Monday, 8 March 2010

Life Without Serotonin

Via Dormivigilia, I came across a fascinating paper about a man who suffered from a severe lack of monoamine neurotransmitters (dopamine, serotonin etc.) as a result of a genetic mutation: Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin

Neuroskeptic readers will be familiar with monoamines. They're psychiatrists' favourite neurotransmitters, and are hence very popular amongst psych drug manufacturers. In particular, it's widely believed that serotonin is the brain's "happy chemical" and that clinical depression is caused by low serotonin while antidepressants work by boosting it.

Critics charge that there is no evidence for any of this. My own opinion is that it's complicated, but that while there's certainly no simple relation between serotonin, antidepressants and mood, they are linked in some way. It's all rather mysterious, but then, the functions of serotonin in general are; despite 50 years of research, it's probably the least understood neurotransmitter.

The new paper adds to the mystery, but also provides some important new data. Leu-Semenescu et al report on the case of a 28 year old man, with consanguineous parents, who suffers from a rare genetic disorder, sepiapterin reductase deficiency (SRD). SRD patients lack an enzyme which is involved, indirectly, in the production of the monoamines serotonin and dopamine, and also melatonin and noradrenaline which are produced from these two. SRD causes a severe (but not total) deficiency of these neurotransmitters.

The most obvious symptoms of SRD are related to the lack of dopamine, and include poor coordination and weakness, very similar to Parkinson's Disease. An interesting feature of SRD is that these symptoms are mild in the morning, worsen during the day, and improve with sleep. Such diurnal variation is also a hallmark of severe depression, although in depression it's usually the other way around (better in the evening).

The patient reported on in this paper suffered Parkinsonian symptoms from birth, until he was diagnosed with dystonia at age 5 and started on L-dopa to boost his dopamine levels. This immediately and dramatically reversed the problems.

But his serotonin synthesis was still impaired, although doctors didn't realize this until age 27. As a result, Leu-Semenescu et al say, he suffered from a range of other, non-dopamine-related symptoms. These included increased appetite - he ate constantly, and was moderately obese - mild cognitive impairment, and disrupted sleep:
The patient reported sleep problems since childhood. He would sleep 1 or 2 times every day since childhood and was awake during more than 2 hours most nights since adolescence. At the time of the first interview, the night sleep was irregular with a sleep onset at 22:00 and offset between 02:00 and 03:00. He often needed 1 or 2 spontaneous, long (2- to 5-h) naps during the daytime.
After doctors did a genetic test and diagnosed SRD, they treated him with 5HTP, a precursor to serotonin. The patient's sleep cycle immediately normalized, his appetite was reduced and his concentration and cognitive function improved (although that may have been because he was less tired). Here's his before and after hypnogram:

Disruptions in sleep cycle and appetite are likewise common in clinical depression. The direction of the changes in depression varies: loss of appetite is common in the most severe "melancholic" depression, while increased appetite is seen in many other people.

For sleep, both daytime sleepiness and night-time insomnia, especially waking up too early, can occur in depression. The most interesting parallel here is that people with depression often show a faster onset of REM (dreaming) sleep, which was also seen in this patient before 5HTP treatment. However, it's not clear what was due to serotonin and what was due to melatonin because melatonin is known to regulate sleep.

Overall, though, the biggest finding here was a non-finding: this patient wasn't depressed, despite having much reduced serotonin levels. This is further evidence that serotonin isn't the "happy chemical" in any simple sense.

On the other hand, the similarities between his symptoms and some of the symptoms of depression suggest that serotonin is doing something in that disorder. This fits with existing evidence from tryptophan depletion studies showing that low serotonin doesn't cause depression in most people, but does re-activate symptoms in people with a history of the disease. As I said, it's complicated...

ResearchBlogging.orgSmaranda Leu-Semenescu et al. (2010). Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin Sleep, 33 (03), 307-314


dearieme said...

"As I said, it's complicated": science works best when you can simplify systems far enough to study them one-variable-at-a-time. It's not remotely as powerful for complicated systems, so there it should be used with due intellectual humility. Whether that comes naturally to medics is a different question.

jgs said...

There is good evidence that 5-HT doesn't play the role in mood and depression that monoamine hypothesis contends (e.g., Robinson, O. J., & Sahakian, B. J. (2009). A double dissociation in the roles of serotonin and mood in healthy subjects. Biol Psychiatry, 65(1), 89-92.) But, I also think it problematic to take this case as evidence of what 5-HT might do in a healthy adult. A genetic condition present from birth is likely to lead to a range of adaptations in the plastic brain, and although deficits are indicative they are questionable evidence. Complicated is the right word!

Anonymous said...

Oh come on! You are right that the biggest finding is that there is no evidence in this case to support the serotonin-depression link. Why not leave it at that? You are really stretching when you start to link sleep problems as necessarily linked to depression. There are many, many reasons why people have sleep problems and most have nothing to do with depression. This paper is just another nail (among many) in the coffin of the serotonin-depression hypothesis.

