New Breakthrough Discovered for Treatment of Depression

A major depressive episode (MDE) is not a disorder in itself, but rather a symptom associated with broader encompassing mental disorders like major depressive disorder (MDD) or bipolar disorder (BD).

To be diagnosed with a major depressive episode one must either have a depressed mood or a loss of interest or pleasure in daily activities consistently for at least a 2-week period. This mood must represent a change from the person’s normal mood and social, occupational, educational or other important functioning must also be negatively impaired by the change in mood. The loss of pleasure gained from engaging in previously rewarding activities as well as the overall lack of interest is called anhedonia and it is the focus of a recent study.

Evidence suggests that standard treatments for depression do little to alleviate the symptoms of anhedonia and often cause reward and emotional blunting, loss of libido, and anorgasmia (inability to orgasm). Currently there are no FDA approved treatments for anhedonia.  Given that over half of patients with diagnosed BD express anhedonia during a depressive episode, and that anhedonia can be directly correlated to suicide completion in patients experiencing a MDE, the need to find a successful treatment for anhedonia is essential.

The Beginning of The Study

A research team from the National Institutes of Health used ketamine, a traditional veterinary anesthetic and sometimes club drug to determine if they could solve this problem.  Ketamine with its distinct mechanism-of-action (glutamatergic NMDA receptor-blocker) has recently been in the spotlight as one in a potential new class of rapid-acting antidepressants (NMDA receptor antagonists) that can lift mood within hours instead of weeks.

Participants in the study had to meet stringent criteria to be included. The sample was comprised of 36 individuals, ages 18-65, with BD I or II without psychotic features. They had to be currently experiencing an MDE for at least 4 weeks and to have failed to respond to at least one adequate antidepressant trial before hospital admission.

Participants received one intravenous dose of ketamine hydrochloride, administered at a subanesthetic dose of 0.5 mg kg−1, and one infusion of placebo (0.9% saline solution) in a double-blind, randomized study conducted over a 4-week period. The drug was administered at two-week intervals. A MADRS score of greater than or equal to 20 on the morning of each infusion was required for study continuation.

Investigators also scanned 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 Results

The scans showed that ketamine activated the dorsal (upper) anterior cingulate cortex, near the front middle of the brain and putamen, deep in the right hemisphere. The research study explained that depressed patients typically experience problems imagining positive, rewarding experiences -- which would be consistent with impaired functioning of this dorsal anterior cingulate cortex circuitry.  Boosted activity in these areas may reflect increased motivation towards or ability to anticipate pleasurable experiences, according to the researchers.

The biggest takeaway from these results is that ketamine, compared with placebo quickly reduced the levels of anhedonia in these patients within 40  minutes.  Also remarkable was that the ketamine injection was found to last up to 14 days in some of the patients.  The investigators also stated that the anti-anhedonic effects of ketamine remained significant even when they controlled for the patient’s depressive symptoms, providing further evidence for ketamine’s role in ameliorating anhedonia levels independent of other depressive symptoms.  No approved treatments for anhedonia currently exist despite its prevalence across multiple psychiatric disorders. Thus, ketamine’s rapid onset (within an hour) on anhedonia levels is a promising clinical finding.

Currently available standard treatments for depression, such as selective serotonin reuptake inhibitors (SSRI’s), have minimal efficacy in treating anhedonia in MDD patients and are associated with negative side effects. For individuals with BD, there has been no research done to assess the effects of mood stabilizers on levels of anhedonia.  The researchers believe their results lend credence to the notion that similar compounds (i.e. other NMDA receptor antagonists) should be explored for their clinical relevance in treating this debilitating symptom of depression. The results further suggest that some subtypes of depression (i.e. melancholic depression) may be particularly suited to treatment with ketamine and its analogs. They believe their results underscore the validity of NMDA receptor antagonists to treat all facets of depression.

Further research is ongoing to develop more practical ways to administer ketamine such as a nasal spray ketamine and other related experimental antidepressants.  Despite the successful outcome of their research, it is important to note that ketamine is not yet an approved drug by the FDA for the treatment of depression. In fact, it is not available by prescription for any use. It is most commonly used in veterinary practice for anesthesia, and abuse can lead to hallucinations, delirium and amnesia. 

Conclusion:  Ketamine may serve as a useful medical treatment for depression.

- Laura Wells

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. Retrieved December 4, 2014, from http://www.nature.com/tp/journal/v4/n10/full/tp2014105a.html

NIH/National Institute of Mental Health. (2014, October 20). New antidepressant: Rapid agent restores pleasure-seeking ahead of other antidepressant action. ScienceDaily. Retrieved December 4, 2014 from www.sciencedaily.com/releases/2014/10/141020105037.htm