Special Issue: Psychopharmacology And Psychosomatic Research
History of Modern Psychopharmacology: A Personal View With an Emphasis on Antidepressants
Domino, Edward F. MD
From the Professor, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan.
Received for publication June 2, 1998;
revision received January 27, 1999.
Address reprint requests to: E. F. Domino, MD, Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109-0632.
Objective: This article provides the chemical basis for the molecular modification of H1 antihistamines in the rational development of some antidepressant and antipsychotic drugs.
Methods: A review of the literature and personal experiences have been compiled.
Conclusions: The contributions of many basic scientists, the crucial observations of clinicians, and the desire of the drug industry to make money have resulted in the currently available psychopharmacological treatments. The future development of psychopharmacology depends on better clinical research to generate new hypotheses of the chemical and behavioral pathology of mental disease. Psychosomatic medicine can make a unique contribution in its interdisciplinary role of stressing brain, body, and mind relationships.
DMT = dimethyltryptamine, 5-MEODMT =5-methoxydimethyltryptamine, MAO = monoamine oxidase, SAR =structure activity relationship, SSRI = selective serotoninreuptake inhibitors.,
MENTAL DEPRESSION IS A MAJOR HEALTH PROBLEM
As we approach the end of the present millennium, it is appropriate to reexamine many human issues including health and disease. In the past 50 years, we have made considerable progress in psychopharmacology as an important basic science and clinical treatment modality of several major mental disorders (1). The present review focuses on mental depression and a personal view of how several important classes of antidepressant and antipsychotic drugs were developed in the past 50 years. As their pharmacological mechanisms of action were discovered, new theories on the biology of psychiatric disorders emerged. Perhaps no other area of psychosomatic medicine provides more evidence that the psyche has profound effects on the soma and vice versa as mental depression.
In 1996, Murray and Lopez (2) assessed human mortality and disability due to disease, injury, and associated risk factors. They documented those existing in 1990 and made projections to the year 2020. Unipolar major depression ranked fourth as a disease burden measured in disability adjusted for life years in 1990. Despite current antidepressant medications, these investigators concluded that in 2020, unipolar major depression will rank second just behind ischemic heart disease as a disease burden. Although one may disagree with their year 2020 projection, at present the risk for unipolar major depression, especially for women in developed countries, is 1 in 10. There is an abundance of evidence that mental depression is associated with increased risk for cardiovascular (3–6) and infectious disease as well as immunological and endocrine changes (3, 7–10). Furthermore, there is an increased risk for cancer (11), stress, migraine, anxiety, suicide (10, 12–14), and allergy (15).
In the 21st century, rational drug discovery surely will be based on fundamental knowledge of the chemical pathology of disease. However, when the chemical pathologic mechanisms of disease are unknown, a combination of systematic and persistent effort, the astute observations of clinicians, a chance discovery and, sometimes, the self-determination of a single person are sufficient to initiate major therapeutic advances. The history of therapeutics is replete with examples, especially in the history of psychopharmacology. Despite that the chemical pathology of psychiatric and psychosomatic diseases near the end of the 20th century is still rudimentary, many excellent medications are now available. How were these drugs found and developed? There are many articles and books available on the history of “modern” psychopharmacology (16–19). The use of psychoactive substances for religious, recreational, experimental and, more recently, psychiatric purposes spans many thousands of years (20–27).
ORIGIN OF MODERN PSYCHOPHARMACOLOGY
The scientific basis of the behavioral effects of drugs in animals began with the pharmacologist D. Macht about 1915. Macht and his associates used experimental tests such as rat performance in mazes, rope climbing for food reward, and various other conditioned reflex behaviors. Macht and Mora (28) coined the term “psychopharmacology” as “virgin soil, full of possibilities” in their study of opioid alkaloids on rat behavior in a circular maze. Each student of the history of psychopharmacology has his or her own views on how the field developed and its landmarks. Many investigators in the basic disciplines of chemistry, biochemistry, physiology, pharmacology, psychology, and toxicology, as well as clinicians dealing with patients, have discovered the remarkable therapeutic effects and the basic mechanisms of current psychoactive drugs.
