Potential Root Cause of Depression Discovered by NARSAD Grantee

Marina Picciotto, Ph.D. - Brain and behavior research expert on depression
Marina Picciotto, Ph.D.

From The Quarterly, Spring 2013

Marina Picciotto, Ph.D., leading a team of researchers at Yale University, has made an exciting discovery in the search for the biological causes of depression and anxiety. Their discovery points to the importance of a signaling system in the brain that was not previously believed to be central in causing depression.

For decades, many scientists have favored a theory of depression that stresses the impact of abnormally low levels of a signal-carrying chemical, called serotonin. The new research by Dr. Picciotto’s team shifts attention to a different signaling chemical, or neurotransmitter, called acetylcholine.

Millions of depressed people take anti-depressant drugs called SSRIs—an acronym for selective serotonin re-uptake inhibitors. Prozac®, Paxil®, Celexa®, Zoloft® and other SSRI medications act to keep message-carrying serotonin molecules from being rapidly reabsorbed by nerve cells. By allowing serotonin to float for longer periods of time in the tiny spaces between nerve cells, called synapses, scientists have theorized the SSRI drugs promote signaling by compensating for abnormally low serotonin levels.

Dr. Picciotto’s new research, published in Proceedings of the National Academy of Sciences in February, turns attention to fluctuations in levels of the neurotransmitter acetylcholine and the larger chemical signaling system it is part of, called the cholinergic system.

“Serotonin may be treating the problem,” Dr. Picciotto says, “but acetylcholine disruption may be a primary cause of depression. If we can treat the root cause, perhaps we can get a better response from the patient.”

Her team’s experiments demonstrate that abnormally high levels of acetylcholine in the brain can cause depression and anxiety symptoms in mice. In the brains of non-depressed mice—and people—an enzyme called acetyl- cholinesterase (AChE) is produced to lower acetylcholine levels. The team showed that when depressed mice were given Prozac®, AChE levels were raised, and abnormally high levels of acetylcholine were thus brought under control. This adds a new dimension to understanding how and why SSRI anti-depressants can alleviate depression.

Yet many depressed people do not get a therapeutic benefit from Prozac® or other SSRI medications. Dr. Picciotto’s research suggests this may be because the root problem is not, after all, low levels of serotonin, but rather, high levels of acetylcholine. By experimentally blocking the “ports,” called receptors, where acetylcholine molecules “dock” with nerve cells in the brain, the team was able to reverse depression in mice.

In still other experiments, the Yale team showed how interruptions in acetylcholine signaling in the brain area called the hippocampus—important in memory and mood—promotes depression and anxiety in mice.

While the relation between the serotonin and acetylcholine signaling systems is not yet fully clear, this new research opens a new possibility to treat the cause of depression and not just its symptoms. With the new hypothesis that it is the disruption of acetylcholine, and not serotonin, that sets depression in motion, further research studies can be undertaken to determine if medications that target acetylcholine rather than serotonin, are more effective in treating depression.

Marina Picciotto, Ph.D.
Charles B. G. Murphy Professor of Psychiatry,
Professor of Neurobiology and Pharmacology,
Assistant Chair for Basic Science Research, Psychiatry,
Yale University;
1996 NARSAD Young Investigator Grantee,
2004 NARSAD Independent Investigator Grantee

Article comments



Acetylcholine Receptors can be activated by Acetylcholine in both ways on binding and releasing from AchR. Artificial disrupting Acetylcholine activities acting to AchR, would disrupt human emotion balance. Have you seen when the Olympic sporters are extremely too happy to cry but unable to laugh when they are received the award for golden plates to their winedon the top of the first games in Olympic campaigning? This is a typical instance of when large amount of Acetylcholine are binding on AchR to cause caused too much activations of mAchR on activating releasing Acetylcholine to feedback suppressing AchR activities. Only at this point, AchE hydrolysis Acetylcholine from binding of AchR could moderately down the sportor’s emotions.

First, congratulations to Marina and the Team!! Way to go, folks!!! We who suffer from depression are eternally grateful for your work. You have no idea.

