“The data are in, and it is clear that . . .a[n] experiment has failed: despite decades of research and billions of dollars invested, not a single mechanistically novel drug has reached the psychiatric market in more than 30 years.”
— H. Christian Fibiger, Ph.D., Vice President and Global Therapeutic Area Head for Neuroscience Research at Amgen, the world’s largest biotechnology company, in the 2012 Schizophrenia Bulletin
Our last post provided a brief history of antidepressants: of the 50s which saw the–accidental–invention of two new models, and of the 80s when a group of drugs, claiming to be a new class (think of the SSRIs and Prozac and on), promoted itself well enough that people expected–and, truthfully, some believed they received–wonders.
In the long run of several decades however, it turned out that these new ‘wonder drugs’, quoting our previous post, “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.”
Let’s say the word we might use to address our unmet hopes about antidepressants is–well, why not “disappointing,” the word the NIMH, who ran the STAR*D depression study, with $35 million dollars in government funding, used. They studied patients treated in all sorts of settings–including psychopharmacological–and in the end what did they have to say? ” “The proportion that responded or remitted and stayed well for a year was estimated to be a disappointing 15%.”
Well, for those who’ve dealt with the new class of antipsychotics–known as “atypicals”– and had things turn out not just their way? “Disappointment” is just the beginning.
First Generation Antipsychotics
“[I]n the 1950s . . .a French surgeon recognized chlorpromazine’s potential in psychiatry. . .Since then, most new psychiatric drugs have been subtle variations on these and a handful of other original molecules. Derisively termed ‘me too’ drugs, these subtle iterations only rarely make a difference to patients. . . .”
Chlorpromazine (who’s Thorazine when he’s at home) was a drug that would radically change the world. Its discovery was serendipitous. Utilizing chlorpromazine (CPZ) as an adjunct to anesthetics, French army surgeon Henry Laborit and his collaborators found that CPZ “produced disinterest without loss of consciousness and with only a slight tendency to sleep,” according to Ban in 2007’s “Fifty years chlorpromazine: a historical perspective.” Laborit, with much insight, tried the drug on one of his manic patients, whose improvement was so dramatic that he [by whom I mean the patient] was discharged within three weeks of first receiving the medication (Lopez-Munoz et al 2005). The drug went into clinical trials with psychotic patients in France, and when the results were published in 1952, they were quite dramatic, and French psychiatrists were sold.
American psychiatrists were a little slower to come ’round, but eventually they became aware of the trials; at that point a company called Smith Kline & French (known today as GlaxoSmithKline) quickly moved to license the drug in 1953. Within a few years, U.S. doctors were using it to treat schizophrenia, mania, and other psychotic disorders. Although it’s hard for me to restrain myself from discussing the great tale before me, I won’t tell you here how Thorazine changed the face of American institutionalization. I ask you to trust me–it did.
Thorazine–and the many “first-generation” (FGA) or “typical” [in contrast to the “second-generation” (SGA) or “atypical”] antipsychotics modeled after it (think Compazine, Haldol, Stelazine, Mellaril, etc.)–work by blocking dopamine receptors in the brain. Simple explanation: the dopamine that is released has fewer places to go and thus has a reduced impact. Science has long operated on the theory that schizophrenia–and bipolar disorder as well–is correlated with excess dopamine in the brain.
These new drugs were extremely important inventions, returning real lives to people who had formerly been institutionalized and treated with insulin shock therapy, lobotomies–repeated ECTs. They were truly wonder drugs.
Unfortunately. . . there is a major problem with first generation antipsychotics: Extrapyramidal Side Effects (EPS). There are 4 main types of EPS, and not one of them is pretty:
- Parkinsonian Symptoms. This includes a slowness in movement, plus a stiffness and rigidity in the neck and limbs. (These symptoms for the most part do, fortunately, remit upon cessation of treatment.)
- Dystonia. Dystonia usually manifests with involuntary movement, prolonged muscle contractions, and often difficulty in swallowing.
