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Clozapine was first manufactured in China in 1976. Clozapine is currently used not only for treatment-refractory schizophrenia (TRS), but also continues to be used in the treatment of patients with non-TRS and other mental disorders; moreover, low-dose clozapine is also used in sedative-hypnotic therapy and in combination with other drugs. There is need for studies in China using various titrations and assessing their risk for myocarditis and aspiration pneumonia. The Chinese clozapine package insert will also greatly benefit from these changes., Competing Interests: Declaration of competing interest In the last 3 years, the authors report no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

This year, we observe sixty's anniversary of the article by a British psychiatrist, Geoffrey Hartigan, demonstrating, for the first time, the possibility of preventing of the recurrence of mood disorders by using lithium salts. Herein, a history of prevention of recurrences of mood disorders both worldwide and in Poland will be presented concerning both lithium and other mood-stabilizing drugs. The merit for verifying the prophylactic lithium effect in the 1960-1970s should be given to Danish researchers, Mogens Schou and Poul Baastrup. In Poland, the first paper on prophylactic lithium appeared already in 1971. In the 1970s, French researchers showed prophylactic activity of valproic acid amide, and Japanese researchers - carbamazepine. In the 1980th, studies on valproic acid amide were performed in the 2nd Psychiatric Clinic of the Institute of Psychiatry and Neurology led by Prof. Pużyński. Since the mid-1990s, 2nd generation of mood-stabilizing drugs has been introduced, including some atypical antipsychotics (clozapine, olanzapine, quetiapine, aripiprazole, risperidone) and anticonvulsant drug, lamotrigine, showing prophylactic activity in bipolar mood disorder. The studies on lithium resulted in the identification of factors connected with its prophylactic efficacy as well as the antisuicidal, antiviral, and neuroprotective effects of this drug. From a sixty-year perspective following Hartigan's article, it seems that his pioneering concept on the possibility of pharmacological influence on the course of mood disorders was fully confirmed. Current Polish recommendations on pharmacological prophylaxis of mood disorders were presented in the books "Standardy leczenia niektórych zaburzeń psychicznych" and "Psychofarmakologia kliniczna", both published in 2022.

The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from 'typical' to 'atypical'. Atypicality is reviewed in reference to its original definition, clozapine's role, and developments that now leave the concept's utility in question. In a similar fashion, drug development is reviewed in the context of the illness' multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness' heterogeneity and complexity. Just as 'atypical' as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat 'schizophrenia'., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The third part of the triptych of my 50-year activity in psychiatry is about psychopharmacology. This way of treatment changed the picture of contemporary psychiatry. The introduction of neuroleptic (antipsychotic) drugs and tricyclic antidepressants in the 1950s resulted in a therapeutic revolution and contributed to the ‛medicalization' of psychiatry and its therapeutic similarity to other non-surgical specialties. Adiscovery of prophylactic lithium activity in the1960s initiated the mood-stabilizing drugs.During the last half-century, the most dynamic was the 1990s when most antipsychotic and antidepressant drugs of the so-called new generation were introduced. The twenty-first century marks a debut of next antidepressant and antipsychotic drugs, some of the latter having long-acting injectable preparations. An interesting event was a demonstration of the antidepressant activity of ketamine. My research domain in psychopharmacology was lithium treatment of affective illnesses. Lithium makes the topic of many papers I authored, more than 150 of them are in the PubMed database. Many clinical and research aspects related to lithium administration have been reported as first in Polish literature and some are pioneering in the world. Recently, I wrote the book Lithium - the amazing drug in psychiatry which has also its English version. I have carried much research on antidepressant drugs, pharmacotherapy of treatment-resistant depression, and mood-stabilizing drugs for which I proposed a modern classification. I participated in European projects EUFEST and OPTIMISE on the optimization of using antipsychotic drugs in schizophrenia. I also performed much research on the antidepressant effect of ketamine and electroconvulsive therapy.

