Psychopharmacologic Discovery: The Relative Contributions of Clinical and Laboratory Studies
Brandon P. Reines, D.V.M.
Discovery of the modern antipsychotic and antidepressant drugs did not, s many believe, begin with laboratory investigations; it evolved throughout ~ 19th century, as organic chemists observed the effects of synthesized ii bcm compounds on the human central nervous system (CNS). Mcllwain las written, "Last century's application of synthetic organic chemicals in medicine can be viewed as an experiment, lasting several generations and contemporaneous with the development of organic syntheses themselves, in which animals and men were exposed to all the main categories of the newly produced chemicals...The main groups of synthetic drugs in fact all acted on the brain [i.e., affected awareness]."1
The discoverers of modern psychopharmacology were clinical investigators who noted mood-altering side-effects of drugs used in clinical practice. Drugs administered for therapeutic purposes often induce unforeseen alterations in human physiology and/or cognition. Physicians who note these alterations are in an ideal position to identify and explain clinical anomalies caused by pharmacological intervention. Many of pharmacology's "lead" compounds, including the psychiatric medications, were discovered in the clinical context.
The discovery of chlorpromazine's antipsychotic action evolved during the 1930s, 1940s, and 1950s, based on the mood-altering side-effects of its predecessors, the antihistamines. In the late 1930s, such dicyclic antihistamines as phenbenzamine, diphenhydramine, and mepyramine were in wide clinical use. The antihistamines' most striking clinical side-effect was CNS depression -- drowsiness.2 In the late 1930s, P. Charpentier had synthesized the first tricyclic antihistamine, promethazine, which had a strong sedative effect. She then synthesized a variety of promethazine analogues, including chiorpromazine. In the early 1950s, the French surgeon H. Laborit, aware of the antihistamines' central-depressant effects, undertook a search for an antihistamine to use as a preanesthetic sedative. Charpentier sent chlorpromazine to Laborit to test as a preanesthetic sedative based on the antihistamines' known CNS depressant effects and the results of animal tests, in particular the mouse pole-climbing test.
When Laborit first administered chiorpromazine to his surgical patients, he was stunned by its effect on the human CNS. The patients seemed to become totally indifferent to their surroundings, experiencing what Laborit called "euphoric quietude."2 As a result, Laborit persuaded his psychiatric colleagues to test chiorpromazine on psychotic patients. Chlorpromazine developed into the first major antipsychotic because clinical application of the drug as a presurgical sedative caused physicians to notice its mood-altering side-effects.
In a recent A.M.A.-sponsored book, F.D. Campion claims that chlorpromazine was discovered by experiments on rodents.3 Campion has written:
In the early 1950's researchers in France who were testing a phenothiazine compound . . . observed some remarkable behavior in the mice they were using. These had been psychologically conditioned, much in the manner of Pavlov's dog, to climb a pole in their cage in response to the sound of a buzzer. The conditioning had been done by sending a sharp jolt of electricity through the floor of their cage at the moment the buzzer sounded.
Having been conditioned, the mice then received doses of phenothiazine. Now when subjected to the electrical charge, the mice would still scamper up the pole. But no longer would they do so merely in response to the buzzer. It was apparent that the phenothiazine acted selectively: it could depress the nervous system of the mice sufficiently to quiet the conditioned reflexes while leaving the psychomotor reactions unimpaired.
On the strength of this finding, the drug was tried on an institutionalized psychotic with such astounding results that he was discharged three weeks later.
