What has been will be again,
what has been done will be done again;
there is nothing new under the sun
–Ecclesiastes 1:9
You know, I’d say there’s a better than even chance that when King Solomon wrote those words–let’s say around 950 B.C.E.–he had no idea he could just as well have been talking about psych meds–but he sure could have been.
Let’s take a step back for a moment to see where we are. Rank, Conti & Goldman wrote in the 2005 issue of The Milbank Quarterly that psychotropic drugs were playing “an increasingly central role in the treatment of mental disorders.” It seemed like it had been the era of the psychotropic drug–particularly the antidepressant and the antipsychotic–for decades now. The drugs’ success could be measured in money–lots and lots of money. The authors note that spending on antidepressant and antipsychotic medications grew 11.9% and 22.1%, respectively, in 2003, while overall spending on drugs grew at 11.5% that same year.
By 2010, one in five American adults was taking a psychotropic medication. The American Psychological Association believe knows just who’s to blame for such an epidemic: Prozac. The APA notes that Eli Lilly, makers of this wonder drug claimed, when the FDA approved Prozac in 1987, it had fewer sider effects than previous antidepressants. The first of the selective serotonin reuptake inhibitor antidepressants, it seemed like something completely new. And everyone wanted in on the action.
So, since Lilly launched Prozac, the use of antidepressants has quadrupled in the U.S. More than 1 in 10 Americans now takes an antidepressants, and NPR claimed in 2011 (and this one’s a total shocker) that antidepressants had become the second most prescribed drug in the country, right after cholesterol-lowering drugs.
Let’s enter the psychotropic time machine to review the history of psychiatric meds. We begin, strangely enough, with attempts to produce chemical alternatives to isoniazid (a drug I’m sure you’re all familiar with), a drug used to treat tuberculosis. Iproniazid, developed in 1952, which, though I’ll bet you 10 bucks no one you know has heard of, still earns the honor of being the very first antidepressant, was similar in structure to isoniazid and thus also meant to treat TB. (For those of you who lie in wait to find places to use this word, this circumstance is just made to use ‘serendipity’. So here I go. . .) In a serendipitous finding, health staff noticed that the patients’ tuberculosis was anything but cured when they were treated with the drug—but the patients, formerly quite depressed due to their chronic illness, showed a marked improvement in mood in a clinical trial.
The effects caused researchers to look into iproniazid’s effects on depressive symptoms. As clinical trials were run on psychiatric patients in the early 50s, one of the researchers actually coined the term ‘antidepressant’ to refer to the drug’s effects. And in 1957 in New York, the first researchers were able to look at a group of depressed patients without tuberculosis–and claim the authors of “Half a century of antidepressant drugs,” a guest editorial in 2007 in the Journal of Clinical Psychopharmacology, 70% of patients who received the drug “had undergone a substantial improvement.”
This treatments that’s sounding so pretty darn good is known as a monoamine (basic Latin here, folks: mono–that’s one– a monoamine is containing one amino group, for example serotonin or dopamine or nerepenephrine–you’ll come back to these folks later)-oxidase (basically meaning an enzyme that catalyzes ‘oxidation’) inhibitor (called an MAOI, for obvious reasons), which prevents MAO enzymes from deaminating (read ‘inactivating’) extra dopamine, norepinephrine, and seratonin, letting these neurotransmitters build up in the brain.
Unfortunately, the drug had a short and tragic life. Approved for depression in 1952, it was withdrawn in 1961 for its extremely inconvenient habit of causing hepatitis in those that took it. But not to worry–it left quite a legacy in copy-cat drugs as Marplan, Nardil, Parnate, Safra, Zyvox, Emsam. All followed its plan of action [which, come to think of it, has a lot to do with this blog’s point], and are still in use today.
The next significant step was the tricyclic antidepressants (TCAs), beginning with imipramine, which itself is still around today.
Again, oddly enough, scientists weren’t even looking for an antidepressant when they came across this one. In the 50s, when both new antidepressants were approved, of necessity the treatment of choice for psychosis was electroshock therapy (ECT). So researchers were actually looking for a treatment for schizophrenia when they ran trials of imipramine. In clinical trials in 1955 it did nothing for psychosis, but was quite effective in mood elevation. Some patients found they were more sociable while others had extra energy–a few dubbed it a “miracle cure.”
Researchers quickly realized they had nothing for schizophrenic psychosis–but they sure had something for depression. Approved by the FDA in 1959 for treating depression, marketed as Tofranil, it is still often–all these years and drugs later–referred to as the “gold standard” of antidepressants, working when numerous other treatments have failed.
However, just because nothing, it seems, in the psych world, helps without hurting, it shouldn’t surprise readers that imipramine causes high rates of hypomanic or manic reactions, particularly in those with preexisting bipolar disorder. Estimates reach as high as 25%.
Imipramine works on several neurotransmitter systems involved in depression, anxiety and other mental conditions. I hesitate to list them again in case you missed them the first time–but what if I change the order? The 3 major neurotransmitters it affects are (everybody, now!) dopamine, norepinephrine, and serotonin.
