Is Depression Caused by Lack of Serotonin?

© Peter Smith –Holistic Medicine Practitioner- (updated 9 March 2013)

The short answer is NO depression is not simply a lack of serotonin; however that doesn’t mean that increasing serotonin is a waste of time.  Even if serotonin deficiency is not the cause of depression raising it does help some people, we take aspirin for headaches but headaches are not caused by a lack of aspirin. 

It may surprise you to know but there is little good scientific evidence to back up the idea that serotonin makes us happy and if it becomes deficient we get depressed, the brain is more complicated than that.  
The so called serotonin hypothesis is really little more than an over-simplistic way of explaining how antidepressants work which has been emphasised and used by the drug companies that manufacture serotonin-based antidepressants to promote and market them. These companies have managed so successfully to promote the simplistic view that depression is caused by lack of serotonin that it's become accepted as true and “common knowledge" among the general public, and even many healthcare professionals. 

The real reason why serotonin-based antidepressants work is not properly understood and it may turn out that raising serotonin is not even the mechanism by which antidepressants produce their antidepressant effects.

One of the flaws in the serotonin hypothesis is that SSRI’s (serotonin raising antidepressant drugs) raise serotonin in the important space between nerve cells (the synapse) quickly, but the antidepressant effect take several weeks to develop.  Research is emerging that at least part of how SSRI’s work is because they help the brain to repair damage from stress chemicals and hormones and this process can take weeks. This may explain why antidepressants take time to work and as I’ll discuss below it may even begin explain both sides of the debate between the people who argue depression is caused by chemical imbalances in the brain verses the people who argue depression is all-in-the-mind and only cured by psychotherapy. Perhaps successful psychotherapy works because it changes the “negative” thoughts, memories and feelings that produce stress hormones and chemicals and this repairs the physical brain in a similar way to antidepressants.

Psychotherapy (which I'm wholeheartedly in favour of) often claims that increasing serotonin activity only alleviates the symptoms of depression and only psychotherapy can get to the root causes of the condition. However there is now more than sufficient evidence showing that the physical and chemical make-up of the brain is different in people with depressive illness and the tendency towards depression following painful life experiences. See illustration.

The PET scan of two brains shows the different levels of activity between a depressed and a non-depressed brain. 

Psychotherapy needs to be honest and admit that in severe, chronic depression as well as bipolar depression talking psychotherapies have not proven themselves to be consistently superior to chemical therapies permanently curing the problem. 
Despite the holes in the simple serotonin hypotheses increasing serotonin activity in the brain either with drugs or with natural therapies can alleviate depression in some people. 

Even though I am fully aware of the limitations of the low serotonin hypothesis I still use remedies to increase serotonin levels to treat depression; and will continue to do so until a better technique comes along.  
Both in my practice and my personal life I have increased serotonin levels by supplementing the amino acid tryptophan and it consistently produces an antidepressant effect in people with the painful “antsy” type depression what I call serotonin dependant depression. 

Imagine you had some kind of supper headache that was so completely intolerable that it became life threatening because you were prepared to do absolutely anything to stop it, even ending your life to end the pain.  Even though aspirin deficiency is not the cause of the headaches if taking aspirin would stop or even just dull the headaches you’d take it when faced with a live threatening condition.  Even if the aspirin only worked 50% of the time (like many antidepressants do) it would still be worth trying.  

The same argument can be applied to depression and serotonin. Just because the cause of depression is much more complex than a simple lack of serotonin let’s not through the baby out with the bath water, antidepressants can be effective in between 30-60% of people who try them according to which research you look at. Some studies showed antidepressants to work barely above a placebo, however meta-analysis (where the results of many studies are considered together) shows the antidepressants do work better than placebos. Interestingly however for mild to moderate depression CBT (a form of psychotherapy) has been shown to be more effective than antidepressants. I’ll compare the effectiveness and place of psychotherapy verses antidepressants in another article. The debate between psychotherapy and brain chemistry is all very interesting but the issue on this page is what role serotonin play in causing depression. 

Having successfully sold us the theory that all depression is caused by serotonin deficiency the next thing to convince us is that antidepressants are the only way to raise serotonin and this is simply not the case. 

