Archive for October 2008
This post started out as a letter to a close relative who is on the verge of being diagnosed with cyclothymia, a mild form of bipolar disorder. The relative has been left out in the cold waiting for a referral to a psychiatrist. This person reminds me too much of myself five years ago, and I have been very worried.
Rather than reference this post with various science articles, I’m simply going to get it out there for now.
The most forward-thinking theory of bipolar disorder is that it is caused by a deficiency of GABA. GABA is a ‘calming’ and ‘regulating’ neurotransmitter. If you imagine GABA as the conductor of an orchestra, if you don’t have enough, all of the other neurotransmitters can get out of hand and start playing their own tunes, and they can swing in whatever direction they want. I believe that the most important thing you can do to control bipolar disorder is to raise your GABA levels.
One important neurotransmitter that is affected by GABA is glutamate. Glutamate is an ‘intelligence’ and ‘wakeful’ neurotransmitter. It’s almost like a volume knob. The more glutamate you have, the faster your brain goes and the louder all the neurotransmitters get. Too much glutamate can actually kill your brain cells. Manic highs are thought to be characterised by high levels of glutamate, characterised by racing thoughts and insomnia, while depressive lows are thought to be caused by low levels of glutamate. When we talk about depression in bipolar disorder, we are not necessarily talking about ‘sadness’, we are talking about a much wider range of symptoms that include grogginess and an increased need for sleep. Low glutamate levels are thought to be associated with some of the symptoms of fibromyalgia. People with unchecked bipolar disorder often describe having to sleep for several extra hours a day, sometimes not being able to get out of bed at all, and feeling hungover and being unable to wake up properly in the morning – very similar to fibromyalgia symptoms.
This isn’t the complete story of what is going on in the brain because bipolar disorder also affects dopamine levels – the ‘attention span’ and ‘pleasure/reward’ neurotransmitter. If you are unable to concentrate and are distracted easily (ADHD), and are unable to get any enjoyment out of the things you are doing, it is a sign that your dopamine levels are too low. Dopamine tends to rise when you are manic and fall when you are depressive.
High dopamine levels are an independent risk factor for bipolar disorder. This is because when dopamine levels become very high, thought becomes delusional and people experience hallucinations – very high dopamine and glutamate levels are thought to characterise schizophrenia. People who have naturally high dopamine levels are more likely to be at risk of delusional/manic episodes as their dopamine is more likely to go too high. A version of a gene called COMT, which causes high dopamine and low adrenaline levels, is associated with bipolar disorder.
However, if you have ADHD, you are to some extent protected from becoming delusional, as your dopamine levels are naturally low. I believe that people with ADHD can experience bipolar disorder quite differently to those who have naturally high dopamine. I believe that they can still have manic highs (insomnia, thoughts racing) caused by high glutamate in which they do not become delusional/hallucinatory, they just get carried away without crossing over into the ‘nuts’ category, as their low dopamine levels protect them from delusions. I believe attention deficit disorder may be characterised by low glutamate levels with low dopamine levels, and attention deficit hyperactivity disorder may be characterised by high glutamate levels with low dopamine levels.
There is a version of mania called ‘irritable mania’. Dopamine can convert quite easily to noradrenaline and adrenaline, which can trigger anger and aggression responses. I believe if you have the version of the COMT gene which causes low dopamine levels and high adrenaline levels, you will more likely experience irritable mania rather than regular delusional mania, in other words, rather than hallucinating or losing your ability to think logically, you will instead get really irritable and angry and lash out at the world. This kind of behaviour is frequently misunderstood as depression.
I believe there are people out there who have ADHD, whose low dopamine levels are protecting them from full-blown bipolar manic episodes. They therefore remain undiagnosed, even though they have the ‘seed’ of bipolar disorder within them, in that their GABA levels are too low and they are experiencing glutamate highs and lows. They will likely be diagnosed with unipolar depression or aggression disorders rather than bipolar disorder or cyclothymia, as they are less likely to recognise that something is wrong during their manic episodes – they simply feel too happy (or too angry), but don’t become delusional. As a result they are treated with drugs – SSRIs – that are totally wrong for their condition, or their aggressive behaviour gets them into trouble with the law, and rather than being diagnosed with a biochemical problem, they are regarded as criminals.