The last half-century, thanks to the efforts of outstanding researchers, brought about great progress in the pathogenesis and clinics of affective illnesses. The catecholamine and serotonin hypothesis delineated in the 1960s have retained significant merit. Since the 1990s, the theories have pointed on excessive immune activation and impairment of neuroplasticity under stress. Since the 1970s, asystematic subclassification of unipolar and bipolar affective disorder has proceeded. Epidemiological studies of the last half-century indicated a significantly higher prevalence of depression compared with previous decades. The 21st century brought evidence for agreater frequency of various forms of bipolar affective disorder. During the last 50years, the etiopathogenesis, diagnosis and treatment of affective disorders were my favorite and fascinating clinical and research topics. This initiated in 1970 when I began my work in the Department of Psychiatry, Medical Academy in Poznan, on account of the introduction of lithium salts for the treatment of these disorders. In 1976-1977, I received afellowship of the National Institutes of Health at the University of Pennsylvania in Philadelphia and participated in research that elucidated the mechanism of lithium transport across cell membranes. I carried out the studies on the pathogenesis of affective disorders for more than 40 years afterward. They concerned abnormalitiesof transport across cell membranes, the activity of stress system, excessive pro-inflammatory activation, molecular genetics, dysfunctions of cognition and neurotrophins, especially the brain-derived neurotrophic factor (BDNF). Atthe beginning of the 21st century, I coordinated two Polish epidemiological projects DEP-BI and TRES-DEP. For my research on bipolar disorders, I received many international awards. I am also the author of the book The faces of manic-depressive illness which had three Polish editions as well as English and Russian versions.

Twentieth-century psychiatry was transformed in the 1950s and 1960s by the introduction of powerful psychopharmaceuticals, particularly Chlorpromazine (Thorazine). This paper examines the reception of Chlorpromazine in the Soviet Union and its effect on the Soviet practice of psychiatry. The drug, known in the USSR by the name Aminazine, was first used in Moscow in 1954 and was officially approved in 1955. I argue that Soviet psychiatrists initially embraced it because Aminazine enabled them to successfully challenge the Stalin-era dogma in their field (Ivan Pavlov's 'theory of higher nervous activity'). Unlike in the West, however, the new psychopharmaceuticals did not lead to deinstitutionalisation. I argue that the new drugs did not disrupt the existing Soviet system because, unlike the system in the West, the Soviets were already dedicated, at least in theory, to a model which paired psychiatric hospitals with community-based 'neuropsychiatric dispensaries.' Chlorpromazine gave this system a new lease on life, encouraging Soviet psychiatrists to more rapidly move patients from in-patient treatment to 'supporting' treatment in the community.

Three cases are presented describing unique clinical responses to aripiprazole in comparison with other second-generation antipsychotics taken by each patient. One case involved an adverse reaction of problem gambling behavior, the second an enhanced antipsychotic response in delusional disorder, and the third a reversal of weight gain that occurred while the patient continued taking olanzapine. Aripiprazole was the first of a subgroup of atypical antipsychotics that are mixed agonists and antagonists of dopamine, likely contributing to unusual responses in some patients.

