Depakote
A medicine for bipolar disorder and a series of crimes, both according to the drug maker.
The Frontier Psychiatrists is this newsletter. Owen Muir, M.D. writes it, and it is a satirical take, personal, or both, on health-related issues of the day.
Dr. Muir is a child and adult psychiatrist. This “medication guides” series is more about storytelling than a straight prescribing guide. I try to include the stale facts supporting my very stated opinions. I hope you enjoy this piece. If you do, consider sharing.
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The American chemist Beverly S. Burton described the synthesis of valproic acid in 18821, and It was thought to be pharmacologically inert until 19632. Depakote (divalproex sodium) was approved by the FDA for the treatment of epilepsy in 1983. Abbott Laboratories worked hard to promote the term “mood stabilizer.” They filed an NDA3 for the use of their epilepsy drug for the newly re-christened “Bipolar Disorder.” This re-branded disorder supplanted the older moniker “Manic-Depressive Illness.” Here is what happened to the use of the term “mood stabilizer” in the published literature over time:
Since the introduction of bipolar disorders—not just one!—in 1980, awareness was needed for a group of disorders, lest oral medications remain underprescribed. Since 1980:
With [the new disorders] emergence, estimates for the prevalence of bipolar disorders have risen from 0.1% of the population having bipolar I disorder (involving an episode of hospitalization for mania) to 5% or more when the definition of bipolar disorders includes the new cyclothymia and bipolar II.
Bipolar Disorder(s) encouraged psychiatrists to consider if their patient might have bipolar disorder. These disorders Not Otherwise Specified their way into the hearts of those who previously quailed at Manic-Depressive Illness. That illness is serious! It was not a casual diagnosis for masters level therapists to attempt. Those patients? Maniacs, all!
A touch of the mood disorder? That sounds less imposing. We were one screening measure away from a problem that even primary care doctors could stabilize! Ah, here we go…the Mood Disorders Questionaire (MDQ). Given my previous review of screening measures for getting struck by lightning, I am not a fan of disastrously inaccurate screening. The MDQ is one such tool:
Further testing in a general population revealed a sensitivity of 0.28 and specificity of 0.974. Another study compared its use in bipolar and unipolar depressive patients and found a sensitivity of 0.58 (but better for patients with bipolar 1) and specificity of 0.67.
Using the MDQ as a screening tool results in catastrophic over-identification—only 18% of people who test positive on the MDQ questionnaire would have bipolar disorder at all. Across America, 25.84 million people would screen positive on the MDQ. Of those, only 4.65 million would have manic-depressive illness.
This makes it an excellent tool… to get more mood stabilizers prescribed. In 1985, approximately 100,000 prescriptions for Depakote were written. Abbott obtained an acute bipolar mania indication from the FDA in 1996. The MDQ was launched in 2000.
By the end of 2000, the number of prescriptions had increased to over 10 million. Abbott developed and validated the MDQ questionnaire itself. It was marketed as a tool for identifying people who may benefit from treatment …with Depakote. It still is prescribed at rate of 12 million prescriptions a year in 2023, according to IQVIA.
Divalproex sodium was originally developed for the treatment of epilepsy—but epilepsy you either have or you don’t. There aren’t masters level epilepsy diagnosticians around making epilepsy II diagnoses when someone is a bad dancer. One of the “quirks” of epilepsy research? We have recognized that effective treatments exist. It is unethical to perform a clinical trial in epilepsy, comparing placebo versus experimental treatment as monotherapy. No such problem problem exists in psychiatry.
We don't give people with real epilepsy fake treatment.
All new epilepsy medicines are studied in poorly controlled Epilepsy, adding the new medicine as an additional treatment vs. placebo. The outcomes evaluate new drugs on seizure frequency in someone taking an epilepsy medicine already. This methodology protects human subjects from unethical experiments. It also subjects all non-research subjects to the vast, uncontrolled deployment of medicines not approved as monotherapy.
We do not have a psychiatric equivalent— we still provide a study drug versus placebo to people with depression or other psychiatric illnesses. There are few exceptions5.
Divalproex sodium, also known as Valproic Acid— when covered with something to make it go down easy in your stomach—gets to the name Depakote. It’s coated…but a K! Now, it was cute! When you're in medical school, they teach you about Depakote— in the context of psychiatry— as a part of a class of medicines called “mood stabilizers.” To be exceptionally clear, this is a misleading category made up to sell more drugs, starting with Depakote. Even at my alma mater, the enlightened University of Rochester, they don’t highlight the pharma companies that developed each Sackler-inspired category title when teaching you the practice of medicine.
I have no idea what a mood stabilizer is supposed to be. I don't know who chose that word, but Abbot ran with it. There is no such thing as a mood stabilizer. It is a brand decision— who doesn't want to gift their patients with pills to provide a stable mood?
What divalproex sodium and its various extended-release formulations do, in addition to its neurological indications for epilepsy and migraine prophylaxis, is provide treatment of acute mania and prevention of recurrent mania in individuals with bipolar disorder.
Readers of this column will be familiar with the fact that your author is one such individual. Depakote was my first “bipolar drug.”
Depakote is Valproic Acid (VPA)
The mechanism of action for VPA involves the enhancement of inhibitory neurotransmission and the modulation of voltage-gated ion channels. This is why it is an anti-epileptic. Readers may recall that cells' hyperpolarization makes them less likely to fire.
The mechanism of broad inhibition is thought to be via inhibiting catabolism (breakdown) of GABA (in the synapse) or preventing GABA from reabsorption by glia and nerve endings6. It’s like a combination of an SSRI but for GABA plus an MAOI, but for GABA. It means more inhibitory neurotransmission from endogenous GABA binding to GABA receptors. Nerves fire less.
