Abilify VI: Compulsive Behavior Lawsuits
The civil litigation around the best selling drug of all time got pretty weird
The Frontier Psychiatrists is a daily healthy newsletter. I've written a series of articles about medications, and the majority of them were one-off. Abilify, at one time the best-selling drug on earth, is an exception. This is part six. I’ll link prior articles with a footnote1 to spare your flow state as a reader because that is pleasurable, a function of dopamine.
Addicted to Abilify (articles)
Abilify (aripiprazole) is an atypical antipsychotic medication that functions as a partial agonist at dopamine D2 receptors. Today's article is about a rare and confusing adverse effect of this drug, that led to a series of civil lawsuits Compulsive behavior, including both gambling and sexual behavior. The allegation is that this medication intended to help individuals with schizophrenia, bipolar disorder, depression, and other neuropsychiatric conditions also created, in some of them, behavior they couldn't control. Dopamine is a complicated chemical in the human brain. I will do a brief overview of dopamine pathways so we can all be oriented.
Dopamine is a monoamine neurotransmitter, meaning it contains one nitrogen in the molecule, right there at the end of the (CH2CH2) hanging off the end of a benzine ring.
There are four subtypes of dopamine receptors commonly found in the brain, referred to as D1, D2, D3, and D4.
Some genes code for the proteins that make up these receptors, with an eon convention that's pretty similar to the above the dopamine D2 receptor is coded by a gene called DRD2. “Dopamine receptor D2.” For once2, scientists didn't make everything impossibly complicated!
Dopamine Pathways in the Brain
The major dopamine pathways in the brain are:
Again, the naming convention is simple, even though it comes up with some complicated names. Dopamine is going from one part of the brain to another part of the brain.
Meso = midbrain
Limbic = limbic system
So going from the midbrain to the limbic system is the mesolimbic pathway.
From the midbrain to the cortex?
Mesocortical!
From the potato nucleus, or tuber for short, to the infundibulum we have the tubero- infundibular pathway. For my neuroscientist readers, that last part was a joke. General public, be advised, that there is no potato nucleus.3. Moving on from spoofing science, today’s article will reward you…by taking you on a journey from deep in the brain, through reward circuitry, all the way to compulsive behaviors and ending on class action litigation. ARE YOU READY?
The neurocircuitry that is the star of today’s article is the mesolimbic pathway, and we will have to dig in a little deeper to highlight the crucial part of the limbic system involved. As a hint, you ardent, regular readers who are addicted to my writing have already encountered this brain structure in the prior article on akathisia! Yes, it’s the Nucleus Accumbens. The pleasure center of the brain. Specifically, the circuit…
connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The ventral striatum includes the nucleus accumbens and the olfactory tubercle.
When you take a dopamine receptor-binding medicine like Abilify, you don’t get to choose which of the four dopamine circuits you interact with. At best, you take a bet4 that the relative dopamine receptor types you want to target are more involved in the circuit you wish to modulate than elsewhere.
Abilify, recall, acts as a very high-affinity partial agonist. That means that if there is a D2 receptor to be had, chances are, Abilify will occupy it preferentially compared to all the other compounds that could do that binding. Abilify will OWN the D2 receptors. This can even be used to beneficial effect—one sassy Abilify “trick” is to use it to prevent the adverse effect of milk letdown5 from the breasts in individuals treated with risperidone6. This is called “galactorrhea” and is a very strange, and oft unsettling experience, especially for men who were not banking on lactating.
It’s a good example of how the circuits work, thus hitting this high point before we get to the big reveal of this article.
Galactorrhea, Etc.
Lactating is a function of the hormone prolactin. Prolactin release is inhibited (kept in check) by the presence of dopamine in the pituitary—the end of the tuberoinfindibular pathway mentioned above! When we block dopamine receptors throughout the brain with risperidone, it includes blockade of these prolactin-inhibiting receptors—and elevated prolactin! Abilify has vastly higher binding affinity in this pathway, however, so it will outcompete risperidone at these binding sites. Since it’s a partial agonist, it will act enough like dopamine in the pituitary. Thus, it inhibits prolactin and prevents milk release from the breasts. This same pathway leads to gynecomastia (breast tissue growth) in males exposed to risperidone, and lest you think this article would abandon you without any civil litigation whatsoever, rest assured—this adverse effect of cousin drug risperidone has already led to $8 billion in settlements from risperidone maker J+J.
This one side effect led to:
13,400 lawsuits had been filed a one time, primarily in Pennsylvania, California and Missouri. Other cases are pending in courts around the United States. Product liability lawsuits continue to be filed, and the company has settled or otherwise resolved some of the U.S. cases. (According to Johnson & Johnson’s 2018 annual report)
The Rewards of Compulsive Behavior (for Lawyers)
Abilify binds to dopamine receptors, and that includes receptors involved in the reward circuitry of the Nucleus Accumbens. This can lead to a change in behavior…
there are reports of patients who experience problem gambling, hypersexuality, obsessive–compulsive symptoms, and other impulsive and/or compulsive behaviors as a result of aripiprazole administration and/or dosage increase
In the reviews of the literature:
the most frequently published impulsivity adverse effect of aripiprazole is gambling, followed by hypersexuality, obsessive–compulsive symptoms/disorder, problem eating, trichotillomania, problem shopping, and kleptomania. These symptoms were experienced both by patients who had previous problems in these areas and those who did not.7
This compulsive behavior has been documented sexually8 and given the sex-negative nature of the culture, I can imagine the following leads to shame and a bias towards underreporting:
After a month of treatment with aripiprazole, Mr A became obsessed about engaging in sexual activities and had a very high libido and an uncontrollable urge to masturbate
The reports became so pervasive the FDA issued a warning on the best-selling drug of all time in May 2016:
Although pathological gambling is listed as a reported side effect in the current aripiprazole drug labels, this description does not entirely reflect the nature of the impulse-control risk that we identified. In addition, we have become aware of other compulsive behaviors associated with aripiprazole, such as compulsive eating, shopping, and sexual actions. These compulsive behaviors can affect anyone who is taking the medicine. (emphasis: your author).