Tardive dyskinesia (TD) is a persistent hyperkinetic movement disorder associated with dopamine receptor blocking agents including antipsychotic medications. Although uncertainty and concern about this drug side effect have vacillated since its initial recognition 60 years ago, recent commercial interest in developing effective treatments has rekindled scientific and clinical interest after a protracted period of neglect. Although substantial research has advanced knowledge of the clinical features and epidemiology of TD, many fundamental questions raised by early investigators remain unresolved. In this paper, we review the early clinical reports that led to the acceptance of TD as an iatrogenic disorder and the lingering controversies that emerged thereafter. Continued research on TD as a serious adverse reaction to treatment may not only enhance patient outcomes and recovery efforts but may also provide insights into both the mechanism of action of antipsychotic drugs and the nosology and pathophysiology of idiopathic psychomotor disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The last decade was characterized by a growing awareness about the severity of dementia in the field of age-related and no age-related diseases and about the importance to invest resources in the research of new, effective treatments. Among the dementias, Alzheimer's plays a substantial role because of its extremely high incidence and fatality. Several pharmacological strategies have been tried but still now, Alzheimer keeps being an untreatable disease. In literature, the number of QSAR related drug design attempts about new treatments for Alzheimer is huge, but only few results can be considered noteworthy. Providing a detailed analysis of the actual situation and reporting the most notable results in the field of drug design and discovery, the current review focuses on the potential of molecular topology as a reliable tool in finding new anti-Alzheimer lead compounds., Methods: Published works on QSAR applied to the search of anti-Alzheimer's drugs during the last 10 years has been tracked. 2D and 3D-QSAR, HQSAR, topological indexes, etc. have been analyzed, as well as different mechanisms of action, such as MAO, AchE, etc. An example of topological indexes' application to the search of potential anti-Alzheimer drugs is reported., Results: Results show that QSAR methods during the last decade represented an excellent approach to the search of new effective drugs against Alzheimer's. In particular, QSAR based on molecular topology allows the establishment of a direct structure-property link that results in the identification of new hits and leads., Conclusion: Molecular topology is a powerful tool for the discovery of new anti-Alzheimer drugs covering simultaneously different mechanisms of action, what may help to find a definitive cure for the disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Sainte-Anne Hospital is the largest psychiatric hospital in Paris. Its long and fascinating history began in the 18th century. In 1952, it was at Sainte-Anne Hospital that Jean Delay and Pierre Deniker used the first neuroleptic, chlorpromazine, to cure psychiatric patients, putting an end to the expansion of psychosurgery. The Department of Neuro-psychosurgery was created in 1941. The works of successive heads of the Neurosurgery Department at Sainte-Anne Hospital summarized the history of psychosurgery in France. Pierre Puech defined psychosurgery as the necessary cooperation between neurosurgeons and psychiatrists to treat the conditions causing psychiatric symptoms, from brain tumors to mental health disorders. He reported the results of his series of 369 cases and underlined the necessity for proper follow-up and postoperative re-education, illustrating the relative caution of French neurosurgeons concerning psychosurgery. Marcel David and his assistants tried to follow their patients closely postoperatively; this resulted in numerous publications with significant follow-up and conclusions. As early as 1955, David reported intellectual degradation 2 years after prefrontal leucotomies. Jean Talairach, a psychiatrist who eventually trained as a neurosurgeon, was the first to describe anterior capsulotomy in 1949. He operated in several hospitals outside of Paris, including the Sarthe Psychiatric Hospital and the Public Institution of Mental Health in the Lille region. He developed stereotactic surgery, notably stereo-electroencephalography, for epilepsy surgery but also to treat psychiatric patients using stereotactic lesioning with radiofrequency ablation or radioactive seeds of yttrium-90. The evolution of functional neurosurgery has been marked by the development of deep brain stimulation, in particular for obsessive-compulsive disorder, replacing the former lesional stereotactic procedures. The history of Sainte-Anne Hospital's Neurosurgery Department sheds light on the initiation-yet fast reconsideration-of psychosurgery in France. This relatively more prudent attitude toward the practice of psychosurgery compared with other countries was probably due to the historically strong collaboration between psychiatrists and neurosurgeons in France.

Methylene blue, first discovered and used as a dye in the textile industry, has long been used for biological staining in histology, bacteriology, and hematology. Because of its unique physiochemical properties, it was the first synthetic drug used in medicine, having been used to treat malaria more than one century ago. Methylene blue was also one of the first drugs used for the treatment of patients with psychosis at the end of the 19th century and was the lead drug in the serendipitous development of phenothiazine antipsychotic drugs in the mid-20th century. It was studied in bipolar disorder in the 1980s and has been investigated in neurodegenerative disorders in recent years. The history of methylene blue from its discovery as a dye to its use as a stain and then its therapeutic application in medicine is an example of how a drug's use can evolve over time through careful observation, clinical needs, serendipity, and the integration of concepts from different disciplines. [Journal of Psychosocial Nursing and Mental Health Services, 54(9), 21-24.]., (Copyright 2016, SLACK Incorporated.)