An area of personal interest has been the impact of chemical structure on pharmacological actions or structure activity relationships (SAR) of psychoactive drugs related to antihistamines. When lecturing to medical students on this subject, I usually elicit a lot of hisses and boos. Hopefully, you, the reader, will not do the same. The big picture on how some psychoactive drugs were developed in the past 50 years depends on the SAR of antihistamines. One wonders why drug companies are able to get exclusive patents for certain psychoactive drugs because the general structural chemical relationships between compounds that affect biogenic amines are well known. We need to go back to D. Bovet and his colleagues in the development of antihistamines in the 1930s and 1940s. Bovet (29) received the Nobel Prize for physiology and medicine in 1957 for his work on synthetic curare-like drugs and aryloxyethylamines as antihistamines. Thousands of antihistamines were studied by many investigators so that by the early 1950s the basic SAR were well established. I was taught in medical school that if you want to make an antihistamine, start with the skeletal chemical structure (30) to the left below. FIGURE 1
The core is a substituted ethylamine present in histamine. An ethylamine group is also present in acetylcholine, catecholethylamines, and indolethylamines, suggesting that antihistamines affect other biogenic amines besides histamine. Substitute in the R1 and R2 positions methyl or other short alkyl groups; the X can be a carbon, oxygen, or nitrogen. Then add aryl R3 and R4 groups and you have an antihistamine. Diphenhydramine has structural relationships that meet the rules for a classic antihistaminic as shown above. We know that diphenhydramine is a predominant H1 antihistamine. With the ethylamine core, it also has atropine-like effects to block the muscarinic effects of acetylcholine (mAChR antagonist) and is a serotonin reuptake inhibitor. The former actions are well known. The latter may surprise you, but that is a tale later in the history of the development of selective serotonin reuptake inhibitors (SSRI).
Antipsychotic or Neuroleptic Drugs Derived From H1 Antihistamines
Shortly after World War II, P. Charpentier and his colleagues at Rhône Poulenc in France synthesized and tested a series of phenothiazine amines, which pharmacologists, D. Bovet, B. Halpern, and R. Ducrot, found have significant and long-lasting antihistaminic properties. One of the most potent was promethazine. Because promethazine had significant central nervous system side effects in man, these actions were explored in various pharmacological assays, including Macht’s rat rope climbing test. The latter was an important preclinical animal test for the study of the central nervous system action of many antihistamines both at Rhône Poulenc and at Merck in the U.S. by Winter and Flataker (31). The therapeutic and marketing success of promethazine prompted the synthesis of many substituted phenothiazines for their possible central nervous system effects. The structure of promethazine fits the classic structure of an antihistamine. Instead of an isopropyl group, what if there was a straight carbon chain propyl group between the two nitrogens? You now have promazine. FIGURE 2
It is well known that adding a halogen to an organic molecule usually increases its potency and toxicity. Therefore, if you wish to make a more potent promazine, add a halogen such as chlorine or one or more fluorines. If you add a chlorine, you make chlorpromazine (4560RP). The basic pharmacology of chlorpromazine was first studied by S. Courvoisier and her colleagues at Rhône Poulenc. By mid-March 1951, just 3 months after it was synthesized, Courvoisier’s group showed that chlorpromazine had an amazingly large spectrum of unique pharmacological actions (32). It was an alpha-adrenergic blocking agent that produced “epinephrine reversal.” It had significant cardiovascular effects. It potentiated the actions of barbiturates. It was an antiemetic and blocked rat conditioned rope climbing. It still had a little antihistamine- and a little atropine-like actions.