The lawsuits came flooding in—over 2800 of them— and over $535 million has been paid out. There is even a special system of multidistrict litigation built to handle massive liability concerns like this:
Multidistrict litigation is a specialized process used by the U.S. District Court system to centralize complex lawsuits for pretrial proceedings. Each lawsuit remains separate, but discovery, depositions, and decisions about common questions of fact are addressed at the same time. The goal of MDL centralization is to save time and money, making the process more efficient for both sides of the case, as well as to provide a more consistent outcome across similar types of cases.
The issue, as I see it with this adverse effect is that, unlike lactating, it’s not obvious that the individuals—many of whom have bipolar disorder, which has hypersexuality as a symptom in the first place—can pick out that the adverse effect is due to the drug. More often, I’d imagine, vulnerable people with stigmatized illnesses blame themselves, or are blamed, for what might well be a more common adverse effect than we recognize.
Even rare adverse effects can be deeply problematic in drugs prescribed on a massive scale globally. In a drug with the billions and billions and billions of global sales of Abilify, what is a few hundred million in civil litigation and federal enforcement between shareholders?
Oh, that is right, some of the real people whose lives were disrupted. Some of them, like in Fight Club (his name is Robert Paulson…who also had gynecomastia thanks to testicular cancer treatment) revealed their deeply personal stories in litigation:
Joseph Edgar
The gambling problems stopped after he stopped taking the drug in April 2014, but he had lost more than $36,000 and faced other mental and physical damages.
Athalean Harper-Mosley
She incurred gambling losses of more than $65,000. Can you imagine? She didn’t have to.
Patrick Parks
Parks began taking the drug around May 2013 and “began compulsively gambling shortly thereafter,” his complaint says. He had already lost more than $75,000 by the time he stopped Abilify.
Rikki Carlson
In December 2010, after beginning Abilify, she began compulsively gambling, eating, and shopping. Those behaviors stopped after she stopped taking the medication in March 2016.
Even lifesaving medicines can have adverse effects. I’m probably alive thanks to this medicine more than once in my life. I took it throughout all of medical school, and either coincidently or more likely thanks to the effective psychiatric care that included aripiprazole, I’m a physician, who had zero mood episodes throughout medical school. I’m not taking it any longer, because my doctor changed the plan, and I work with my doctor. That is the balancing act—Abilify is complicated, and not as helpful as we’d like. It has serious risks. And the very fact that I can write 6 articles in one week on this drug is, itself, an epiphenomenon of having this medicine having kept your author well, for many years, tolerably.
Prior hit drug-themed articles include:
Effexor, Buspar, Risperdal, Zyprexa, Neurontin, Xanax, Klonopin, Paxil, Prozac, Clozaril, Lamictal, Lithium, Latuda, Ambien, and generally Benzos, specifically maybe Benzos leading to death by suicide, Geodon, Zoloft, Auvelity.
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Prior articles include:
Abilify III: Bipolar Depression
Akathisia (aka Abilify IV)
Abilify V: Federal Enforcement
As well as honorable mentions as part of my articles about CATIE (Part 1 and Part 2), a large NIH-funded trial in which Abilify was compared to other medications for schizophrenia.
this is a lie. they do.
The tuberoinfundibular pathway breaks the pattern of “from-to.” Both tubero and infundibureferrred to the location in the hypothalamus of the dopaminergic neurons and they project to the pituitary. Can you tell I used to teach neuroanatomy lab?
GET IT? foreshadowing.
Mazher, O. A., Maneta, E., & Hall, W. (2018). Treatment of risperidone-associated hyperprolactinemia with aripiprazole. Journal of clinical psychopharmacology, 38(5), 529-531.
Gupta, S. C., Jagadheesan, K., Basu, S., & Paul, S. E. (2003). Risperidone-induced galactorrhoea: a case series. The Canadian Journal of Psychiatry, 48(2), 130-131.
Akbari, M., Jamshidi, S., Sheikhi, S., Alijani, F., Kafshchi, P., & Taylor, D. (2024). Aripiprazole and its adverse effects in the form of impulsive-compulsive behaviors: A systematic review of case reports. Psychopharmacology, 1-15.
Bulbena-Cabré, A., & Bulbena, A. (2016). Aripiprazole-induced hypersexuality. The Primary Care Companion for CNS Disorders, 18(6), 26650.
Thanks to @A Madman's Miscellany for the repost
My skinny wife is only half-joking when she threatens to leave me if my MOOBs get bigger than her boobs. I don't think I've had Risperdal -- but who can remember one of 20? What other drugs can I blame for this embarrassing condition and remove it as a moral failing in her eyes? And which bikini tops can I buy in odd sizes to go with my boxer shorts bathing suits?