The so-called chemical revolution has produced a vast historiographical corpus. Yet the patient's voice remains surprisingly absent from these stories. Based on the archives of the Institut de Psychiatrie (Brussels), this paper traces the introduction of Largactil as recounted in patient letters, physician records and nurse notes. The paper thus contributes to the history of therapies from below, but also participates in the historiographical debate about whether the introduction of neuroleptics can indeed be considered a revolution.

This series of columns has 3 main goals: (1) to explain class warnings as used by the United States Food and Drug Administration, (2) to increase awareness of movement disorders that may occur in patients treated with antipsychotic medications, and (3) to understand why clinicians should refrain from immediately assuming a diagnosis of tardive dyskinesia/dystonia (TD) in patients treated with antipsychotics. The first column in this series began with the case of a 76-year-old man with major depressive disorder who developed orofacial dyskinesias while being treated with aripiprazole as an antidepressant augmentation strategy. It was alleged that a higher than intended dose of aripiprazole (ie, 20 mg/d for 2 wk followed by 10 mg/d for 4 wk instead of the intended dose of 2 mg/d) was the cause of the dyskinetic movements in this man, and the authors were asked to review the case and give their opinion. The principal basis for this theory of causation was the class warning about TD in the package insert for aripiprazole. The rationale for concluding aripiprazole caused TD in the 76-year-old man led to this series of columns about aripiprazole, its potential--if any--to cause TD, and the presence of a class warning about TD in its package insert. The central point is to illustrate why class warnings exist and their implications for practice. The first column in this series focused on the historical background, incidence, prevalence, risk factors, and clinical presentations of tardive and spontaneous dyskinesias and concluded with a discussion of diagnostic considerations explaining why clinicians should avoid making a diagnosis of TD until a thorough differential diagnosis has been considered. This second column in the series reviews the pharmacology of aripiprazole and the preclinical and phase I translational human studies that suggest aripiprazole should have a low to nonexistent risk of causing TD compared with other antipsychotics. The third column in the series will review the systematic clinical trial data and "real-world" data on TD and the use of aripiprazole as adjunctive treatment with antidepressants for major depressive disorder to see whether these data support the conclusion of a low to nonexistent relationship between aripiprazole treatment and the development of TD. The fourth and final column in the series will consider the type of study that would need to be performed to avoid a specific class warning, focusing on the TD class warning as an example and discussing why such studies are rarely done.

We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price's Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price's Law, with scientific production on clozapine showing linear growth (r=0.8691, vs. r=0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor>2. Among the countries generating clozapine research, the most prominent is the USA (PI=24.32), followed by the UK (PI=6.27) and Germany (PI=5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic.

Objective: Neuroleptics were introduced into North America 60 years ago. The credit for this advance is generally accorded to Heinz Lehmann. I sought to explore whether Lehmann really was the first North American psychiatrist to study the effects of chlorpromazine (CPZ) and to provide a more balanced view of its application in a clinical context., Method: I searched for historical documents and published articles in several libraries and interviewed psychiatrists active from 1952-1970., Results: The first article in English was published in the July volume of the Archives of Neurology and Psychiatry in 1954 (n=71). Another article, written in French by Roland Saucier and published in a journal called Le Saguenay Médical, also described the effects of CPZ on a Canadian psychiatric population in August 1954 (n>200). However, the first prescription for CPZ was written by Roland Saucier, who brought the product back from Paris after a fellowship there. Ruth Kajander, in Ontario, was also one of the first prescribers of this drug, following her study of its use in anesthesia and a publication in the proceedings of a symposium., Conclusion: The contents of the 2 naturalistic studies were compared. Lehmann's study started 1 month before that of Saucier. Lehmann was the first North American psychiatrist to publish an article on CPZ, but Roland Saucier nevertheless made an important contribution, being the first to prescribe this drug in North America and reporting results for a study with a sample size 3 times that of Lehmann's study.