The claim is misleading on a number of counts. First, phenothiazines were not tested on animals for behavioral effects until Laborit had identified the clinical phenomenon of phenothiazine-induced ataraxia. Campion misrepresents the discovery of chlorpromazine's antipsychotic properties as an "accidental" laboratory discovery. Reines4 argues that provivisection propagandists, in order to secure priority of discovery for laboratory studies, often misrepresent the process of medical discovery as a fortuitous consequence of accidental laboratory findings. In fact, the theory that chlorpromazine would prove an effective antipsychotic was deduced from Laborit's clinical observations -- not animal experiments. Second, most of the early animal behavior experiments failed to reproduce the calming effect Laborit had seen in his patients.5 Third, the selection of chlorpromazine was based on results of an animal test researchers considered useful in identifying a superior preanesthesthtic sedative, not an effective antipsychotic. Finally, the pole-climbing test was uninterpretable. Apart from the difficulty of extrapolating from one species to another, the test results did not necessarily reflect sedation. The drug's on the mice might have been, instead, balance impairment, loss of muscular tone, apathy induction, or some other physiological or psychological alteration. It was Laborit who recognized chiorpromazine's potential as an antipsychotic. At most, the pole-climbing experiment dramatized Laborit's clinical hypothesis that phenothiazines have profound effects on the human CNS.
Tricyclic Antidepressants, Benzodiazepines, and Dibenzodiazepines
While lithium and the monoamine oxidase inhibitors were discovered serendipidously, many other psychotropic drugs, including the tricyclic antidepressants, benzodiazepines, dibenzodiazepines, and other neuroleptics evolved out of the work on chlorpromazine. The structures of these psychotropics were "deduced" from chlorpromazine's structure. (Fig. 1-3)
The phenothiazines, tricyclic antidepressants, and dibenzodiazepines are all tricyclics. Along with the benzodiazepines, they are all congeners of chlorpromazine. In fact, the scientists who synthesized the tricyclic anti-depressants and the benzodiazepines have acknowledged being inspired by chlorpromazine's structure.6
Indeed, the tricyclic antidepressants were originally developed as antipsychotics. During clinical trials, however, R. Kuhn found that their primary effect was CNS stimulation rather than depression. That observation led Kuhn to test the tricyclic imipramine as an antidepressant.7 Sulser and Mishra have written:
It was the discovery by Delay and Deniker [following Laborit's work] in France of the unusual therapeutic value of chlorpromazine in the treatment of psychosis that revived clinical research interests in the structurally related iminodibenzyl compounds [tricyclic antidepressants]. The similarities in pharmacological properties of chlorpromazine and some of the iminodibenzyl derivates prompted Roland Kuhn, at the Psychiatric Clinic in Munsterlingen, Switzerland, to test some of these new compounds synthesized by the Geigy chemists as potential antipsychotic agents in patients with various psychiatric disorders, including endogenous depression. .. . Further clinical studies with another compound of this series that was structurally more similar to chlorpromazine . . . now known to be imipramine . . . resulted in the unexpected discovery of the therapeutic value of imipramine in the treatment of endogenous depression.8
Kuhn did not perform animal behavior studies to convince his colleagues of imipramine's potential efficacy in combatting endogenous depression. He was able to convince other psychiatrists based on clinical data alone.
Dr. E. Stembach's synthesis of the first benzodiazepines was also inspired by chiorpromazine's tricycic structure, on which he patterned the dicyclic structure of chiordiazepoxide (Librium) and diazepam (Valium).6 The compounds were tested for efficacy on animals rendered artificially aggressive by experimental manipulations. According to W. Haefly, the compounds' "taming effect," particularly in "vicious cynomolgus monkeys," especially impressed pharmacologists.9 The relationship between experimental aggression and human anxiety, however, is not at all clear. Although animal experiments were often used to dramatize the clinical potential of chlorpromazine's various analogues, dramatic impact should not be equated with scientific content. It was Laborit's, Kuhn's, and Stembach's clinical hypotheses that ushered in the era of modern antipsychotic, antidepressant, and anxiolytic chemotherapy.
Monoamine Oxidase (MAO) Inhibitors
MAO inhibitors' antidepressant effect, like that of the dicyclic and tricyclic compounds, was discovered in humans. N.S. Kline, who was intimately involved with the discovery, recalls iproniazid's side-effect of "euphoria" in tuberculosis patients.
