Is serotonin conclusively linked to depression?

Question

Some highlights from the article "The Depressing News about Anti-Depressants":

ever since a seminal study in 1998, whose findings were reinforced by landmark research in The Journal of the American Medical Association last month, that evidence has come with a big asterisk. Yes, the drugs are effective, in that they lift depression in most patients. But that benefit is hardly more than what patients get when they, unknowingly and as part of a study, take a dummy pill—a placebo. As more and more scientists who study depression and the drugs that treat it are concluding, that suggests that antidepressants are basically expensive Tic Tacs.

One team of researchers wondered if antidepressants were "a triumph of marketing over science." Even defenders of antidepressants agreed that the drugs have "relatively small" effects. "Many have long been unimpressed by the magnitude of the differences observed between treatments and controls," psychology researcher Steven Hollon of Vanderbilt University and colleagues wrote—"what some of our colleagues refer to as 'the dirty little secret.' "In Britain, the agency that assesses which treatments are effective enough for the government to pay for stopped recommending antidepressants as a first-line treatment, especially for mild or moderate depression.

But if experts know that antidepressants are hardly better than placebos, few patients or doctors do. Some doctors have changed their prescribing habits, says Kirsch, but more "reacted with anger and incredulity."

Doctors see with their own eyes, and feel with their hearts, that the drugs lift the black cloud from many of their depressed patients. But since doctors are not exactly in the habit of prescribing dummy pills, they have no experience comparing how their patients do on them, and therefore never see that a placebo would be almost as effective as a $4 pill. "When they prescribe a treatment and it works," says Kirsch, "their natural tendency is to attribute the cure to the treatment." Hence the widespread "antidepressants work" refrain that persists to this day.

Right about here, people scowl and ask how anti-depressants—especially those that raise the brain's levels of serotonin—can possibly have no direct chemical effect on the brain. Surely raising serotonin levels should right the synapses' "chemical imbalance" and lift depression. Unfortunately, the serotonin-deficit theory of depression is built on a foundation of tissue paper. How that came to be is a story in itself, but the basics are that in the 1950s scientists discovered, serendipitously, that a drug called iproniazid seemed to help some people with depression. Iproniazid increases brain levels of serotonin and norepinephrine. Ergo, low levels of those neurotransmitters must cause depression. More than 50 years on, the presumed effectiveness of antidepressants that act this way remains the chief support for the chemical-imbalance theory of depression. Absent that effectiveness, the theory hasn't a leg to stand on. Direct evidence doesn't exist. Lowering people's serotonin levels does not change their mood. And a new drug, tianeptine, which is sold in France and some other countries (but not the U.S.), turns out to be as effective as Prozac-like antidepressants that keep the synapses well supplied with serotonin. The mechanism of the new drug? It lowers brain levels of serotonin. "If depression can be equally affected by drugs that increase serotonin and by drugs that decrease it," says Kirsch, "it's hard to imagine how the benefits can be due to their chemical activity."

Is this article true? What evidence is there that serotonin is linked to depression?

Answer 1

It's all about the receptors, really. There are 7 families of serotonin receptors that perform different functions within the brain, and according to Wikipedia 14 different subtypes have been discovered.

The article assumes that a blanket level of serotonin would be sufficient to "perk" up the brain, wherein it is much more complicated. Serotonin serves to modulate the level of excitation or inhibition depending on the circumstances. Most of the "effect" from today's antidepressants is related to modulating projections from the dorsal raphe in the brainstem to dopaminergic neurons in the frontal cortex, but some of the serotonergic neurons in the basal ganglia can be hyperactive in situations where there is mild psychosis. So, depending on the etiology of the depression, suppressing those neurons local to that portion of the anatomy can actually be helpful.

So, it's less to do with the transmitter that is being discussed, and everything to do with which subtypes of receptors are being agonized or antagonized. While we have learned a tremendous amount about the relationships between neurotransmitters at different nuclei, we still have a lifetime or more of research to go.