From a historical perspective, this article describes the use of antipsychotic long-acting injections (LAI) in the treatment of schizophrenia, a disorder that was defined in the final years of the 19th century. An efficient treatment for schizophrenia was discovered only in 1952 with the introduction of chlorpromazine, a phenothiazine derivative. Fairly soon, antipsychotics became available as LAI. The first compounds were fluphenazine enanthate (1966) and decanoate (1968) whose development is attributed to G.R. Daniel, a medical director at Squibb & Sons. Other first-generation antipsychotics long-acting injections (FGA-LAIs) were introduced in a rapid succession in the 1960s and 1970s. FGA-LAIs made a key contribution to the development of community psychiatry. As neuroleptics emptied psychiatric hospitals, it was important to ensure that patients could be taken care of in outpatient facilities. FGA-LAIs prevented covert non-compliance. Compliance was further reinforced by the social and psychological support of patients. The introduction of second-generation antipsychotics (SGA) led to a loss of interest in FGA-LAIs. This is evidenced by a drop in the number of papers published on this topic. The interest in LAI was revived with the introduction of the first SGA-LAI in 2003. Four different preparations have been approved in the decade between 2003 and 2013. SGA-LAIs differ from FGA-LAIs in the technology that is used to produce the depot effect, and also in the treatment objectives. The rationale for using SGA-LAIs is not only to prevent relapses due to treatment interruption, but also to achieve more constant plasma levels in order to reduce side effects due to excessive plasma levels and loss of efficacy due to insufficient plasma levels. Also, treatment objectives are no longer limited to controlling acute symptoms. Treatment objectives now include the alleviation of negative symptoms and cognitive deficits that are key prognostic factors., (Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Henri Laborit was one of the founders of modern neuropsychopharmacology, having discovered, or participated in, the discovery of chlorpromazine, gamma-OH, clomethiazole, and minaprine. He also put forward a theory regarding the necessity of counteracting the negative consequences of defense mechanisms during anesthesia or behavioral inhibition. The scope of his work covers neurophysiology, pharmacology, psychiatry, and psychosomatics. His independence of spirit meant that most of his research was not done within university settings.

This paper examines factors involved in the theory and practice of emergency sedation for behavioural disturbance in psychiatry in the mid-twentieth century, and the emergence of the concept of 'rapid tranquillisation'. The practice received little attention until the arrival of antipsychotic drugs, which replaced older sedatives and became the agents most strongly associated with the treatment of aggression and challenging behaviour. Emergency sedation was subsequently portrayed in psychiatric literature and advertising as a therapeutic and diagnosis-driven endeavour, and the concept of rapid tranquillisation emerged in this context in the 1970s. Use of non-antipsychotic sedatives, like the benzodiazepines, is barely visible in contemporary sources, and the research suggests that antipsychotics became the mainstay of rapid tranquillisation strategies because of beliefs about their specific therapeutic properties in psychosis and schizophrenia, and not because of demonstrated superiority over other agents.

This article demonstrates that psychoanalysis and socially oriented psychiatry were crucial to the understanding and adoption of the first effective psychopharmaceuticals in North American psychiatry. In the 1950s and the early 1960s, psychoanalysts, socially oriented psychiatrists, and biologists collaborated, debated, and organized interdisciplinary conferences to situate the biochemistry of new psychopharmaceuticals, such as chlorpromazine, in the broader psychosocial context of patients' lives. Psychoanalytical and sociological perspectives not only helped American psychiatrists explain the mechanism of drug action in research but also established the professional authority of psychiatrists over the new pharmaceuticals. As modern pharmacology narrows its focus to microscopic targets in the body, I argue that this early drug research illustrates the present-day need for holistic and interdisciplinary approaches to drug response that acknowledge the psychosocial significance of psychiatric medication in the lives of individuals.