The conclusion I draw from these research results is that depression appears to arise from either too much acetylcholine or from too little acetylcholine. Therefore, would it not be ideal to seek within the cholinergic system for the REGULATOR and target how to ASSIST THAT? If we can understand the cholinergic system's acetylcholine regulator, someone might devise a treatment or medication that assists its stable functioning. That might help people prone to major depression AND those with bipolar mood disorder. (I'm guessing bipolars - or at least ultra-rapid cyclers - experience wildly swinging levels of acetylcholine, since clearly that too is some problem of dysregulation.) Even if I'm wrong about the bipolar mood disorder operating similarly, stabilizing the acetylcholine regulator would at least HELP MORE PEOPLE: those with too much acetylcholine AND those with too little acetylcholine.

Also, could you please, in conversations, advocate replacing the term "mental illness" with "neurological disorder?"I am not unusual in my experiences as a "mental patient." Like most "mental patients" (another goodie), I have been judged and abandoned by 99% of my (former) friends; and most of my family. Their brains work fine, and they assume mine is the same; so they don't see why I can't do what they do. Most people apparently see depressed peoples' negative thought patterns and words as an attitudinal issue, a thought-based or "mental" problem, so they expect us to just change it. They don't understand our attitudes and thoughts are just symptoms caused by a severe ORGANIC DYSFUNCTION.

"Mental illness" doesn't connote that to people. Identifying it more correctly as a Brain Disorder or Neurological Dysfunction reminds the listener that THE BRAIN IS AN ORGAN, A VERY IMPORTANT ORGAN that can render us pretty darn dysfunctional when it doesn't work right. It also indicates that depression is a MEDICAL condition, not laziness or a bad attitude, that actually does render us unable for long periods to think clearly, clean our homes, put things away, cook for ourselves, do laundry, keep up with bills, keep up our appearance, or even take baths.

Losing the respect of all my friends worsened my depression. I've lost all trust in people who claim to be loving. Everybody talks about love, but I have yet to find anybody willing to help me. I've turned to public and private agencies for help but do not meet their age or income guidelines (since they don't take into account the cost of prescription meds). I see a counselor thanks to insurance, but home care isn't covered by my insurance. I've spent entire days calling number after number suggested to me as a possible source of help but have over and over been denied access to desperately needed home support services. Some won't help because I have Medicare. Others won't help because I don't have Medicaid. And "Unless you are in a wheelchair," said the lady at the only local charity doing such work voluntarily, "you don't need help." This kind of ignorance is hurtful and harmful. When I began to develop sores that spiraled across my body , the dermatologist just snarled at me in disgust, "It isn't scabies. Go home and clean your house!" Her insult is typical - and frustrating. People just don't seem to know depression is a MEDICAL disorder, an organ dysfunction which renders us unable to solve problems, take action, seek happiness, etc. We deserve help just as much as people with different organ problems; for example, the pancreas. The world doesn't insult diabetics, refuse to help them, or demand that they just change themselves.

As for me, my doctor now reports I'm malnourished (affecting my decision making and increasing the fatigue from the depression). Bugs have been nesting in my skin and house seven months now. I am covered with large sores and scars despite four head-to-toe coatings of pyrethrin (poison) cream and four Ivermectin tablets (the poison in Frontline) the doctors prescribed. Despite my using bed bug spray and lice shampoo. Despite diatomaceous earth on my carpets. My house is nasty, the kitchen piked with unwashed dishes and rotting cat food; my piles of stuff continue to grow. I rarely eat real food, and the house has been more than I can handle for along time. I wander room to room trying to bring order but have trouble making decisions and never finish things I start. Haunted, haggard eyes stare back in the mirror. The ironic thing is I'm educated, I'm bright, and when I was well I was a teacher for many years at the toughest school in the city, upholding with love and dedication the safety net for "at-risk" teens. Now I'm the one "at-risk," but it seems there's no safety net for me. It's no wonder so many of us commit suicide.

