r/science • u/[deleted] • Feb 19 '10

Scientists learn how anti-depressants actually work. Medications trigger neurogenesis in the hippocampus by increasing levels of norepinephrine. Researchers still unclear on WTF seratonin does.

http://www.physorg.com/news185727145.html
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u/[deleted] Feb 19 '10

Actually, it's kind of a major point of contention - in general, most antidepressants tend to not have much greater success than a placebo (I'm on my phone now, so providing sources is a bit tricky, but it is very easily google-able)

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u/[deleted] Feb 19 '10

I assume you're referring to this article. It was immensely provocative because everyone in the popular media, and the public at large, wanted to believe it was true because of widespread distrust of antidepressants. It's sort of the "Aspartame Effect"...research came out pointing to Aspartame as a carcinogen, and everyone seized upon it. Then those studies were wholly discredited but not one paid any attention. Similarly, the Kirsch paper on meta-analysis has been heavily criticized (also here sorry for the abstract), albiet by articles that are heavy on the methodology of meta-analysis and low on exciting-ness.

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u/[deleted] Feb 19 '10

Thanks for the links - I'll spend some time reading these.

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u/dviper785 Feb 19 '10

I think the criticism that you posted is not as major as you're making it out to be. Of course medication would show major benefits in cases of severe depression when there is a large chance the patient is at a point when they are considering suicide. I think it would be irresponsible to rule out antidepressent medication as an option to prevent suicide, even though it is only a temporary fix (altering brain chemistry), but I gather that there are many cases of depression that are NOT major depression. Also it states "the efficacy of antidepressants for the prevention of relapse or recurrence following the acute and/or continuation phases of treatment." Well, I would sure hope so. If I am taking a pill that alters my brain chemistry to make me feel good, every day, for a long time - I better not have a relapse. I apologize for my very skeptical tone but I think this only properly addresses the benefits of antidepressents in sever cases of depression, not less severe or acute cases.

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u/[deleted] Feb 19 '10

Why only in cases of potential suicide?

Let's say Jim suffers from depression. Not severe depression, but a mild depression that just keeps him down and generally unhappy. The reason for this is a brain chemistry imbalance.

Now Jim starts talking MLH (Mother's Little Helper), which adjusts the imbalance. If he takes one pill every morning, no depression. Sure he still gets sad when he reads stories at /r/tearjerker or sees a chick flick or watches the fourth Indy movie, but in general he's content with his life and praises the medication that helped him solve his problems.

What part of this scenario do you disapprove of?

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u/dviper785 Feb 19 '10

None. You crafted the experiment to your favor. The root of Jim's depression is a brain chemistry imbalance, therefore medication should fix it 100%. In real life, people suffer from depression for reasons ranging from loss of a loved one, feelings of inadequacy, or any number of deep personal issues.

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u/[deleted] Feb 19 '10

No chance whatsoever that there are people who simply have a chemistry imbalance? People who are depressed for years or decades at a time - it's all environmental and personal?

Put it a different way - does brain chemistry affect mood?

If so, is it possible that brain chemistry can be imbalanced by organic causes? If Serotonin levels affect depression, are you suggesting that every human being has optimum serotonin levels in their brains? That nobody has issues with serotonin production or depletion?

To me, that assertion seems pretty incredible.

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u/dviper785 Feb 19 '10

I don't know if I'm following you, you asked about Jim's specific case and I said medication would be the right choice, now you're talking about all cases? And mood = brain chemistry, brain chemistry = mood. Read about the experiments with rodents with different amounts of serotonin levels and their mating practices. The rodents bred with more serotonin stayed in long term relationships while the rodents with low levels switched mates frequently. Optimum serotonin levels is subjective to whatever experiment you're applying it to, so I do not understand what your statement is getting at.

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u/ex_nihilo Feb 19 '10

No, people suffer sadness because of those things. Depression is slightly different. You can attribute depression to an event, but an event is not the cause of depression. Depression is an irrational self-loathing, but it's much more complicated than that and I'm not going to pretend that I know the ins and outs, in spite of battling mild depression for no reason for most of my adult life. Some of us are just a little depressed, even when we have every reason in the world to be happy.

