A new study shows longer-term use of generic ketamine for severe depression is safe and effective, but researchers say access to the low-cost option remains limited by funding gaps.
Generic ketamine has been successfully used to help people with treatment-resistant depression (TRD) for up to six months, reducing symptoms and improving overall quality of life, new research shows.
The study, published in the Journal of Affective Disorders, analysed real-world clinical data from 65 patients treated with generic racemic ketamine - a low-cost formulation of ketamine - between 2021 and 2024. The drug was found to be effective, safe and well tolerated when treatment was carefully monitored.
The study led by UNSW Sydney and Black Dog Institute adds to growing evidence of the antidepressant effects of generic ketamine, which is far cheaper than the patented S-ketamine nasal spray, Spravato, which was added to Australia's Pharmaceutical Benefits Scheme (PBS) for TRD this year.
"There's a huge difference in costs, but both have been shown to be really effective," said senior author Professor Colleen Loo , a clinical psychiatrist and researcher with UNSW and Black Dog Institute. "But only one is subsidised by the government and formally approved, while the other more affordable option is used off-label."
Spravato costs between $500 and $900 per dose, though patients only pay up to $31.60 per script under the PBS, while generic racemic ketamine costs $5 to $20 per dose.
Real-world evidence from clinical settings
The researchers analysed data from 65 people with Major Depressive Disorder or Bipolar Affective Disorder, who had previously failed to respond to at least two antidepressant medications.
The patients were treated with generic racemic ketamine for an average of five months - ranging from two to six months - across inpatient and outpatient settings at three clinics which are part of the CARE Network .
Ketamine was given by injection or taken orally, anywhere from twice a week to every three weeks, based on individual responses and tolerability.
Treatment outcomes and patient response
Depressive symptoms decreased notably during the first eight weeks and remained stable over six months.
More than a third (35%) of patients responded to treatment within eight weeks, increasing to 44.2% by six months, while just over a quarter (26.2%) of patients were in remission at their last check in. Suicidality scores also improved for 73.3% of patients, as did quality of life scores.
"We've seen the great impact generic ketamine can have for people with treatment-resistant depression," said first author Clara Massaneda-Tuneu, a psychiatrist and PhD candidate at UNSW and Black Dog Institute.
"These people are often feeling hopeless after receiving other treatments which haven't worked, so the fact they can receive a treatment that not only improves their mood, but sustains the improvement, is quite impressive."
The treatment was well tolerated by most patients, and no serious adverse events or cases of misuse were reported.
The clinics used the Ketamine Side Effect Tool (KSET) during treatment, a structured framework that guides clinicians on what to assess before, during and after treatment.
"It's important to monitor side effects and safety for all kinds of treatments - especially ketamine or psychedelics," said Dr Massaneda-Tuneu. "These are novel treatments, and we cannot just rely on self-reporting from patients as it isn't always reliable."
Study fills key evidence gap
The study follows a previous four-week randomised controlled trial (KADS), led by Prof. Loo, which demonstrated the short-term safety and effectiveness of generic ketamine for TRD.
"Research studies on generic drugs tend to focus on the first month of treatment, because these studies are very expensive," Prof. Loo said. "Typically, only patented new drugs, with commercial sponsorship, get studied at that level for one to two years.
"But in the real world, in the clinic, ketamine is used for weeks to months, and sometimes even longer, so we needed to examine the impacts when it's given longer term."
The study was retrospective and relied on clinical data, which led to incomplete records at some timepoints and excluded patients who discontinued treatment before eight weeks. There was no control group, making it difficult to isolate the effects of ketamine from other treatments like antidepressants and therapy.
The researchers are now conducting a clinical trial directly comparing generic racemic ketamine and S-ketamine in a controlled environment, but say the current study offers valuable insights into how ketamine works in real-world settings.
"In the reality of daily life people are changing antidepressants, changing therapists and all sorts of things," Prof. Loo said. "So it's very important to examine what treatment looks like in that context."
The researchers will continue to track retrospective data so they can examine outcomes over several years to understand the effectiveness and safety of ongoing treatment.
Bridging the divide between evidence and access
While demand for the treatment is growing, use of the lower cost option has been limited by a lack of coordinated government support to help translate the research into accessible treatment.
As generic ketamine lacks a commercial sponsor, there is currently no mechanism to progress it through the TGA approval process - a necessary step before Medicare funding can be considered, regardless of how strong the evidence is, Prof, Loo said.
"All our research and clinical work shows that ketamine is the most important development in treatment for severe, difficult-to-treat depression, in the last 80 years. The next challenge is to get the treatment funded by Medicare, so that everyone who needs this treatment can access it," said Prof. Loo.