SSRI Drugs are Not the Only way to Increase Serotonin

You can for example supplement the amino acid L-tryptophan (the basic building block of serotonin) to increase the brain's natural production of serotonin. There are herbs like St Johns Wort that raise serotonin and even bright light therapy has been shown to increase serotonin levels and produce a natural antidepressant effect; SAM-e, EPA fish oil and rhodiola are other example of substances with antidepressant effects. These kind of remedies produce antidepressant effects without the side-effects antidepressant drugs can cause. One of the most consistent and fast acting antidepressant techniques I use is supplementing tryptophan, the effectiveness of this supplement (for Serotonin Dependent type Depression) strongly suggests that serotonin does play at least some role in some types of depressive illness, but other neurotransmitters (dopamine and phenylethylamine) should also be investigated.

Serotonin is not the Only Neurotransmitter Worth Looking at as a Cause of Your Depression 

An unfortunate consequence of overemphasising the importance of serotonin is that the role of other neurotransmitters such as dopamine and phenylethylamine in mental health problems has been sidelined. I believe one of the reasons why serotonin based treatments fail to help many people is that they're depression may involve these other neurotransmitters. To address this I promote the idea of broadening our thinking and categorising depression in terms of other neurotransmitters.
So far I've identified three clinically useful categories:
  • Serotonin Dependent Depression
  • Dopamine Dependent Depression
  • Pheylethylamine Deficient Depression
There is research showing that abnormal and exaggerated inbuilt stress responses cause physical damage to the brain and this appears be the root cause of depression. Later we’ll look at what we can do about this, but first let's start the case against the serotonin hypothesis of depression. 

The Serotonin Hypothesis

The two main arguments against the serotonin hypothesis are:-
  • Firstly the scientific evidence that serotonin is involved in depression does not stand up under scrutiny and people use the weaknesses in this science to argue that depression does not involve brain chemistry at all and it’s all in the mind. 
  • Secondly it is argued that the serotonin and chemical hypothesis of depression has been manufactured and pushed (on the back of little scientific proof) by the multibillion-dollar pharmaceuticals industry; I've seen quotes that the profits from antidepressants have been in excess of $80 billion. 

Problems with the Serotonin Hypothesis 

  1. Despite all the research to prove the theory that the lack of serotonin actually causes depression solid evidence has not been forthcoming. If low serotonin levels were responsible for depression then we should be able to induce depression in people by decreasing or blocking serotonin, however the results of such studies have failed to proven this. Going in the other direction it is observed that increasing serotonin levels does not always alleviate a depressed condition. In my opinion however this does not undermine the role of brain chemistry in depression it’s equally possible there is an imbalance in another neurotransmitter such as dopamine at play. 
  2. A second problem in the simplistic serotonin hypothesis is that if low serotonin levels were really the cause of depression then increasing levels of serotonin with SSRIs should alleviate the symptoms right away. But this is not what happens, it can take more than a month before serotonin-based antidepressants begin to alleviate the symptoms.
  3. A third problem is how poorly serotonin-based antidepressants actually work. They don't work at all in some people and in others they only produce a partial cure. Depending on how the trials are conducted I've seen studies showing serotonin-based antidepressants to be effective in as little as 30% of patients and the most optimistic and favourable results I've ever seen published claimed antidepressants worked in about 60% of patients even this if not much better than half. With any medicine one has to weigh up the potential benefits vs the side effects; with this poor success rate one can make a convincing argument that in cases of mild to moderate depression which could be equally or even better managed with natural therapies the benefits gained by antidepressants are often outweighed by the potentially harmful side effects. 
One must also consider the long-term outcome. Natural therapies such as psychotherapy, exercise and better diet have been shown to [INSERT REF] lead to long-term benefits whereas when you stop taking the antidepressants you probably have the same lifestyle and are basically the same person you were before you took them.  
I agree with all the above arguments that the serotonin hypothesis of depression is far from proven as it stands and lacks merit, however none of that changes the fact that for some people and in some situations chemical antidepressant treatments are helpful. My point of view is that I'm primarily concerned with finding and applying effective solutions that are currently available. Increasing serotonin can work as a treatment for depression in some cases, however antidepressant drugs are not the only way to increase serotonin levels, there are both herbs and amino acid nutrient treatments that can raise serotonin levels and without the side-effects of pharmaceuticals. Then there are completely alternative yet proven solutions such as the antidepressant effect of exercise, eliminating junk food, dosing up on omega-3 fish oils and bright light therapy. Bright light therapy was once thought to be helpful in cases of SAD syndrome winter depression only but has been proven to be a reliable and fast acting antidepressant in any type of depression.
It has also been shown that cognitive behavioural therapy CBT is of equal or superior benefit to antidepressants in cases of mild to moderate depression. CBT is not the only useful therapy for depression in fact I believe there are superior approaches, it is just the most scientifically researched.
Another important point is that there are other neurotransmitters (dopamine and phenylethylamine) beside serotonin which probably play a role in depression and particularly bipolar syndrome. Once the pharmaceutical industry has invested hundreds of millions of dollars in manufacturing and patenting a compound it will obviously be heavily invested in wanting to market and sell that compound to recoup its costs and maximise profits. Driven by economics the pharmaceutical industry will invest more in research that backs up the theories behind their current line of drugs than into new alternate areas of research. In other words the serotonin hypothesis gets a disproportionate amount of publicity and research funds because it promotes and markets the highly profitable SSRI's. Whereas effective, low-budget but unpatentable treatments such as better diet and exercise, bright light therapy and herbal medicines are starved of adequate research funds. Sometimes people have said to me if natural therapies worked why wouldn't they be more developed, but when you look into the truly enormous costs of medical R&D you realise that major funding will only go into approaches that can patented and generate enough profits to attract investors.

