Major depressive disorder affects around 14.8 million people in the US, making it the leading cause of disability for people aged 15-44. Could ketamine offer some welcome respite?
Despite the huge numbers of sufferers and reams of research, depression still holds many mysteries.
The exact pathways that induce depression are still not well understood. Medication is available and relatively successful, but the mechanisms by which it works are still partly shrouded.
Current depression medication can take weeks or months before its antidepressant capabilities come to the fore. Additionally, the side effects of the most common depression medication can be unpleasant.
Any new drug that might work faster and have fewer side effects is jumped on by researchers and clinicians alike. The latest drug, heralded by some as a new wonder drug for depression, is ketamine.
Ketamine has been found to have a marked and prompt positive impact for many depressed patients. The calls for it to be rolled out on a wider scale are growing in volume. An editorial in the latest edition of the Medical Journal of Australia, however, raises sensible doubts.
The article written by Colleen Loo, of the University of New South Wales in Sydney, Australia, voices concerns about introducing ketamine before enough studies have been conducted testing its efficacy and long-term effects.
What is ketamine?
Ketamine is perhaps most well known as an illicit drug, often referred to as "horse tranquilizer" by the media. Ketamine is used to sedate large animals, but it is also used widely used in emergency medicine and to sedate young children.
Ketamine is a dissociative agent and induces a trance-like state. It also has pain-killing, sedative and memory-loss effects. Usefully, heart function, breathing rate and airway reflexes remain intact when under the influence.
One of the major reasons ketamine is not used as an anesthetic for adults is its hallucinatory properties. But, it is still preferentially chosen in cases where ventilation equipment is not available or for patients with any kind obstructive airway issues - predominantly because it suppresses breathing much less than most other available anesthetics.
Technically, ketamine is classed as an NMDA receptor antagonist - a group of anesthetics that inhibit the action of the N-Methyl-D-aspartate receptor (NMDAR). NMDAR is activated by glutamate, a common excitatory neurotransmitter involved in learning and memory.
Ketamine's actions are more complicated than other NMDA receptor antagonists; it works on a number of pathways, including opioid receptors and monoamine transporters (involved in the transport of dopamine, serotonin and norepinephrine).
Ketamine and depression
Recently, ketamine has been investigated for its potential use in the battle against depression. Although data is still fairly scant, the studies so far report some fairly impressive results.
Studies (although all small-scale) have revealed that small doses of ketamine (sub-anesthesia) can relieve even stubborn depressive symptoms within 24 hours. Compared with the weeks or months involved in standard depression treatments, it is understandable that there is quite a fuss being made about this new approach.
Two of these studies compared ketamine against electroconvulsive therapy (ECT) - regarded as one of the most potent biological treatments for depression. The results, for the small sample of patients, showed either comparative or better effects than ECT.
Standard antidepressants tend to work on serotonin or norepinephrine pathways, whereas ketamine works, predominantly, via the glutamate pathway. This novel mode of action is another reason ketamine has been raising hopeful eyebrows.
So what are the drawbacks of ketamine?
The major problem the pro-ketamine lobby faces is the lack of data; currently, across the board, only around 200 participants have been involved in clinical trials. Added to this is a lack of information on the long-term effects of ketamine use.
Studies carried out so far infer that ketamine's antidepressant effects are only short-lived; therefore, ketamine might need to be administered relatively regularly. This, in turn, leads to concerns about its long-term effects, an increase in tolerance and even cravings.
The majority of information we have on long-term use comes from studies involving individuals who take ketamine recreationally. As such, they are not controlled, and the amounts of ketamine ingested vary and exceed the levels that are necessary for its antidepressant effects.
The data that do exist in regards to chronic use point to some fairly undesirable risks, such as kidney and bladder dysfunction and possible cognitive impairment.
Another issue with the research so far concerns ketamine's optimal administration. Most clinical trials have utilized an intravenous infusion. Other methods include sublingual, intramuscular and subcutaneous delivery. This disparity makes comparisons between studies trickier still.
In Loo's editorial, she raises the concerns that if ketamine is rushed into the pharmacy as an antidepressant, any negative consequences might scupper its use in the future:
"If ketamine is prematurely applied clinically to treat depression, before research has determined how (and if) it can be effectively and safely used to achieve lasting remission of depression, the end result may be disillusionment and even abandonment of this otherwise promising therapy."
A drug that holds obvious promise needs to be thoroughly tested before it is released to the public at large. Depression is such a difficult illness to treat, we need as much firepower as we can lay our hands on. We do not want to lose a such a potentially useful drug because we jumped the gun.
Medical News Today recently covered research showing that mom's favorite child is more likely to be depressed.