The double-blind, randomized clinical trial is the first to assess combining ketamine with a low-cost protective learning program, researchers note.
They add that the findings are an important step toward long-lasting depression treatment for millions of patients whose depression does not improve following first-line therapies.
“One of the biggest challenges in psychiatry and psychology is seeing evidence of longer-term benefits and longer-term compliance,” lead investigator Rebecca B. Price, PhD, associate professor of psychiatry and psychology, University of Pittsburgh, told this news organization.
“Anything that can get somebody well quickly and keep them well for some length of time is really exciting – and a whole paradigm shift for how things have been done up to now,” Dr. Price said.
The findings were published online in the American Journal of Psychiatry.
About one-third of patients with depression remain treatment-resistant even after trying different medications at different doses and at different combinations, the investigators note.
Ketamine and esketamine, a nasal spray formulation of the drug, have been shown previously to improve symptoms in patients with TRD. While the benefits are evident within a few hours of treatment, the effects often wane after just a few weeks.
Ketamine and esketamine must be administered in a clinical setting and patients must be monitored for at least 2 hours after treatment. Repeat dosing is costly, both in time and expense, so clinical researchers have been studying ways to extend the drug’s effects without additional treatments.
The new study combined ketamine treatment with a computer-based active automated self-association training (ASAT) program that the researchers developed. It uses positive words and imagery to promote positive self-image and self-worth.
The trial included 154 adults with treatment-resistant unipolar depression whose symptoms persisted after therapy with at least two medications. Participants received an IV infusion of ketamine 0.5 mg/kg plus active ASAT (n = 53), saline plus active ASAT (n = 51), or ketamine plus sham ASAT (n = 50).
The active program used words like “sweet,” “lovable,” and “worthy” that appeared on the screen interspersed with images of people smiling and the patient’s own photo. Participants were also asked to complete certain mouse-tracking tasks during the session.
The sham ASAT was similar but included neutral words and images. ASAT and sham ASAT were delivered twice daily over 4 consecutive days for 20 minutes.
Results showed that ketamine rapidly and significantly reduced depression scores within 24 hours of treatment (group-by-time interaction: standardized beta, –1.30; 95% confidence interval, –1.89 to –0.70).
Depression scores in the ketamine-plus-ASAT group remained low and stable over a 30-day period, compared with the saline-plus-ASAT group (standardized beta, –0.61; 95% CI, –0.95 to –0.28).
Participants who received ketamine plus sham ASAT saw initial improvement in symptoms immediately following infusion, but depression symptoms returned after a few weeks.
While researchers hoped to see positive effects from ASAT, “I certainly did not expect to see something so clear to jump right out,” Dr. Price said.
The investigators are now examining whether the computer program can be administered effectively remotely and whether its effects are equally beneficial following treatment with esketamine.