Though serotonin is thought of as the ‘happiness’ neurotransmitter, there’s a lot of evidence that dopamine is more important to happiness in bipolar than serotonin. Low serotonin levels tend to cause OCD and may be involved in aggression. SSRIs can trigger manic episodes in people with bipolar disorder, however. This may actually be because they cross react somewhat with dopamine receptors. Serotonin has multiple different purposes in the brain, and seems to be more of a regulator than a happy/sad neurotransmitter. We have recently observed in the media, the revelation that SSRI’s don’t actually help depression in most people. McManamy makes a very good argument as to why it is dopamine, not serotonin, that we need to worry about in bipolar disorder. Perhaps we need to re-examine our fixation with serotonin.
Raising GABA levels
Ultimately, the way to fix bipolar disorder is to raise GABA levels.
Firstly, a ketogenic diet or low carbohydrate diet can do this. This creates ketones, and the ketones increase several calming neurotransmitters in the brain, particularly GABA levels. This is why a ketogenic diet can help people with epilepsy, which is also caused by too much glutamate/too little GABA.
You can induce some of the effects of a ketogenic diet without having to be on one by taking vinegar. Believe it or not, the main ketone produced on a low carb diet is acetic acid, i.e. vinegar. A tablespoon or two of vinegar before every meal actually produces similar effects to low carbing, and will raise your GABA levels. Unfortunately vinegar is digested and destroyed very quickly, so the effect doesn’t last very long.
Valproate (valproic acid) works on bipolar disorder because it is very, very similar in structure to vinegar and ketones. It’s rather more potent because it takes the body longer to break it down than ketones or vinegar.
Alcohol is similar in structure to acetic acid and has a similar action on the body in that it raises GABA levels. It usually contains lots of impurities that can also make things worse, however, and its effect is very short-lived, and the alcohol withdrawal can actually make you feel worse. If you drink, you need to be very careful about how much you drink, what you drink, and you need to drink regularly, for example, one measure every evening, and be very self-controlled. I would stick to whisky, vodka or gin as they don’t contain the harmful impurities that are problematic for failsafers. Wine and beer contain amines, glutamates, salicylates and SLAs.
A natural alternative to valproate that you can buy in the shops, is the herb valerian, which contains valeric acid. All herbs come with some risk and side effects, but valerian is known to increase GABA in the same way as vinegar and valproate, again, having a very similar structure. A popular over the counter remedy you can get from most pharmacies is ‘Kalms’, and this contains valerian. Take the Kalms Stress version, and avoid the Kalms Sleep version, unless you want to, uh, fall asleep and get a hangover. If you take valerian, you must not under any circumstances get pregnant, as it is similar in structure to valproate, which can cause deformaties and some types of autism in foetuses.
You can actually obtain GABA itself online, though you have to order it from America because it’s illegal to sell in the UK. I have tried taking GABA, though not recently. I found it gave me very vivid dreams.
Another alternative is glutamine, an amino acid that opposes glutamate. The brain makes GABA from glutamate, glucose, and glutamine. You don’t always want to oppose glutamate, but I find it very helpful if I am grumpy or sugar-craving after meals. Theanine is another amino acid with a similar effect. It is found in tea, which is why tea makes you feel calm (however, tea also contains salicylates which will have longer lasting adverse effects).
A secondary regulatory neurotransmitter that interacts with GABA and that might help is taurine.
Two other herbal remedies that raise GABA by rather complicated drug-like actions are kava kava, and scullcap/skullcap.
There is a strong possibility that herbal remedies will make you feel hungover. I would test them all one at a time and see how they make you feel. Don’t take ten things at once!
Calcium is also thought to raise GABA levels through ion channel signalling mechanisms, though it will also raise glutamate levels and dopamine levels. Magnesium opposes the effects of calcium on glutamate. I tend to take calcium when I want to stay awake, use my brain, and extend my attention span, and magnesium when I need to sleep. Do not underestimate the usefulness of calcium! It can make a big difference to your mental state.
Allegedly, if you have the patience for it, relaxation techniques like yoga and meditation can also raise GABA levels. This is probably why perennially moody stars like Madonna and Gwyneth Paltrow witter on about yoga so much. I find that going and sitting somewhere dark and quiet and reciting a mantra/some lyrics/some poetry in my head can help calm me down sometimes.