So what does Cause Depression?& what does it tell up about Developing More Effective Treatment?

I’ll develop the psychological causes of depression elsewhere here we are looking at brain chemistry. 

The Story so Far.

From: Neurobiology of depression: an integrated view of key findings. Maletic et al. International Journal of clinical practice 2007 December 6:
Genetics can give us a predisposition towards being more vulnerable to or significantly affected by environmental stresses. In some people a combination of genetic predisposition and external environmental factors combine to cause the production of a higher than normal levels of the stress hormone cortisol. One consistent finding in the brains of people with long-term depression and bipolar syndrome is that they have an enlarged HPA-axis. The HPA-axis (hypothalamic-pituitary-adrenal axis) refers to the parts of the brain and glandular system that produce stress response hormones; in brief: when the mind perceives stress it tells the hypothalamus which tells the pituitary gland to release a hormone (ACTH) that travels through the blood and activates the adrenal glands to make more stress hormones cortisol and adrenalin. It is not known yet which comes first, do people with a tendency towards depression start out with an already enlarged HPA-axis or do depressing experiences (e.g. bereavement) make the HPA-axis grow larger. 
It is thought that the persistently elevated levels of cortisol cause changes in our brains (especially the hippocampus) such that the receptors for cortisol become desensitised (get used to if you want) and this diminishes the normal healthy feedback controls that should switch off stress-induced cortisol production. So the depressed brain loses the ability to effectively down-regulate stress responses and stress hormones remain elevated.  
Persistent elevated levels of cortisol may reduce the levels of serotonin and dopamine in our brains. Serotonin and dopamine are types of neurotransmitters known as monoamines. After they are produced and released monoamines are quickly broken down by an enzyme called monoamine oxidise A (MAO-A). An older generation of antidepressant drugs (called MAOI’s) block the activity of this enzyme increasing the life span of serotonin and dopamine and it is or at least was thought this is how they produced an antidepressant effect. The activity of MAO-A has been observed to be increased during depression and it is thought that this is the result of higher levels of cortisol.
To summarise:
Increased Stress Responses >> Persistently Elevated Cortisol >>Increased MAO-A activity >> Decreases levels of Serotonin and Dopamine
Another effect of persistent stress responses and over activity of the HPA-axis is overproduction of compounds called cytokines. Cytokines are proteins that our immune system uses to send signals about potential threats to our cells.  To maximise our chances of survival during times of danger our HPA stress response increase the production of cytokines to boost immune activity just in case we get cut and injured and have to fight an infection. 
However excessive long-term cytokine activity can actually damage tissues and even in extreme cases be fatal. The Spanish flu that caused the 1918 the world flu pandemic sent millions of people's cytokine immune responses into hyperdrive causing death in what is called a cytokine-storm. In the case of depression it looks like excessive cytokine production may damage delicate brain tissues and end up causing disruption in normal healthy brain activity, with loss of appetite, fatigue, hypersensitivity to pain reduced libido etc. i.e. all the symptoms of depression. 
Yet another observation in people with depression is reduction in the levels of proteins called brain-derived neurotrophic factor (BDNF). BDNFs (a type of neurotrophin) are important proteins that protect the integrity and function of nerve and brain cells and are found to be consistently diminished in people with depression. It's possible that the long-term damaging effects elevated cortisol and cytokines deplete the levels of these proteins, alternatively it could be that the low levels of BDFN proteins found in depressed persons leaves the brain more vulnerable to damage from the elevated levels cortisol cytokines. Either way the effect is the same and a region of the brain called the hippocampus becomes damaged, which is exactly what is consistently seen in the brains of people with long-term depression or a vulnerability to depression. 
A study in 2008 (The antidepressant fluoxetine restores plasticity in the adult visual cortex. Vetencourt et al. 10.1126/science.1150516) appeared to suggest that fluoxetine (Prozac) in some way positively influences neurotrophins and BDNF activity allowing these compounds to repair the damage to the brain caused by cortisol and cytokines, and that this may be as important as increasing the level of serotonin in producing an antidepressant effect. 
Perhaps this explains why antidepressants take several weeks to begin to work despite raising serotonin levels quickly.

