When it takes more than a minute to describe how many medications you're taking...time to take a closer look.

Yesterday I was lunching with a dear friend, who mentioned that one of HIS friends has started to have problems with diabetes. I knew this friend also has Alzheimer's disease, so, knowing that many brain and nervous system-targeted medications can provoke insulin resistance and diabetes, I started asking questions about this person's medications.

We called the friend we were discussing for a complete list. Sure enough, in the battery of medications he had been prescribed...was valproic acid, or Depakote. Depakote is well documented to promote the development of metabolic syndrome--a cluster of problems including hypertension, insulin resistance, diabetes, and high cholesterol. Much of the research in this area has focused on women, because polycystic ovary syndrome, a feminine variant of metabolic syndrome, is also correlated with Depakote use. If you're looking for research on the effects of Depakote in men, it's there, it's just a little harder to find.

New research is suggesting that there is a link between diabetes and Alzheimer's disease. Some researchers even call it diabetes of the brain, and there is some evidence to suggest that diabetes medications such as metformin can help delay the progression of Alzheimer's syndrome.

So here we have a guy who has been prescribed a seizure medication, which has likely provoked his problems with diabetes, which is likely worsening his Alzheimer's disease...and what do you know? It seems as though now that he is on galantamine (Reminyl) for his Alzheimer's disease, he's started noticing tremors. I'd bet money on the possibility that the seizure meds are adjusted upward as a result.

So you can see where I'm going. Not only does this keep this poor guy's physicians busy, it pads the pockets of more than one pharmaceutical company, in progressively more expensive chunks.

My friend asked me what I would do? Well, I must qualify that I am not a prescribing medical doctor. I am a registered dietitian who studies the brain and nervous system. But this is where I'd go.

1. Based on the evidence that seizure disorders respond well to omega-3 fatty acids, I'd up those to a DHA equivalent of 1000 mg per day.
2. To help those omega-3's be most effective, I'd teach this person my "S" and "C" rule (avoid, as much as possible, all fats and oils beginning with the letters "S" and "C"...canola being the only exception). I know my friend and his friend eat out quite a bit and it likely is a significant source of these oils.
3. If you reduce the seizure and tremor activity, you reduce the need for seizure medication, and minimizing medications is always very important.
4. I would consider an alternative seizure medication with less potential for disrupting hormone balance. The one that I have seen repeatedly and successfully used in women to achieve this is lamotrigine (Lamictal). Of course, there may be a reason we do not know of that this would not be appropriate, but if this has not been considered it's certainly worth a try.
5. Less Depakote (or potentially no Depakote) potentially also means less insulin resistance, which provides the possibility that the Alzheimer's medication could be reduced. Again, less meds....fewer side effects.
6. Finally, acetyl l-carnitine has been shown to effectively reduce symptoms of diabetes as well as Alzheimer's disease. It also improves cholesterol profiles. And...it has repeatedly and specifically been found to effectively counter the negative side effects of Depakote. I have seen this cited so often recently I can't understand why it is not automatic for any physician prescribing Depakote to simultaneously recommend carnitine.

This trend, of treating one symptom, letting side effects develop, then treating them with other meds that create other side effects, which eventually build vicious cycles of ever-increasing doses of medications...in recent years...has spiraled out of control. The field of nutritional psychiatry is just out of the starting gate. But I'm hooked on its potential. Hopefully in this case, and for others who find this blog, we can help back our friends out of these pharmaceutical corners, save them some money, and improve their overall quality of life.



Luef G, Abraham I, Trinka E, Alge A, Windisch J, Daxenbichler G, Unterberger I, Seppi K, Lechleitner M, Kramer G, Bauer G. Hyperandrogenism, postprandial hyperinsulinism and the risk of PCOS in a cross sectional study of women with epilepsy treated with valproate. Epilepsy Res 2002 Jan;48(1-2):91-102.

Tan H, Orbak Z, Kantarci M, Kocak N, Karaca L. Valproate-induced insulin resistance in prepubertal girls with epilepsy. J Pediatr Endocrinol Metab 2005 Oct;18(10):985-9.

Aydin K, Serdaroglu A, Okuyaz C, Bideci A, Gucuyener K. Serum insulin, leptin, and neuropeptide y levels in epileptic children treated with valproate. J Child Neurol 2005 Oct;20(10):848-51.