In the United States in the early 1950s, Smith, Kline and French developed a coronary vasodilator, that unfortunately, caused significant nausea and vomiting. The company was looking for an antiemetic that would reduce the nausea and vomiting produced by its coronary vasodilator and thus, learned about 4560RP. Subsequently, Smith, Kline and French negotiated an agreement with Rhône Poulenc to study 4560RP in the U.S. and gave it the code name SKF 2601. At the time, I was a young student. K. Unna, my mentor at the University of Illinois in Chicago, was a consultant to Smith, Kline and French. He obtained SKF 2601 for animal pharmacological testing and asked me to study it in dogs. We found that, although SKF 2601 prevented apomorphine-induced vomiting, the animals were sedated and had significant hypotension. We concluded that SKF 2601 was an antiemetic with many side effects. We did not feel it was worthy of additional scientific pursuit. I was soon to learn a big lesson!
When H. Laborit contacted Rhône Poulenc in 1951 for a better compound than promethazine to include in his “lytic cocktail” to induce artificial hibernation for surgical anesthesia (33, 34), chlorpromazine was the logical choice. A year later, Laborit et al. (35) suggested that chlorpromazine alone be used in psychiatry to potentiate barbiturate sleep therapy, among other possible uses. By early 1952, Delay and Deniker (36) and Deniker (37) used chlorpromazine alone in psychiatric patients; the therapeutic effects were spectacular! When I learned that chlorpromazine (SKF 2601) was an antipsychotic in schizophrenic patients, I was amazed and thanked my lucky stars that we did not publish our “dumb” conclusions. The lesson I learned was to test the compound in humans with the correct disease before writing it off as therapeutically useless. By molecular manipulation of the chemical structure of the antihistamine, promethazine, the first antipsychotic was discovered! It took a drug company, medicinal chemists, basic pharmacologists, an ardent promoter, clinical psychiatrists, and patients with the appropriate illness for a major new therapeutic advance. The stage was now set for “me too” and also much better antipsychotic drugs (38). By replacing the chlorine group of chlorpromazine with a trifluoromethyl group, one obtains trifluoperazine (Stelazine, [SmithKline Beecham Consumer Healthcare, Pittsburgh, PA]). Add a terminal ethyl alcohol group to trifluoperazine and you have fluphenazine. FIGURE 3
Make a decanoate or enanthate ester of fluphenazine, and you have long-acting depot fluphenazine decanoate or enanthate. Instead of the phenothiazine heterocyclic ring, substitute a thioxanthine heterocyclic ring. With the rest of the “tail amines” of the substituted phenothiazines, one can make a whole new series of substituted thioxanthenes such as thiothixene. Better yet, use other heterocyclics and end up with clozapine or one of the newer “atypical” antipsychotics chemically and pharmacologically similar to clozapine such as the thienobenzodiazepine-derivative, olanzapine (Zyprexa®). FIGURE 4
Another early major development in antipsychotic drugs was haloperidol. Its beginnings were in a small Belgian company that P. Janssen inherited from his parents. About 1953, Janssen decided that the company could only survive if it had exclusive patented drugs. They decided early to first work with anticholinergic derivatives (39). His success in all aspects of pharmaceutical development is truly remarkable (40). In 1957, one of Janssen’s lead chemicals, a butyrophenone derivative of normeperidine, had a mixture of narcotic and neuroleptic effects in animals. Subsequent molecular modifications led to the development of the potent antipsychotic, haloperidol, and the potent mu opioid analgesic, fentanyl. FIGURE 5
When haloperidol was tested clinically in Belgium and surrounding countries in Europe, it was found to be an effective antipsychotic. Janssen offered the U.S. rights to market haloperidol to Searle. The clinical pharmacologists at Searle gave large doses of haloperidol to human volunteers. These volunteers promptly developed an alarming incidence of extrapyramidal symptoms. Because of these marked side effects, Searle rejected haloperidol, but later McNeil Laboratories decided to market it in the U.S. In Europe, psychiatrists allowed nurses to titrate their patients with haloperidol, and therefore, less severe extrapyramidal side effects were seen. Both haloperidol and fentanyl were huge clinical, therapeutic, and economic successes! Another lesson learned! Go “low and slow” with your drug-dosing schedule. Titrate your patients individually to a therapeutic effect.