So you see, it's very important to change what we call this. Until the public really groks that it's a medical condition, we who suffer depression will continue to be by and large treated with disdain.

Isabella Ringen How can I reach you? I don't know if you will see this or not but I am interested in this topic and would like to talk to you .

Isabella, How well said & how sad! I feel your pain. As one well educated woman to another, I REALLY KNOW EXACTLY HOW YOU FEEL! I was a very successful Psych/Mental Health RN ( of all things ) It was my passion, as a single mom of a child ( adult ) with bipolar & a teen with dyslexia, ADHD & central auditory processing disorder, I now feel like the blind leading the blind. I suffer from MDD, ADHD, GAD, insomnia & sleep apnea. I'm also being tested for RA & have osteoarthritis. I'm 53 yrs young & I have asked, begged, cried, pleaded, prayed, hoped for, researched & sought help for myself as well as for my son. But to no avail. In addition I am also a veteran, as I was an officer in the Navy Nurse Corps. I echo your EXACT DESPAIR & desperation. I have helped so many young & old alike. But as stated there is no help to be found. Please don't give up hope. Because I know there has to be help in the near distant future.

Isabella, Your insights about what you have gone through and still going through with depression are very, very deep. I'm going to read your comment again because you have a lot of insights and wisdom about these issues. You have taught me a lot. Thank you sooo much. My e-mail address is katealsin@gmail.com. I agree with what you said 100% ~Kate

In your article you write: "For decades, many scientists have favored a theory of depression that stresses the impact of abnormally low levels of a signal-carrying chemical, called serotonin.". That is completely incorrect. The serotonin hypothesis of depression has been disproved over 30 years ago, before Prozac even came to market. There has been absolutely no conclusive or circumstantial evidence that serotonin and depression are linked.

Hundreds of clinical trials prove otherwise. Show me your studies and data from over thirty years ago, and tell me again how relevant that is in today's medicinal progressiveness.

Even with those hundreds of studies, you can still find refractory patients not responsive to serotonin modulation.

I wonder how this relates to nicotine, seeing as how that boosts acetylcholine. I'm depressed, smoking helps ...sometimes.

You know, it's interesting. I haven't had depression recently (it runs in my family) but when I did, I would wake up one day saying "holy crap, I haven't smoked a single cigarette in over a week, and I didn't even realize it!" Now, I don't smoke more than two or three cigarettes a day, but the desire (I wouldn't really call it a craving the majority of the time) will still hit me at least once a day, even If I'm abstaining.

Perhaps my Acetylcholine levels were out of control, suppressing the desire to smoke at all?

The results of the study reported in this article are encouraging for increasing our understanding of the neurochemical mechanisms related to depression. However, there are many forms of depression and I suspect that most of the primary neurotransmitters act together and affect each other in myriad ways we still don't know about. In addition, the actions of secondary messengers and other possible influences must be taken into account. Psychiatric illness cannot be accurately pinned to any single neurotransmitter.

These findings might help explain why taking substantial doses of choline supplements over a course of months seemed to precipitate episodes of increased, chronic depression in me. I had started to take choline supplements as a possible aid to cognition and mood, but my mood worsened during the time I was taking these supplements. This is a casual observation. I'm not familiar with the science of how choline supplements might affect acetylcholine in the body, but my understanding is that there may be a correlation.

In line with the study reported in this article, it might be wise to observe and document the experience of people and animals treated with acetylcholine agonists like piracetam, celastrus paniculatus, and other nootropic compounds. The increased popularity of supplementation with alleged nootropic substances over the past few decades may have ramifications for this type of investigation. In addition, if supplementation with acetylcholine agonists were to lead to rising incidences of depression, as this study suggests it might, this could become a public health issue.

I have always been doubtful that "low" serotonin causes depression. I do, however, believe low serotonin causes anxiety. For one, SSRIs work better for anxiety disorders, which are more chronic than depression. As someone with OCD, I have noticed that SSRIs do help with anxiety, but flatten mood and increase sleepiness, which is.....DEPRESSING. I have been on SSRIs for 15 years, and have not slept normally since starting them. Problem is, when I stop or switch, the anxiety comes roaring back. I LOATHE these drugs but am now dependent on them....