Pylvanen V, Pakarinen A,Kniop M, Isojarvi J. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav 2006 May;8(3):643-8.

Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993 Nov 4;329(19):1383-8.

Rasgon NL, Reynolds MF, Elman S, Saad M, Frye MA, Bauer M, Altshuler LL. Longitudinal evaluation of reproductive function in women treated for bipolar disorder. J Affect Disord 2005 Dec;89(1-3):217-25.

Roste LS, Tauboll E, Morkrid L, Bjornenak T, Saetre ER, Morland T, Gjerstad L. Antiepileptic drugs alter reproductive endocrine hormones in men with epilepsy.  Eur J Neurol. 2005 Feb;12(2):118-24.

Pylvanen V, Pakarinen A, Knip M, Isojarvi J. Characterization of insulin secretion in Valproate-treated patients with epilepsy. Epilepsia 2006 Sep;47(9):1460-4. Neurology. 2008 Sep 2;71(10):750-7.

Beeri MS, Schmeidler J, Silverman JM, Gandy S, Wysocki M, Hannigan CM, Purohit DP, Lesser G, Grossman HT, Haroutunian V. Insulin in combination with other diabetes medication is associated with less Alzheimer neuropathology. Prescrire Int. 2007 Oct;16(91):197-8.

McCain KR, Sawyer TS, Spiller HA. Evaluation of centrally acting cholinesterase inhibitor exposures in adults. Ann Pharmacother. 2007 Oct;41(10):1632-7.

López-Pousa S, Garre-Olmo J, Vilalta-Franch J. [Galanthamine versus donepezil in the treatment of Alzheimer's disease] Rev Neurol. 2007 Jun 1-15;44(11):677-84.

Schrauwen E, Ghaemi SN. Galantamine treatment of cognitive impairment in bipolar disorder: four cases. Bipolar Disord. 2006 Apr;8(2):196-9.

Aarsland D, Hutchinson M, Larsen JP. Cognitive, psychiatric and motor response to galantamine in Parkinson's disease with dementia. Int J Geriatr Psychiatry. 2003 Oct;18(10):937-41.

Isojarvie JI, Rattya J, Myllyla VV, Knip M, Ovine R, Pakarinen AJ, Tokay A, Tapaneinen JS. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol 1998 Apr;43(4):446-51.

Ribacoba-Montero R, Martinez-Faedo C, Diaz C, Salas Puig J. [Remission of polycystic ovary syndrome associated with valproic acid in an epileptic female]. Rev Neurol 2003 Apr 1-15;36(7):639-42.

Bruno G, Scaccianoce S, Bonamini M, Patacchioli FR, Cesarino F, Grassini P, Sorrentino E, Angelucci L, Lenzi GL. Acetyl-L-carnitine in Alzheimer disease: a short-term study on CSF neurotransmitters and neuropeptides. Alzheimer Dis Assoc Disord. 1995 Fall;9(3):128-31.

Thal LJ, Carta A, Clarke WR, Ferris SH, Friedland RP, Petersen RC, Pettegrew JW, Pfeiffer E, Raskind MA, Sano M, Tuszynski MH, Woolson RF. A 1-year multicenter placebo-controlled study of acetyl-L-carnitine in patients with Alzheimer's disease. Neurology. 1996 Sep;47(3):705-11.

Sano M, Bell K, Cote L, Dooneief G, Lawton A, Legler L, Marder K, Naini A, Stern Y, Mayeux R. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. FASEB J. 1992 Dec;6(15):3379-86.

Carnitine supplementation enhances Depakote activity

For the last few months I've been reading carnitine research (there's a boatload of it and it's completely kept me out of trouble!)

It is pretty well documented that people taking valproic acid (Depakote) have a problem maintaining carnitine levels. To the point where, after doing this research, I have no problem saying that anyone on Depakote should automatically be placed on L-carnitine as well.

Anyway, I just found an article reporting that carnitine supplementation in conjunction with Depakote use enhanced the levels of Depakote in the brain. In other words, if you use carnitine while using Depakote, you won't need as much Depakote. And if you're not using as much Depakote, you're not as likely to experience the side effects that make people not want to comply with the regimen, such as weight gain, infertility, acne, yadayadayada.