So What Can We Do to Change Excessive Stress Responses that may be a central Cause of Depression?

What useful conclusions can we draw from this interesting research? I believe reducing stress responses (and over activity of the HPA axis) should be considered a top priority for long-term recovery from depression. 
I have never measured or set out to specifically reduce the levels of cytokines in my practice, however I’ve been employing and developing techniques to reduce unhealthy stress responses and elevated cortisol for over 20 years. Initially I employed relaxation response training as an adjunctive treatment for IBS and hypertension, however it proved itself to be an effective therapeutic tool for many ailments. 
Your goal is to down-regulate the over activity in your HPA-axis and there are two ways to do this, I recommend you do them both:
1 / Change any memories, feelings and thought processes that cause or at least contribute to your tendency to overly produce unnecessary stress responses. 

In practical terms it does not matter whether you are overproducing stress responses because your internal physiology is built this way or you carry a lot of emotional baggage because you lived through particularly challenging significant emotional experiences, either way you can still benefit. 
This may be where good psychotherapy comes in, by remodelling painful memories and changing ways of thinking that provoke stress responses in the HPA axis. Earlier I said I spent I spent tens of thousands of pounds on years of therapy, today no longer believe this is necessary and recommend therapy techniques that focus on the mental process involved in depressed thinking rather than focusing on the feelings and content of the depression is a much quicker and cheaper option. Doing therapy that involves exploring feelings during the middle of a bout of severe depression is sometimes not possible and one has to wait while chemical based treatments initiate some improvement, however talking therapy that sidesteps painful feeling content and develops thinking processes can always be employed. To achieve these goals I use a combination of NLP and cognitive hypnotherapy because of their renowned ability to quickly and efficiently remodel I would say detoxify painful traumatic memories which act as a source of stress provoking psychology.
2/ Undergo a training program that directly teachers your brain and nervous system how to switch on what is called your relaxation or parasympathetic relaxation response. 
Switching on your relaxation response automatically switches off all stress responses in your system and believe it or not with training this is something that you can learn to do.
Options to achieve this include first and foremost parasympathetic relaxation training then meditation. You can significantly and permanently change your stress responses within 3 to 6 months using simple and side-effect free training techniques that take about half an hour a day. 
See Parasympathetic Relaxation Response Training page. [Still UNDER CONSTRUCTION]  
These techniques require a much greater investment of time and money than a simple prescription of antidepressants however the long-term benefits are considerable stay with you for life.

What You Can Change & What You Cannot. 

I must make something clear: despite the emerging evidence that stress responses may play a central role in causing depression (at least in some people) I’m not suggesting that simply doing stress reduction techniques on their own is the definitive cure for depression. If this was the case then meditation and relaxation response training should produce a 100% cure rate (if depressed people could do them). There are studies showing positive anti-depression benefits from meditation but there is no evidence that on its own it cures depression. What I am saying is that stress reduction techniques should be accorded with a much greater therapeutic importance, and that properly treating depression involves more than popping SSRI’s. 
I myself have done over a hundred hours of relaxation trading, coherent breathing training, Buteyko breathing and countless hours of meditation including a stint of an 1¼ every day for two and a half years. This has given me the ability to switch off stress responses with a simple shift in my mental focus and a few deep breaths, and it significantly reduced the impact bipolar syndrome has on me enabling me to live a much healthier and functional life with what can be a disabling condition. I would say it helped me to work or live with the brain I’ve got (play the cards I was dealt so to speak) but I didn’t grown a new brain!  If you think you have a highly strung nervous system (or even if you don’t think you’re highly strung) do try a 6 month training program of stress reduction techniques and see what it can do for you. Just to be clear when I say stress reduction techniques I am referring to techniques that train you to gain control over your internal physiology such as parasympathetic relaxation training and meditation, not stress reduction techniques that try to manage external sources of stress like writing a to-do list at the start of the day. My six-month training programme includes three months of parasympathetic relaxation response training done lying down and three months sitting meditation, each method taking half an hour a day. These two techniques seem to achieve slightly different effects so I include both to cover more bases.