Henri Laborit (1914-1995) was a French military MD. He contributed to the discovery of an important molecule that has changed the face of psychiatry, namely chlorpromazine, which became the first drug in the class of first-generation antipsychotics, which later led to the dopamine hypothesis of schizophrenia. He did not receive the Nobel Prize for this discovery, unlike Daniel Bovet who get the Nobel Prize for the discovery of antihistaminics. Henri Laborit is also the author of a book that has contributed to the popularization of neurosciences in France, "The Praise of flight" (1976).

The history of drug treatments, and particularly the discovery of certain molecules, led toan evolution in psychiatric practices. The discovery of the therapeutic properties of chlorpromazine in 1952 by Jean Delay and Pierre Deniker revolutionised the relational process between patients and caregivers.The perspectives are encouraging, notably in the areas of schizophrenia and mood disorders.

Two revolutionary drugs were introduced into psychiatry in the early 1950s for the treatment of agitated mental patients - reserpine and chlorpromazine. These drugs initiated the modern era of drug treatment for schizophrenia and other psychoses. Early research revealed that, although the pharmacological profiles of the two drugs overlapped considerably, they had different mechanisms of action. The mechanism of action of reserpine was determined first: it depletes monoamines from the brain and other tissues. By contrast, chlorpromazine has little or no effect on brain monoamine concentrations. The mystery created by two drugs that have similar pharmacological profiles but different mechanisms of action is the chlorpromazine enigma. For about eight years after the mechanism of action of reserpine was determined, researchers followed several false leads about the mechanism of action of chlorpromazine. Then, in 1963, Arvid Carlsson and Margit Lindqvist proposed that chlorpromazine (and haloperidol) work by blocking "monoaminergic" receptors. It was quickly determined that dopamine receptor blockade was the most important action. Although the idea of chemical communication between central neurons had yet to gain wide acceptance, this idea was central to resolving the chlorpromazine enigma.

When "antipsychotic" drugs were introduced into psychiatry in the 1950s, they were thought to work by inducing a state of neurological suppression, which reduced behavioral disturbance as well as psychotic symptoms. This view was reflected in the name "neuroleptic." Within a few years, however, the idea that the drugs were a disease-specific treatment for schizophrenia or psychosis, and that they worked by modifying the underlying pathology of the condition, replaced this earlier view, and they became known as "antipsychotics." This transformation of views about the drugs' mode of action occurred with little debate or empirical evaluation in the psychiatric literature and obscured earlier evidence about the nature of these drugs. Drug advertisements in the British Journal of Psychiatry reflect the same changes, although the nondisease-specific view persisted for longer. It is suggested that professional interests rather than scientific merit facilitated the rise of the disease-specific view of drug action. The increasing popularity of atypical antipsychotics makes it important to examine the origins of the assumptions on which modern drug treatment is based.

The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.

Chlorpromazine initiated effective pharmacotherapy for schizophrenia 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. Psychosis remains the primary aspect of psychopathology addressed, and core pathologies such as cognition and negative symptom remain unmet therapeutic challenges. New clinical and basic neuroscience paradigms may guide the near future and provide a more heuristic construct for novel and innovative discovery.

More than half a century ago, Delay and colleagues have discovered, quite accidentally, that antihistamine (chlorpromazine) relieves psychotic symptoms. This discovery prompted further investigation through a series of performed experiments aimed to elucidate the antipsychotic mechanism of action. Initial results have shown that antipsychotic drugs in experimental animals lead to "neuroleptic effect" (indifference). However, not until the end of 1960s, it becomes clear that all previously known antipsychotics block dopamine receptors, particularly postsynaptic D2 receptors. The next three decades marked the development and application of these so-called classic neuroleptics in the treatment of psychotic patients. During the nineteen nineties, as a result of ongoing efforts to achieve greater efficiency and reduce the scope of side effects, novel antipsychotics were synthesized (second generation antipsychotics--SGA). As a result the notion of serotonin-dopamine antagonist (SDA) was formulated. According to one of the hypothesis, "new", so called atypical antipsychotic drugs strongly block the serotonin (5-HT2), and weakly block the dopamine (D2) receptors. Yet, there is still a debate as to the molecular basis of atypicality, whether it is in dopaminergic and serotonergic antagonism of neurotransmission or it lays exclusively in the modulation of dopaminergic system and dissociation rate at the level of D2 receptors in specific brain regions. Although the synthesis and use of antipsychotics in clinical practice have radically changed not only the basic approach to the patient, but also the quality of life of millions of people, the question remains whether this is just "old wine in new glasses".

