The Norwegian Medical Products Agency (Direktoratet for medisinske produkter or DMP) has published its health technology assessment (HTA) of intravenous ketamine for treatment-resistant depression (TRD). It said that it was commissioned to conduct the review in the context of growing interest in ketamine’s potential in the disorder.

The agency reviewed 19 randomised controlled trials (RCTs) and 2 other trials (total N=1,761; none of the studies were conducted in Norway) to reach the following conclusions (lifted directly from the document):

• Ketamine vs. ECT: Multiple ketamine infusions probably improve response rates more than ECT (moderate certainty evidence).
• Ketamine vs. saline: Single ketamine infusions probably improve response rates more than saline (moderate certainty evidence).
• Ketamine vs. midazolam: Single ketamine infusions may/probably improve response rates more than midazolam (low/moderate certainty evidence).
• Ketamine vs. esketamine: There may be little or no difference in response rates between single infusions of ketamine and esketamine (low certainty evidence).
• Ketamine ≥0.5 mg/kg vs. <0.5 mg/kg: A single high dose ketamine infusion may improve response rates (slightly) more than low dose ketamine (low certainty evidence).

Results of its analysis for multiple infusions and long-term (>3 month) efficacy were “generally inconclusive due to very low certainty.”

The group chose ECT as the comparator for the purposes of its health economic evaluation in the Norwegian context. Its cost-comparison analysis [1] suggested that the cost of a treatment series involving 6 infusion sessions over the course of 3 weeks was NOK 18,000, ($1,800) vs. NOK 28,000 – 42,000 ($2,800 – $4,200) for a twice- or thrice-weekly regimen of ECT. (For a single treatment with IV ketamine it was about NOK 3,000 ($300) versus one ECT treatment at NOK 4,700 ($470).)

Given the fact that ketamine is generic (the authors use a price of NOK 306 ($30) for the cost of all consumable materials used in each IV ketamine session, which includes things like a venous cannula and eye mask as well as the ketamine itself) and there is no patented drug product involved in ECT, the primary cost in both treatment series was personnel. [2]

Ketamine is already used off-label for TRD in the country, but such use has been relatively niche.

The Ketamine Unit at Østfold Hospital’s DPS Nordre prepared a 24-page protocol for the use of ketamine in TRD (PDF, machine-translated to English PDF). (Back in 2022, the hospital submitted an application for ketamine for TRD’s approval, which led to the present HTA report from the DMP.) Among a trio of public hospitals, around 350 patients have been treated via that protocol—we preview the outcomes in our wrap-up, below.

That protocol includes provisions of some kind of psychotherapy following the ketamine infusion, integration, as well as preparatory sessions, regular check-ins throughout the induction phase, and stipulations around what treatment rooms should feature (dimmable lights, duvets, noise-cancelling headphones, and so on).

“While not a universal solution”, the report writes, “ketamine’s potential inclusion in Norway’s specialist healthcare system could reduce financial barriers and substantially improve outcomes for both patients and their families.”

Despite EMA approval for TRD, Johnson & Johnson’s esketamine nasal spray (Spravato) has not received public financing approval in the Norwegian health system. That means it’s out of reach for the vast majority of Norwegians, who rely on the public health system.

But, the studies included in the HTA had relatively small sample sizes and heterogenous designs, as well as short follow-up periods. That, coupled with the lack of Norwegian studies, limits the strength of the evidence and its applicability to the national context, the agency states.

What’s more, despite potentially offering a more efficient alternative to ECT, the authors note that the successful integration of IV ketamine for TRD into the health system “would require clinician training, standardised protocols, and equitable access to avoid socioeconomic disparities.” There is also a need for policymakers to “address concerns around ketamine’s potential for misuse and abuse”, they add.

Still, their conclusion is broadly positive: “Intravenous ketamine is probably comparable or less costly than ECT provided sufficient capacity in terms of personnel.”

It is unclear what impact the analysis will have on real-world practice.

Cecilie Byholt Endresen, President of the Norwegian Association for Psychedelic Science, told Psychedelic Alpha that, “while this is not yet a formal reimbursement decision, the HTA is an important step toward potential inclusion in the public healthcare system.”

“It will now serve as the basis for deliberations by the Ordering Forum (Bestillerforum) and the Decision Forum (Beslutningsforum),” she continued, “which are expected to rule on a possible introduction into the public specialist health service in August.”

Even still, a positive decision at the national level would be followed by individual, local hospitals to implement.