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Not Lower Levels of Serotonin, but Damaged Brain Synapses as the Origin for Mental Depression

Reporter: Aviva Lev-Ari, PhD, RN

Israeli discovery matches right antidepressant for each patient

Genetic study suggest that depression may be caused not by lack of serotonin, but because of damage to the brain synapses.

It all comes down to a simple blood test (illustrative).

It all comes down to a simple blood test (illustrative). Photo by Dreamstime

By Ido Efrati
Published 01:00 09.12.13
A new discovery by Tel Aviv University researchers may make it possible to prescribe the most effective antidepressant based on a simple blood test, avoiding the long and often difficult process of medication adjustments that is currently done by trial and error.The scientists were able to identify genes in blood cells that are linked to the creation of receptors in brain cells and that respond differently to antidepressants in different people. The study by Dr. David Gurwitz and Dr. Noam Shomron, which was recently published in the journal Translational Psychiatry, could change perceptions about the origins of depression and the mechanisms that trigger it.

“People suffering from depression are in great distress and find it very difficult to go through the process of treatment adjustments, which can take weeks or months,” said Shomron, who heads the Genome High-Throughput Sequencing Laboratory at TAU’s Sackler Faculty of Medicine. “We chose to focus on paroxetine, a very common drug for depression, which is sold in Israel under the trade names Seroxat, Paxxet, Paxil, Parotin and Paroxetine-Teva. We were looking for a faster, easier and more effective way to find out how [paroxetine] would affect a particular patient.”

Paroxetine belongs to the SSRI family of drugs that inhibit the re-absorption of serotonin in the brain, the best-known and most popular of which are Prozac and Cipralex. “These drugs do not help all those suffering from depression, and in many cases one must keep trying drugs from other families by trial and error. Meanwhile, the patients and their families suffer,” explained Gurwitz, who heads the National Laboratory for the Genetics of Israeli Populations at Sackler.

One of the interesting things about the research is that it did not involve people suffering from depression. Rather than examine the effect of the drug on patients, the researchers added paroxetine to 80 samples of cultured white blood cells taken from healthy volunteers.

The results showed that in some cases the drugs inhibited cell division in the cultures significantly, while in others the delay was relatively minor. The researchers then focused on those cases with the most extreme responses: the 10 cultures that were most affected by the addition of paroxetine, and those least affected. The aim was to see whether there were significant differences between the two extremes on the genetic and molecular levels. By using a genetic chip, the researchers were able to perform a comprehensive molecular profile of all the selected samples.

“The result surprised us so much that we started to check if we’d made some mistake,” said Shomron. “We discovered that the single biggest difference between the two groups was the level of expression of a gene known as CHL1. Until then, no one had ever linked that particular gene to depression.”

Dr. Gurwitz noted, however, that the protein encoded by the gene CHL1 is recognized in scientific literature as essential for creating synapses (connections between neurons) in the brain. “Our findings suggest that depression may be caused not by lack of serotonin, as is written today in medical books, but because of damage to the synapses, probably resulting from a lack of proteins that repair synapses damaged by stress,” he says.

Giving the researchers a boost is a large clinical study recently published in the United States involving some 1,400 patients treated with the antidepressant Citalopram. Those findings also suggest a link between the gene CHL1 and the response to depression treatment.

Since the 1990s, Gurwitz said, hundreds of genetic studies have dealt with antidepressants. “But almost all of them began with the assumption that the main cause of depression is a lack of serotonin in the brain.” The approach of the two Israelis was totally different, he said. “We chose to look at all the genes of the human genome, about 25,000 genes and see which are affected by antidepressants. We believed the genetic diversity between people would surely be reflected in their response to drugs, which can be measured in vitro.”

The two said that this new insight could lead to a new type of antidepressant, which, instead of boosting serotonin levels in the brain – which are associated with depression, but probably not the cause – could improve the process of repairing damaged synapses.