Iproniazid had been introduced some years earlier as an experimental treatment for tuberculosis.. . . As a side effect, however, there developed an odd problem. The patients felt too good. They overexerted themselves and generally ignored the medical safeguards their condition required. Iproniazid's potential as a mood drug had gone largely unnoticed because psychiatrists at the time just weren't thinking along those lines. As the climate changed, however, a few researchers began to investigate it in a tentative way.10
Kline had good reason to expect iproniazid to have mood-elevating properties. Prior to clinical studies on depressed patients, he had reviewed the literature and found that, for unclear reasons, iproniazid had been clinically tested as a tranquilizer (i.e., CNS depressant). Not surprisingly, iproniazid had failed as a tranquilizer. Kline had ample clinical evidence to justify a clinical trial of iproniazid as an antidepressant, but he first used animal results in an intriguing way to convince his colleagues.
In early 1956, pharmacologists had used iproniazid on reserpine-treated animals in order to prevent reserpine's calming effects. This research was inspired by the knowledge that iproniazid elevated the mood of human tuberculosis patients. The animals did become hyperactive upon iproniazid administration; the results, however, were ambiguous. Lehman and Kline have reported that they were uncertain as to what was causing the "antidepressant" effect: "We were not sure at first whether the animal results were due primarily to iproniazid (Marsilid) or to the Marsilid-reserpine combination and so we tried both approaches. In due course, we found that Marsilid alone could achieve the desired psychic energizing effect [in animals], and thereafter we concentrated the research on the use of the single drug."10 This expressed uncertainty is odd, given that Kline was well aware -- long before 1956 animal tests -- that reserpine is a human tranquilizer, not a mood-elevating substance. In fact, he had already helped introduce reserpine into clinical use as a tranquilizer. Apparently, Kline was also aware of iproniazid's mood-elevating effects in humans. The available clinical data, therefore, were sufficient to lead Kline and his co-workers to theorize that iproniazid would be an effective antidepressant in patients. Evidently, the animal studies were performed to convince members of the hospital staff that the clinical data on iproniazid's effects were accurate. In any case, Kline's contention that the animal experiments showed that "Marsilid alone could achieve the desired psychic energizing effect" is simply false. Iproniazid's "psychic energizing effect" could not be evaluated with animal experiments because subtle psychic phenomena can only be studied in humans.
In a recent paean to animal behavior studies, Pincus et al. maintained, "It is essential to recognize the vital importance of research use of animals to progress in psychiatric practice and knowledge. . . . Lithium, a drug whose clinical potential was first suggested by animal experiments, has dramatically benefitted hundreds of thousands of manic-depressive patients."11 Similarly, in Newsday, F. Goodwin of ADAMHA claimed that experiments on guinea pigs led to discovery of lithium's antimanic action.12 Goodwin did not discuss the origin of the main antipsychotics and antidepressants, presumably because psychopharmacologists know that these were discovered in the clinical setting and that the lead compounds would not have been detected by the common animal behavior tests.13 In contrast, few psychopharmacologists know how lithium's antimanic effects were discovered. The drug's "clinical potential" was not "first suggested by animal experiments."
Discovery of lithium's antimanic properties is generally attributed to laboratory studies. In 1949, Australian physician John Cade injected guinea pigs with lithium ion. Rapidly, the guinea pigs became unresponsive to stimuli. Generations of historians have assumed that Cade's guinea pigs were rendered inactive by lithium's calming effect. Kline,14 however, has argued that the guinea pigs were likely poisoned by the lithium. The fact that there are such varied interpretations testifies to the impossibility of studying subtle psychic phenomena in nonhuman animals.
Reines4 argues that Cade's interpretation of his guinea pig results were biased by his knowledge of 19th century clinical literature indicating lithium's mood-altering properties.13 Lithium caused depression among patients who were being treated for various conditions, such as gout.15 In fact, the drug was used to treat various mood disorders, such as depression and "gouty mania," in the 1880s and 1890s.16,17 Cade even reviewed lithium's CNSdepressant side-effects in the introduction to his classic paper.18 Nevertheless, many modem pharmacologists either are unaware of or choose to ignore the older clinical literature. Discovery of lithium's antimanic action fits the historical pattern: Lithium's mood-altering side-effects were first identified in humans.
