A New Lead in Depression Treatment: Ketamine and Anhedonia
A major depressive episode, or MDE, is not technically a disorder on its own. It shows up as a feature of larger conditions, including major depressive disorder (MDD) and bipolar disorder (BD). For a clinician to label something an MDE, a person has to carry either a depressed mood or a flattened sense of interest and pleasure across most of their daily life, and it has to stick around for two weeks or longer. The mood has to depart from what is normal for that individual, and it has to drag down how they manage work, school, relationships, or other parts of life that matter to them.
One piece of that picture has its own name: anhedonia. It describes the shrinking of interest and the draining of pleasure from things that used to feel good. A recent study put anhedonia at the center. The problem is that the usual antidepressants tend to do little for it, and they can add their own troubles: blunted reward and emotion, reduced libido, and anorgasmia (the inability to reach orgasm). There is no FDA-approved medication aimed specifically at anhedonia. More than half of people diagnosed with bipolar disorder report anhedonia during a depressive stretch, and the symptom tracks with completed suicide among those in a major depressive episode. So a working treatment is not a minor want.
A research group at the National Institutes of Health turned to ketamine to see whether they could move the needle. Ketamine is best known as a veterinary anesthetic and, in other settings, as a club drug. What makes it interesting here is its mechanism. It blocks the glutamatergic NMDA receptor, and that unusual route has pushed it forward as a candidate in a fresh category of fast-acting antidepressants, the NMDA receptor antagonists, which can raise mood in hours rather than the weeks older drugs demand.
Getting into the study was not easy. Thirty-six people took part, between the ages of 18 and 65, all with bipolar I or II and none with psychotic features. Each had been in a major depressive episode for a minimum of four weeks, and each had already tried at least one adequate course of antidepressants without relief before being admitted. The design was double-blind and randomized, running across four weeks. Participants got one intravenous dose of ketamine hydrochloride at a subanesthetic level of 0.5 mg per kilogram, and on a separate occasion they received a placebo infusion of 0.9% saline. Doses came two weeks apart. To stay in the study, a person needed a MADRS score of at least 20 on the morning of each infusion.
The team also ran brain scans on a portion of the ketamine group, using positron emission tomography (PET). PET follows radioactively tagged glucose through the brain and lights up the regions drawing energy.
The scans pointed to two areas. Ketamine switched on the dorsal anterior cingulate cortex, sitting toward the front and middle of the brain, and the putamen, buried in the right hemisphere. People with depression often struggle to picture positive or rewarding experiences, and that difficulty fits with faulty circuitry in exactly this dorsal anterior cingulate region. When those areas pick up activity, it may signal a renewed pull toward pleasure, or a restored capacity to look forward to it, the researchers suggested.
The headline result: next to placebo, ketamine cut anhedonia within 40 minutes. Nearly as striking, the effect held for as long as 14 days in some participants. And when the investigators statistically removed the influence of the patients' other depressive symptoms, the drop in anhedonia was still there, which argues that ketamine works on anhedonia in its own right rather than merely dragging it along with a general lift in mood.
Given that nothing on the approved list targets anhedonia, and that the symptom cuts across many psychiatric diagnoses, a drug that acts on it inside an hour is a finding worth chasing. The standard options, such as selective serotonin reuptake inhibitors (SSRIs), barely touch anhedonia in MDD and carry their own costs. For people with bipolar disorder, nobody has even studied whether mood stabilizers affect anhedonia at all.
The authors read their data as a reason to test other NMDA receptor antagonists for the same clinical use. They also raised the possibility that certain forms of depression, melancholic depression among them, might respond especially well to ketamine and compounds like it. In their view, the work supports NMDA receptor antagonists as a route to treating depression across the board. Work continues on more usable delivery methods, a nasal spray version of ketamine among them, along with other experimental antidepressants in the same family.
A caution belongs here. Ketamine is not an FDA-approved treatment for depression, and it cannot be prescribed for any purpose. Its common role remains veterinary anesthesia, and misuse can bring on hallucinations, delirium, and amnesia. Still, the evidence suggests ketamine could become a genuinely useful medical tool against depression.
Sources: Lally, N., Nugent, A., Luckenbaugh, D., Ameli, R., Roiser, J., & Zarate, C. (2014, October 14). Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. NIH/National Institute of Mental Health. (2014, October 20). New antidepressant: Rapid agent restores pleasure-seeking ahead of other antidepressant action. ScienceDaily. Reporting by Laura Wells.