- Akathisia comes third in my list, but, having had it myself, I assure you it takes no backseat in terms of degree of suffering. It involves an internal sense of restlessness along with mental unease, and general unrest. It’s not uncommon to see patients pacing the hallways, or swinging their legs. But after akathisia it gets really really ugly when we get to . . .
- Tardive Dyskinesia. . . .
MedicalNewsToday clarifies that dyskinesias are “involuntary, often hyperkinetic movements of various types that have no purpose and are not fully controllable by the patient. Some are random, some rhythmic, most are very odd looking and socially stigmatizing.” Tardive dyskinesia (TD) is the later–and more permanent–onset of some of those earlier EPS movement side effects. The following are just possibilities of what you can experience with TD:
- Involuntary movements of the tongue or mouth
- Jerky, purposeless movements of legs, arms, or entire body
- Facial grimacing
- Eyes pull to one side
- Tongue moves in mouth
- Tongue protrudes out of mouth
- Head pulls to one side
After reading all that, and imaging a life spent with your body jerking and thrusting, your tongue protruding, and your eyes rolling to one side, you see why a new med, one that treat mania and psychosis, but does not cause EPS or TD, would be welcomed with open arms–and would be worth paying for. A lot. A whole lot.
Enter the second generation antipsychotics.
Second Generation Antipsychotics
“[T]he time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”
Peter Tyrer & Tim Kendall, www.thelancet.com, January 3, 2009
Meanwhile, back at the ranch, Sandoz , having developed a new drug in the 60s–truly new–was busy sitting through clinical trials in the 70s.
In fact, the drug, clozapine had actually been around for decades. Interestingly, it had first been used to treat depression. That didn’t turn out all that well, but the psychotic depressed patients had a seen a significant improvement. It would have been smooth sailing to FDA-approval for the drug, but clozapine, probably one of the most effective antipsychotics, typical or not, and without the most frightening side effects of the first-generation antipsychotics, can cause something called agranulocytosis. This serious–and I mean serious –side effect means it can cause the bone marrow to fail to make enough white blood cells. In 1975, after some subjects died from the agranulocytosis, Sandoz voluntarily withdrew its drug. And that, it seemed, was that.
But. . .here’s why it pays to be better than the competition. The clozapine’s potential to treat schizophrenia–even the hardest-to-treat cases–with a minimal risk of EPS when compared to the other drugs, led the FDA and Sandoz to run the U.S. Clozaril (clozapine’s grown-up name) study. Clozaril was so clearly superior to Thorazine in a 6-week trial on treatment-resistant schizophrenics that the study led to clozapine’s approval in 1990–with obligatory weekly monitoring of white blood cell counts.
An effective antipsychotic that did not cause EPS–who had heard of such a thing? It was completely, well, atypical. And thus Clozaril became the first of the atypical antipsychotics, the first of a number of drugs that would come to copy its secrets–and charge a serious amount of money for the favor.
Like the older drugs, Clozaril targets dopamine receptors–but it targets fewer of them than the older generation antipsychotics. Since dopamine receptors are the ones that control body movements, if they’re blocked, tremors–like those from Parkinson’s disease–can occur. But Clozaril focuses less on the dopamine receptors (although all antipsychotic drugs target these to some extent)–and thus EPS doesn’t occur. Additionally, in a new means of treatment, the drug interacts more with other receptors, particularly serotonin. Clozaril apparently acts as an antagonist to serotonin receptors–which just means it blocks them (it doesn’t really antagonize them in the way my younger brother could go for me when we were little). The theory still goes that we need to block a certain number of dopamine receptors in order to decrease what are called the “positive” (which is really stretching the connotation of the word) symptoms of schizophrenia (i.e. hallucinations, delusions, disorganized thinking)–but as long as that task is accomplished, the drug can get a lot more done working with other neurotransmitters.
Other companies–observing the success of a drug that worked on dopamine but did not cause EPS and knowing that this drug was handicapped by its impact on the white blood cells–knew they ought to get a foot in this entryway fast. All that was needed was a drug modeled on clozapine–that didn’t cause blood trouble.
