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Help on the horizon for treatment resistant depression


Depression is like a kick while you’re already down. Sometimes there is no real reason for it, sometimes it is triggered by some serious life issues, but clinical depression always has very real neurological roots. Unfortunately, while we know that certain areas of the brain are smaller in a depressed person, we don’t know why or what effect it has on a person. Worse, SSRI’s the “gold standard” for depression can have no — or worse ill — effects on the person taking the drugs.

Now researchers have found that mice genetically deficient in serotonin — a crucial brain chemical implicated in clinical depression — are more vulnerable than their normal littermates to social stressors. Following exposure to stress, the serotonin-deficient mice also did not respond to a standard antidepressant, fluoxetine (Prozac), which works by boosting serotonin transmission between neighboring neurons.

The new results may help explain why some people with depression seem unresponsive to treatment with selective serotonin reuptake inhibitors (SSRIs), the most common antidepressant drugs on the market today. The findings also point to several possible therapeutic strategies to explore for treatment-resistant depression.

“Our results are very exciting because they establish in a genetically defined animal model of serotonin deficiency, that low serotonin could be a contributing factor to the development of depression in response to psychosocial stress — and can lead to the failure of SSRIs to alleviate symptoms of depression,” said senior author Marc Caron.

The exact causes of depression are unclear. Although scientists have traditionally thought that low brain serotonin could cause depression, the idea is difficult to test directly and increasingly controversial. At the same time, researchers have gained a greater appreciation for the many environmental factors — especially stress — that can bring on or worsen depression.

In the new study, researchers used a transgenic mouse strain called Tph2KI that has only 20-40% of normal levels of serotonin in its brain. These mice harbor an extremely rare mutation that was first identified in a small group of people with major depression.

The researchers have been studying how the Tph2KI mice respond to different kinds of stress, showing previously that serotonin deficiency can affect susceptibility to some types of stress but not others, findings that may have implications for understanding how low levels of serotonin could contribute to mental illness.

In the new study, the group tested the responses of these mice to a type of psychosocial stress: social defeat stress.

The team stressed out mice by housing them each with an aggressive stranger mouse briefly every day for 7-10 days. Later, the scientists examined whether the test mice would avoid interacting with an unfamiliar mouse — a depression-like behavior.

A week of social stress was not sufficient for normal mice to show signs of depression, but the serotonin-deficient mice did. Longer periods of stress exposure led to depression-like behavior in both groups.

The researchers then found that a 3-week treatment with Prozac following the stress exposure alleviated depression-like symptoms in normal mice, but not mutant mice.

Prozac and other SSRIs work by blocking the ability of cells to recapture serotonin, so it makes sense that the drugs would be less effective in animals with abnormally low levels of serotonin to begin with.

Few case studies have suggested that targeting a brain area called the lateral habenula could help alleviate treatment-resistant depression. This area is known as a ‘punishment’ region of the brain because its neurons are active in the absence of reward. Scientists think that an overactive lateral habenula might trigger depression.

In the new study, the group targeted the lateral habenula with a designer drug and receptor (called DREADDs for ‘designer receptors exclusively activated by designer drugs’) that allows them to control the activity of particular neurons in a living animal. Inhibiting lateral habenula neurons reversed the social avoidance behavior in the serotonin-deficient mice, they found.

Although DREADDs aren’t appropriate for use in humans, showing that the lateral habenula-targeted drugs can be used to alleviate depression-like behavior in animals is “an important first step.”

“The next step is to figure out how we can turn off this brain region in a relatively non-invasive way that would have better therapeutic potential,” lead author, Benjamin Sachs said.

Another clue for potential new therapies came from biochemical comparisons of the brains of the mutant and normal mice. The researchers found that social stressors seemed to change where in the brain the signaling molecule β-catenin is being produced in normal mice, but not in the Tph2KI mice.

Taken with other evidence, these new findings suggest that serotonin deficiency may block a critical molecular pathway that includes β-catenin and that may be involved in resilience.

“If we can identify what’s both upstream and downstream of β-catenin we might be able to come up with attractive drug targets to activate this pathway and promote resilience,” Sachs said.

Good news for people who suffer from depression that isn’t well treated with SSRI’s, more importantly this is good news for people who suffer from depression in general.

