A Gene For Depression

[Manicsleep]

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http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2011.10091319v1

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A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families.

Interesting research. Another group got the same locus at almost the same time from what I have read/heard.

It is also interesting to note how many more genetic research articles are being publishes on a regular basis in the field of psychiatry. Given the logarithmic nature of this type of technology, I wonder how long until we truly do have a very good sense of what is going on in the mind.

Anyways...fascinating stuff.​

..

 

[firedoor]

Maybe we can analyze Michael Jackson's genes to learn if Billy Jean truly wasn't his lover.

But in the meantime, check out these jeans:

http://www.artistwd.com/joyzine/music/def_leppard/joe_elliot.jpg

 

[9point75]

I don't understand... smoking is good for depression?!?! Or is it the other way around?

 

[Manicsleep]

Smokin genes!

 

[Suedehead]

i got a hard time thinking about how we are to look for genes that predispose one to 'depression.' almost like looking for genes that predispose one to 'being human.'

depression as a concept has been difficult to for me to grasp. do we have a qualitatively unique depressive syndrome that would have some sort of heritability? or is 'depression' a quantitative problem, a case where someone is having 'too much' of something that is normal? I don't know how to chase the heritability of the latter. the former... sure.

seems we should keep looking for heritability of other, more specific, traits rather than trying to pin down an umbrella concept like depression - i.e. resilience or optimism or extraversion or mood reactivity, etc.

 

[Bartelby]

depression as a concept has been difficult to for me to grasp. do we have a qualitatively unique depressive syndrome that would have some sort of heritability? or is 'depression' a quantitative problem, a case where someone is having 'too much' of something that is normal? I don't know how to chase the heritability of the latter. the former... sure.

Even if depression is an exaggeration of a normal grief response it would be interesting to know if certain brains are "fertile ground" for that kind of response and why. DSM-IV depression is also a well defined concept that should have a high inter-rater reliability and it may actually be easier use DSM-IV depression as an operational definition in genetic studies than to try to operationally define, say, resilience. Honestly something like "resilience" or "optimism" sounds more fuzzy than "meets criteria for major depression."

 

[Suedehead]

Even if depression is an exaggeration of a normal grief response it would be interesting to know if certain brains are "fertile ground" for that kind of response and why. DSM-IV depression is also a well defined concept that should have a high inter-rater reliability and it may actually be easier use DSM-IV depression as an operational definition in genetic studies than to try to operationally define, say, resilience. Honestly something like "resilience" or "optimism" sounds more fuzzy than "meets criteria for major depression."

yes, but 'meets criteria for major depression' is terribly non-specific, UNLESS MDD is a qualitatively unique phenomenon. I'm just not sure that it is.

Yeah, I just threw out 'resilience' and 'optimism.' my point for depression is the same you are making for my alternatives - depression is fuzzy. not sure if heritability is something we can chase with genetics. but if we broke depression down into more relavent traits that WOULD have concrete heritability, then hooray.

DSM notwithstanding. Our current conception of depression captures such a broad population.

Now, responsiveness to SSRIs might be fun to chase genetically.

 

[Manicsleep]

I wonder if this population does better with buproprion and may have a greater basis in dopamine than other NTs.

 

[Suedehead]

I wonder if this population does better with buproprion and may have a greater basis in dopamine than other NTs.

totally. or perhaps our definitions of depression need to be refined - more emphasis on subtypes (I know the ones we have already).

 

[loveoforganic]

yes, but 'meets criteria for major depression' is terribly non-specific, UNLESS MDD is a qualitatively unique phenomenon. I'm just not sure that it is.

Yeah, I just threw out 'resilience' and 'optimism.' my point for depression is the same you are making for my alternatives - depression is fuzzy. not sure if heritability is something we can chase with genetics. but if we broke depression down into more relavent traits that WOULD have concrete heritability, then hooray.

DSM notwithstanding. Our current conception of depression captures such a broad population.

Now, responsiveness to SSRIs might be fun to chase genetically.

I would be surprised if any mental illness, be it qualitatively or quantitatively different from a healthy mind, is going to be accounted for by a single gene. Unless you believe (and I'm not challenging or supporting this belief) that depression results completely from a transactional/experiential/cognitive interplay without any inherent biological stuff, such as (completely made up example) a mutated neurochemical receptor that has slightly decreased binding affinity relative to the native protein, I think there can be utility in tracking genetic differences. With genes isolated, you can look between those populations and see what the differences, physically, actually are, before depression is even present.

