AEDs and Suicide Risk

Do all Anti-Epileptic Drugs Increase the Risk of Suicide


In May 2008, the results of a meta-analysis conducted by the FDA showed an increased incidence of suicide in patients taking anti-epileptic drugs (AEDs). Specifically the analysis included carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide. Not wanting to single out specific agents, the FDA added a black box warning to all AEDs for suicide risk.


The statement was immediately contested. The greatest point of criticism is that this blanket statement encompassed over 20 different medication which all have differences in affects on receptors and mechanisms of action. Additionally, patients with epilepsy have a higher risk of suicide than the general population, especially in the post-ictal phase of a seizure. Finally, the AEDs are life-saving medications. The statement put forth by the FDA was scrutinized due to concern that patients would stop taking the medications, which would lead to seizure and risk of death.


In 2007, an extensive review article discussing nuances between therapies was published in Drug Safety. Phenobarbital and phenytoin have established suicide risks, however, based on effects on serotonergic receptors, it is hypothesized that certain AEDs would have a protective effect. Author, Kalinin, proposed that carbamazepine, oxcarbazepine, valproate, and lamotrigine would prevent suicide secondary to improvements in cognitive function. In contrast, topiramate, tiagabine, vigabatrin, gabapentin, levetiracetam, and zonisamide all have negative effects on mood, though studies examining the clinical risk associated with most of these AEDs had not yet been conducted at the time of this review. Kalinin expressed that epilepsy itself comes with risks, and the negative effects of AEDs may be additive to existing problems with mood, more so than causative.

In addition to seizures, epilepsy does not come without risks. Patients with epilepsy have been found to have a significantly higher risk of suicide compared to the general population. Additionally, patients with epilepsy have an increased risk of depression, anxiety, psychoses, and high incidences of depression in the post-ictal phase after a seizure.


In the early 1990’s, observational studies showed that up to 1/3 of patients who commit violent suicide are deficient in folic acid. AEDs cause folate deficiency; which is acknowledged by heavy supplementation of folic acid during pregnancy, yet the majority of patients on an AED are not taking folic acid supplementation. Later studies have shown that low folate levels correlate to low levels of serotonin, which could lead to depression. Decreased folic acid levels in patients on an AED has not been proven to cause depression and there is very little available evidence.

In a study by Olesen et al published March 2010, researchers identified patients prescribed an AED between 1997-2006 with an epilepsy diagnosis and identified risk of suicide in comparison to suicide risk with carbamazepine treatment. This study also found an over-all risk of suicide, but risk was only significantly increased specifically with clonazepam, valproate, phenobarbital, lamotrigine, and levetiracetam.


The following month, a cohort study by Patorno et al was published in JAMA identified patients started on an AED between 2001-2006 and followed for 180 days. The risk of combined outcome of suicide, suicide attempt, or violent death was compared to that of topiramate as a baseline. Gabapentin, lamotrigine, oxcarbazepine and tiagabine all had increased risks of suicide in comparison to topiramate. However, patients in the study may have been taking the study medication for an indication other than epilepsy, so the results do not adequately reflect the correct patient population.


A nested case-control study published in Neurology in July 2010 divided AEDs into four categories: barbiturates, conventional AEDs, new AEDs with low risk of depression (oxcarbazepine, Lamotrigine, gabapentin, pregabalin) or new AEDs with high risk of depression (levetriacetam, tiagabine, topiramate, vigabatrin). The study showed that only new AEDs with high risk of depression were associated with increased risk of suicide.

While each of the three afore-mentioned studies was useful in showing only certain medications were associated with increased risks, the studies were not consistent in identification of higher risk medications. The studies also failed to analyze patients separately by psychiatric co-morbidities. A patient with depression has a higher risk of suicide compared to a patient without a psychiatric co-morbidity, yet the incidence of psychiatric co-morbidities were not identified in the previous studies.