Lowering glutamate levels
Mania and hypomania aren’t just characterised by happiness, they are also characterised by irritation and anger. As I mentioned, this is because high dopamine levels can convert easily to the closely related neurotransmitter, adrenaline. When you are feeling angry and stressed, this is as much a sign of mania as happiness is. Mania symptoms also include having a racing brain, feeling as though your thoughts are very intelligent and well-crafted, having insomnia, having nightmares and poor sleep, waking too early feeling fantastic, and buzzing about the place feeling really hyperactive.
Vitamin K actually protects against high glutamate levels and helps the body to use up excess glutamate by converting it into the bone-building/clotting protein GLA. I find it very useful for calming me down, helping me sleep, and stopping me from feeling angry. The type of vitamin K you need is a version called K2. I use a Vitamin Research Products brand, which is ideal as you can open the capsule and portion out smaller doses. You can buy it online in the UK from nutricentre. It might make you quite sleepy if you overdo it, but it is very valuable to have around as it works quite quickly. Don’t take it for an extended period though (i.e. every day for a week), as you may give yourself a cold or unbalance your mood in other ways by inducing vitamin A and vitamin D deficiency, which are used up by the same bone-building processes.
Theoretically, B6 should help you to lower glutamate by converting it into GABA. Unfortunately I find it gives me brain fog – perhaps because it lowers glutamate too much.
Raising glutamate levels
You should only ever try to raise glutamate levels when you have brain fog, hangover symptoms, and you can’t wake up in the mornings, otherwise there will be trouble!
I find the best thing is a dose of B12. I use a Metabolics brand ‘adenosylcobalamin’ product, also available from nutricentre. It will make you feel much better, but you should never take a whole capsule as it can trigger mania, anger, and insomnia. I also get strange trapped nerve sensations in my shoulders and neck if I take too much. I take the tiniest sprinkle I can, and even that can make my heart pound sometimes.
Some people find that folic acid is also useful. It depends on your genes. I would only take very small doses (50-100mcg, a quarter to half a tablet) to trial it, as it triggers hypomania and dependence in me very easily. I find I tend to need increasing doses each day to stay free of brain fog and then have an awful comedown if I stop taking it. It might be useful in a very, very small dose.
It is easy to overdo these supplements, so remember that you can calm down high glutamate levels with vitamin K. You might end up falling asleep at your desk though! It’s always best to err on the side of caution with these supplements.
Raising dopamine levels
This would be useful if you are having concentration problems or feel like you don’t care about doing anything. Calcium supplements are supposed to increase dopamine levels. I do find that a glass of goat’s milk helps me to concentrate on my writing.
Avoiding neurotransmitters in foods
There came a point in my late 20′s when a low carbohydrate diet just wasn’t having a strong enough effect on me anymore, and I started going downhill again until I found the failsafe diet. It IS very important to avoid neurotransmitters in foods, be they amines or glutamates. Salicylates mess with dopamine levels, trigger a type of glutamate receptor called an NMDA receptor that is thought to be involved in depression, and inhibit GABA production by blocking calcium ion channels. Salicylates tend to cause brief happy-high feelings just after you eat them, then cause depression, ADHD and brainfog the next day. While ever your GABA levels are too low, neurotransmitters in foods will just send you whatever which way they can, so you will always be up/down/angry/confused.
The worst offending foods are chocolate, cheese, pork, tomato, citrus fruits, grapes, other tropical fruits, broccoli and dark leafy greens. You must avoid all the listed additives, especially colourings and flavourings and (obviously) MSG and flavour enhancers because they will give you ADHD and contribute to depression. Check the food labels of everything before you buy it, including vitamins. They are sneaky and get everywhere. Better still, don’t buy food that’s in packages, it’s always got some crap in it.
It’s also rather important to avoid caffeine. Caffeine is a weak substitute for dopamine and adrenaline. It affects me in the same way as folic acid, and I need increasing amounts to stay free of brain fog and feel like I can wake up in the mornings. The adrenaline it creates will contribute to you feeling angry and stressed.
Ultimately, if you have bipolar disorder, the drugs you will be prescribed are lithium, valproate, or lamotrigine. They do help. Sometimes there is no natural solution. If you do not have the self control to manage your problems with the methods I describe above, you NEED to be on prescription drugs for your own safety.