So. . . .first came the most obvious ‘me-too’ drugs. WebMed points out that when scientists realized the effectiveness of imipramine (initially 70% of depressed patients responded at some level), they hurried themselves along to the labs and created drugs based on imipramine’s three-ring (tricyclic–tricky, huh?) chemical structure, and, they write, “Before long, laboratories all over the country began churning out tricyclic clones, each one a little different from, but none any better than, imipramine itself.”
Later a real innovator thought to add another link, and then we had the tetracyclics (not, to be honest, well-known, but they’ve got one with name-recognition–how’s about ‘Remeron’? Ok?)–but all, in essence, on the same model.
As science writer Sylvia Wrobel put it in the November 2007 issue of the Journal of the Federation of the American Societies for Experimental Biology, the MAOIs and the tricyclics (and, yes, the tetracyclics, too) work essentially the same way: they interfere with the regular release and reuptake of those neurotransmitters we all now know and love.
The MAOIs do it by not allowing enzymes to destroy these neurotransmitters; the TCAs go ahead and block the reuptake of them. In essence, both leave more neurotransmitters around for the nerves to use. Scientists put this all together in the early 60s–and came to the realization that they could actually design a drug that could focus on only one neurotransmitter at a time.
It seemed the course of medicine changed in 1987 when the FDA approved Prozac, the first SSRI, or selective serotonin reuptake inhibitor. In controlling the number of neurotransmitters the drug acted upon, scientists seemed able to control the side effect profile, a serious matter. And Prozac certainly did seem to have fewer side effects than the MAOIs or the TCAs.
But in essence, the mechanism behind Prozac was just an alteration of that used by the TCAs and MAOIs–a billion dollar alteration, it’s true, but one that researchers, a couple decades later, have come to question the value of. Meanwhile, copy-catting was quick and profitable. Think Luvox, Paxil, Zoloft, Lexapro, Celexa. . .
Of course once the concept of selectively choosing your neurotransmitter arrived, why should the other two be left out? The first serotonin-norepinephrine reuptake inhibitors work by (I’m sure you could teach this by now) inhibiting the reuptake of serotonin and norepinephrine. The first SNRI was Effexor, introduced by Wyeth in 1994. For “me-too’s” think Cymbalta or Pristiq.
And last but certainly not least–I’ve always been a dopamine fan, even though I feel it’s tragically under-represented in re-uptake land) is. . .well, dopamine.
So we come to (and this is it, for now, you’ve really hung in there) the norepinephrine-dopamine reuptake inhibitor (NDRI)–and I feel it’s kind of insulting your intelligence to tell you what it does–but you end up with greater concentrations of, well, you know. There’s not much point in belaboring this because I believe at this point there’s only one antidepressant in this category. But there’s no need to feel sorry for it, since it’s re-created itself twice so it has company. We’ve got: Wellbutrin, Wellbutrin SR (sustained release–but I guess they just mean ‘a little bit sustained’ because then they came out with. . .), and Wellbutrin XL (which I think means an extended release pill that you can take just once daily) [I’m quite open to correction on this.]).
But what is most disappointing, is that the new meds, which supposedly brought us a new model, with better efficacy and an improved side effect profile–well, they may, in fact, have brought us none of the above.
Because, as you can probably see for yourself, TCAs and SSRIs work in precisely the same manner–it’s just that SSRIs are more selective in which neurotransmitter they’re inhibiting reuptake of. And though MAOIs might seem quite different, in the end they just increase the levels of the exact same neurotransmitters (this time by inhibiting that enzyme that would inactivate them). So the model of action for all three is really in essence the same.
Good Old King Solomon–he had antidepressants pegged.
As a short addendum, it turns out that the new antidepressants don’t necessarily have better efficacy either. I’ll keep this short. Let’s take a look at Professor Ian Anderson, Professor of Psychiatry at the University of Manchester Director of the Specialist Service for Affective Disorders in Manchester,and what he’s written. First off, in the April 2000 issue of the Journal of Affective Disorders he writes that “[o]verall efficacy between the two classes [SSRIs and tricyclics] is comparable but SSRIs are not proven to be as effective as TCAs in in-patients.” Not that promising, but perhaps the new meds just aren’t meant to deal with such serious depressions.
But as if he’s continuing a conversation, Anderson writes on, in the 2001 British Medical Bulletin, summarizing his search of 108 meta-analyses of antidepressant use in depression. His findings were somewhat all over the place, but one thing seemed clear: there was little difference in efficacy between old and new antidepressants.
The Annals of Internal Medicine in its 2011 issue ran a systematic review of data from 234 studies looking at first- and second-generation antidepressants and found “no substantial differences in efficacy for the treatment of MDD. Statistically significant results were small and are unlikely to have clinical relevance. No differences in efficacy were seen in patients with accompanying symptoms or in subgroups based on age, sex, ethnicity, or comorbid conditions.”
Now, if you’re a new second-generation AD, that’s a real bummer.
However, there was a difference mentioned by Anderson: the SSRIs were generally much more tolerable. (Remember: you always have to have something nice to say.)
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And thus, for drugs that aren’t particularly new concepts, that are not remarkably more efficacious, and that do carry their own side effect profile, a fair amount of resources and money have been spent.
In fact, in 2010, Americans spent $11.6 billion for these antidepressants–which seems like kind of a rip-off–until you read about the way the antipsychotics . . .
