In the past 150 years it has been noted that the onset of depression is occurring at higher rates and at younger ages that ever before. This data could be the result of factors including an increase in patients coming forward to be diagnosed, improved diagnoses, or simply better record keeping. Whatever the reason, it is estimated that 15 to 20% of the population is experiencing symptoms of major depression at any given time, with a greater occurrence in women than in men. Many are affected by this disorder and a cure has yet to be found. But before we continue, a distinction must be made between major depression and “reactive depression” in which a person may feel depressive symptoms because of a single event like the loss of a loved one or a failure of some kind. Major depression is a prolonged state in which an individual may display a number of symptoms including depressed mood, loss of interest in most activity, change in body weight or appetite, changes in sleep patterns, psychomotor agitation or retardation, fatigue, difficulty concentrating, feelings of worthlessness or guilt, and suicidal thoughts. Depending on the severity of the depression a patient may display many, or only a few of these possible symptoms.

Research has yet to find a definitive neurological cause for depression and other affective disorders. Studies of fraternal and identical twins have attempted to determine the role of nature versus nurture on the matter and animal models of depression as well as human studies have been used to develop drugs and other treatments for depression. Through this work different hypotheses have developed about the neurochemical basis of depression. Some are convinced a monoamine imbalance is responsible while others say it is an issue with serotonin dysfunction. These hypotheses have led to the development of different treatment methods and the utilization of a few classes of drugs. Drug classes include monoamine oxidase inhibitors, tricyclics, and selective serotonin reuptake inhibitors (SSRIs) which all have slightly different mechanisms of action in the brain when treating depression. What is most interesting is that after all this research and development none of these drugs stand out as the best treatment for depression. They all tend to improve depressive symptoms anywhere from a week to a month after drug therapy begins, and they all carry different, sometimes nasty, side effects. The main reason for the current love affair with SSRIs in the medical world is that they carry the most favorable set of undesirable side effects, not that they treat depression best.

Enter ketamine. This compound has a street reputation as a club drug and is derived from phenylcyclidine (PCP), another drug known for its powerful and potentially dangerous psychological and addictive affects. Both drugs were originally developed as alternative analgesics (pain relievers) to drugs like barbiturates that had a higher risk of respiratory depression and subsequent death. PCP and ketamine did produce analgesia, just not in the way they were originally thought to do so. Patients report feelings of detachment from their own body and reality when under the influence of these drugs. They can’t feel pain because their minds are off in another reality, essentially too distracted to feel anything. At high doses PCP and ketamine have been shown to induce schizophrenic symptoms in humans, or worsen previously existing schizophrenia, and research on schizophrenia uses ketamine to bring about a schizophrenic state in animal test subjects. So how on earth can a drug like this have any useful therapeutic application?

http://drug-effects.us/what-is-ketamine

http://www.guardian.co.uk/society/2010/apr/02/drugs-ketamine-bladder-problems-incontinence

Researchers at Yale University and the National Institute of Mental Health have recently found that administering a low dose of ketamine to a patient affected by major depression has been able to lift the patient’s mood and subdue the depression for about a week at a time. It is an astounding find given the known effects of ketamine on the mind. One study reported that 70% of patients treated with ketamine experienced an improvement in mood. One of the best parts about the treatment is that it takes effect immediately, unlike the other antidepressants on the market, which can take up to a month to work. It has also proven effective even to patients who have been resistant to other treatments. Ketamine is already an FDA-approved analgesic, usually used in veterinary settings, so further studies of this compound are now being developed in humans.

The mechanism of action for this drug is not yet clear but it is known that ketamine and PCP are nonselective NMDA receptor antagonists. They affect the glutamate pathways within the brain and also seem to have the remarkable affect of strengthening and restoring synaptic connections. In the human model of depression where it is thought that symptoms are caused by atrophy of neurons in various brain areas, it makes sense that ketamine is an affective treatment because it encourages neuron regrowth and connection. This may be done through the production of brain derived neurotrophic factor (BDNF) or other molecules that influence neuron health and maintenance. More work must be done to determine how this unlikely drug accomplishes its therapeutic affects. There are still dangers associated with taking ketamine, especially if it only works for a week at a time to treat depression and repeated use has already been shown to produce schizophrenic symptoms in some. It is an amazing and surprising find and hopefully it leads to more improved treatments of affective disorders like depression.