The most recent study examining risk of suicide with AEDs was published in August 2010 in the New England Journal of Medicine. The study was a meta-analysis including over 5 million patients receiving any 10 of 11 AEDs included in the FDA meta-analysis (carbamazepine, gabapentin, Lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide with the exclusion of felbamate, not marketed in the UK). Patients were followed until end-point (suicide or suicide attempt) or until the end of the study period. Patients were categorized into having epilepsy, depression, bipolar disorder, a combination of disorders, or none of the three identified indications. There was an increased risk of suicide identified for patients taking an AED without depression, bipolar disorder, or epilepsy, however, for patients with one of these three indications, there was no increased risk.

The results of this study have prompted the FDA to plan to go back and review data on suicides with AEDs. Currently, the warning is still attached to all AEDs but patients should be counseled based on the medication that they are currently receiving. Levetiracetam and barbiturates have been consistently linked to mood changes and increased risk of suicide. Other medications such as gabapentin, topiramate, oxcarbazepine, lamotrigine, and valproate have shown increased risk in some studies, and in others, none.


The benefit that these medications provide to patients living with epilepsy far outweighs the risk. The risk of seizure and seizure complication is greater than the absolute risk of suicide. Additionally, patients suffered high risks of depression and suicide in the post-ictal phase of seizures, especially generalized and temporal front-lobe. Preventing seizures and post-ictal depression also prevents suicide. Patients should be warned of the risks, but also educated on the benefits. It is essential that patients with epilepsy maintain good adherence to their medication regimen and the black box warning for suicide may frighten patients into not taking their medication if they are not adequately counseled on prescription of the medication.


While this myth has not been fully “busted”, it will be interesting to see how the FDA and ILAE recommendations will change as a result of recent evidence.

References:


Kalinin VV. Suicidality and antiepileptic drugs: is there a link? Drug Safety 2007;30(2):123-142.


Bell GS et al. Suicide and epilepsy. Current Opinion in Neurology 2009;22:174-178.


Wolfersdorf M et al. Red-cell and serum folate levels in depressed inpatients who commit violent suicide: a comparison with control groups. Pharmacopsychiatry 1995;28(3):77-79.


Olesen JB et al. Antiepileptic drugs and risk of suicide: a nationwide study. Pharmacoepidemiology and Drug Safety 2010;19:518-524.


Patorno E et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010;303(14):1401-1409.


Andersohn F et al. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicideal behavior. Neurology 2010;75:335-340.


Arana A et al. Suicide-related events in patients treated with antiepileptic drugs. NEJM 2010;363(6):542-552.

Blood and Chocolate

Theobroma cacao.  Food of the Gods. Xocoatl.

Origins of chocolate are traced back to before the Aztecs, who believed chocolate had divine properties and had even used cacao beans as currency.  Before sacrifices to the gods, victims were given chocolate to drink and when the Spanish arrived, mistaking Cortes for the snake god, Quetzalcoatl, Montezuma served them chocolate.

The legend of Quetzalcoatl has since been immortalized in Downtown San Jose’s Cesar Chavez park.  My brother was patient enough to pose for me next to it on my last trip home.

Chocolate has since been adopted by cultures and civilizations throughout the world, and while we may not still be feeding it to our victims before sacrifice, our love of chocolate has driven intrigue and research into closer examination of its delicious properties.  

In vogue today is the effects of chocolate on blood pressure.  Chemical components in dark chocolate have been shown to have preventative effects on stroke and trials have consistently shown that consumption of cocoa daily can lower systolic blood pressure up to 4.5 mmHg. 

Why do we care about high blood pressure? High blood pressure is treated to prevent a heart attack or stroke and to prevent other complications, like heart or kidney failure.

A review of the literature by Desch et al was published at the beginning of the year in the American Journal of Hypertension.  Desch sites that interest in the effects of chocolate on blood pressure originated from observation of the Kuna indians, who consumed large amounts of chocolate and who had low rates of high blood pressure.  Closer examination revealed that chocolate contains a lot of plant flavanols, which have been previously shown to have beneficial effects on blood pressure. 