Edit: I started typing with one idea in mind, but ended with another, so if that's confusing I can rephrase

 

[Suedehead]

I would be surprised if any mental illness, be it qualitatively or quantitatively different from a healthy mind, is going to be accounted for by a single gene. Unless you believe (and I'm not challenging or supporting this belief) that depression results completely from a transactional/experiential/cognitive interplay without any inherent biological stuff, such as (completely made up example) a mutated neurochemical receptor that has slightly decreased binding affinity relative to the native protein, I think there can be utility in tracking genetic differences. With genes isolated, you can look between those populations and see what the differences, physically, actually are, before depression is even present.

Edit: I started typing with one idea in mind, but ended with another, so if that's confusing I can rephrase

some conditions, I believe, reflect qualitative differences in brain structure and/or function. Schizophrenia, dementia, delirium, bipolar disorder (true bipolar, not bipolarity, whatever that is).

you're right, we prolly won't find a single gene to account for these conditions. but the fact that they are qualitatively unique conditions suggest fundamental causation which could be traced to gene clusters.

Like for schizophrenia... I bet genetic studies will help us understand it more - may reveal that there are actually 10-20 different 'kinds' of schizophrenia that may respond to more specific treatments.

I like genetic studies for these types of conditions because I think they'll open doors.

I just don't know if that's possible for 'depression' because our concept is too general as depression results from all kinds of jazz, like transactional/experiential/cognitive interplay, like you say.

 

[Enkidu]

yes, but 'meets criteria for major depression' is terribly non-specific, UNLESS MDD is a qualitatively unique phenomenon. I'm just not sure that it is.

But hypertension is not qualitatively unique from normal blood pressure, but we can still talk about genes predisposing to hypertension.

Maybe some degree of depressive qualities are normal, but too much is harmful, so that the demarcation between the two could be arbitrary in the way that it is for blood pressure.

But isn't MDD qualitatively different? It seems like MDD involves acute episodes of depression where thinking becomes qualitatively different.

 

[Suedehead]

But hypertension is not qualitatively unique from normal blood pressure, but we can still talk about genes predisposing to hypertension.

Maybe some degree of depressive qualities are normal, but too much is harmful, so that the demarcation between the two could be arbitrary in the way that it is for blood pressure.

But isn't MDD qualitatively different? It seems like MDD involves acute episodes of depression where thinking becomes qualitatively different.

when people become severely depressed, they are qualitatively different, yes. what I'm asking is whether a depressive disorder is qualitatively unique. Is MDD an entity in and of itself? - does it follow a certain course, start at a certain age, have a certain treatment response, a certain heritability? the answer is YES for schizophrenia or IDDM, etc. Not sure for MDD because our DSM conceptualization of MDD captures too diverse a population.

I like your analogy to hypertension, though. because everyone has a blood pressure and everyone gets depressed. it's the quantitative potential that lead to dysfunction.

I could dig on gene studies that help describe what predisposes one to hypertension or depression. but I don't think there will ever be 'hypertension' or 'depression' genes or clusters of genes because they are not conditions unto themselves (excepting the homogenoous diopathic types with a certain course, heritability, treatment response, symptomatology, etc, etc). depression and hypertension are generally (not always) results of predispositions + lifestyles.

maybe that's what I was originally asking. I could dig on gene studies that assess heritability of predisposing traits to depression. But my brain fogs when we have a study assess the heritability of "major depressive disorder." I just don't see MDD as we know it as a homogenous, consistent, predictable condition.

 

[Enkidu]

when people become severely depressed, they are qualitatively different, yes. what I'm asking is whether a depressive disorder is qualitatively unique. Is MDD an entity in and of itself? - does it follow a certain course, start at a certain age, have a certain treatment response, a certain heritability? the answer is YES for schizophrenia or IDDM, etc. Not sure for MDD because our DSM conceptualization of MDD captures too diverse a population.

I see what you mean, but this seems to be an inherent problem of defining conditions syndromally, like we do in the DSM.

