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major depressive disorder. Six years later, a study of 17 patients with treatment-resistant major depressive disorder found that 71% experienced a substantial reduction in symptoms - more than 50%- within just 24 hours of receiving ketamine. In contrast, the same participants showed minimal improvement after receiving a placebo saline injection. A retrospective review at a private clinic in SA found that among 154 patients receiving ketamine infusions for depression, the response rate was 60.6% and remission 32.4%. Suicidal ideation dropped by 50%. Why is ketamine gaining popularity? Rapid Antidepressant Effects: Ketamine has been reported to provide fast-acting antidepressant benefits in individuals with treatment-resistant depression, often within hours of administration. Reduction in Suicidal Ideation: It may significantly decrease suicidal thoughts, providing a crucial intervention for those in crisis. Anxiety Relief: Ketamine may help alleviate symptoms of anxiety disorders, including generalised anxiety disorder (GAD) and social anxiety disorder (SAD). Pain Relief: Ketamine is well known for its pain-relieving (analgesic) properties. Dissociative Effects: Some individuals report experiencing an “out-of-body” sensation, which may offer a different perspective on their thoughts and emotions. Neuroplasticity : Ketamine has been shown to promote neuroplasticity, supporting the growth of new neural connections and potentially aiding recovery from various mental health conditions. Why is there concern regarding ketamine use in clinical depression? • Ketamine is an anaesthetic agent, and high doses can cause deep sedation and loss of consciousness. Large doses may lead to dangerously slowed breathing and increase the risk of death. • Research has linked long-term ketamine misuse to several harmful effects, especially among individuals who use the drug daily. • The most serious of these is ketamine-induced ulcerative cystitis, commonly called “ketamine bladder.” • Other common side effects of ketamine include increased blood pressure and heart rate, hallucinations, delirium, and irrational behaviours. After ketamine infusion, patients may experience anxiety, confusion, dizziness, drowsiness, and intense euphoria. • Ketamine has been associated with rapid development of tolerance, which may require increasing doses. • The level and frequency of dosing are connected to the risk of hepatotoxicity, especially with prolonged infusion or frequent use in therapeutic settings. What about the South African context? • In South Africa, ketamine is approved by the South African Health Products Regulatory Authority (SAHPRA) solely for use in the induction and maintenance of general anaesthesia, as well as for minor surgical or diagnostic procedures. • Its use for treating mood disorders, including depression, is not currently authorised. • Ketamine is classified as a Schedule 5 substance, which restricts its prescribing and distribution. Although off-label use for treatment-resistant depression has gained local attention, there is no formal SAHPRA approval or national clinical guideline supporting this indication. • Professional organisations have cautioned against the increasing number of clinics offering ketamine infusions for depression without robust oversight or solid evidence. • These concerns are exacerbated by ongoing supply pressures and the risk of diversion, underscoring the need for stringent regulation. Below is a case vignette illustrating the application of ethical principles of ketamine use in psychiatric practice. A 49-year-old female high-school teacher from Soweto, presented with a 10-year history of episodic major depressive disorder. Her condition progressively worsened over the past 18 months, leading to functional decline and absenteeism from work. She reported persistent low mood, anhedonia, psychomotor slowing, poor sleep, and episodic passive suicidal ideation without plan or intent. She had previously undergone various pharmacological trials, including: • Two SSRIs (sertraline, escitalopram) • One SNRI (duloxetine) • Mirtazapine • A trial of atypical antipsychotic augmentation (quetiapine) She was unable to complete cognitive-behavioural therapy because of difficulty with engagement during depressive episodes. She expressed interest in Electroconvulsive Therapy (ECT). The psychiatrist informed her that bilateral ECT carries a risk of short-term and sometimes persistent memory impairment, which may impact her ability to return to teaching. He encouraged her that some patients consider ketamine therapy because it is less disruptive to cognition, and they experience improvement within days. He discussed off-label IV ketamine infusions, which were available at a private ketamine- therapy centre in Sandton. Ethical considerations Autonomy • The psychiatrist should provide full disclosure of treatment options, including evidence- based risks, costs, and MHM | 2025 | Volume 12 | Issue 5 | Evaluating the ethical implications of off-label ketamine use in clinical practice MHM Issu 5 | 2025 | MENTAL HEALTH MATTERS | 21 MHM