I don’t think it did much for me. However, no one told me—that I recall— that the medicine was supposed to work to make you well. I knew I had an illness that made me feel bad, so I took it. I kept taking it, even though it didn’t do much for me. Many others, it seems, were in the same boat. But it does work for some.
It is effective in bipolar disorder, but with less evidence supporting this assertion than I would like. I summarize some of that data below…
Patients don’t discontinue it as often as other drugs for bipolar disorder:
When it comes to preventing mania relapse, however…it does not seem to do that:
It also has very small-scale meta-analysis data to suggest efficacy in bipolar depression:
We identified four trials, with a total sample size of 142 patients. The relative risks of response (RR=2.10, p=0.02) and remission (RR=1.61, p=0.04) were significantly greater for divalproex than placebo. Mean response rates were 39.3% for divalproex and 17.5% for placebo, and mean remission rates were 40.6% and 24.3%, respectively.7
Metabolism and Side Effects of Depakote
The first drug for manic-depressive disorder, Lithium, is a pain in the ass for doctors. It is also a pain in the ass for patients. This is because it requires monitoring. You have to get blood levels. Depakote requires less monitoring. Slightly less monitoring is very appealing for busy people.
Unlike lithium, which is the third element on the periodic table and is just peed out after it’s filtered in the kidneys, valproic acid is metabolized in the liver. This drug has phenomenal metabolic variability due to the underlying genetic variations in how human livers function.8 Blood work needs to be obtained, and sometimes, if we are not carefully monitoring liver function, there can be life-threatening side effects, including liver failure. The risk profile got even worse for some. Then, the lawsuits came.
Mechanism of Robust Corrupt Profiteering and Regulatory Action
Between 2007 and 2012, four sealed qui tam actions were filed against Abbott pursuant to the False Claims Act, 31 U.S.C. § 3730(b), asserting illegal marketing of Depakote for non–FDA approved uses. The following statements may seem inflammatory. They are all from a settlement Abbott made with the government, and Abbott agreed were true:
On February 1, 2011, the qui tam actions were unsealed as the United States and fifteen state governments intervened. Another state followed two months later. After the consolidation of those actions, on May 7, 2012, Abbott agreed to pay $1.6 billion to resolve the criminal and civil claims against it. As part of that settlement, Abbott admitted to knowingly promoting the sale and use of Depakote for uses that the FDA had not approved as safe and effective, including behavioral disturbances in dementia patients, ADHD, schizophrenia, and other psychiatric conditions. Abbott also admitted this unapproved use promotion included making false and misleading statements about the safety, efficacy, dosing, and cost-effectiveness of Depakote for some of those uses, and specifically marketing Depakote to nursing homes to control behavioral disturbances in dementia patients (as an alternative to antipsychotic medications that carried additional federal regulatory restrictions). Abbott also admitted to paying illegal remuneration to health care professionals and long-term pharmacy providers to induce them to promote or prescribe Depakote.
It is also worth noting that Depakote causes horrific birth defects in about 10% of pregnancies in exposed women— and has been hit with a further flurry of lawsuits for these problems. The first wasn’t until 2010, 30 years after the drug hit the market. Some of the cases have not gone Abbott’s way, and others they have won.
As of this writing, lest $1.6b sounds like a “big fine,” the market cap of Abbott is $170.33 billion, and its sister company AbbVie—which now sells Depakote— has a market cap of $269.59 billion, which makes their fines a scant 0.35% of their current combined market capitalization.
Since 2000, Abbott is up 588%. AbbVie is up 363% since its spin-off listing in Jan 2013.
No world exists in which these criminal practices stop when more profitable to pursue them, even if you get caught. The only way to reduce the chance is to take away all the money a company makes after criminal behavior. We don't let the mafia keep its money. We put the Dons in jail. If we did not, they would spin out wildly profitable enterprises like AbbVie, too. Personal criminal liability and financial ruin are limited bulwarks against this behavior. Absent consequences worse than the benefits? We can expect more death and deception.
This has been article is another in my series about one drug or another. Prior installments include Geodon, Ambien, Prozac, Xanax, Klonopin, Lurasidone, Olanzapine, Zulranolone, Benzos, Caffeine, Semeglutide, Lamotrigine, Cocaine, Xylazine, Lithium, dextromethorphan/bupropion and Adderall, etc.
On the propyl derivatives and decomposition products of ethylacetate. Am Chem J. 1882; 3: 385-395
Lopez-Munoz F, Baumeister AA, Hawkins MF, Alamo C; The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth., Actas Esp Psiquiatr. 2012; 40: 34-42
Department of Health and Human Services (1995) NDA 20-320: Depakote.
Hirschfeld RM. The Mood Disorder Questionnaire: a simple, patient-rated screening instrument for bipolar disorder. Prim Care Companion J Clin Psychiatry 2002; 4:9–11
The esketamine trials (particularly for the “Major Depressive Disorder with Suicidal Ideation” FDA-label studies, ASPIRE I and ASPIRE II used this design, with co-administered oral antidepressants, to address the concerns of unethically withholding “proven” active treatments (a.k.a. oral meds) from depressed patients.
Bialer, M. Why are antiepileptic drugs used for nonepileptic conditions? Epilepsia 53, 26–33 (2012).
Bond DJ, Lam RW, Yatham LN. Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis. J Affect Disord. 2010 Aug;124(3):228-34. doi: 10.1016/j.jad.2009.11.008. Epub 2009 Dec 30. PMID: 20044142.
Zhu, M., Li, H., Shi, L., Chen, X., Luo, J., & Zhang, Z. (2017). The pharmacogenomics of valproic acid. Journal of Human Genetics, 62(12), 1009-1014. https://doi.org/10.1038/jhg.2017.91