Depression is a widely-spread disease, with over 264 million people being affected worldwide.1 For a subset of patients suffering from major depressive disorder (MDD), administering low doses of the anaesthetic drug ketamine has changed treatment standards in the last 20 years. Back then, it was first shown to have measurable therapeutic effects within hours after administration.1 However, its exact mechanism of action remained a mystery – until now. Mikael Tiger (Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet and Stockholm Health Care Services, Sweden) and his team recently published a study showing ketamine’s mode of action, which might additionally pave the way for new treatment possibilities in the future.3
Deciphering ketamine’s effects via brain imaging
In 2018, Dr Tiger and colleagues published a review pointing out the potential of targeting serotonin (5-HT) 1B receptors in the treatment of depression.4 The claim was made mainly based on mouse studies and the previous finding that 5HT 1B receptor binding is less frequent in patients who suffer from MDD.5 Hence, the researchers asked themselves if ketamine might affect these specific receptors. To answer this question, the team around Dr Tiger recruited 30 patients and randomised them to receive either ketamine (n=20) or placebo (n=10). The effects on the brains of the study participants were recorded via positron emission tomography (PET) imaging before and after the treatment.3
Visible effects on 5-HT1B receptor binding
The PET imaging, which included a radioactive marker specifically binding 5-HT1B receptors, revealed an unknown effect of ketamine – it increased the 5-HT1B receptor binding in the brain.3 Binding to 5-HT1B receptor leads to the release of dopamine, which possibly explains the positive effects of ketamine in patients with depression.6 Once more, Dr Tiger and his colleagues convincingly showed its effect in MDD. Ketamine led to a response in more than 70% of patients who received the drug.3
5-HT1B receptors – a future target?
Ketamine has led to a paradigm shift in depression treatment. But despite being very effective, it does not come without side effects. The drug has been shown to lead to addiction in some patients.3 Hence, the main finding of the study might not actually be the mechanism of action of ketamine, but rather the role of 5-HT1B receptors. The authors make a strong statement, saying that “compounds that could combine the striking antidepressant effects of ketamine with longer duration of effect, and hopefully without the inherent risk of abuse well known for ketamine, could further revolutionize the field.”3 That said, we should definitely keep our eyes open for novel options entering the treatment landscape of depression in the near future.
- GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2018;392:1789-858
- Berman RM et al. Biol Psychiatry. 2000;47:351-4
- Tiger M et al. Transl Psychiatry. 2020;10:159
- Tiger M et al. Psychopharmacology 2018;235:1317-34
- Tiger M et al. Psychiatry Res. 2016;253:36-42
- Alex KD, Pehek EA. Pharm Ther. 2007;113:296-320