Researchers always seem to concentrate on internal mechanisms and never on the external factors that can cause illness. There are only a few external agents - viruses, parasites, toxins, fungi, bacteria, radiation, nutrition [food], pharmaceuticals and gases that have an effect on us and if you trace the cause of all illnesses you always eventually get back to one of these root causes. Depression isn't caused by serotonin imbalance or acetylcholine imbalance or any other sort of endogenous chemical imbalance, it is caused by attack viruses and bacteria, poor nutrition, low frequency radiation, parasitical ivasion [lyme's disease for example causes depression] and drugs like statins, ACE inibitors, proton pump inhibitors and so on.
It is about time researchers stopped this drugs are the cure for everything approach and started to look for rrot cause and realise the drugs are one of the causes of illness

Yes certain stressful stimuli (endogenous or exogenus) may lead to one developing a psychratric condition. Cells have the ability to adapt to change but have limits. I would encourage anyone to read up on research within stress and its effects on biological systems.

Just because serotonin may or may not have an effect (assuming subjective questionnaires count) on mood and anxiety, doesn't mean serotonin is the modulating agent. In fact given the data with response rates and time for efficiency I would argue that it's role is less significant.

I disagree, however, about the comment on drugs. Perhaps not so much for cures but certainly for support their in symptomatic relief. Until gene therapy or advances in regenerative medicine, medication is the only relieving factor. Though your notion of cause and effect is valid I'm afraid people are missing the point.

The brain is a complex organ system and it's certainly time to move on from a simplistic point of view where everything is some how related to "imbalance of chemicals". Research has moved on from this point, therefore, it's time for everyone too as well.

I would definitely like to see more on this topic. I have been searching for a reason why my sleep is disrupted, I am having random muscle/nerve pain, and I do suffer from depression that is attached to PMS. Now that I am entering peri-menopause, I find the symptoms are worse. Is it possible that some hormonal aspect of menopause is causing a disruption to Acetylcholine levels?

My story and symptoms *exactly*, Kelly. This research and research into the interplay of hormones in major depression, and also PMDD, is fascinating and critical.

Anticholinergics like dextromethorphan, diphenhydramine, atropine, scopalamine (etc) have robust immediate-acting anti depressant and anti anxiety properties, antagonisizng and agonizing the receptor still leads to the same depolorazation concept hence why cholinergic agonist such as percactem, choline, arecoline and nicotine can also temporarily allieviate anxiety / depression, agonist however will cause tachyphlaxis alot more faster / psychological dependance and increase cortisol if used for long periods of time :)

Don't know why no one has drawn a link to the anti-cholinergic properties of the tricyclic antidepressants (amitriptyline, imipramine, etc.). At least in severe, chronic, melancholic, psychotic, or refractory depressed states (unipolar or as part of bipolar illness) the tricyclics, especially the tertiary amines, seem to be more effective to a statistically significant degree (no advantage in mild to moderate depression). This could be part of the reason. Unfortunately, messing with acetylcholine is a tricky thing to do without messing with a wide variety of bodily functions, i.e. toxicity...

I have been depressed for 10 years, tried numerous meds. It is so hard taking care of my kids at times I'm desperate for help. Please feel free to email me. Msjenniecarlson@gmail.com

I have known about the choline/depression link for a long time. I noticed that when I eat Lecithin I become depressed. It has high levels of choline. All this is really not so new. Where do you think the word "melanCHOLy comes from? The choline link has been in the air since way back. Bravo to these researchers for bringing this to light again.

Out of curiosity, do you smoke or consume nicotine in any way?

I'd be willing to be in a 'study' if it would help medicine gain insight and relieve this
debilitating illness. I too feel isolated, friendless, and suspect by my family...peers, and acquaintances.