Monika's Bottom Line
Doctors should have a carnitine chip inserted in the medication-prescribing region of the brain that does not allow them to script this med without also scripting this supplement.

Sakemi K, Takada G. Effect of carnitine on valproic acid concentrations in serum, brain, and liver. Pediatr Neurol. 1998 Apr;18(4):331-3.

Sometimes it's what you CAN'T see that you should be paying attention to

I've been in this field for many years. Back when I started, and was learning about diabetes, I was taught that the best way to measure whether or not a diabetic had good blood glucose control, was to monitor blood glucose. When records looked good, we assumed all was good. Diabetics knew better. They often manipulated their diet and knew how to eat around the readings, and could straighten out a few days before a doctor's appointment with healthy readings.

These days, the glycosylated hemoglobin test is considered a more accurate assessment. It can give the practitioner an idea of what goes on, on average, all of the time. And people who are not compliant between doctor visits can't manipulate the science behind how the test does its job.

What I've learned from this, is that sometimes, even though things look good on the surface, there are problems underneath. And we should never assume that there are no problems just because we can't see them.

Enter epilepsy.

It has been known for quite awhile that certain antiepileptic medications can deplete the body of carnitine, a nutrient that is needed for healthy weight maintenance and to protect the brain against aging. In fact, older studies recommend supplementing carnitine in persons on medications such as valproic acid (Depakote) in order to minimize problems associated with carnitine deficiency.

Researchers recently compared carnitine levels in children on three other medications (vigabatrin or Sabril*, lamotrigine or Lamictal, and topiramate or Topamax). Clinically the only group with significantly lower carnitine levels were those on valproic acid.

If the conclusion of this study was that carnitine levels were not compromised by the other three medications, that would have been logical. However, the researchers also stated that because there were no apparent symptoms related to carnitine deficiency, that doing anything about it may not be necessary.

I happen to have spent the last few months going through several hundred pages of abstracts on carnitine, and with all due respect, I must disagree. I've got dozens of papers suggesting that carnitine is important to protect the brain against oxidation; in fact, it's been proposed by numerous researchers to be a potentially important agent in the fight against Alzheimer's disease.

With all the research I'm having to wade through, I cannot believe that it is not standard practice to recommend carnitine supplementation to anyone receiving valproic acid for any reason. My list of references is very, very long and I'm only up to the year 1992. If you happen to be reading this and would like me to spend another post detailing these references when I am finished, I would be happy to do so. Simply reply to this post so I know you'd like the information.

Just because we can't see everything happening in the brain...doesn't mean we shouldn't be doing anything about the things that we do know and can do something about.

Zelnik N, Isler N, Goez H, Shiffer M, David M, Shahar E. Vigabatrin, lamotrigine, topiramate and serum carnitine levels. Pediatr Neurol. 2008 Jul;39(1):18-21.

*Sabril is sold in Canada.

For women with epilepsy--get the facts straight before you worry

Here's an interesting abstract. I post it partly for the important medical information it provides but also to comment on the interesting editorial twist that may affect how readers interpret the information.

The subjects: women with epilepsy and the children they bore.
The question: whether epilepsy affects the development of those children. (As quoted by the authors of the study, "We aimed to ascertain the prevalence of cardiac malformation (CM) and its association with antenatal exposure to an antiepileptic drug (AED) in infants of mothers with epilepsy.")

At 3 months of age, 462 babies born to mothers with epilepsy were examined by a cardiologist to see if they had at least one of several heart defects: atrial septal defect, tetrology of Fallot, patent ductus arteriosus, pulmonic stenosis, ventricular septal defect, tricuspid regurgitation, and transposition of great arteries. Possible correlations between the existence of these defects and any of the following were evaluated: mother's epilepsy history, use of antiepileptic medications in the first trimester of pregnancy, mother's age, seizure frequency during pregnancy, and folate supplementation.

There were a few significant relationships. Prematurely born children were more likely to have heart defects. Use of more than one medication was also a significant contributing factor. And there was a trend, though not significant, for children whose mothers who had used valproic acid (Depakote) to have heart defects. No relationships to mother's age, epilepsy history, seizure frequency, or folate usage were noted.