Answer 2

I suppose at face value, the answer to the question "Is serotonin linked to depression?" would 'yes'. However, if the question was "Is Major Depressive Disorder or Dysthimia the result of deficits in serotonergic signaling?" the answer becomes much less black-and-white. First, to piggyback on Chuck's response, it is very important to consider 5-HT (serotonin) receptor subtypes, since different subtypes can play significantly different roles in modulating a massive amount of cognitive and physiological processes. These range from autonomic functions such as pupil dilation, appetite, sexual arousal etc..., to high level cognitive and social behaviors/functions such as aggression, mood, impulsiveness, addiction etc. It is a gross oversimplification to think in terms of "more" or "less" serotonin being the grand underlying factor in depression. Certainly, like most every aspect of a biological system, there are going to be consequences when there are critical deficits or excessive amounts of neuromodulatory chemicals such as serotonin, but there are many other factors that clinicians and researchers have found to be important relative to depression.

Some of these are not surprising and pretty intuitive, such as dysregulation of other neurotransmitter systems, particularly monoamines such as dopamine, norepinephrine, and epinephrine as these chemicals also modulate mood and arousal.

Recent research has also shown that antidepressants such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs), to name a few, owe their therapeutic qualities, at least secondarily, to increased neurogenesis in hippocampus which also explains the improvement in general cognitive function many depressed individuals report when successfully treated. (1) Some researchers argue that this is actually the primary mechanism underlying the attenuation of depressive symptoms when using these pharmacological therapies.

Other connections have been made to increased inflammation (2) as an important factor in depression. Depressive symptoms have actually been shown to be caused by long term interactions from adipose tissue (a major source of inflammation) on neural regulatory systems.

So, I'll wrap this up by saying that yes, serotonin is linked to depression. The link is still just that, a link. For a variety of historical reasons, relating serotonin to depression somehow comes off as a hot topic of debate, but this is because of gross oversimplifications that are provided to the public by the media, pharmaceutical companies, clinicians and even the researchers studying depression and the neurophysiology behind it.

1. Castrén E (March 2005). "Is mood chemistry?". Nat Rev Neurosci. 6 (3): 241–6. doi:10.1038/nrn1629. PMID 15738959.

2. Shelton RC, Miller AH. Inflammation in depression: is adiposity a cause? Dialogues Clin Neurosci. 2011;13(1):41-53.

Answer 3

Although I did not want to post anymore, lol (and btw it has nothing to do with drama, its cause I spend too much time here and its distracting me from my real job too much), I wanted to enlighten and challenge the typical SSRI theory.

I think Chuck already owned it quite a bit though. Anyways,

Meet Tianeptine:

What is Tianeptine? Tianeptine is a novel french pharmaceutical that is actually a selective serotonin reuptake ENHANCER. Wtf? An enhancer? But I want more serotonin flooding my synapses!

Tianeptine is kind of a weird drug as it seems to do many things. For instance, it can give one an initial stimulatory affect through some crazy downstream dopamine processes.

The general theory as to why it works (I've actually taken it before, I don't think I was consistent enough though), can be summed up in a weird and hard to describe way: it promotes neurogenesis to certain parts of your brain that have apparently been injuried over the years or worn out. I always thought the concept was interesting in that it's one of the only drugs that really has a long term outcome of not taking it anymore.

The french are very clever sometimes. But yeah, if SSRI's work AND SSRE's work? Then...is it really all serotonin?

Answer 4

Now I didn't read the whole discussion beforehand, just skimmed through it. Maps.org /Yale Uni is doing quite a bit interesting research on the topic, having better results than any existing antidepressants could dream of. Psilocybin/ LSD/ DMT/ MDMA could be far out to read up on, but psychedelics/ empathogens may be the future answer to a part of the question.

If you check out the Cochrane library on LSD, they also show a significant effect on the global brain communication after intake, which may be beneficial to reset the "loops" that the depressed/ dysfunctional/ addictive brain is in.

I also like the "Deep Rest" (ref: Jim Carrey?) interpretation of depression. It comes to tell your body to take some time off, de-stress, process known or unknown traumas and to find who you are and your purpose here on earth -whatever that may be. Most people don't have time to get to know themselves today, so they rather work long hours to fit into the majority of well adjusted misfits.

For me, I get energy from learning new things at my own pace, finding new subjects of digging into, sharing and discussing knowledge and philosophy, helping people where I can ++. Many places pay people who doesn't even truly care, or care for the wrong reasons, to do these things. But now we're over to worldbuilding.

Follow the money, and you are on the right path to the wrong solution.