Is the recent discovery of the antidepressant bupropion an exception to the rule of clinical discovery? Bupropion, structurally unrelated to other antidepressants and antipsychotics, has been touted by some investigators as a triumph of animal modelling.19 However, the drug's initial chemical structure was based, in part, on the structure of drugs that tend to confer sympathomimetic properties.20 Sympathomimetics, such as amphetamine, are well-known CNS stimulants. Indeed, there is evidence that bupropion's development was inspired by the structure of amphetamine,21,22 which had been used, with limited success, as an antidepressant in the 193Os.23,24
In order to ensure that the FDA would permit clinical trials, however, bupropion's manufacturers tested it for efficacy on a series of animal models of depression. Interestingly, the widely used tetrabenazine suppression test was not encouraging. (Tetrabenazine is a reserpine analogue.) Bupropion had a relatively low potency compared to other antidepressants. Also, unlike most antidepressants, bupropion, at peak effect, conferred less than 50% antagonism of tetrabenazine.25 Bupropion passed the L-dopa potentiation test, but Cooper et al. acknowledge that this test "has been shown to produce a relatively large number of false positive responses."25 Finally, bupropion was encouraging in the "behavioral despair model" that tests a drug's ability to relieve immobilization of rats drowning in a water-filled beaker. This model is based on Seligman's "learned helplessness" model of human depression. It is, however, impossible to determine why bupropion-treated rats swim longer. Perhaps they are less depressed. Perhaps they are relieved of a "panic attack" type syndrome. Perhaps they are affected physiologically, for example, by muscle excitation or increased respiratory drive.
Even though animal modelers attribute bupropion's discovery to the animal models of depression, this is not valid for two reasons. First, the animal models are of doubtful relevance to human depression. Second, the animal tests did not indicate strongly that bupropion would prove an effective antidepressant. The bupropion story is typical: A clinical hypothesis (i.e., amphetamine's known mood-altering effect) prompted the animal modelers' work. In conclusion, animal experiments cannot reliably predict human reactions, just as they cannot confirm or disprove human-derived data. Medical researchers, however, continue to point to laboratory results when those results appear to support their hypotheses.
Critique of Current System of Psychoactive Drug Development
Currently, psychoactive drug development consists largely of screening analogues of known antidepressant or antipsychotic compounds with animal models or with in vitro receptor binding assays. While the value of receptor binding assays is now undergoing evaluation, the track record of animal models in psychopharmacologic drug screening is notoriously poor. S. Gershon notes that the results of psychopharmacologic efficacy experiments on animals have not significantly correlated with efficacy in patients.25 Sitaram and Gershon have concluded:
Two major points emerge from our readings; the surprisingly poor track record of most if not all animal models to date (a) in accurately predicting clinically effective antidepressants and (b) in generating new and conceptually liberating hypotheses of the pathophysiology of depression. These observations are highlighted by the fact that almost every significant advance in antidepressant drug treatment from the discovery of iproniazid and imipramine to the recently introduced "second generation" class of antidepressants has resulted either from astute clinical observations or serendipity; a far cry from a planned, predictive, screening test. In fact many second generation antidepressants such as iprindol, mianserin, trazodone and salbutamol should be classified as "false negatives" on the conventional drug screening models (i.e., ineffective during preclinical screening but clinically efficacious). Conversely, a series of compounds, predicted to be at least as effective as imipramine, were reported to be clinically ineffective (i.e., false positives).26
Given the low preclinical-clinical correlation, animal behavior tests appear to be a poor method for screening congeners of parent psychoactive compounds. Gershon notes that the second and third generation antidepressants are not clearly more effective than the parent compounds originally detected in human studies in the 1950s and 1960s. Gershon and co-authors comment, "One wonders about those compounds that might have been clinically useful but could not make it through these conventional tests. Whether the 'censorship' practiced by these animal models prevented us from developing novel antidepressants remains an unanswered question."27
In defiance of their own observations, Sitaram and Gershon go on to express confidence that improved animal models will show greater utility.26 Animal models are unlikely to lead to the development of novel drugs for treating depression, schizophrenia, bipolar disorders, and other psychological disorders. It is impossible to determine the extent to which artificially induced psychological "disorders" in nonhuman animals resemble the psychiatric syndromes of human patients. Green and Costain have noted fundamental problems with the animal models: "We do not believe there is any totally satisfactory animal model of psychiatric disorder. Drugs cannot therefore be given to a 'pathological' brain to make it normal but rather to a 'normal' brain, thereby perhaps changing it to an 'abnormal' state. Changes that occur may thus be of a reflection of brain neurotransmitter systems attempting to minimize the changes being produced by the drug."28 Animal models of human psychological disorders are inherently flawed -- at best, inaccurate; at worst, completely invalid.