There was a time when all conditions were defined syndromally, with varying degrees of prognostic specificity. There were a lot of ways that abdominal pain could turn out, since there are a lot of different pathologies that present like that. There are only a few ways that sudden loss of speech can turn out, since there are only a few pathologies that present like that. Depression is like a psychiatric stomache ache.

Its obvious why genetic studies for depression are premature. Genetic studies of stomache would have been too, some pathologies have strong genetic causes, some are purely environmental, and there are a lot of things that could be going wrong.

Before we find the gentic cause of a heterogenous syndrome, we have to associate at least some cases of it with a specific pathology. If 1% of people with MDD have some kind of lab finding or aberrant receptor expression, or neurodegenration, then we can look for genetic links for them, but probably not the undifferentiated group. And we can be certain that there are some distinct changes in the brain, because if there is a change in function there must be some physical difference that led to that change.

Well, I'm skeptical about all genetic studies in psychiatry because they're shots in the dark. But maybe that's just my bias.

 

[Suedehead]

I see what you mean, but this seems to be an inherent problem of defining conditions syndromally, like we do in the DSM.

There was a time when all conditions were defined syndromally, with varying degrees of prognostic specificity. There were a lot of ways that abdominal pain could turn out, since there are a lot of different pathologies that present like that. There are only a few ways that sudden loss of speech can turn out, since there are only a few pathologies that present like that. Depression is like a psychiatric stomache ache.

love it.

Its obvious why genetic studies for depression are premature. Genetic studies of stomache would have been too, some pathologies have strong genetic causes, some are purely environmental, and there are a lot of things that could be going wrong.

Before we find the gentic cause of a heterogenous syndrome, we have to associate at least some cases of it with a specific pathology. If 1% of people with MDD have some kind of lab finding or aberrant receptor expression, or neurodegenration, then we can look for genetic links for them, but probably not the undifferentiated group. And we can be certain that there are some distinct changes in the brain, because if there is a change in function there must be some physical difference that led to that change.

Well, I'm skeptical about all genetic studies in psychiatry because they're shots in the dark. But maybe that's just my bias.

really like how you put this. something hopefully may come of our shots in the dark in the way you enumerated.

I'm skeptical, too. but for the psych conditions that fit a disease model (schizophrenia, dementia, true bipolar), I'm more hopefull.

 

[Manicsleep]

Great points enkidu.

MDD is like a bad ache.
with psychotic features, like an acute abdomen or perhaps fever etc?

Although we have imaging modalities like fMRI, SPECT, PET that can give us pretty detailed info, its still nothing like what a surgeon can do.

We can't say, well lets just have a look around in there. Also, the brain is a tad bit more complicated. I am glad we have people like you who understand that to get to 100% understanding you have to go through 1 through 99 first. Good luck, I really hope you pick neuropathology as a career with psychiatric illness as your focus.

 

[PETRAN]

love it.



really like how you put this. something hopefully may come of our shots in the dark in the way you enumerated.

I'm skeptical, too. but for the psych conditions that fit a disease model (schizophrenia, dementia, true bipolar), I'm more hopefull.

Good, but i can't see how you equate "dementia" with schiz./bipolar. IMO they don't even belong together. Most of the times, "dementia" results from clear-cut neurodegenerative/neurological disorders like Alzheimer's/Pick's/Lewy-Body/Vascular/Parkinson's/Huntington's/MS. All these have demonstratable neuropathology and they fit the disease model already. Individuals decline with the progress of degeneration. Schiz., schizoaffective and bipolar-1 (or other stupid DSM discrete categorizations) can be summed as "psychoses" (or "psychosis" with affective features, although IMO all psychoses have a crucial emotional component), a collection of extreme experiences and behaviours with no known neuropathology (the latest fad is the "neurodevelopmental" hypothesis, lets see if its nore than a fad like many previous models and theories). Quite different to neuro conditions which are clear-cut medical conditions no doubt about that!

