History of the Discovery and Clinical Introduction of Chlorpromazine

Article (PDF Available)inAnnals of Clinical Psychiatry 17(3):113-35 · July 2005with 4,842 Reads 
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DOI: 10.1080/10401230591002002 · Source: PubMed
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The historical process of discovery and clinical introduction of chlorpromazine, one of the greatest advances of 20th century medicine and history of psychiatry, is analyzed. In this review, we have studied the original works of pioneers in the discovery and clinical use of chlorpromazine, as well as the contributions of prestigious researchers (historians, pharmacologists, psychiatrists, etc.) about this topic. The discovery of phenothiazines, the first family of antipsychotic agents has its origin in the development of German dye industry, at the end of the 19th century (Graebe, Liebermann, Bernthsen). Up to 1940 they were employed as antiseptics, antihelminthics and antimalarials (Ehrlich, Schulemann, Gilman). Finally, in the context of research on antihistaminic substances in France after World War II (Bovet, Halpern, Ducrot) the chlorpromazine was synthesized at Rhône-Poulenc Laboratories (Charpentier, Courvoisier, Koetschet) in December 1950. Its introduction in anaesthesiology, in the antishock area (lytic cocktails) and "artificial hibernation" techniques, is reviewed (Laborit), and its further psychiatric clinical introduction in 1952, with initial discrepancies between the Parisian Val-de-Grâce (Laborit, Hamon, Paraire) and Sainte-Anne (Delay, Deniker) hospital groups. The first North-American publications on chlorpromazine took place in 1954 (Lehmann, Winkelman, Bower). The introduction of chlorpromazine in the USA (SKF) was more difficult due to their strong psychoanalytic tradition. The consolidation of the neuroleptic therapy took place in 1955, thanks to a series of scientific events, which confirmed the antipsychotic efficacy of the chlorpromazine. The discovery of the antipsychotic properties of chlorpromazine in the 1950s was a fundamental event for the practice of psychiatry and for the genesis of the so-called "psychopharmacological revolution."
  • ... Of course, this is not the first case of a nonpsychiatric drug demonstrating positive psychiatric effects. Chlorpromazine, the first antipsychotic, was initially used as a component of general anesthesia, and its psychoactive effects were first noted by a surgeon [24]. Likewise, iproniazid, the first monoamine oxidase inhibitor, was initially developed as an anti-tubercular agent and its psychoactive effects were only fortuitously discovered later [25]. ...
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    Background: Cancer patients are disproportionately affected by generalized anxiety and major depression. For many, current treatments for these conditions are ineffective. In this case report, we present a serendipitous case of anxiety and depression improvement following administration of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib. Case presentation: A 61-year old woman with a 20-year history of mild depression developed recurrent ovarian carcinoma and was placed on niraparib for maintenance chemotherapy. With the original onset of ovarian cancer, she experienced an episode of major depression that was resolved with sertraline. After recurrence of ovarian cancer, she experienced a recurrence of major depression and a new onset of generalized anxiety that failed to completely respond to multiple medications. After beginning niraparib therapy the patient noticed a rapid resolution of the symptoms of her anxiety and depression, an effect that was limited to 10-14 days. Due to bone marrow suppression, the patient was taken off and restarted on niraparib several times. Each discontinuation of niraparib resulted in return of her depression and anxiety, while each recontinuation of niraparib resulted in an improvement in her mood and anxiety. Conclusions: This case demonstrates rapid and temporary improvement of anxiety and depression following niraparib administration. There is ample preclinical data that PARP signaling may play a role in psychiatric illness. A small amount of indirect data from clinical trials also shows that niraparib may have psychiatric benefits. Further research on PARP inhibition and its potential psychoactive effects is sorely needed.
  • ... Six publications by Delay & Deniker set the stage for the introduction of chlorpromazine in psychiatry. 8,9 The antipsychotic effects of phenothiazines and other typical antipsychotics (e.g., the butyrophenones) remain unsurpassed to date. Clozapine is a phenothiazine. ...
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    A number of older substances display such marked, consistent efficacy that their absence from guidelines or consensus initiatives did not discourage clinicians from continued prescribing to their patients. Unfortunately, many of those efficacious medications have vanished from Brazilian drugstore shelves over the past 20 years. Tranylcypromine and phenelzine (the most studied non-selective MAOIs), maprotiline (the only selective noradrenaline reuptake inhibitor), imipramine (the gold- standard, most effective antidepressant for severe ‘‘mel- ancholic’’ depression), pimozide (particularly efficacious for Tourette syndrome), penfluridol (a long-acting oral antipsychotic which could be taken once a week), and lithium carbonate have been gone from our pharmacies either temporarily or for good.
  • ... The therapy of schizophrenia was largely unsuccessful until the first generation of dopamine D2 receptor blocking neuroleptic medication was discovered in 1950 which shifted the focus on the chemical imbalances in the brain (for historical context, see López-Muñoz et al., 2005). The new medication allowed for the treatment of schizophrenia outside the context of a hospital by greatly reducing 1 Introduction 2 psychotic symptoms. ...
  • ... GİRİŞ Şizofreni, pozitif, negatif ve bilişsel belirtilerle karakterize, genellikle akademik, iş veya sosyal ilişkiler gibi önemli işlevsellik alanlarında yeti yitimi ile giden kronik, ağır bir ruhsal bozukluktur (1,2). Şizofreni tedavisinde antipsikotik ilaçların yeri tartışılmazken, şizofreni hastalarının büyük çoğunluğunun (%84) takiplerinde oral antipsikotik ilaç (OA) tedavisine devam etmediği ve uzun dönem takiplerinde %40-50'sinin tedaviye uyum göstermediği dikkat çekmektedir (3,4,5,6,7). ...
  • ... Therefore, EAG channel inhibitors have high therapeutic potential for treatment of both cancer and neurological disorders. CH is an Food and Drug Administration-approved drug that has been extensively used as an antipsychotic medication (42). Our study presents a strong rational for repurposing CH for treatment of cancer and neurological disorders. ...
    Ether-a-go-go (EAG) potassium selective channels are major regulators of neuronal excitability and cancer progression. EAG channels contain a Per-Arnt-Sim (PAS) domain in their intracellular N-terminal region. The PAS domain is structurally similar to the PAS domains in non-ion channel proteins, where these domains frequently function as ligand-binding domains. Despite the structural similarity, it is not known if the PAS domain can regulate EAG channel function via ligand binding. Here, using surface plasmon resonance (SPR), tryptophan fluorescence, and analysis of EAG currents recorded in Xenopus laevis oocytes, we show that a small molecule chlorpromazine (CH), widely used as an antipsychotic medication, binds to the isolated PAS domain of EAG channels and inhibits currents from these channels. Mutant EAG channels that lack the PAS domain show significantly lower inhibition by CH, suggesting that CH affects currents from EAG channels directly through the binding to the PAS domain. Our study lends support to the hypothesis that there are previously unaccounted steps in EAG channel gating that could be activated by ligand binding to the PAS domain. This has broad implications for understanding gating mechanisms of EAG, and related ERG and ELK channels, and places the PAS domain as a new target for drug discovery in EAG and related channels. Upregulation of EAG channel activity is linked to cancer and neurological disorders. Our study raises a possibility of repurposing the antipsychotic drug chlorpromazine for treatment of neurological disorders and cancer.
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