Neuroskeptic said...

jgs: That's a good point, but in this case the symptoms resolved with 5HTP i.e. serotonin replacement. Just like the Parkinsonian symptoms resolved with L-dopa. (They also stopped the L-dopa as a test, and the motor symptoms reappeared). So maybe there were also developmental changes but something was going in adulthood.

anon: Lots of people have sleep problems and aren't depressed, but sleep problems (and diurnal variations) are a symptom of depression. We have no idea why they happen but they do happen, at least in severe depression.

petrossa said...

hypothyroidism causes all the effects one sees in depression which adds to the suspicion depression is not an affliction in and of itself but rather a range of symptoms brought on by various underlying causes.

The serotonin effect on depression is in my view more that of a numbing down of emotions, negative and positive.

Mike said...
This comment has been removed by the author.
ML, MD said...

I am not sure who was the first to call serotonin the brain's "happy chemical". In any case, it's a misleading name at best. It is not the serotonin that affects one's affect, or motor function, or any of the myriads of behaviors, but specific serotonin receptors that may increase, decrease, or have no affect on mood at all.
By analogy, it's not the "accelerating" foot that speeds up our cars but a specific gas pedal. Conversely, the same foot can press on the brakes.

pj said...

I think the evidence from knockout experiments in animals comprehensively undermines your argument that the lack of depression in this man shows that a shortage of serotonin doesn't underlie depression.

The developmental plasticity of the brain, even in the abscence of quite a neurodevelopmentally important signal like serotonin, is such that compensatory mechanisms could easily mask this effect.

In fact it is quite remarkable how normal little mouses can be despite knocking out really quite fundamental biological pathways.

Neuroskeptic said...

pj: That's a good point. A year ago there was a study reporting on knock-out mice with no serotonin at all which I blogged about.

They were essentially normal, slightly underweight (contrast with this guy), showed some abnormalities in despair test models of depression but not always in the unexpected directions; we weren't given any data on sleep, but that suggests it wasn't grossly abnormal.

I'm certainly not saying that serotonin isn't involved in depression, I think the evidence from acute tryptophan depletion studies is pretty convincing that it is - but equally, I don't think it can be a simple case of low serotonin = low mood. What the relationship actually is, is a Nobel Prize waiting to happen.

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Admin said...

I think a person without serotonin may have central sleep apnea syndrome, because the breathing centers from the brain are affected.

sp00k00ps said...

However, serotonin is not exactly a “hapy brain chemcial” (when it comes to mood). It is actually a mood regulator. Dopamine however IS a “feel good” neurotransmitter.

My theories on why he wasn’t depressed are…

1. He was able to generate just enough dopamine to keep himself happy.

2. Another feel good hormone is phenyethylamine, it could have been he was able to produce enough of this to keep himself happy.

3. If serotonin IS an anti-depressant, he was able to make enough of it to mantain a happy disposition.

4. He DID have just enough serotonin to keep him happy (in the case it is the anti-epressant neurotransmitter).

5. He was BORN with the condition, so his brain could have made new pathways to keep him happy (whereas the tryptophan depletion is something one would rely on so taking it away could result in the more sad depression, as it is a withdrawal). Therefor, the brain does not have a quick chance to react and cope.

5. There IS a type of depression that we do not fully see as ‘true depression’. There are actually various types of depression, but not all of them have the classic stereotyped “oh, life is horribly unbarable…” sadness. This depression has sympoms like apethy, lethargy, chronic boredom, fatigue and thus, feeling the need to sleep a lot, (otherwise known has ‘the blahs’ by Julia Ross) which it sounds like he had. Thus, he could have very well been depressed, just not the sad, pitiful “woe is me” type we so often diagnose as depression.

sp00k00ps said...

Oh, on the tryptophan depletion studies, again they are relying on the amino acid to produce the neurotrnamitter in which they are already depleted in, thus causing mood descrease.

On another note, serotonin also interacts with the pain-killing (and probably because of this mood lifting) neurotransmitter. So, a person could have low serotonin, but high enough endorphins to keep them feeling ulifted despite a drop in serotonin.

If a person were to be low in the endorphin, however, then have a drop in serotonin, the lowered serotonin could cause less endoprhins to be released in the brain, and again, lowering mood this way, via the indirect endoprhin connection.

What jgs said is correct, that a genetic condition, one not aquired from appetite or abuse of the neurons, can be worked around via adaptation and the connections of new pathways. Very well said!

sp00k00ps said...

In the study, they also did say there was "some mood lowering" so, some might be a little but not severe. Perhaps, for some peiple it is not severe enough to cuase out right sad melecholy type of depression, especially if another 'feel-good' neurotranmitter is elevated in the brain to make up for the loss.

spookoops said...