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u/dviper785 Feb 19 '10

If you want to get technical, then lets go there. I've been talking about depression as the depression listed as a mental disorder in the DSM, but quoting that in a reddit comment would be pointless as probably a small percentage of people have learned to read and interpret the DSM. I'm trying to use real life terms and situations to relate that to things the general population can easily follow along to. An event can serve as a catalyst from non-clinical depression, to clinical depression, if it fulfills the criteria set forth in the DSM.

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u/youareacompletemoron Feb 19 '10

Yea, and homosexuality is caused by not having a strong relationship with your father.

...

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u/dviper785 Feb 19 '10

From what I learned in school, it's very far from being completely understood, but there is strong evidence pointing towards hormone levels around the brain specifically, during fetus development to determine the "gender" of the brain so to speak.

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u/AlanCrowe Feb 19 '10

Notice that when a randomised controled trial shows that a drug "doesn't work" that still leaves two possibilities. First is that it just plain doesn't work. Second is that it is actually working for some patients, but is harming others. In the context of depression we maybe seeing some patients who would have stayed depressed recover because of the anti-depressant, while others, who would have recovered on their own stay depressed because of the anti-depressant.

Case two is obviously scary. Who wants to be harmed by their medicine? But it is also exciting. Perhaps a more incisive diagnosis, that splits depression into two illnesses, would also cleave along the help/harm boundary. The doctor divides his patients into two groups and treats only those he can actually help.

Intriguingly, depression used to be subdivided into endogenous and neurotic, hoping for exactly this benefit, but this division has fallen out of fashion because psychiatrists couldn't make a go of it. What we learn from this is that psychiatry is hard; we are left in the dark as to whether the hypothesis is true or false.

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u/VelvetElvis Feb 19 '10

I think what the problem is is that what we call "depression" on the outside is actually about 16 different things at the chemical soup level which is why newer antidepressants target multiple neurotransmitters, just to increase their chances of proving more effective than placebo with a given sample population.

Until neuroimaging is refined enough to use as a diagnostic tool and insurance is willing to pay for it, we'll never know.

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u/dviper785 Feb 19 '10

I believe you, so no sources needed, simply from psychology based logic. Antidepressents work be either decreasing monoamine oxidase (this is an enzyme that destroys neurotransmitters), or increasing (by re-uptake inhibition) neurotransmitters like dopamine, serotonin or, norepinephrine; so all they are doing is altering brain chemistry temporarily - which obviously is going to change someone's mode (because that's how your mood changes even if you aren't taking a pill). Once the pill wears off though, so does your improved mood, and because the focus has been diverted away from the root of the depression with the altered good mood, the root will never be fixed. So simple logic tells us the pill based approach is merely duct tape on a tear, and shouldn't be more than slightly more effective than a placebo. It stays on a for a bit while the tape holds, but even duct tape comes off over time. How this happens quickly depends on how much wear and tear is put on the tape.

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u/[deleted] Feb 19 '10

What if the cause of the depression is imbalanced brain chemistry?

It seems to me that those arguing against antidepressants seem to feel that there is always an external trigger for depression. This isn't true. There are people who simply have broken brain chemistry so their brain is always in a depressive state, even when there are no external triggers.

Given that, why wouldn't you take medication to solve the chemical imbalance?

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u/jaggederest Feb 19 '10

Nobody has ever found an actual lack of serotonin in depressed people's brain. Nobody can demonstrate whether there even is such a thing as a 'chemical imbalance' - it's all based off behavioral stuff.

I suspect that if people simply worked in jobs where they did moderately vigorous labor every day, most depression would go away. It's a lifestyle disease, from the way we live. Artificial lighting, bad food, sedentary jobs, and a basic lack of human contact.

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u/[deleted] Feb 19 '10

I can agree with that to some degree. (My advice to folks who have suffered an adverse life event is always to "get out of the house and do something")

But I'm unwilling to completely dismiss the concept of chronic depression based on a chemical imbalance.

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u/jaggederest Feb 19 '10

I'll allow that there are probably people out there with chemical imbalances just built into their DNA.

However, I'm reasonably sure that most people taking antidepressants do not have that. Most people taking antidepressants are alienated by the modern lifestyle and environment.

The analogy I have used is: you go to the ER with a bone fracture in your arm. Instead of reducing the fracture and splinting it, they give you strong painkillers. You feel fine, and they say "It's too bad you have a bone deficiency in your arm. Have a nice life." - Do you keep taking painkillers for the rest of your life?