Johnson and Johnson’s Janssen Pharmaceutica division was the second horse out of the gate with Risperdal (risperidone), approved by the FDA in 1993. By 1996 there were over 1 million prescriptions written for the drug. That same year, Eli Lilly got out its own atypical, Zyprexa–a phenomenal success. In fact Lilly thought it might have ‘the next Prozac‘ as the Zyprexa became of one Lilly’s most profitable drugs, doubling sales from 2002-2003 to $8 billion.
Lots of people joined the party. It wasn’t just mental health treaters who went nuts over the new drugs–it was health practitioners from all fields. This is a staggering statistic, but in 2011, Abilify and Seroquel, two of the drugs from this new class, were the–take a breath for this–fifth and sixth best-selling prescription drugs in the entire U.S. Atypical antipsychotics alone were prescribed to 3.1 million Americans that year, to the tune of (second breath) $18.2 billion as reported by the September 12, 2012, New York Times.
Look–that’s a great ride, but, really, once Clozaril broke new ground. . .well, what was so new to be had that was worth billions of dollars?
At a certain point, people–people who mattered, I mean, not people like me–started to ask questions about these –very expensive–atypical “miracle drugs.” Questions like–did they really work any better than the old, FGAs? Did the side effects that these, the SGAs, inevitably had–were they better or worse than those from the typical antipsychotics? (It’s true–it can’t be taken away, that they don’t usually have EPS or TD, but we’re looking at weight gain, and diabetes, and hyperlipidemia, and myocarditis–all to go into on a different day–but none very pleasant.)
In short, was anyone getting better, were they suffering less? All the while (this was no question)–the price tag was staggering.
New studies question whether the second generation atypicals really do their job. While it’s true that the atypicals may block an extra neurotransmitter receptor-or even two–fundamentally an antipsychotic, in order to work, blocks dopamine receptors–and that’s what all antipsychotics, typical or atypical, do.
In fact, writes Dr. Leslie Citrome, MD, MPH, Clinical Professor of Psychiatry & Behavioral Sciences at New York Medical College in “Understanding the Efficacy of Modern Antipsychotics,” (8/25/11):
“Despite the apparent dichotomy of SGAs and FGAs, there is extensive heterogeneity among FGAs and SGAs and overlaps between them in terms of their effects.”
Her message is dittoed by Dr. Steven E. Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute and author of “Psychiatric Drug Development: Diagnosing a Crisis,” written just this past April 12,
“Antipsychotic drugs act on several different neurotransmitter receptors in the brain, but the critical shared mechanism of all current antipsychotic drugs is blockade dopamine D2 receptors, the same mechanism of the prototype antipsychotic drug chlorpromazine, discovered in 1950..
Sometimes, you can’t win for losing.
Although the story is a little longer (let me be honest–a lot longer; I’m taking pity on you and giving the shortest version I can manage), we’re going to close here with a few quotes and of course some incisive comments by me.
Sadly, the atypicals were not only not novel in their mechanisms but didn’t hold up in terms of efficacy–and had their own nasty side effects to boot. This is before you even talk about money.
Well before the $18.2 billion was spent on antipsychotics in 2012, researchers had sensed there was trouble.
Take, for example, a December 2000 article published in the esteemed British Medical Journal, John Geddes first author, entitled–innocently enough–“Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis.” After looking at over 2,649 patients in 52 randomized trials comparing the atypicals with the typicals, the authors concluded, “there is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics. Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects (EPS).”
Out there, for all to read in the online version of the Lancet, on January 3, 2009, Peter Tyrer of the Department of Psychological Medicine, Imperial College of London, and Tim Kindall from the National Collaborating Centre for Mental Health, Royal College of Psychiatrists’ Research Unit, wrote:
“[The SGAs] as a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective.”
What I’m hearing–and I’ve been trying hard to listen–is that the new antidepressants aren’t new and aren’t necessarily better–and it’s the same for the new antipsychotics.