The scientists at Janssen developed many more unique haloperidol and fentanyl derivatives. One early combination of the neuroleptic droperidol and analgesic fentanyl has been widely used to produce neurolept analgesia and anesthesia. The latter is a variation on Laborit’s “lytic cocktail” of meperidine, promethazine, and chlorpromazine as an anesthetic combination for surgical patients.
After “missing the boat” on chlorpromazine, I became more involved with new drugs in anesthesia. With G. Corssen, we obtained droperidol and fentanyl from Janssen via McNeil Laboratories. I initiated a series of tests in dogs with both agents individually and in combination. The results were impressive. Corssen and I were able, through McNeil’s FDA application and local human use committee approval, to use the neuroleptic droperidol and the analgesic fentanyl in surgical patients and, thus, we helped to introduced Innovar® in the U.S. as neurolept analgesia (41).
In their 1995 chapter on antipsychotic agents, Janssen and Awouters (42) summarized the wide variety of neuroleptics useful in the therapy of schizophrenia. Especially interesting is the battery of laboratory tests used to determine the relative dopaminergic, tryptaminergic, noradrenergic, histaminergic and cholinergic antagonist activity of antipsychotic drugs. The high incidence of extrapyramidal side effects with potent selective D2 dopamine receptor antagonists, such as fluphenazine and haloperidol, coupled with the clinical success of clozapine with its wide spectrum of pharmacological activity, initiated the search for a new generation of “atypical” antipsychotics with minimal extrapyramidal side effects. The reason for the inclusion of laboratory tests of tryptaminergic or serotonergic (5-HT2) receptor antagonistic activity is another story.
The discovery of LSD-25 by Hofmann at Sandoz in 1943, and his subsequent isolation of psilocybin and other naturally occurring hallucinogens (43, 44), prompted many basic scientists to study their mechanisms of action. These hallucinogens are all chemically related to serotonin (5-hydroxyindolethyl amine, 5-hydroxytryptamine, 5-HT). Tryptamine is a trace amine in the body with an unknown function; serotonin is an important neurotransmitter in the brain and gut. A prevalent theory in the 1950s to 1970s was that an excess of tryptamine-like hallucinogenic substances were either partial agonists or antagonists of serotonin. There are multiple 5-HT receptors. Substituted indoles that act on 5-HT2 receptors include tryptamine, LSD-25, dimethyltryptamine (DMT), and 5-methoxydimethyltryptamine (5-MeO DMT). The trace amine, tryptamine, present in your body and mine, in large doses in humans is hallucinogenic (45). By the 1970s, the indole hallucinogen hypothesis of schizophrenia was a debated topic, pro and con. I was part of a team of basic scientists and clinical psychiatrists at the Lafayette Clinic in Detroit and wrote a review on the evidence that the indolealkylamine theory of schizophrenia was worth pursuing (46). At that time, several unique potential antipsychotics were synthesized by Professor Protiva at Charles University in Prague, including octoclothepin and methiothepin. The Hoffmann-LaRoche Company in Basle felt methiothepin was unique in that it had both dopaminergic and tryptaminergic antagonistic actions. However, its dopaminergic antagonism was predominant and in human volunteer trials the drug produced the expected extrapyramidal side effects. Hoffmann-LaRoche decided not to market methiothepin but J. Gottlieb, Director of the Lafayette Clinic in Detroit, was still very interested in studying it in schizophrenic patients. I was assigned to study the basic pharmacology of methiothepin compared with chlorpromazine. We found that methiothepin was an excellent DMT antagonist (47) and felt it should be tested in therapy resistant schizophrenic patients. I was sent to Prague by Gottlieb to negotiate a patent agreement with representatives of the then communist government of Czechoslovakia. We wished to test methiothepin in schizophrenia patients in Detroit with FDA approval and, if successful, arrange to market it in the U.S. My total frustration with the Czech foreign trade representatives, who felt American capitalists were out to cheat them, caused that approach to grind to a very rapid halt. Many years later, the Janssen group tested potential antipsychotics with a mixture of D2 and 5-HT2 antagonist actions that led to the development of risperidone (Risperdal, [Janssen Pharmaceuticals, Inc.,]), as one of a new generation of atypical antipsychotics. Shades of methiothepin all over again!