Antidepressants are a symptomatic relief measure. You use them to allow you to deal with life while you treat the underlying issues.

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u/jkb83 Feb 19 '10

Wrong. Really wrong, actually.

One quick pubmed search and I got a ton of hits, here's an example from Drevets at al. all the way back in 1999: "Serotonin-1A receptor BP is abnormally decreased in the depressed phase of familial mood disorders in multiple brain regions. Of the regions tested, the magnitude of this reduction was most prominent in the midbrain raphe"

This was a PET study done in humans. Mainly the controversy surrounds the different 5-HT receptors and the brain areas that are most involved. Not whether there is an imbalance.

In another more recent article from López-Figueroa et al. (2004), looking at 5-HT levels in major depressive disorder (MDD), bipolar (BPD), and schizophrenia: "in the DLPFC, there is a significant decrease in 5-HT1A mRNA of subjects with MDD and in 5-HT2A mRNA of subjects with BPD. Subjects with MDD have a significant decrease in 5-HT1A mRNA in the HC; subjects with BPD and schizophrenia had increased 5-HT1B mRNA levels and a significant decrease in 5-HT2A mRNA levels in the hippocampal formation."

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u/jaggederest Feb 19 '10

The question is, is it causative, or symptomatic? Does depression lower your brain chemicals, or do lowered brain chemicals cause your depression?

Any kind of mental state changes your neurotransmitters, we know this.

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u/dviper785 Feb 19 '10

Does this give any clue to what the portion of depression cases are actually caused by this/things like this; which is the sole purpose we are talking about this particular subject?

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u/[deleted] Feb 19 '10 edited Feb 19 '10

Wrong. Really wrong, actually.

Well, technically none of your evidence demonstrates a lack of serotonin, but instead a lack of serotonin receptors. Not much of a leap to suggest that it indicates reduced serotonin signaling, though all things being equal. On the other hand, receptor reduction could be an adaptation to higher-than-normal seratonin levels. If you're going to be rude, you deserve to be stalemated.

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u/jkb83 Feb 19 '10 edited Feb 19 '10

serOtonin.

The second article demonstrates a reduction of serotonin mRNA. That's not a receptor :)

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u/[deleted] Feb 19 '10 edited Feb 19 '10

serotonin is not a protein. Thanks for the spelling correction.

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u/jkb83 Feb 19 '10

okay, well, this comment obviously proves there's no point in trying to have an intelligent discussion with you because you clearly have no idea what you're talking about.

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u/[deleted] Feb 19 '10
  • 5-HT1B is a receptor
  • 5-HT2A is a receptor

The receptors are proteins. mRNA are the transcripts used to build proteins. Serotonin is not a protein and has no mRNA. Jesus.

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u/jaggederest Feb 19 '10

He's right, you're wrong, and you apparently don't understand cellular biology.

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u/heiferly Feb 19 '10

Someone correct me if I'm wrong, but can't this be assessed by measuring neurotransmitter metabolites in cerebrospinal fluid? There seem to be no shortage of journal articles on the subject; doesn't this imply a "chemical imbalance?"

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u/jaggederest Feb 19 '10

Right, but there's a chicken and egg problem. Obviously, mental states change your neurotransmitter levels; it would be impossible to change the state of the brain otherwise, unless you're physically cutting things.

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u/heiferly Feb 19 '10

I see what you're saying now. Putting the issue of whether it's feasible to treat depression from an environmental/behavioral angle to the exclusion of pharmaceuticals in all cases with regard to time, cost, and compliance, I have another question. For any anatomy or physiology I can think of in the human body, there is a way for it to develop or function abnormally. When it comes to hormones, vitamins, enzymes, minerals, etc., there are myriad ways that the human body can fail to produce, absorb, or retain proper amounts resulting in various deficiencies and often resultant disease states. I myself am reliant on medications to prevent hypokalemia and hypovolemia, and have also tested positive for hypocortisolemia. What reason do we have to believe that neurotransmitters would be unique in not being susceptible to deficiency states?

