base. Some trials have follow-up measured in weeks, and relapse has been observed as repeated treatments are reduced or stopped. There is limited high-quality evidence showing how often a person remains well for six or twelve months without a maintenance programme. Selectively retaining participants who respond well can make results look stronger than they would be in ordinary practice, while people with co-occurring substance use, psychotic symptoms or severe physical illness are often underrepresented. An acute response does not establish a durable remission.

Placebo responses, expectations and difficulty maintaining blinding add further complexity. Sedation and dissociation can reveal whether a participant has received active treatment, and some outcomes depend heavily on self-report. Nevertheless, blinded trials and consistent benefit across several studies make a wholly placebo explanation unlikely. The fair position is neither dismissal nor a claim of a guaranteed cure: ketamine has a credible short-term effect, while questions remain about who benefits, how long the benefit lasts, which route and schedule should be used, and how relapse should be prevented.

Benefits, risks and unanswered questions

For a carefully selected patient, the speed of response is itself meaningful. A reduction in suicidal ideation, if it occurs, may happen before mood and function fully improve, which makes early follow-up and a clear safety plan essential. Benefits reported in research include less severe depressed mood, reduced hopelessness and renewed engagement with treatment. These outcomes are more useful when framed as possibilities rather than promises. Some people experience no antidepressant benefit, and a perceived “reset” can reflect altered perception, temporary euphoria or the emotional impact of receiving an intensive treatment rather than lasting remission.

Acute adverse effects include dissociation, sedation, dizziness, nausea, headache and blurred vision. Blood pressure and heart rate may rise, and rare events include hypertensive crises, arrhythmia, new psychosis or severe agitation. Screening should address cardiovascular disease, uncontrolled hypertension, previous mania or psychosis, current substance use, pregnancy and breastfeeding, as well as interacting medicines. Benzodiazepines, opioids, other sedatives and alcohol can increase impairment; medication review must lead to coordinated decisions rather than abrupt patient-directed changes. Nasal esketamine is administered under supervision with blood pressure and pulse monitoring and at least two hours of observation under approved product information.

Long-term evidence is less reassuring, particularly when infusions are repeated indefinitely. Anaesthetic and psychotomimetic effects can be misused, and people with a history of ketamine or other drug use deserve careful assessment instead of automatic exclusion or dismissal. Consent should address dependence potential, diversion, driving, the expectation that dosing is not taken home, and what happens if mood worsens. In Australia, sudden deterioration or suicidal thinking warrants immediate clinical assessment; Lifeline is available on 13 11 14 and the Suicide Call Back Service on 1300 659 467. A treatment plan should name who reviews warning signs outside clinic hours.

Australian pharmacy and regulatory realities

Regulation shapes what Australian pharmacists can actually offer. Esketamine nasal spray is approved by the TGA for treatment-resistant depression in adults and is PBS-listed under specialist access criteria. It is supplied through specialist pathways and administered under supervision, rather than dispensed as an ordinary take-home antidepressant. Intravenous ketamine used for depression is generally off-label and does not receive the same PBS subsidy; private consultation and administration fees may still apply even when the medicine itself is subsidised. State and territory drugs and poisons legislation also affects how non-approved formulations are stored, supplied and compounded.

In Melbourne, Sydney and Brisbane, ketamine programs may operate in private clinics, day hospitals or specialist public services, with referral routes and waiting times varying widely. Regional patients can face additional travel costs and waits for psychiatry, while telehealth has broadened access to psychological care but not eliminated access issues. A GP Mental Health Treatment Plan can support Medicare-subsidised psychology, yet it does not fund a ketamine course. Pharmacists may encounter requests for repeat antidepressants or over-the-counter sleep products before a patient reaches a prescriber, making it useful to ask about current suicide risk, substance use and the care plan rather than simply discussing the medicine request.

Quality assurance matters in this market. AHPRA registration of the treating practitioner, the product being supplied, fees, emergency arrangements and continuity of psychiatric oversight can all be checked before treatment begins. Pharmacists can contribute through medication reconciliation, interaction screening, blood pressure review where appropriate, patient education and follow-up, including monitoring with a validated tool such as the PHQ-9. Reporting suspected adverse reactions through the TGA’s adverse event system also supports safer practice. Where pharmacists have the credentials and scope to administer treatment, a written protocol should cover observation, escalation and handover.

Turning evidence into responsible practice

Shared decision-making is where evidence becomes usable. Before treatment, the prescriber and patient should agree on the target symptoms, the likelihood of short-term benefit, the uncertainty about maintenance, baseline measures of mood and function, and how progress will be judged. A response should not be treated as permission to ignore psychosocial contributors or other prescribed medicines. Psychological treatment, sleep, physical activity, alcohol and cannabis reduction, and practical social support remain useful alongside ketamine, according to the patient’s goals and preferences.

Pharmacy review should focus on discrepancies that could undermine safety: an unsupported switch to a different ketamine route, unclear monitoring, concurrent sedatives, missing psychiatric follow-up or a plan to stop all conventional treatment without discussion. Broader pharmacist perspectives can help connect emerging clinical debates with the practical demands of community practice. Clear documentation should include the agreed indication, formulation, route, schedule, consent, observed outcomes and review date, with significant changes communicated to the prescriber and the patient’s usual healthcare team.

Australian pharmacy teams can help make access more equitable by checking regional and telehealth options, explaining the difference between subsidised medicine and private service fees, and supporting continuity when a patient moves between services. They can also reinforce that a promising response is not a cure and that repeated prescribing should follow a documented review rather than an open-ended arrangement. If a patient asks you about ketamine, arrange a documented evidence-and-safety review with the treating clinician that covers expected benefit, acute risks, monitoring and a relapse plan before any further supply.