Many people with major depressive disorder get no relief from current treatments. Newer combinations of existing medications might help, researchers report in the May 6 issue of JAMA Psychiatry.

Persistent low mood, a loss of interest in previously enjoyable activities, lack of energy, feelings of worthlessness, poor concentration and appetite, and suicidal thoughts are symptoms of major depression. A significant percentage of adults suffering from it don’t get much relief from conventional antidepressant therapies. Doctors then have to look for alternative therapies to help these patients.

“At least one-third of adults with depression do not respond to at least two trials of conventional antidepressant therapies. These patients are considered to have treatment-resistant depression, and alternative therapies should be considered for such patients,” says UConn School of Medicine psychiatric epidemiologist T. Greg Rhee.

Rhee and colleagues at Harvard, Yale, and the University of Toronto, among others, have two recent studies in JAMA Psychiatry evaluating existing drugs used in new ways to treat major depression. One looks at the efficacy of intravenous ketamine, and the other at combinations of antidepressants with anti-psychotics.

Ketamine was originally developed as a fast-acting surgical anesthetic. There is also evidence it can rapidly alleviate depression in some individuals. The US Food and Drug Administration has approved esketamine, a version of the ketamine molecule, in nasal spray form as a treatment for depression. But intravenous ketamine is still being evaluated.

The researchers analyzed 26 existing randomized controlled trial studies that compared intravenous ketamine with controls. They found that ketamine was more effective than a placebo over the short term of a few days, but the effects were less pronounced after a few weeks. And ketamine seemed to work about as well as esketamine. Both drugs were very effective in rapidly reducing suicidal impulses in people who were in immediate danger of harming themselves.

Their second JAMA Psychiatry study compared how well combinations of antidepressants with antipsychotics worked in people with treatment-resistant depression. The researchers performed a meta-analysis of 22 studies, looking both at reduction of depressive symptoms and at side effects of the drugs. They found some antipsychotics were significantly more likely to help decrease symptoms of depression. But the antipsychotic that was most likely to help, lumapeterone, was also most likely to be discontinued by the patient because of side effects.

“These studies could potentially guide practicing psychiatrists and other clinicians to consider these new approaches of modalities for patients with moderate to severe depression, who did not previously respond to conventional antidepressant therapies,” says Rhee.

Rhee also adds, “we plan to conduct population-level epidemiologic studies to further examine effectiveness and safety profiles of these treatment options.”