Antidepressants Derived From H1 Antihistamines
The therapeutic and commercial success of N-aminoalkylphenothiazines such as promethazine, promazine, and chlorpromazine, initiated an enormous effort in the molecular modification of the polycyclic phenothiazine ring structure and its N-aminoalkyl side chain. Häfliger and Schinder, in 1951 US Patent 2,554,736, replaced the sulfur bridge of the phenothiazine ring of promethazine with an ethylene bridge to synthesize imipramine, a weak antihistaminic and mild anticholinergic with sedative properties in normal human volunteers. It took a clinical psychiatrist, Kuhn (48, 49) to discover that of some 500 patients with various psychiatric disorders that were treated, only those with endogenous depression with mental and motor retardation showed a remarkable improvement after about 1 to 6 weeks of daily imipramine therapy. The first clinically useful tricyclic antidepressant was discovered! It did not take long for the diamine structure of an additional N-CH2 group in imipramine to be substituted with a C=CH group in amitriptyline. Amitriptyline was another tricyclic antidepressant which soon became widely used clinically. If dimethylamines work, why not try monomethyl amine derivatives? Hence, desimipramine (Norpramin, [Hoechst Marion Roussel, Kansas City, MO], Pentofrane®) and nortriptyline (Aventyl®, Pamelor, Novartis Consumer Health Inc., Summit, NJ) became clinically useful antidepressants. They are metabolites of the parent compounds imipramine and amitriptyline. FIGURE 6
If halogen substitution strategy worked with the substituted phenothiazine antipsychotics, why not try it with tricyclic antidepressants like imipramine? This resulted in the development of clomipramine (Anafranil, [CibaGeneva, Pharmaceuticals, Inc, Summit, NJ]). The family of tricyclic antidepressants were shown to have many different pharmacological properties, but blockade of norepinephrine uptake into noradrenergic neurons seemed to be the most important and led to the then widely accepted norepinephrine hypothesis of depression. Clomipramine was unique among tricyclic antidepressants in that in vitro it blocked the uptake of serotonin into serotonergic neurons with high potency. In vivo, its demethylated metabolite, desmethylclomipramine, was an inhibitor of norepinephrine reuptake.