 

[Suedehead]

Good, but i can't see how you equate "dementia" with schiz./bipolar. IMO they don't even belong together. Most of the times, "dementia" results from clear-cut neurodegenerative/neurological disorders like Alzheimer's/Pick's/Lewy-Body/Vascular/Parkinson's/Huntington's/MS. All these have demonstratable neuropathology and they fit the disease model already. Individuals decline with the progress of degeneration. Schiz., schizoaffective and bipolar-1 (or other stupid DSM discrete categorizations) can be summed as "psychoses" (or "psychosis" with affective features, although IMO all psychoses have a crucial emotional component), a collection of extreme experiences and behaviours with no known neuropathology (the latest fad is the "neurodevelopmental" hypothesis, lets see if its nore than a fad like many previous models and theories). Quite different to neuro conditions which are clear-cut medical conditions no doubt about that!

right. no known neuropathology. But I put schizophrenia and TRUE bipolar in a disease model because while we don't have any known neuropathology (yet) these conditions follow a very consistent and generally predictable pathology (when correctly diagnosed) - meaning they have a very particular course, heritability, treatment response and symptom cluster. Such congruency suggests a DISEASE process. As we learn more about schizophrenia and TRUE bipolar disorder (I agree with Nassir Ghaemi and don't think schizoaffective disorder is an entity unto itself), the neuropath will likely become more apparent and they will be more 'neurologically' conceptualized. that's my guess, at least.

 

[Manicsleep]

You are absolutely correct suedehead. There is a disease process and if you follow these people over time you will see a clear degeneration. We may not know what that is yet but we are getting closer.

What we have here is failure of recognition. If something can be recognized in a unidimensional sense, it tends to resonate better. Which is why a picture is worth a thousand words and why lawyers know its more important to 'sound' good than to actually have a good argument. We don't really understand dementia much better than depression but because we can see the pretty pictures we believe we do.

 

[Doc Samson]

In terms of evidence supporting neurodegeneration in schizophrenia, here's a snippet (cut and pasted since I'm too lazy to summarize right now) from an article currently in review on psychosis and morphology of the corpus callosum:

Schizophrenia has also been associated with a thinned corpus callosum, with schizophrenia patients shown to have both smaller callosal size at baseline and more pronounced decline in size over time than healthy controls. Moreover, schizophrenia patients with poor outcomes have been shown to have more prominent loss of callosal size than patients classified as having good outcomes.

I'd be happy to provide the refs for the cited studies if anyone's interested.

 

[Evidence Based]

In terms of evidence supporting neurodegeneration in schizophrenia, here's a snippet (cut and pasted since I'm too lazy to summarize right now) from an article currently in review on psychosis and morphology of the corpus callosum.

I'd be happy to provide the refs for the cited studies if anyone's interested.

I'd love the refs if you have them. I have a little familiarity with the lit on neurodegeneration in Sz, but more knowledge is good right?

(Sorry to parachute into the thread, carry on.)

 

[Ibid]

Schizophrenia has also been associated with a thinned corpus callosum, with schizophrenia patients shown to have both smaller callosal size at baseline and more pronounced decline in size over time than healthy controls. Moreover, schizophrenia patients with poor outcomes have been shown to have more prominent loss of callosal size than patients classified as having good outcomes.

.

I am not saying they are not on to something but when I read some of this a few months ago what occurred to me is that people with completely severed corpus callosum do not develop schizophrenia like symptoms. So perhaps atrophy is worse than nothing but then people with all sorts of corpus callosum damage, that being the more common state, don’t develop schizophrenia either, that I know of, maybe they do.

 

[Enkidu]

I am not saying they are not on to something but when I read some of this a few months ago what occurred to me is that people with completely severed corpus callosum do not develop schizophrenia like symptoms. So perhaps atrophy is worse than nothing but then people with all sorts of corpus callosum damage, that being the more common state, don't develop schizophrenia either, that I know of, maybe they do.

Well, the corpus callosum contains fiber tracts from a bunch of different brain regions, so a thinning of this region is a sensitive indicator that there has been neurodegeneration somewhere. But the symptoms may not be directly related to the corpus callosum, but they could be a different consequence of the underlying neurodegneration. It's a cool finding though.

Incidentally, doesn't a severed corpus callosum lead to a "split mind"? Maybe that's what Bleuler was thinking about 😛

 

[Ibid]

Well, the corpus callosum contains fiber tracts from a bunch of different brain regions, so a thinning of this region is a sensitive indicator that there has been neurodegeneration somewhere. But the symptoms may not be directly related to the corpus callosum, but they could be a different consequence of the underlying neurodegneration. It's a cool finding though.