- J. Daniel Bireley

Sources:

Ketamine Relieves Depression By Restoring Brain Connections – NPR

Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents - Trends in Neurosciences

Meyer, Jerrold S., and Linda F. Quenzer. Psychopharmacology: Drugs, the Brain, and Behavior. Sunderland: Sinauer Associates, 2005. Print.

It has been said “The most exciting phrase to hear in science, the one that heralds new discoveries, is not ‘Eureka!’ but ‘That’s funny…’” (Isaac Asimov), and a recent observation by a Harvard Medical School lab studying the brain chemistry of Bipolar Disorder has researchers uttering that precise phrase…as well as the one alluded to in the title of this post.

The initial study prompting such observations recruited patients suffering specifically from Bipolar Disorder, also known as Manic-Depression, for 20-minute brain scans in an MRI.  MRI scans subject patients to a harmless magnetic field and pulses of radio waves to create detailed structural images of various body parts, in this case, the brain.  While the procedure is painless and relatively short, it can be unpleasant for reasons wholly unrelated to the magnets and radio signals; patients frequently report unrelated bodily discomfort or claustrophobia.  For this reason it was all the more surprising, according to one researcher, that patients participating in the study started to report mood elevations (that for some lasted days or even a week) following the scan.  One patient even subtly suggested that the researchers had slipped her something without her permission.

Patient undergoing TMS treatment for depression

The use of magnets to improve the effects of depression is not uncharted territory in neuroscience and it might even sound familiar to some.  Transcranial magnetic stimulation, or TMS, is another technique that has recently been adapted to depression therapy, yet it is more akin to electroconvulsive, or “electroshock”, therapy (ECT) than MRI.

TMS uses a magnetic field to induce a relatively small electric current, without causing seizure or loss of consciousness, to stimulate the left prefrontal cortex, the area thought to be under-active in depression.  Whereas ECT treatments are utilized only in the most extreme depression cases because of the risk of seizure and necessity of sedation, TMS carries much fewer risks and can be used for more mild depression. While the exact mechanisms are still not known, particularly the roll of seizure for the antidepressant effects, both ECT and TMS have been cleared by the FDA.

But the magnet employed in MRI does not excite specific brain regions (if it did the entire imaging method of functional magnetic resonance imaging, fMRI, would be ineffective) and it is certainly not strong enough to induce seizures.  After observing the curious side-effects of their initial study, the aforementioned researchers set up a small preliminary study with both bipolar and normal controls who confirmed respectively that the effects were not placebo, and that even those without depression can experience the mood-boosting effects of MRI.

So could a new depression treatment soon be joining the ranks of such accidental scientific breakthroughs as penicillin and Post-It notes?  At this point it really is unclear.  The actual mechanism of the mood-boosting effects of MRI on depressed patients is not yet understood, nor have the effects been generalized to unipolar depression.  However, the safety of exposure to MRI has been confirmed by the FDA and a lack of total understanding regarding what causes the “miraculous” effects of that other magnet-based depression treatment, TMS, as well as a host of other medical treatments (including lithium for Bipolar Disorder) certainly has not prevented their use.

Picture Unrelated

The study, powered by C. Nathan DeWall of the University of Kentucky, gave volunteers either acetaminophen or placebo, and then subjected them to a game of virtual ball-toss.  Over time, subjects were gradually rejected from the game.  Those who had been given the analgesic demonstrated signs that they experienced fewer feelings of rejection, as was inferred through brain imaging of the anterior cingulate cortex, an area associated with feelings of emotional pain and desperation.

DeWall and his colleagues also demonstrated the effects of acetaminophen on a person’s moral judgment.  When confronted with typical ethical quandaries, such as whether or not it’s right to sacrifice one person to ensure the safety of others, subjects showed less hesitancy in declaring their moral choice.

Though these researchers are quick to point out that no one should expect to correct their emotional problems with such a common drug, I think it’s important to realize just how effective a small chemical push towards recovering from a refusal could be.  So often, when met with defeat or failure, it’s our natural reaction to dwell on our lack of fortune, to lose confidence or determination, or simply to become angry and resentful.  In a world where there’s a constant competition for success, our failings become exaggerated, and our emotional anguish increases.  As more and more Americans (over 27 million) elect to take strong psychotropic prescription antidepressants, it’s comforting to think that a slight mood improvement can be afforded through more mild drugs like Tylenol.  Of course, acetaminophen has its own dangers, and causes liver failure if abused.  Still, whether one is applying to graduate schools and jobs, or asking someone out on a date, a little Tylenol couldn’t hurt.

Social Analgesics- Gary Stix