The title of this article is perhaps a bit strong! Why would fluctuations in the cholinergic system be more of a "Root Cause" of depression than fluctuations in the serotonergic system? Both are signaling neurotransmitters; both may be symptoms not causes, downstream from whatever the primary causal factors are. Any thoughts from the scientists out there?

I'm actively dying from Terminal Depression. I've become a reluctant expert in the field of treatment refractory depression because my psychiatrists are unable (or unwilling) to examine the latest research. In an effort to save my own life, I have done extensive research and concluded that my particular type of illness (agitated melonholia) is due to an HPA Axis dysregulation. I think the Acetylcholine link might shed some light on why 30-years of SSRI/SNRI and other meds have not worked for me. I've also tried rTMS, ECT, Neurofeedback and Ketamine without even a moment of relief. Please keep up the good work, there are so many of us out here who are truly dying waiting for something, anything that might make life just a little more tolerable.

The idea that choline is the root cause of depression is not new and NOT discovered by Marina Picciotto. It was put forth by Janowsky and his collegues already in the 1970s (see reference below).

Why it was forgotten is the big question. I can only find two answers: a dysfunctional academy who couldnt separate the wheat from the chaff and the corrupting influene of Big Pharma who had already set its mind on a new class of drugs (the SSRIs, which we now know are pretty ineffective). Both problems are still with us today.

Janowsky, D. S., el- Yousef, M. K., & Davis, J. M. (1974). Acetylcholine and depression. Psychosomatic Medicine, 36 (3): 248-257.

I sometimes experience sudden plunges in mood which can be difficult for those around me to deal with, and which are difficult for me to deal with, too.

Sometimes, getting out of the house, taking exercise or other distraction techniques help, but when my mood is low, motivation is also affected, so it is a real effort to carry through with activities which may be helpful.

Also, I find that when I am feeling like this, I get into very negative and unhelpful thought patterns.

I have had depression and anxiety symptoms since my teens (I am now 49). They have come and gone depending on all sorts of factors. But what I am experiencing now (over the last few months) is different in that my mood is plunging suddenly and for no apparent reason.

Whenever my anxiety becomes unbearable, I take meclizine an over the counter drug normal used for seasickness/vomiting. It is also an acetylcholine blocker. It does the trick. Within an hour my anxiety is gone.

The research depicted above and various comments following thereafter, especially Eshe, explain why Diphenhydramine HCl, Citrate, (and other suffixes) quell anxiety. It is an anti-histamine and an acetylcholine antagonist. If over production of acetylcholine (or a normal production of acetylcholine TO THE EXCLUSION OF serotonin) helps to cause depression then that explains why many depressed people self-medicate with nicotine, usually in the form of smoking cigarettes. Nicotine binds to nicotinic acetylcholinic receptors - heck, the word acetylcholine is built in to the word: "nicotinic acetylcholinic". Nicotine has an anxiolytic effect, albeit in small doses, presumably because of this mechanism. The opposite effect, or stimulatory effect, occurs in larger doses. The above research also explains why suicide rates are higher during the spring (depending on hemisphere: Northern Hemisphere = March, April, May, Southern Hemisphere = September, October, November). People who are susceptible to allergies AND depression manufacture more histamine as an allergic response during the spring. It is not due to lack of vitamin D production from less exposure to UV light due to shorter days which exacerbate the depression, although it is a contributing factor. The suicide rates don't lie. They can not be dismissed. There is a cause and effect. If the anti emetic medicines are acetylcholine and histamine blockers and acetylcholine causes runny noses and watery eyes then obviously acetylcholine contributes to depression because of the reasons I just showed (depression worse during the spring caused by histamines and acetylcholine). You should also notice that after a night of sleep after having taken a sleep aid your mucous membranes are dry in the morning. I mention this because, although the sleep aid promotes drowsiness, prevents insomnia, and quells anxiety, it's side effect is dry mucous membranes. Why is this not obvious to everyone, everywhere in the mental health industry that depression is acetylcholine dependent? One person commented that it was noted in the 1970s. Perhaps it is just too big a ship to turn around.

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