If chocolate is to be recommended for blood pressure, it needs to be eaten daily to keep blood pressure consistently down.  Additionally, the 4.5 mmHg drop seen is not going to be enough for the majority of patients diagnosed with hypertension; traditional medications and other lifestyle modifications will be needed.  Not to be forgotten either, is that this is the era of obesity; when scientists are seriously considering putting statins into fast food orders, is encouraging increased consumption of dark chocolate to treat blood pressure really the answer?

Another interesting area regarding hypertension treatment is that every patient really is a unique and beautiful snowflake, meaning high blood pressure is driven through different mechanisms in different patients, especially patients of different ethnic backgrounds.  

Umscheild et al site that while African-American patients are more likely to have a better understanding and awareness of hypertension, they are less likely to have controlled blood pressure despite treatment.  African-Americans are also significantly more likely to have strokes and kidney failure, compared with the rest of the population.  Umscheild’s research on disparity published in January 2010 showed that providers were just as likely to intensify blood pressure therapy for African-Americans as they were for other patients, indicating that there is another reason for disparity than negligence in the health care system.

Most concerning to me is the increasing amount of evidence showing that fluctuations in blood pressure place patients at risk of cardiovascular events.  An analysis by Rothwell et al published in the Lancet in March 2010 found that fluctuations in blood pressure between office visits was a predictor of cardiovascular events and stroke independent of mean blood pressure.

I can hardly remember to take my multivitamin daily; how many patients with high blood pressure are unable to successfully adopt taking their blood pressure medications daily into their routine?  For patients with high blood pressure who don’t feel sick and are now told that they will have to take a daily (or twice daily) pill for the rest of their life to treat a risk that is poorly understood by the patient, it must be difficult to work up the motivation to take as directed.  

Evidence from trials like Rothwell's really show where a pharmacist can step up to play a role in reducing risk.  For patients consistently late in filling prescription for blood pressure medications, pharmacists have the opportunity to talk to the patient about risks, help them to better understand the benefit of taking the medication, and the risks associated with non-compliance.  

One last final shout out to Mr. Ghirardelli, who arrived in San Francisco, CA during the gold rush and discovered that he could make more money selling hot chocolate to crusty miners than actually panning for gold.  His chocolate remains awesome and delicious to this day.

References:

Bensen A.  A brief history of chocolate.  Smithsonian.com 2008.

Shah ZA et al.  The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway.  Journal of Cerebral Blood Flow & Metabolism 2010.

Desch S et al.  Effect of cocoa products on blood pressure: systematic review and meta-analysis.  American Journal of Hypertension 2010;23(1):97-103.

O'Riordan M.  The "MacStatin": Fast food with some ketchup, salt, and a statin to go.  theheart.org 2010.

Umscheild CA et al.  Racial disparities in hypertension control, but not treatment intensification.  American Journal of Hypertension 2010;23(1):54-61.

Rothwell PM et al.  Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.  The Lancet 2010;375:895-905.

Ubiquitous

u-biq-ui-tous- adjective: existing or being everywhere, esp. at the same time; omnipresent

Coenzyme Q10, also known as ubiquinone, is the Lady Gaga of herbal supplements. New to the scene, kind of different, really interesting, has potential for a lot of great things, but no one seems to know what to make of it.

Ubiquinone has been known to biochemists for years, but the concept of using it as a dietary supplement came about relatively recently.

So... what is coenzyme Q10? The name is appearing more and more in the aisles of pharmacies and health food store and its celebrity as a supplement rivals that of vitamin D. However, coQ 10 is not a vitamin; it is naturally synthesized in the human body (in contrast to a vitamin, which is obtained through diet).