Aye, In the work I read that was not how they sold it though. They proposed what I thought was a spurious mechanism based on the thinning.

No reason to think the results could not be replicated. Ill tell you a story though, a few years ago now in a dusty cupboard I found some equipment that Proff X, long dead now, must have used to demonstrate effect X regarding this very structure. Quite excited with my find I blew the dust off, yes all the bits and bobs are here, this is the actual stuff I thought to myself. And as you do got to wondering as you do when you find an old engine, radio or the like "will it fire up?". What It I came to realise was that whatever else the old buzzard never got those results with that gear. It was the gear described in the paper but you had to see it set up to spot the problem.

I replicated the "result" easily technology having moved on, so it was a bit like Mendel and his peas. The data was fake but it just so happened the idea was right. Funny old game.

Incidentally, doesn't a severed corpus callosum lead to a "split mind"? Maybe that's what Bleuler was thinking about 😛

lol

 

[PETRAN]

Interesting, the callosal theory. This reminds me of that old theory in which "hearing voices" was because one hemisphere was talking to the other or something (had something to do with julian jaynes?). There was also a similar one for bipolar, in which when the right hemisphere takes over is "depression" whereas when the left one is taking over is "mania". Interesting stuff but i'm not sure if they are valid or not. For what i know, the split-brain cases that Sperry and Gazzaniga tested and followed through-out the years haven't developed schiz. or bipolar. Search for the studies if you haven't by the way, they are very interesting IMO. Pictures were flashed in the two visual fields and whilst the left hemisphere could "say" what it (or he/she?) saw, the right could just paint it with the left hand. It is also interesting that when the patients were asked about what hey have seen, they reported only the stimulus that fell on the right VF-left hemisphere. The right-hemisphre-left-hand could select the correct stimulus though and when the split-brain individual was asked for the reason they chose the specific stimulus they just made-up an excuse. The researchers went as far so as to make the two hemispheres play poker by exchanging hands and visual fields lol crazy.

 

[Enkidu]

PETRAN, I've noticed that you seem to be skeptical about finding molecular or morphological correlates to mental illness. My view is that inasmuch as diseases like schizophrenia and MDD represent altered mental function, there must be altered physiology. Altered physiology, in turn, requires that some molecular feature must also be altered. The basis of this way of thinking is the idea that neural function is completely a function of the behavior of the neurons and their molecular machinery.

Is this not what you believe? I wonder if you could outline your view, if you think that diseases like schizophrenia may be present in brains that are not discernibly different from normal.

I know that some people believe that mental illnesses are somehow not real, that they are only defined by society or something, so they don't form a natural category that could have a neural correlate. If this is your view, I could understand your skepticism that we wouldn't be able to correlate schizophrenia with pathological findings (since the pathology would somehow be in our society, not the labeled individual). Is this what you believe? I'm not sure why else you would be so skeptical.

 

[PETRAN]

PETRAN, I've noticed that you seem to be skeptical about finding molecular or morphological correlates to mental illness. My view is that inasmuch as diseases like schizophrenia and MDD represent altered mental function, there must be altered physiology. Altered physiology, in turn, requires that some molecular feature must also be altered. The basis of this way of thinking is the idea that neural function is completely a function of the behavior of the neurons and their molecular machinery.

Is this not what you believe? I wonder if you could outline your view, if you think that diseases like schizophrenia may be present in brains that are not discernibly different from normal.

I know that some people believe that mental illnesses are somehow not real, that they are only defined by society or something, so they don't form a natural category that could have a neural correlate. If this is your view, I could understand your skepticism that we wouldn't be able to correlate schizophrenia with pathological findings (since the pathology would somehow be in our society, not the labeled individual). Is this what you believe? I'm not sure why else you would be so skeptical.

I totally believe that mind and behaviour are the result of the brain (im doing a neuropsychology PhD). I'm very skeptical about how useful is to search for molecular (and not neural) correlates of these states. In the end of the day, there will be molecular differences for any psychological state (even for extroversion-introversion and religious belief), i'm not sure if with the present day technology and scientific methods we can find anything of value deep-down in the countless molecules, gene expressions and proteomics that occur all the time.