Mental Illness Stress & Heart Disease

Did you know that living with bipolar syndrome significantly increases your risk of developing heart disease perhaps even doubling it above the national average! This is probably due to persistently elevated levels of the stress hormone cortisol. A similar effect occurs in long-term endogenous depression. You can permanently change the way stress responses affect your health and overcome excessive stress induced cortisol levels by training your own internal physiology how to switch off stress responses. 
Purely based upon clinical observations (and not on scientific research) I believe this type of training can train you to shorten the life span of your stress responses from hours or even days to minutes; but I’m not convinced it significantly reduces the number or the intensity of the stress responses you make.  I have observed an effective way to reduces the number and intensity of the stress responses you make in the first place is to remodel stressful memories and reprogram stress triggers with NLP and hypnotherapy.  
My treatment approach to depression is to combine both the above techniques with balancing brain chemistry using natural remedies, adding fish oils, stabilising blood sugar, bright light therapy and exercise. Once the condition is improved and you have maintained a period of stability you can try coming of the supplements to balance your brain chemistry and see if your brain can maintain your mental health and make adjustments as needed. 

The Bottom Line

 The serotonin and brain chemistry model of depression is badly incomplete and imperfect, we need a lot more research into all areas physiological, psychological and environmental about the causes and treatment options for mental illness; including questioning whether mild depression is even an illness. 
However just because big business has an investment in promoting a scientific hypothesis about serotonin that isn't the whole picture doesn't detract from the fact that mental illness can respond to chemical treatments. 
Although I wholeheartedly recommend the benefits of psychotherapy for everyone with depression let's not throw the baby out with the bathwater, for severe or endogenous depression and bipolar depression talking therapies often do not provide a completely adequate alternative. Research has consistently show a combination of chemical and talking therapy to b the most effective way forward b far. [INSERT REF]
I argue in favour of and use on myself non-drug treatments to change brain chemistry, such as amino acids, supplements, exercise and bright light therapy etc. because of their flexibility and virtual lack of side-effects. Although I accept that the serotonin hypothesis is fundamentally flawed boosting serotonin levels somehow works. I've often noted how many of the people that poke holes not only in the serotonin hypothesis that the entire police that brain biochemistry and physiology play a role in causing depression do not actually have mental illness themselves. When you're living with a painful and potentially a life-threatening illness what you want is any practical solution that can help. Brain chemistry affects how you feel as I've said elsewhere could you talk or hypnotise a person high on narcotics or drunk on alcohol into a sober condition? Brain chemistry and physiology sets the stage in which our mind, social conditioning and learnt experiences operate. 
  • Serotonin Dependent Depression
  • Dopamine Dependent Depression
  • Phenylethylamine deficient Depression
  • Bipolar Treatment

My Personal Serotonin & Brain Chemistry Story 

To the people who pick holes in the theory that serotonin and brain chemistry in general is involved in mental health problems I would share that before my bipolar depression was properly medicated I was the person with the supper headache that was so intolerable I was prepaired to try anything to stop it including ending my life. I really gave the psychological non-chemical hypotheses a good go, from my early 20s until my early 40s I flat out refused to accept that I had chemical imbalance in my brain, I didn’t want to believe it, it seemed to permanent and scary; I wanted to and chose to believe that it was all in my mind and that with enough psychotherapy I would become permanently cured. In pursuing this goal I invested tens of thousands of pounds in multiple forms of psychotherapies. The psychotherapy was fantastically helpful in giving me perspective on my depressed feelings lessening their impact and equipping me with useful mental techniques and coping mechanisms. 
The psychotherapy genuinely made me feel better and improved my ability to cope so much so that I would occasionally mistakenly believe that could take myself off all my medication, only to find myself facing life-threatening illness again within a few months. Whenever this happened it was always changing my brain chemistry (with natural therapies) that consistently came to the rescue and re-stabilised the condition, booking extra sessions with my therapist did not solve the problem.
Today to control my bipolar syndrome I take daily supplements to increase dopamine levels (except on days when I sense I’m entering a manic phase), and supplements to increase my serotonin levels about three days a week, occasionally more. I also use and benefit from the relaxation training and psychological coping techniques I learned. 
On this simple and safe regimen I can unhealthy bipolar symptoms. However when I stop taking the supplements my mental health starts slipping within one to two weeks. Without supplementing serotonin precursors I will quickly begin to develop painful and gloomy feelings with a pessimistic worldview, without supplementing dopamine precursors I gradually lose all the enthusiasm and motivation I otherwise have for my working and life. 
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