CoQ is a bright orange, lipophilic substance that acts as an antioxidant and plays a major role in oxidative phosphorylation in mitochondria. It resides in the inner layer of the lipid bilayer membrane of mitochondria and accepts electrons from NADH. Protons are then pumped from the mitochondrial matrix into the inter membranous space, creating an electrical gradient. As protons cross back though the membrane, they pass through a proton channel where ATP synthase uses the energy to add a phosphate group to ADP, creating ATP, the energy currency of cells. Coenzyme Q has also been shown to regenerate active forms of the vitamins E and C. Its reduced form, ubiquinol, is present in all tissues.

Circa 1990, it was discovered that HMG-CoA reductase inhibitors (aka statins), designed to inhibit the production of LDL cholesterol, also inhibited the synthesis of coenzyme Q10. Additionally, LDL cholesterol serves as a transporter of coenzyme Q, therefore reductions in LDL would also theoretically reduce the amount of coenzyme Q in blood circulation. As a result, it was hypothesized that repleting CoQ could eliminate some of the side effects associated with statin therapy; namely, myalgias and rhabdomyolysis.

The mechanism for statin induced myalgias is still unknown, but it has been hypothesized that the reduction in coenzyme Q10 may, at least, be a contributing factor. Studies subsequently showed that CoQ supplementation could replete plasma and muscle levels of coenzyme Q, however, they failed to show a reduction in myalgias. Mabuchi et al concluded in 2007 that reduction in CoQ levels was a primary effect of statins and that supplementation with 100 mg/day of CoQ significantly boosted plasma levels. There was, however, no significant difference in myalgias or liver function tests.

In 2007, Marcoff and Thompson’s meta-analysis published in the Journal of the American College of Cardiology, carefully dissected the outcomes of studies and showed that a lot of questions remain unanswered. There have been very few studies specifically looking at muscular levels of coenzyme Q10 in patients with statin induced myalgias, and the question of whether decreased coenzyme Q10 levels can cause mitochondrial dysfunction remains unanswered despite some preliminary studies. Additionally, the meta-analysis failed to demonstrate a clear benefit though the use of coenzyme Q10 supplementation in patients taking a statin.

Despite the plethora of small trials examining coenzyme Q supplementation, larger and better powered trials are needed. As it stands, coenzyme Q is not recommended with statin therapy or as a treatment for statin induced myalgias.

References:
Meisenberg G, Simmons WH. Principles of medical biochemistry. 2nd ed. Mosby-Elsevier 2006.

Mabuchi H et al. Effects of CoQ10 supplementation on plasma lipoprotein lipid, CoQ10 and liver and muscle enzyme levels in hypercholesterolemic patients treated with atorvastatin: a randomized double-bling study. Atherosclerosis 2007;195:e182-e189.

Marcoff L, Thomson MD. The role of coenzyme Q10 in statin-associated myopathy: a systematic review. Journal of the American College of Cardiology 2007;49(23):2231-7.

Wynn RL. The effects of CoQ10 supplements on patients taking statin drugs. General Dentistry 2010;58(3):168-170.

Akhenaten & Vitamin D

As a native Californian, I have grown up worshiping the sun, and really, who doesn’t?  The star to which we owe our very existence and worshiped in ancient cultures.  The Egyptian pharaoh preceding Tutankhamun even banned the worship of any other god BUT Aten, the sun disk, and renamed himself “AkhenATEN”.  Providing more than just warmth and great beach days, the sun allows the occurrence of certain essential biochemical processes, such as photosynthesis and the production of vitamin D.

Vitamin D is a lipid soluble vitamin that can be obtained through dietary means, or through sun exposure.  UV-B rays penetrating the skin catalyze the production of a pre-cursor to vitamin D, which then must travel to the liver then the kidneys for activation.  Maintaining adequate vitamin D levels has been associated with decreased risks of breast and colorectal cancers, psychiatric disorders, multiple sclerosis, rheumatoid arthritis, and type 1 diabetes. Vitamin D inhibits renin production in the kidneys, has immunomodulatory effects on lymphocytes, and increases the absorption of calcium in the gut.