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

Although glutamate was first hypothesized to be involved in the pathophysiology of schizophrenia in the 1980s, it was the demonstration that N-methyl-D-aspartate (NMDA) receptor antagonists, the dissociative anesthetics, could replicate the full range of psychotic, negative, cognitive, and physiologic features of schizophrenia in normal subjects that placed the "NMDA receptor hypofunction hypothesis" on firm footing. Additional support came from the demonstration that a variety of agents that enhanced NMDA receptor function at the glycine modulatory site significantly reduced negative symptoms and variably improved cognition in patients with schizophrenia receiving antipsychotic drugs. Finally, persistent blockade of NMDA receptors recreates in experimental animals the critical pathologic features of schizophrenia including downregulation of parvalbumin-positive cortical GABAergic neurons, pyramidal neuron dendritic dysgenesis, and reduced spine density.

In psychiatry, pharmacological drugs play an important experimental role in attempts to identify the neurobiological causes of mental disorders. Besides being developed in applied contexts as potential treatments for patients with mental disorders, pharmacological drugs play a crucial role in research contexts as experimental instruments that facilitate the formulation and revision of neurobiological theories of psychopathology. This paper examines the various epistemic functions that pharmacological drugs serve in the discovery, refinement, testing, and elaboration of neurobiological theories of mental disorders. I articulate this thesis with reference to the history of antipsychotic drugs and the evolution of the dopamine hypothesis of schizophrenia in the second half of the twentieth century. I argue that interventions with psychiatric patients through the medium of antipsychotic drugs provide researchers with information and evidence about the neurobiological causes of schizophrenia. This analysis highlights the importance of pharmacological drugs as research tools in the generation of psychiatric knowledge and the dynamic relationship between practical and theoretical contexts in psychiatry., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society., (Copyright © 2012 Elsevier Inc. All rights reserved.)

This article explores the transformations in the regime of practice and discourse concerning chronic mental illness in French psychiatry in the post-war period and the role played by chemotherapy in these transformations. From the 1950s and 60s on, chronicity was reconstructed as a new experience, involving a new set of expectations, of dilemmas and negotiations, and involving new types of actors giving a new meaning to what they were doing with patients. While some psychiatrists thought that neuroleptics could open the way to active treatment of these pathologies, in effect this project faced a series of obstacles: some came from psychiatric ideologies, others from the conditions of psychiatric work. As a result chronicity acquired a new uncertain and elusive shape. Based on an examination of the interplay of meaning and action in psychiatrists' recourse to neuroleptics in the treatment of their chronic patients, this article seeks to highlight the difficult construction of the idea of chemotherapy in post-war French psychiatry and, more generally, the transformations in its notion of therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Psychiatrists have often referred to the discovery of new psychopharmaceutical drugs in the 1950s as a 'therapeutic revolution', which allowed physicians to observe und measure therapeutic effectiveness easily. Contrary to this view, this article will argue that psychiatrists needed the patient's subjective voice to evaluate the effects of the drugs. In a micro-analysis of hospital records of the first patient to be treated with chlorpromazine in the Heidelberg clinic in 1953, I show the different perspectives of doctors and patients on the diagnosis and treatment.The analysis points up how difficult it was to get an impression of the drug's effectiveness.The article emphasizes the importance of the new perspective that includes the patient's voice in the history of psychotropic drugs after 1945.