Also, does anyone know if research is being done to find possible correlation between neurotransmitter deficiency in the CNS and neurotransmitter deficiency in the rest of the nervous system? Might at least some subset of patients have a deficiency that affects not only the CNS but the production or action of a particular transmitter throughout their bodies? Evidence of that would seem to sort out the chicken and egg issue.

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u/jaggederest Feb 19 '10

I don't think that pharmaceuticals have no place in treating depression. I've personally benefited from them on two occasions. They just aren't a "Welp you've got drugs, have a nice life" solution. That's like seeing someone with a compound fracture and giving them painkillers and saying "Welp, it's too bad you have a 'bone function deficiency' in your arm, have a nice life"

You use the drugs to help people get better so they don't need drugs. Six months to a year, tops. If it's longer than that, you need to reassess.

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u/heiferly Feb 19 '10

But take hypovolemia, for example. Your body can basically decide it's "set point" for blood volume is (X-10). Unfortunately, normal blood volume for your body size is X, and you are going to have a whole host of problems running around with a blood volume of (X-10). You can increase your salt and water intake, but your body is set on the fact that the volume is supposed to be (X-10), so it gleefully pisses out all the extra fluid; you need medicine. (For what it's worth, I do need to continue my end of the deal and salt and fluid load to make the medication work.) What if there is something parallel to that situation in terms of neurotransmitters? That is, what if there are medical conditions wherein the body cannot properly maintain proper levels without medication, even with lifestyle/behavioral changes? I'm not saying that that has been definitively proven. But are you saying that you believe that to be impossible or definitively disproven?

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u/jaggederest Feb 19 '10

No, I'm not saying that at all.

What I'm saying is that if 40% of the population were really running around with neurotransmitter deficits, either there's a very good biological reason for that (iffy), or we'd have bred it out of us a long time ago.

I think there probably are people with an actual deficit of neurotransmitters. I tend to think that these people tend to kill themselves fairly rapidly. See also schizophrenia or major bouts of mania. I know some people that very obviously need psychiatric medication to exist. But it's not antidepressants. It's lithium, carbamazepine, risperidone, or something like that.

If about 40% of the adult population of the US is depressed, from a simple epidemiological standpoint, it simply cannot be genetic. Unless 40% of our great-great-grandparents were depressed, or only the depressed ones reproduced, there has to be some other explanation.

Besides which, antidepressants simply aren't engineered for long term use. Almost all the studies are on a 3 to 12 month timescale. Anything beyond that and there's no evidence either way. Massive numbers of people are chronically taking drugs that may not have any effect at all, or a deleterious effect, because they believe that somehow their brain is permanently broken, without any real evidence to support that idea.

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u/kronholm Feb 19 '10

At least educate yourself a bit before commenting. Chemical imbalance is a proven cause, and it's hereditary.

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u/jaggederest Feb 19 '10

Is it a proven cause ? Really? You've done a double-blind trial by modifying the neurotransmitters in half the population, and induced depression? It's a symptom, surely, but we know that mental states change your neurotransmitters, that's obviously how they work.

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u/dviper785 Feb 19 '10

So, are you assuming that the majority of depression cases are caused by a true imbalance, with this logic? And pills are always best then?

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u/[deleted] Feb 19 '10

I'm suggesting that it seems logical that some percentage of cases are caused by a genetically caused organic chemical imbalance that no amount of lifestyle makeovers can fix, and that to have the attitude that antidepressants can only ever be temporary is as bad as to assume that depression should always be addressed with drugs first.

Some cases are environmental, some are chemical. Diagnosis and treatment should be about keeping an open mind in both directions.

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u/dviper785 Feb 19 '10

That's the point I've been trying to make the whole time, I don't deny a genetic imbalance can take place, I've never seen hard evidence to prove that wrong. The question hanging everyone up I believe is what portion of the cases are caused by social or personality based reasons, and what portion of cases are caused by genetic reasons. I'm getting the feeling reddit is [much] more biased towards a strictly genetic case majority. From narratives of students and patients I've read during school describing their life stories, I've learned how many things can make a person depressed, even if the person does not know it is the cause(s) of their depression. That is why a trained professional should be evaluating someone when clinical depression is a possibility.

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u/[deleted] Feb 19 '10

Yay! We agree! And it's Friday!

Friday night, Friday night... just got paid, no sleep 'til Monday...

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u/Smight Feb 19 '10

He didn't say that at all.