Another thing: the name of this article is misleading: "Life WITHOUT serotonin". It's not like the guy DID NOT have ANY serotonin at all, he was just severely low in it, which is NOT the same as not having any at all.

sp00k00ps said...

In regaurd to what jgs said "there is good evidecne that 5-HT does not play a role in mood and depression..." take that from people who actually HAVE depression and have used it WITH results that state it DOES play a role.

So, you're saying that if a healthy person who had serotonin had their serotonin taken away, zapped to zero, that their mood would be just the same as when they had serotonin? i don't think so.

Also, 5-HTP does not just work on serotonin, it also works on endorphins, our most potent painkiller. In fact, it's not so much low SEROTONIN that causes depression, but the fact that serotonin also influences other neurotransmitters. Serotonin, IN ITSLEF is NOT the antidepressant neurotranmsitter.

It's the endoprhins (a class of dopamine) that is a member of the enkephailins, our most influencing good mood chemcials.

5-HTP not ONLY rasies serotonin, but also the enorphins, and THERE'S where the magic of 5-HTP comes in.

Also serontin DOES raise the endoprhins, the reason why serotonin boosting supplements can take so long to work is because by increasing the enorphins through serotonin, it can take up to a full YEAR to get the nedoprhins high enough to notcie a difference. THAT is what the serotonin/good mood debate/clash/never ending argument comes in. There's a whole other side to the issue that 1. fails to be ackowledged 2. fails to be looked into and 3. fails to be of interest to many pepple, especially in the medical field...

Anyway, since no one seems to be reading in the comments, i might as well get off of the site entirely.

Anonymous said...

I apologise if my comment comes off as harsh, but I am sick of people cliaming this one, single "study" as crutial "evidence" or "proof" that serotonin does not affect mood.

Poeple don't seem to take into account several, obvious things, that I, not even having a degree in, can see are clearly obvious differences.

1. Trypophan depletion studies have found that by reducing the intake of tryptophan DOES IN FACT casue changes in mood. Does anyone find this as proof serotonin does play a role in mood? NO!

2. HE WAS BORN WITH VERY LITTLE SERONTIN, NOT NONE AT ALL! The title is misleading and false. He was not born WITHOUT serotonin, it was just very little. The title itself is a mockery of the whole issue.

2. If he was born without it, his brain could adapt to it. People who have NORMALLY FUNCTIONING serotonin receptors that suddenly undergo a drop do not know how to adapt quickly, so, there would be adverse reactions.

3. If he was born with it, he wouldn't have the ability feel life with a serotonin rich brain, to have it drop and feel the difference.

4. This does NOT explain the drugs that boost serotonin, like Ecstacy. This drug, known as the "love drug" boosts serotonin in the brain, thus, this provides crutial evidence that serotonin DOES IN FACT play a role in mood.

5. This is study of just ONE person, not taking into account all of the other people who have, in fact, benifitted from L-tryptophan and 5-HTP.

It appears that people seem to look at one thing in general to prove a point, and when they find what they are looking for, there is no interest in looking to ther sources.

Thus, from just this one person, this single study, without looking at all other sources, classified it as "proof" when there are several other factors to look into that bebunk this one, single, miniscule "finding".

6. Not to mention, this is NOT a study of several people with this condition, therfor, there is not enough to be replicated to prove it is legitimate "evidence".

I am amzed as to just how dim whitted some people are taking these things. They find one thing that matches their OPINION (not fact, opinion) and confrim it as "proof" without taking into account the vast, neumerous other reports and studies on the same material.

So, yes, THIS one man might not have had depression, but what about other hundreds or people who have this condition? There is not enough repeated evidence to actually prove this, that serotonin does not play a role in mood.


I find that in cases like these, it sems that 'proof' is more so about opinion nowdays in these findings and not actual, profound, repeated, replicated findings that amount to the same criteria.

So that being said I hope people will start to actually explore these paths instead of looking one single thing and claim it as "true". If that is the case, we're only spreading lies, dumbing people down and making society more ignorant about something that could end up saving a persons' life (yes, depression and suicide is where i'm getting at).

I hope I've taught people something with this comment and have given people the education of looking into something before maing a final decision.

Neuroskeptic said...

Thanks for the interesting comment; I'll reply next week when back from holiday.

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Anonymous said...

I think serotonin is not involved in happiness and wellbeing directly, but is involved in social bonding and empathy. I have Aspergers and severe unipolar depression and medicated myself for years with SAMe and Lexapro. When I tried dopamine related drugs such as Adderall instead I achieved far superior mood elevating effects, but a significant loss of empathy and reduced desire to communicate. The 5-ht7 receptor has been shown to be connected with bonding emotions in MDMA and 5-meo-dmt. I believe the success in treating depression with SSRIs and serotonin precursors and agonists is from the social bonding effects of serotonin, and those who lack serotinin are truly cut off from feelings of connectedness in a real and experiential way, creating literal alienation and subsequent depression. Humans are social creatures by default and languish and decline in isolation.