Benjamin D. Sachs, Jason R. Ni, & Marc G. Caron (2015). Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress Proceedings of the National Academy of Sciences of the United States of America : 10.1073/pnas.1416866112

6 responses

  1. Megan

    From what I understand in this article, the Prozac and SSRI’s are reuptake inhibitors. They work by preventing the serotonin from being reuptaken and thus allowing it to excite the receptor longer. It is said in the article that the these types of medication aren’t showing high success rates on people and lab animals with severely low serotonin to begin with because even when the serotonin isn’t being reuptaken, there is still little of it. So my question is, could pairing these reuptake inhibiting medications with a diet high in tryptophan and carbohydrates and low in phenylalanine increase the effectiveness of these medications? A diet high in tryptophan, when it doesn’t have too many other large amino acids to compete with, should help increase serotonin levels.


    February 12, 2015 at 8:16 am

    • That’s a really good question, I’m not sure that artificially trying to raise serotonin levels by diet would help change anything unless you were already deficient. A quick search around didn’t show much in the way of a clear answer unfortunately. So really your guess is as good as mine.


      February 13, 2015 at 12:45 pm

    • Mitch

      A good thought. We treat low-levels of dopamine associated with Parkinson’s Disease with a pre-cursor for Dopamine called L-Dopa. But the problem (as hinted at in your comment) with Large Neutral Amino Acids is that they are in everything, and they share a common transporter across the blood-brain barrier. So even trying to up your levels in diet (or supplement your levels artificially) of one or two LNAAs still means they have to compete for space on the transport and raising one, will lower all the others.

      So at thanksgiving when your uncle implies that you are sleepy because of the Tryptophan in the turkey, that is erroneous. Turkey has all 20 LNAAs (although it does have a high level of tryptophan just like all poultry), so to get enough bump to affect your sleepiness would require you to eat your body weight in turkey (don’t try).


      February 23, 2015 at 10:41 am

      • Any comment that talks about eating your body weight in turkey is a winner to me. Thanks for expanding on what I was trying to say, obviously I was not as eloquently as you managed to do it. Now don’t mind me as I try to eat my body weight in turkey…


        February 23, 2015 at 12:31 pm

  2. Aaron

    From the point of view of someone who has been personally affected by depression in my life and others, this is truly excellent news, especially since I’m also familiar with people who aren’t responsive to SSRIs. Regarding the DREADDs (which is an ominous sounding name, by the way), could you expand a little on how exactly those are created, and why they’re unsafe for humans? I’m familiar with how receptor sites and neurotransmitters function, but I’m unfamiliar with the term, and the function. Pardon if it sounds silly, but do the scientists involved actually create a receptor and attach it to the lateral habenula, which is then targeted by synthetic neurotransmitters?


    February 24, 2015 at 9:56 pm

    • Not quite, my understanding is limited since I’m not particularly familiar with the field of research, however my understanding of it is as follows.

      DREADD, which I agree sounds more like a super villians weapon than something in science, is modification of the g-protein coupled receptors (GPCR’s) to respond to a specific synthetic chemical (technically termed ligand) rather than what it originally would respond to (which may have been several different things like hormones, or in this case neurotransmitters).

      Since I don’t know your level of knowledge on the subject, I will add that GPCR’s control a lot of cell functions so targeting a particular set and effectively shutting them off or on can give us insights to how they work (which is the point of the paper really).

      So the real question, how are these receptors created, there are a few ways, however the end result is going to be genetic engineering (as far as I know the only way to accomplish this). In particular this study (I believe) used something called mutagenesis, which is definally not something that should be done with humans, it involves the use of a mutagen (which is something that would typically be considered toxic so definitely not to be used on humans) to alter the receptors allowing us to non invasively (and in vivo instead of in vitro) see what these receptors control by creating a specific chemical (drug) to activate it exclusively (as in nothing made naturally could activate it).

      Sorry that was so long, but I hope that explains it at least a little bit, definitely not a silly question at all and thanks for taking the time to actually ask, frankly it’s what I’m here for and why I do this. If you have any other questions, comments, or thoughts, please don’t hesitate to ask.


      February 24, 2015 at 10:33 pm

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