The development of geriatric psychopharmacology was built on advances in geriatric psychiatry nosology and clinical pharmacology and on increased investment in aging research by the National Institute of Mental Health and by academic institutions. Application of the US Food and Drug Administration's geriatric labeling rule provided further impetus. Developments in the knowledge about 3 principal classes of medications (antidepressants, antipsychotics, and treatments for Alzheimer's disease) illustrate the trajectory of geriatric psychopharmacology research. Nonetheless, the loss of information about age effects that has resulted from applying age exclusion criteria in studies limited to either younger adults or geriatric patients is regrettable. Antidepressant trials have moved from studying younger and medically well "geriatric" samples to focusing on "older old" persons and those with significant medical comorbidity including coronary artery disease, cerebrovascular disease, and dementia. Increased specificity is reflected in studies of relationships between specific neuropsychological deficits, specific brain abnormalities, and antidepressant responsiveness. Clinical trials in older adults have demonstrated that the efficacy of antipsychotic medications continues across the lifespan, but that sensitivity to specific side effects changes in older age, with poor tolerability frequently mitigating the benefits of treatment. Treatments for Alzheimer's disease have fallen within the purview of geriatric psychopharmacology. The research focus is increasingly shifting from treatments to slow the course of cognitive decline to studies of early diagnosis and of interventions designed to prevent the development of deficits in vulnerable individuals. The importance of geriatric psychopharmacology will grow further as the average lifespan increases all over the world., (© Copyright 2010 Physicians Postgraduate Press, Inc.)

This column is the second in a series on central nervous system (CNS) drug development. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 2) reviews the history of CNS drug development from the 1960s to the 1990s. During the 1960s, researchers acquired a much clearer understanding of basic CNS pharmacology (e.g., biogenic amine transmitter systems in the brain) and developed the first animal models of psychiatric illness that could be used to test potential psychiatric medications. During the 1970s, drug development scientists used their expanded understanding of receptor binding affinity and the theories and techniques developed in the 1950s and 1960s to produce new CNS-active medications. They did this by adding or reducing affinities for certain regulatory proteins (e.g., receptors) to increase positive effects and/or minimize adverse effects. The development of newer antipsychotics and antidepressants is discussed to illustrate this process. The next column in this series will review CNS drug development during the first decade of the 21st century and discuss what directions we can expect the field to take in the next 10 to 20 years.

This column begins a new series on central nervous system (CNS) drug development. This series will review developments up to the present day and end with a forward-looking perspective on what to expect over the next 10-20 years. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 1) reviews the history of CNS drug development from the period before written history through the golden era (i.e., late 1940s-early 1960s) in which the first modern medications for anxiety, bipolar, depressive, and psychotic disorders were discovered by chance. It also describes the early era of rational drug development in which other agents (e.g., thioridazine, fluphenazine, haloperidol, imipramine) were developed based on those first agents. The blueprint laid down for development of antibiotics is reviewed in relation to its impact on CNS drug development. The impact of the blockbuster business model and modern marketing/sales approaches on CNS drug development is also discussed.

The Musée Rolin of Autun, Burgundy (France) owns an interesting and rather large picture, entitled Le médecin guarissant phantassie, purgeant aussi par drogues la folie; it was originally painted on wood and was used as a shop-sign at the Cosseret Pharmacy, at 20 Grand Rue Chauchien, Autun, from the beginning of the XVIIth century to 1897. A naive description, the same that might have been by the clients, gives more fright than trust in the treatments on display. In the background, before rows of bottles, a medical action that looks like a purge is in progress. In the foreground a torture scene must be interpreted. The juxtaposition and alteration of traditional medical elements tend to spread confusion in the spectator's mind and introduce him into a world where reality is disturbed. This communication aims at showing that this picture about evacuation of madness has a medical meaning, showing that this icon of the evaciation of madness refers to medical theories, from Galen to Vesalius, and is a satirical representation of quacks'practices.