The Lilly Suicides

I already blinked to this AdBusters project, but Richard DeGrandpre’s “Lilly Suicides” essay has just been reprinted on AlterNet. Rebecca Blood pointed me to the article, soliciting my comments. Here goes:

There are three distinct problems here. The first is what Prozac and the other SSRIs actually do in the way of worsening people’s agitation, and what that might lead to in behaviors. The second is the corporate response. And the third is the societal attitude toward the issue. [To get what I’m saying here fully, you should have read the ‘Lilly Suicides’ article already…]

Clinicians have never been unclear about the adverse effects of the SSRIs and the care required to manage them properly. It is pretty certain that they can cause akathisic restlessness and agitation. At its worst it is pretty much excruciating torture, although that degree of akathisia is very very rare – perhaps just enough to account for the handful of well-publicized cases the article and others like it refer to? I’ve treated literally thousands of patients with SSRIs, was part of the pre-marketing clinical trials for Prozac before its approval and release, etc. i.e., I’ve been using these meds since the mid-80’s, and I’ve never seen a patient agitated enough to want to jump from heights or compelled to jump in front of traffic. It is usually more like a bad case of the jitters from, e.g., too much caffeine. It certainly is true, as the Healy study whose description starts out the AlterNet article indicates, that this effect is a physiological reaction to the drug even when given to a healthy nondepressed subject, but it is not clear to me what the “dangerously agitated and suicidal” impact he describes Zoloft as having on two of his volunteers actually means in clinical rather than histrionic terms. I’m dubious without more detail.

Nevertheless it is notable to me that so many of the gruesome suicides, or murder-suicides, noted in the article occur just after  the patient has been put on the drug, and before its antidepressant benefits can accrue. It seems you have a situation of adding agitation on top of preexisting depression during this initial period of drug use. The depression itself might not have been severe enough to make the patient suicidal, but patients may interpret the new-onset painful agitation pessimistically — as is the case in depression — as a worsening of their illness and more evidence that their recovery is hopeless. This was a big problem when the SSRIs were first introduced in the late ’80’s. They were not yet considered “first-line” antidepressants and were often reserved for use with the most desperately ill depressed patients who had previously failed all the preexisting classes of antidepressant medication. All their hopes were riding on the new drugs, and the prescribing doctors were swept up in the ‘hype’, as is the case whenever a supposed breakthrough class of medication is introduced. (There’s a joke in psychiatry, indeed throughout medicine, about how we should “use it or lose it”, i.e. hurry up and prescribe new drugs before the bloom is off the rose and they lose the benefit of everyone’s blind enthusiasm toward them… which really does, through the placebo effect, make them more effective at the outset…) So when such patients don’t get better on SSRIs any more than they did on their previous antidepressants, they are more and more despondent. Their last, best hope has failed them… Now I know that’s not the typical story in the AlterNet article, but it does illustrate the expectancy effect.

Moreover, the side effects of an SSRI are worst in the first few days of use, before the body acclimatizes to the medication. They are exacerbated by introducing the drug in too abrupt a fashion rather than easing the dosage up gradually. Finally, the “jolt” the patient gets from starting the antidepressant may provide the energy for them to act on a plan they were too listless to implement up to that point.

The agitation caused by starting SSRI treatment is not usually so severe, emergent and abrupt that it cannot be anticipated, prevented, and treated with careful attentive treatment. Such prudent care is lacking in the modern treatment environment for a number of reasons. First, ‘managed care’ pressures doctors to achieve results rapidly, which translates into starting the drugs at too high a dose and increasing the dosage too frequently. Seond, ‘managed care’ translates into pressure to spend too little time with patients, or to see them too infrequently. Finally, as I never hesitate to point out, a coalescence of pharmaceutical-marketing and ‘managed-care’ influences have caused prescribing to shift more and more to the primary care MDs, family practitioners, internists, etc., rather than the psychiatrists, IMHO creating even less adequate care than the psychiatrist would have given in the equivalent situation. This is not always the case; several of the AlterNet vignettes were of people treated by psychiatrists, but it contributes…

There are also several other adverse effects of SSRIs (and all other antidepressants) which are alluded to in the article but which are a different risk than akathisia. First, the SSRIs produce part of their beneficial effect, I and a subset of psychiatrists are convinced, by a sort of therapeutic numbing. If the medication works, things just don’t get to you so much, your skin is thicker in a way. Now this is abit reductionistic I know, but, physiologically, this is probably a function of the drug’s actions in damping down the function of parts of the frontal lobes. Because the frontal lobes also control inhibitions, it is possible that in some cases the “frontal lobe apathy” they create, particularly if exaggerated, could remove inhibitions against impulsive and even heinous acts; this would be especilly true for people who are motivated, and stopped from acting up, by concern about people’s opinions or reactions. With the SSRIs, one could care less, so to speak. One does care less…

