Ketamine, recently the focus of research as a rapid-acting antidepressant that can ease symptoms within hours instead of weeks, is now being studied as a fast-acting mood-lifter to treat bipolar patients.
In a National Institutes of Health (NIH) trial, the drug — sometimes referred to as Special K and long used as an animal anesthetic and a party drug — restored pleasure-seeking behavior independent of its antidepressant effects, according to researchers.
In fact, researchers report that within 40 minutes after a single infusion of ketamine, treatment-resistant depressed bipolar disorder patients experienced a reversal of a key symptom — a loss of interest in pleasurable activities. What’s more, that reversal lasted up to 14 days, researchers reported.
Brain scans traced the drug’s action to boosted activity in areas at the front and deep in the right hemisphere of the brain, according to researchers.
“Our findings help to deconstruct what has traditionally been lumped together as depression,” explained Carlos Zarate, M.D., of the NIH’s National Institute of Mental Health (NIMH).
“We break out a component that responds uniquely to a treatment that works through different brain systems than conventional antidepressants — and link that response to different circuitry than other depression symptoms.”
Considered one of two prime symptoms of both depression and bipolar disorder, anhedonia is the loss of the ability to look forward to pleasurable activities. No effective treatments for anhedonia have been found to date.
Based on their previous studies, the NIMH researchers expected ketamine’s therapeutic action against anhedonia would be traceable — like that for other depression symptoms — to effects on a mid-brain area linked to reward-seeking and that it would follow a similar pattern and time course.
To test their theory, the researchers infused the drug or a placebo into 36 patients in the depressive phase of bipolar disorder. They then detected any mood changes using rating scales for anhedonia and depression.
By isolating scores on anhedonia from scores on other depression symptoms, the researchers discovered that ketamine was triggering a strong anti-anhedonia effect sooner — and independent of — the other effects, they report in the study, which was published in the journal Translational Psychiatry.
Levels of anhedonia plummeted within 40 minutes in patients who received ketamine, compared with those who received the placebo, according to the researchers, who add the effect was still detectable in some patients two weeks later.
Other depressive symptoms improved within two hours, the researchers noted. The anti-anhedonic effect remained significant even in the absence of other antidepressant effects, suggesting a unique role for the drug.
Next, the researchers scanned the brains of a subset of the ketamine-infused patients, using positron emission tomography (PET), which shows what parts of the brain are active by tracing the destinations of radioactively-tagged glucose — the brain’s fuel.
The scans showed that ketamine jump-started activity not in the middle brain area they had expected, but rather in the dorsal (upper) anterior cingulate cortex, near the front middle of the brain, and putamen, deep in the right hemisphere.
Boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences, according to the researchers.
Depressed patients typically experience problems imagining positive, rewarding experiences, which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry, they said.
However, confirmation of these findings must await results of a similar NIMH ketamine trial nearing completion in patients with unipolar major depression, the researchers noted.
Other evidence suggests that ketamine’s action in this circuitry is mediated by its effects on the brain’s major excitatory neurotransmitter, glutamate, as well as downstream effects on a key reward-related chemical messenger, dopamine.
The findings add to mounting evidence in support of the antidepressant efficacy of targeting this neurochemical pathway, according to the researchers. Ongoing research is exploring, for example, potentially more practical delivery methods for ketamine and related experimental antidepressants, such as a nasal spray, they noted.
They add, however, that ketamine is not approved by the U.S. Food and Drug Administration as a treatment for depression. It is mostly used in veterinary practice, and its abuse can lead to hallucinations, delirium, and amnesia.