So even though there were only three identified contributing factors, two of which involved antiepileptic medications, the authors were allowed to title their publication in a way that somewhat masked this relationship. It also, for someone skimming research abstracts, could lead to an impression that epilepsy itself, and not the way in which epilepsy is treated, is the problem.

I am a diligent scientist and try to get the facts straight before I put anything on this blog, or in anything I write. But anyone reading this blog knows that all you have to do is turn on the evening news and see how vague headlines become top news stories and "facts" are generated without any meat behind them.

It's simply not fair to generalize to all mothers with epilepsy. There were an awful lot of babies in this study who did not have heart defects, 426 to be exact. That's a lot of unnecessary fear to be putting out there for women with epilepsy. Of course, the take home message is that women of childbearing age may not be the most appropriate candidates for valproic acid, but somehow that got lost in the analysis.

Thomas SV, Ajaykumar B, Sindhu K, Francis E, Namboodiri N, Sivasankaran S, Tharakan JA, Sarma PS. Cardiac malformations are increased in infants of mothers with epilepsy. Pediatr Cardiol. 2008 May;29(3):604-8.

Some kinder, gentler options for epilepsy

Epilepsy is one of those disorders that I think we just assume is medical, and that medication and complex neurological procedures are the only options for treatment. This is where I have to disagree! A lot of epilepsy is metabolic and nutritional, and it's exciting to see colleagues researching some of these kindler, gentler options.

This particular study focused on children with mental retardation, a demographic where epilepsy is very common.

The bad news is, only 20% of these children were even given metabolic testing.

The good news is, twenty-eight percent of those children chosen in the study, who had been given metabolic testing, were shown to have some kind of metabolic abnormality. That percentage jumped to 75% when the seizures were originating from multiple locations! In 22% of the children studied, a carnitine deficiency was identified, and that was linked to their medication--valproic acid or Depakote. Carnitine is an easy to find, very practical supplement to use in situations such as this.

The researchers concluded that a systematic evaluation of mentally retardation would help to identify those who have a metabolic (and potentially treatable) component to their seizure disorder.

The good news is...if they can get the word out to other practitioners, the other 80% of those kids can also have the world of nutritional therapies opened up to them as treatment options.

Parikh S, Cohen BH, Gupta A, Lachhwani DK, Wyllie E, Kotagal P. Metabolic testing in the pediatric epilepsy unit. Pediatr Neurol. 2008 Mar;38(3):191-5.

Epilepsy, medications, heart disease, and dietary strategies

In recent years, researchers have identified that elevated homocysteine levels are associated with cardiovascular risk. This compound builds up in the blood when it cannot be converted into methionine. Two important nutrients, folate, and vitamin B-12, are important in this chemical reaction; when deficient, homocysteine can accumulate and cause problems.

For people with epilepsy, this is important to know, as some common epilepsy medications can decrease folate and vitamin B-12 levels, and in turn increasing cardiovascular risk.

In a recent study, children receiving carbamazapine (Tegretol) and valproate(Depakote) had statistically lower folate and higher homocysteine levels than children without epilepsy who were not on these medications.

There are several strategies you might consider if your child needs to be on these medications:

1. Give your child a daily multivitamin supplement containing folate and vitamin B-12.
2. Know your dietary sources of folate and include them in your family's meals on a regular basis: fortified cereal, sunflower seeds, dried beans and peas, and leafy greens.
3. Know your dietary sources of vitamin B-12 and include them in your family's meals on a regular basis, namely meat and dairy products.
4. Consider using a fish oil supplement. Their omega-3 fatty acids have shown promise in helping to control seizures. Using the supplement may not eliminate the need for the medication, but it may reduce the necessary dose and therefore reduce the associated side effects.
5. Limit the use of pro-inflammatory fats and oils, as they reduce the effectiveness of omega-3 fatty acids. They're easy to remember: any oil, alone or in food, beginning with the letters "S" or "C". The only exception to this is canola oil.

Vurucu S, Demirkaya E, Kul M, Unay B, Gul D, Akin R, Gokçay E. Evaluation of the relationship between C677T variants of methylenetetrahydrofolate reductase gene and hyperhomocysteinemia in children receiving antiepileptic drug therapy.Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan 28