The anomalous CNS side-effects of marketed drugs have inspired past psychopharmaceutical discoveries. Davis, reviewing the historical record, recognizes the importance of the clinical setting as a source of psychoactive drug discovery:
Many of the psychotropic drugs were discovered by chance when they were administered for one indication and observed to be helpful for an entirely different condition. The history of the development of both the antidepressants and the antipsychotic drugs points up the fact that major scientific discoveries can evolve as a consequence of clinical investigation, rather than eductions from basic animal research.29
Postmarketing Surveillance and Psychoactive Drug Discovery
Clinical pharmacologist L. Lasagna of Tuft University has written, "I agree that most of the prototype drugs in psychopharmacology were discovered by smart clinicians who saw things happen in humans that were not expected (chiorpromazine, imipramine, LSD, benzodiazepines)."15 Given that the process of drug discovery for mental illness relies on identifying mood-altering side-effects, new classes of psychoactive compounds are unlikely to be discovered outside the clinical setting. The implications for research strategy are unambiguous: It is essential to systematically monitor marketed drugs' side-effects on the human CNS. In the U.S., postmarketing surveillance (PMS) is still in a rudimentary stage.
The potential of PMS as a means of drug discovery has not gone unrecognized. In 1980, in the Final Report of the Joint Commission on Prescription Drug Use, Melmon wrote:
Another objective of PMS is to discover beneficial drug effects (anticipated or unanticipated) after a drug has been marketed. Although it is not possible to systematize serendipitous discoveries, it is desirable to approach the discovery of new indications for drugs more systematically. For example, careful follow-up of published reports of new effects of marketed drugs ... or the monitoring of trends in medical events (e.g., cardiovascular deaths) in our population may provide useful clues about unanticipated beneficial effects of drugs. This objective is by no means a trivial one, as many additional beneficial effects of drugs have been discovered after the drugs have been approved for marketing. Such discovery is not only beneficial for populations having a disease treatable by the new use of an approved drug, but also represents an improvement in safety and economy in drug development, since many new uses may reduce the cost of development and simultaneously prevent unnecessary exposure of subjects to potentially toxic and/or ineffective experimental drugs.30
Mcllwain contends that most drugs affect the human CNS in some way.1 Consequently, the potential of PMS to uncover novel psychiatric medications appears to be bright. Indeed, the clinic continues to produce promising psychoactive drugs. In 1990, Greenberg noted that a schizophrenic patient responded dramatically to famotidine, a histamine H2 receptor antagonist that the patient was receiving as treatment for peptic ulcer disease.31
Robinson and Kurtz, too, have noted the potential of PMS to uncover drugs with which to treat brain disorders:
Perhaps a look into the past can give a glimpse of the future. In this regard, the potential of serendipity cannot be overlooked when evaluating treatment strategies. Throughout the history of medicine, there are examples of significant advances coming about as a result of careful clinical monitoring of a drug that was supposed to do something else but had an effect in an unpredicted direction. Iproniazid [which caused euphoria] in tuberculosis patients leading to the new class of [antidepressant] monoamine oxidase inhibitors is an outstanding example, as are the tricyclic antidepressants originally developed as antipsychotics.32
In conclusion, post-marketing surveillance is potentially the most efficient and reliable strategy for discovering new psychopharmaceutical agents.
Acknowledgement: I would like to thank the Ahimsa Foundation, whose support made this project possible.
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