Following on from a previous post in which exposure to methylation supplements like folate during pregnancy appears to increase the risk of food chemical intolerance symptoms in children by causing DNA hypermethylation, there are also hints that DNA hypermethylation can be harmful in a different way:
ScienceDaily (Aug. 1, 2008) — Autopsies usually point to a cause of death but now a study of brain tissue collected during these procedures, may explain an underlying cause of major depression and suicide.
The international research group, led by Dr. Michael O. Poulter of Robarts Research Institute at The University of Western Ontario and Dr. Hymie Anisman of the Neuroscience Research Institute at Carleton University, is the first to show that proteins that modify DNA directly are more highly expressed in the brains of people who commit suicide.
These proteins are involved in chemically modifying DNA in a process called epigenomic regulation. The paper is published in Biological Psychiatry.
The researchers compared the brains of people who committed suicide with those of a control group who died suddenly, from heart attacks and other causes. They found that the genome in depressed people who had committed suicide was chemically modified by a process that is normally involved in regulating the essential characteristics of all cells in the body. As Poulter explains, “We have about 40,000 genes in every cell and the main reason a brain cell is a brain cell is because only a small fraction of the genes are turned on. The remaining genes that are not expressed are shut down by an epigenetic process called DNA methylation.”
The rate of methylation in the suicide brains was found to be much greater than that of the control group. Importantly, one of the genes they studied was shown to be heavily chemically modified and its expression was reduced. This particular gene plays a major role in regulating brain activity. “Interestingly, the nature of this chemical modification is long term and hard to reverse, and this fits with depression,” says Poulter.
“The whole idea that the genome is so malleable in the brain is surprising. Finding that epigenetic mechanisms continue to influence gene expression is pretty unusual,” says Poulter, who is also a professor in the Department of Physiology and Pharmacology at Western’s Schulich School of Medicine & Dentistry. “These observations open an entirely new avenue of research and potential therapeutic interventions.” The research was funded through the Canadian Institutes of Health Research. Autopsies Reveal Changes To DNA In Major Depression And Suicide
The gene in question that becomes hypermethylated is the GABA-A receptor. Here’s the associated abstract:
BACKGROUND: Epigenetic mechanisms may be involved in the reprogramming of gene expression in response to stressful stimuli. This investigation determined whether epigenetic phenomena might similarly be associated with suicide/depression.
METHODS: The expression of DNA methyltransferase (DNMT) mRNA was assessed in several brain regions of individuals who had committed suicide and had been diagnosed with major depression relative to that of individuals who had died suddenly as a result of factors other than suicide.
RESULTS: The DNMT gene transcripts’ expression was altered in several brains regions of suicides, including frontopolar cortex, amygdala, and the paraventricular nucleus of the hypothalamus. Importantly, an increase of both mRNA and protein expression was found in the frontopolar cortex. In addition, although transcript abundance of various forms of DNMT was highly correlated in normal control subjects, this coordination of DNMT isoform expression was diminished in suicide brain. Further, within the frontopolar cortex, gene-specific aberrations in DNA methylation were apparent in the gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit promoter region, the transcript of which is underexpressed in suicide/major depressive disorder (MDD) brains. Indeed, three cytosine/guanosine sites were hypermethylated relative to control subjects. Finally, we found that DNMT-3B mRNA abundance was inversely correlated to alpha1 mRNA abundance.
CONCLUSIONS: These data show that DNMT mRNA expression was altered in suicide brain, and this change in expression in the frontopolar cortex was associated with increased methylation of a gene whose mRNA expression has previously been shown to be reduced. These observations suggest that epigenetic mechanisms may be associated with altered gene expression in suicide/MDD. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes
Why is this important to failsafers?
Well, ketosis (low carbing) raises GABA levels. GABA levels are thought to be deficient in people with bipolar disorder and autism. The manic/depressive swings associated with bipolar disorder are thought to be caused by the subsequent deregulation of glutamate. During manic phases, glutamate levels are too high, and during depressive phases, glutamate levels are too low. I will write more on this subject soon.
Salicylates are thought to interfere with DNA methylation – they are thought to protect against DNA hypomethylation. Does this go as far as increasing the risk of DNA hypermethylation? It would not surprise me.
In the brain, salicylates are thought to act on excitatory NMDA receptors (a form of glutamate receptor). They are also thought to block GABA release by acting on calcium channels.