Selective Serotonin Reuptake Inhibitors as Antidepressants
Although most pharmacologists by the 1960s thought the primary mode of action of tricyclic antidepressants was to inhibit norepinephrine reuptake, some reexamined the actions of diverse antihistamines on the reuptake of various biogenic amines, especially serotonin. The serotonin hypothesis of depression was championed only by very few psychiatrists, such as Coppen in England (50). Isaac and Goth (51, 52) found that tripelennamine (Pyribenamine®), d-chlorpheniramine (Polaramine®), and diphenhydramine all had cocaine-like effects in reducing [3H]-norepinephrine uptake which did not correlate with their antihistaminic actions. Subsequently, Barnett et al. (53) studied 19 different antihistamines in a series of animal tests for antidepressant action. About half of the compounds showed potential antidepressant effects. Again, there was no correlation with their antidepressant and antihistamine activities. In 1969, Carlsson and Lindqvist (54) studied selected opioid analgesics and antihistamines as monoaminergic reuptake blockers with emphasis on interactions with serotonin, its precursor 5-hydroxytryptophan, and the MAO inhibitor, nialamide. Several antihistaminics showed considerable activity, especially chlorpheniramine, but more on norepinephrine than serotonin reuptake. They noted that diphenhydramine was inactive against norepinephrine but active against serotonin. In 1969, two Russian pharmacologists, Lapin and Oxenkrug, the latter now in the U.S., proposed an increase in brain serotonergic mechanisms as a determinant of antidepressant effects (55). They summarized evidence that an increase in brain noradrenergic mechanisms caused the energizing and motor stimulating effects of the then available antidepressants, but an increase in serotonergic mechanisms was responsible for their mood-elevating effects. A year later, Molloy and Rathburn at Eli Lilly began a search for structural analogs of diphenhydramine as possible antidepressants. Their research approach was very rational inasmuch as it was based on the above reports that certain antihistamines, including diphenhydramine, were inhibitors of serotonin reuptake and had antidepressant properties in laboratory models. The phenoxyphenylpropylamine structure was Eli Lilly’s basic molecule for chemical substitutions. It is drawn so as to compare it with the substituted methoxyethylamine antihistamines such as diphenhydramine. Wong et al. (56, 57) summarized the development of fluoxetine, the first SSRI, as an antidepressant drug. With the phenomenal clinical and commercial success of fluoxetine as an antidepressant, many other pharmaceutical companies quickly developed their own exclusive SSRI. FIGURE 7
More than 50 years ago, no one would have predicted that molecular manipulation of the basic structure of antihistamines would provide so many different, useful psychopharmacological agents. In 1964, the medicinal chemist, Biel (58), summarized the chemical rationale for developing MAO inhibitors and tricyclic antidepressants. He referred to the fact that the latter were molecular modifications of antihistamines: perhaps you’ll agree in 1999, that a lot of other antipsychotics and antidepressants are, as well.
FUTURE DEVELOPMENT OF NEW PSYCHOPHARMACOLOGICAL TREATMENTS OF DEPRESSION
The major lesson to be learned from the history of modern psychopharmacology is that medicinal chemists and pharmacologists can synthesize and test new chemicals once a new therapeutic lead becomes available, sufficient to motivate a pharmaceutical company to make the financial investment to develop a patentable drug. Molecular manipulation to obtain a me-too drug can produce new therapeutic leads once the agent is introduced into human medicine. It is the task of the astute clinician to observe carefully the response of the patient, especially when given a new therapeutic agent. Chance identification of the unique therapeutic properties of a new drug may lead to important breakthroughs such as those obtained with chlorpromazine, imipramine, and fluoxetine as modifications of an antihistamine. Variations on any theory of the biochemical abnormality of a given disease are crucial. Although the norepinephrine reuptake theory of the action of tricyclic antidepressants was dominant years ago, because both clinical and pharmacological evidence suggested a role for serotonin eventually led to the development of SSRI, again by molecular modification of an antihistamine. Currently, the role of various neurotransmitters in mood disorders such as norepinephrine (59), dopamine (60), serotonin (61), and acetylcholine (62), as well as neuroendocrinology (63), neuropeptides (64), psychoneuroimmunology (65), biological rhythms (66), and the reproductive cycle (67) is discussed widely. The data indicate that brain, body, and mind relationships are extremely complex in dealing with mood disorders, as is true of most psychiatric disorders. Current knowledge of the biology of mood disorders (68) is ample evidence of mind-body complexities.
A well known belief of many basic scientists, is “if we understand what is broken, it should be possible to fix it.” There are examples in medicine where detailed knowledge of the biochemical mechanisms of various diseases (eg, AIDS) paid off in the development of new therapeutic agents. At the end of the 20th century, we must recognize that our current theories involving the chemical pathologic mechanisms of psychiatric and psychosomatic diseases, because of their complexities, are primitive. Yet, we need not despair. Progress in the past 50 years has been truly remarkable. What wonderful new treatments will be available 50 years hence? This will happen only if we increase our research efforts now, especially in all branches of psychosomatic medicine.
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