Neuroleptics: Difference between revisions

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== Origins ==

Chlorpromazine was synthesized in 1950 by the French pharmaceutical company Rhône-Poulenc as the compound RP-4560, developed from the phenothiazine family that had earlier yielded antihistamines.<ref name="lopezmunoz2005">López-Muñoz F, Alamo C, Cuenca E, et al. (2005). History of the discovery and clinical introduction of chlorpromazine. ''Ann Clin Psychiatry'' 17(3):113–35.</ref> The surgeon Henri Laborit observed that it produced calmness without heavy sedation and suggested a psychiatric use. In 1952 the psychiatrists [[Jean Delay]] and [[Pierre Deniker]], working in Paris, published the first clinical reports of its use in psychotic patients.<ref name="lopezmunoz2005"/> The medicine was marketed in France as Largactil in 1952 and approved in the United States, as Thorazine, in 1954.<ref name="lopezmunoz2005"/>

[[Chlorpromazine]] was synthesized in 1950 by the French pharmaceutical company Rhône-Poulenc as the compound RP-4560, developed from the phenothiazine family that had earlier yielded antihistamines.<ref name="lopezmunoz2005">López-Muñoz F, Alamo C, Cuenca E, et al. (2005). History of the discovery and clinical introduction of chlorpromazine. ''Ann Clin Psychiatry'' 17(3):113–35.</ref> The surgeon Henri Laborit observed that it produced calmness without heavy sedation and suggested a psychiatric use. In 1952 the psychiatrists [[Jean Delay]] and [[Pierre Deniker]], working in Paris, published the first clinical reports of its use in psychotic patients.<ref name="lopezmunoz2005"/> The medicine was marketed in France as Largactil in 1952 and approved in the United States, as Thorazine, in 1954.<ref name="lopezmunoz2005"/>

Its introduction is widely held to have contributed to the deinstitutionalization movement of the 1950s through the 1970s, during which large numbers of long-term psychiatric inpatients were discharged; historians note that this shift had multiple social and policy causes alongside the arrival of the new medicines.<ref name="lopezmunoz2005"/>

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== First- and second-generation neuroleptics ==

The medicines introduced from the 1950s onward — chlorpromazine, [[haloperidol]] and others — are described as '''first-generation''' (or "typical") neuroleptics. They are generally understood to act mainly as antagonists at the dopamine D<sub>2</sub> receptor, and this activity is thought to be related both to their effects and to their characteristic movement-related side effects; the account is a widely used model rather than a complete explanation.<ref name="lyman2025"/>

The medicines introduced from the 1950s onward — [[chlorpromazine]], [[haloperidol]] and others — are described as '''first-generation''' (or "typical") neuroleptics. They are generally understood to act mainly as antagonists at the dopamine D<sub>2</sub> receptor, and this activity is thought to be related both to their effects and to their characteristic movement-related side effects; the account is a widely used model rather than a complete explanation.<ref name="lyman2025"/>

A '''second-generation''' (or "atypical") group followed, distinguished largely by a reportedly lower tendency to cause movement-related effects. [[Clozapine]], first introduced in Europe in 1971, is generally regarded as the first second-generation neuroleptic.<ref name="crilly2007">Crilly J (2007). The history of clozapine and its emergence in the US market: a review and analysis. ''Hist Psychiatry'' 18(1):39–60. PMID 17580753.</ref> The distinction between the two generations is widely used but has been described as imprecise, since the agents within each group differ considerably from one another.<ref name="lyman2025"/>

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== Clozapine and blood monitoring ==

Clozapine was withdrawn from several markets after 1975, when a cluster of cases of [[agranulocytosis]] — a severe loss of white blood cells — in Finland was associated with eight deaths.<ref name="idanpaan1975">Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva I (1975). Clozapine and agranulocytosis. ''Lancet'' 2(7935):611. PMID 51442.</ref> On the basis of trial evidence indicating greater effectiveness in treatment-resistant schizophrenia, it was later reintroduced — approved in the United States in 1989 — under a system of mandatory blood-count monitoring that remains a condition of its use.<ref name="kane1988">Kane J, Honigfeld G, Singer J, Meltzer H (1988). Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. ''Arch Gen Psychiatry'' 45(9):789–96. PMID 3046553.</ref>

[[Clozapine]] was withdrawn from several markets after 1975, when a cluster of cases of [[agranulocytosis]] — a severe loss of white blood cells — in Finland was associated with eight deaths.<ref name="idanpaan1975">Idänpään-Heikkilä J, Alhava E, Olkinuora M, Palva I (1975). Clozapine and agranulocytosis. ''Lancet'' 2(7935):611. PMID 51442.</ref> On the basis of trial evidence indicating greater effectiveness in treatment-resistant schizophrenia, it was later reintroduced — approved in the United States in 1989 — under a system of mandatory blood-count monitoring that remains a condition of its use.<ref name="kane1988">Kane J, Honigfeld G, Singer J, Meltzer H (1988). Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. ''Arch Gen Psychiatry'' 45(9):789–96. PMID 3046553.</ref>

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