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The eTNS System. (PRNewsFoto/NeuroSigma)

Reporter: Howard Donohue, PhD (EAW)

Following the arrival in the 1990s of a drug for treating depression called fluoxetine (better known by its brand name, Prozac) – a “selective serotonin reuptake inhibitor” (SSRI) – it’s probably fair to say that not many drugs have become as deeply engrained in the public’s general awareness as those of this type. Perhaps one reason for this could be the sheer number of people affected by depression and to whom SSRIs are relevant as a possible treatment (one study has estimated that depression affected upwards of 30 million Europeans in the year 2010 [1]). Perhaps another reason could be the various controversies that have surrounded SSRIs over the years, from stories of increased suicide risk in children [2] to evidence of biases and the “selective” publishing of clinical data favoring the effectiveness of these drugs [3]. Of course, despite the controversies, SSRIs (along with other classes of antidepressant drug) continue to be a mainstay, but let’s not forget, amid their popularity, that there are other ways to treat depressive illnesses. And in maximizing the benefits of treatment for the individual, it’s important to realize that any one of these approaches might work well for one person, but not for another. Among the non-pharmacologic ways to treat depression are psychological approaches, for example cognitive behavioral therapy, or alternatively, “brain stimulation” approaches such as electroconvulsive therapy (ECT). ECT is a method to induce a mild seizure in the patient by means of electrical activity applied to the brain via electrodes connected to the temples.

On the subject of ECT; you could be forgiven for thinking that it’s not very nice, especially if you’ve seen the plights of characters like Randle Patrick “Mac” McMurphy, portrayed by Jack Nicholson in One Flew Over the Cuckoo’s Nest or Russell Crowe’s portrayal of Dr. John Nash (based on the real-life Nobel Laureate in Economics by the same name) in A Beautiful Mind. Nonetheless, despite the treatment in Hollywood of ECT as a sinister, repressive, and even brutal procedure, the reality is obviously different and it continues to have a place in medical practice for the treatment of severely depressed patients to this day. This isn’t to say that controversies don’t exist within the medical community concerning certain side effects (such as memory loss), but in balancing this, we should remember that many – if not most – medical procedures have their drawbacks (hopefully, the benefits will far outweigh the drawbacks). Putting aside any thoughts on whether ECT is good or bad, it is recognition and consideration of the drawbacks that helps drive the evolution of medical technologies.

So, in illustrating the evolution that is happening in the field of brain stimulation for treating neurological disorders (in this case, depression and also epilepsy), the recent approval in Europe of an “external Trigeminal Nerve Stimulation” (eTNS) technique provides an excellent example. The technique, called the MonarchTM and exclusively licensed to Neurosigma Inc. (a Los Angeles-based medical device company) “for the adjunctive treatment of epilepsy and major depressive disorder, for adults and children 9 years and older”, is a non-invasive form of neuromodulation therapy [4]. It was invented at the University of California, Los Angleles (UCLA) and has been in development for over 10 years [4]. It works by using a low-energy stimulus to stimulate branches of the trigeminal nerve, a nerve that can affect the activity of several key brain regions believed to be involved in depression and epilepsy. In contrast to ECT, the stimulus is restricted to the soft tissues of the forehead without direct penetration to the brain, which thereby facilitates a non-invasive form of neuromodulation [4]. Following European approval, Neurosigma affirmed in a press release that eTNS is “supported by years of safety and compelling efficacy data generated in clinical trials conducted at UCLA and the University of Southern California (USC)” [4]. In realizing the future potential of eTNS, Neurosigma’s business strategy is now geared toward steps for its adoption at major epilepsy and depression centers in the EU, as well as endeavors to make it available to patients in the US and other countries [4].

To answer the question of whether eTNS will rise to prominence as an effective treatment in the fight against depression and epilepsy, only time will tell. But if it does, as well as being a valuable addition to the armamentarium against these debilitating diseases, maybe its non-invasive nature will mean that the film directors have a harder time in “demonizing” it for dramatic effect. Well anyway, let’s hope so.

References

  1. Wittchen et al. Eur Neuropsychopharmacol 2011: 21:655-79.
  2. http://news.bbc.co.uk/2/hi/health/3656110.stm
  3. Turner et al. N Engl J Med 2008; 358:252-60.
  4. http://www.prnewswire.com/news-releases/neurosigma-receives-ce-certification-168578146.html

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