Another adverse effect of the SSRIs and all other antidepressants is the induction of mania. A depressed patient may always be an ‘undeclared’ manic depressive (bipolar), which is an accident waiting to happen if you give an antidepressant. It can’t be avoided; you can only discover their bipolar tendencies when their first antidepressant treatment makes them manic — which is a different form of disinhibition, hyperactivity and agitation than akathisia, but can result in the similar dangerous behaviors. The Forsyth vignette in the article, in which one day he feels better than good and the next commits a “maniacal” act, may actually be a “manic”, as in bipolar illness, act.

Finally, SSRIs, and other antidepressants, can also induce psychosis, or unmask it in a depression that was already headed in a “psychotic depression” direction. You get that feeling in murder-suicides — that the reasoning it takes to decide to kill your family or spouse as well as yourself is often delusional rather than just depressed. As the author describes the Forsyth murder-suicide, these were “senseless acts that were simply unimaginable to those who knew (him).”

By the way, one added reason for a rate of suicide 5-6 times that of the tricyclics, the older class of antidepressants, was not only the contributions I’ve mentioned above to an attitude of laxity in prescribing the SSRIs, but that there had been an attitude of hypervigilance with the tricyclics. This is for one simple reason : overdose. While SSRI overdose is trivial from the point of view of medical complications, and nonlethal, tricyclic overdoses KILL, because they have direct effects on cardiac conduction. Prescribers of tricyclics were never lulled into the false sense of security they were to have with the SSRIs.

So much for the effects of the drugs. On to the manufacturers’ stances. I believe the thrust of the article, that the corporations pursued a substantial coverup of the adverse effects and adverse outcomes from their medications. Lilly probably would have gone under if Prozac tanked, for example. It represented a third of the company’s revenue for many of its years, and it has not come up with a really viable successor cash cow. So every day that it postponed any threat to Prozac’s profitability was another good day for the company. Ironically, the evidence of the coverup — the appearance of guilt, etc. — is what is damning, not the data on the drugs’ effects. The damage awards and culpability findings are all going to revolve around the contention that the companies should have known, did know, should have warned, did not warn, with due diligence. As I’ve stated above, I don’t really think these companies are marketing truly dangerous drugs that inherently hurt just to enhance their coffers. Properly managed and prescribed, the SSRIs have been breakthroughs in depression treatment, with relatively minor prices to pay — the akathisia risk and, as I wrote last week, the discontinuation syndrome (esp. with Paxil) — if doctors are experienced, aware, and have the time to follow patients on these drugs with due care. If Lilly and other co’s hadn’t spent more than a decade fighting their rearguard action, lawsuits would probably not be able to reach the “deep pockets” of the pharmaceutical industry and would have stopped where they ought to — with the individual prescribing clinician, as malpractice actions. And the standard for malpractice is whether there was negligence and whether that negligence caused a forseeable and avoidable harm. Stupid greedy Lilly, Glaxo, etc. etc…

Finally, societal attitudes. Look at the article; the author thirsts for a righteous story around the size of the Karen Silkwood or Erin Brockovich sagas (“a final conclusion seems unavoidable: that next to Big Tobacco and the marketing of cigarettes, the selling of the SSRIs is perhaps the deadliest marketing scandal of the 20th century. “). Glory calls! One example is calling akathisia “the most terrifying potential side effect” of these drugs. It simply is not that terrifying! The article also extrapolates from an estimate that only 1% of serious side effects are ever reported to the manufacturers’ surveillance programs to conclude that the number of Prozac-related suicides must be 100x greater than the incidents on record. There are lies, damn lies, and statistics… Additionally, to make the Case of the Evil Corporations more dramatic, the crusaders lump together various physiological reactions to the medications and diverse adverse outcomes in a manner which is all too plausible to an uncritical and psychopharmacologically nonastute public, neatly fitting deep-seated biases against psychiatric drugs and the stigma of mental illness.

And by the way, the introduction of newer antidepressants which no longer work via a solely serotonergic mechanism has absolutely nothing to do with the liabilities of the SSRIs, unlike the author’s contention in the final paragraph. Medications that work by a serotonin-based mechanism alone are just not suitable for everyone or everything… which is the market the pharmaceutical companies want to capture…