Most people immediately think of bones when calcium comes to mind.  However, calcium is an essential element in many biological processes, such as muscle contraction and heart conduction.  As a result, it is essential that levels of calcium within the blood are maintained within a specific range.  High levels of calcium results in excessive thirst, and can eventually cause lethargy, muscle weakness, and heart rhythm changes.  Low levels may result in stiff aching muscles and confusion. 

Under non-pathological conditions, excess serum calcium is moved into the bones out of the circulation and low circulating calcium causes calcium leaching from the bones through signaling from parathyroid hormone and calcitonin.  Long term leaching of calcium from the bones to maintain adequate concentrations of calcium in the blood stream eventually leads to osteopenia and osteoporosis.  Vitamin D also helps to increase absorption of calcium.

In July 2010, the Boston Medical Journal published the shocking results of a meta-analysis by Bolland et al.  The final analysis compiled data from 11 double blind randomized control trials where subjects took calcium without vitamin D compared to placebo.  The trial showed a statistically significant increase in heart attacks for patients supplemental calcium (HR 1.31, p0.035), although no statistically significant increase in risk of death. 

Further analysis showed that the risk was increased only when daily intake was above 805 mg/day of calcium, which is still only a moderate dose.  Rather than proving that calcium supplementation is bad, this study demonstrates the importance of vitamin D, which had been excluded from the study due to previous analyses showing decreased mortality with vitamin D supplementation with calcium. 

In response to patient concerns that calcium supplementation will increase their risk of myocardial infarction (aka heart attack or MI), I would suggest that patients taking calcium supplements ensure that they are getting adequate vitamin D from the sun, dietary intake or supplements.  Further studies and analyses are needed to show specifically what recommendations health care providers can make to keep patients safe as well as to fully understand the reason for increased risk of MI.

Vitamin D supplementation has become the latest hot topic; as such there is a variety of literature covering many different benefits it may provide.  For the sake of time and entry length, I will cover one more article published in July 2010 in AIDS.

Previous literature reported high rates of vitamin D deficiency in patients living with HIV/AIDS, so Welz and colleagues set out to examine potential risk factors in HIV positive patients.  Results of the study indicated that the winter season (when patients are exposed to less sun), black ethnicity (a patient population that needs longer sun exposure to produce adequate vitamin D), CD4 count nadir of less than 200 cells/mcL, and a medication regimen containing efavirenz were associated with vitamin D deficiency.  Age, sex, renal function, and other anti-retroviral medications were not associated with increased risk.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor recommended in combination with two medications from the NRTI class as one of the first line regimens for treatment-naïve patients with HIV.  It is a component of the first ever one pill a day anti-retroviral regimens and is not associated with fat redistribution, as seen with the buffalo hump formation after use of protease inhibitors. 

This trial indicates that it may be beneficial for patients taking efavirenz to take moderate daily supplementation of vitamin D to avoid long-term complications of vitamin D deficiency and for cardiovascular protection.

Akhenaten may have not known about the existence or biochemical significance of vitamin D, he was most certainly correct in proclaiming the sun the most important “god” for ensuring life on earth.

References:

Mayo Clinic electronic resource.  http://www.mayoclinic.com/health/vitamin-d/NS_patient-vitamind accessed 8/12/2010.

The Merck Manuals: online medical library.  http://www.merck.com/mmhe/sec12/ch155/ch155b.html accessed 8/12/2010.

Booth M.  The secret history of the world.  The Overlook Press NY; 2008.

Holick MF et al.  Vitamin D deficiency: a worldwide problem with health consequences.  American Journal of Clinical Nutrition 2008;87(4):1080S-6S.

Bolland MJ et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.  BMJ 2010;341:c3691.

Welz T et al.  Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase.  AIDS 2010;24(12):1923-1928