As many neuroscientists put it, it is like trying to prove that a chair broke because the electromagnetic forces of the molecules have been overriden, whereas the chair was actually broken because a very fat person sat upon it. You could actually look at the molecules of the chair and say "ohh this is why the chair broke, because the molecules (e.g the electromagnetic forces that comprise the bonds) tha make the chair have been pulled apart" but this says nothing about the actual cause-effects and nothing about the nature of the chair ,its' shape, why it is used for (sitting) and hence how it broke (large-scale interactions between the chair's mass, shape etc. with the weight, the body-type and the sitting posture of the person etc.). I personally haven't seen anything convincing that proves that psychosis is neurodegenerative (this was actually the older view, hence "dementia praecox").


According to the current scientific consensus. psychosis is not neurodegenerative but neurodevelopmental (like ADHD, learning dissabilites, mental ******ation or autism) this somehow sounds more "right". In the end of the day ALL behaviour is "neurodevelopmental" and the reason that each individual is unique is because he/she is wired differently. Autism, ADHD or psychosis (or depressive and anxious trates as well as some cognitive-styles) could be the "extreme" versions of possible spectrums (which happen to be "dysfunctional"). So, it would be much more clever to look at bigger-scale dynamics at the level of neural networks and systems that are known to produce certain behaviours and how these systems change in response to complicated genetic-choice-environment interactions. This would be a trully "neuro-relativity" theory (and this is the view of many neuroscientists). Molecular level is not the most appropriate level of explanation for this behaviour of the system (although this doesn't mean that it is useless. You could gain some insights from it as well. You are just not going to understand the "big picture", just some snippets here and there). It is like trying to explain a rape because the serotonin molecules of the rapist moved in certain ways and interacted with certain other molecules. Not very helpful or explanatory.

 

[Enkidu]

In the end of the day, there will be molecular differences for any psychological state (even for extroversion-introversion and religious belief), i'm not sure if with the present day technology and scientific methods we can find anything of value deep-down in the countless molecules, gene expressions and proteomics that occur all the time.

I understand what you mean. It wouldn't make sense to find the molecular correlate of me wanting to have korean food, for instance. But this is something very high-level. The fact that a person is psychotic is not like the fact that they want a certain food.

It's more plausible that a person is psychotic because of a very fundamental defect in their brain, the way we see cognitive defects in people with dementia or Huntington's disease. For instance, we wouldn't expect neurotransmitter receptor blockade to be able to change very high-level brain processes, like the types of food we like, but it is effective in treating aspects of psychosis and depression.

Now I would agree that the content of a person's delusions is likely to be high-level and impenetrable on a molecular level. I wouldn't think that there would be a molecular correlate of hearing this type of voice vs. that type of voice, for instance.

According to the current scientific consensus. psychosis is not neurodegenerative but neurodevelopmental (like ADHD, learning disabilites, mental ******ation or autism) this somehow sounds more "right"

Well, I don't think that this is necessarily a consensus view. There are a lot of theories on the cause of schizophrenia, and each has a certain amount of evidence behind it. But regardless, neurodevelopmental defects are molecular/morphological defects. If schizophrenia is primarily a neurodevelopmental disease, then that means that discrete cellular and molecular events failed to happen and the result is an abnormal brain. It would be odd if defects during embryonic development would result in such wildly abnormal behavior as psychosis without any population of cells being abnormal.

So, it would be much more clever to look at bigger-scale dynamics at the level of neural networks and systems that are known to produce certain behaviours and how these systems change in response to complicated genetic-choice-environment interactions.

Well if we were much more clever then we would be able to do this, but we're not. Instead we're stuck with the tools that we have. I'm not saying that we will be able to explain everything about the brain with molecular biology, but we have every reason to think that schizophrenia and MDD are disorders that should leave a molecular/cellular trace.

By starting with a molecular trace we may eventually be able to follow it to a cause, and one day we may have an explanation. This is how we study every other disease, and I think this is the way to study psychiatric disease as well, even if they relate to a system that we don't fully understand.

 

[Manicsleep]

Ethanolamine Phosphate.

 

[Ibid]

Ethanolamine Phosphate.

I can see how this might have some limited utility in a culture like Japan where people might be less inclined to be expressive about feelings or subjective experiences.

In a Western context I see serious comedy potential.

 

[Majesty]

Ethanolamine Phosphate.

I just hope they don't make this some marketing scam where you have to go and order from one company who has a monopoly.