Objective:Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.Method:A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.Results:Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimu...

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

New data on the pharmacology of tricyclic antidepressants (TCAs), their affinities for human cloned CNS receptors and their cytochrome P450 enzyme inhibition profiles, allow improved deductions concerning their effects and interactions and indicate which of the TCAs are the most useful. The relative toxicity of TCAs continues to be more precisely defined, as do TCA interactions with selective serotonin reuptake inhibitors (SSRIs). TCA interactions with monoamine oxidase inhibitors (MAOIs) have been, historically, an uncertain and difficult question, but are now well understood, although this is not reflected in the literature. The data indicate that nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs), and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs. Clomipramine is the only available antidepressant drug that has good evidence of clinically relevant serotonin and noradrenaline reuptake inhibition (SNRI). These data assist drug selection for monotherapy and combination therapy and predict reliably how and why pharmacodynamic and pharmacokinetic interactions occur. In comparison, two newer drugs proposed to have SNRI properties, duloxetine and venlafaxine, may have insufficient NRI potency to be effective SNRIs. Combinations such as sertraline and nortriptyline may therefore offer advantages over drugs like venlafaxine that have fixed ratios of SRI/NRI effects that are not ideal. However, no TCA/SSRI combination is sufficiently safe to be universally applicable without expert knowledge. Standard texts (e.g. the British National Formulary) and treatment guidelines would benefit by taking account of these new data and understandings.

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Tricyclic antidepressant pharmacology and therapeutic drug interactions updated

Considering increasing number of pathogens resistant towards commonly used antibiotics as well as antiseptics, there is a pressing need for antimicrobial approaches that are capable of inac...

Antimicrobial photodynamic therapy – what we know and what we don’t

The 1950s saw the clinical introduction of the first two specifically antidepressant drugs: iproniazid, a monoamine-oxidase inhibitor that had been used in the treatment of tuberculosis, and imipramine, the first drug in the tricyclic antidepressant family. Iproniazid and imipramine made two fundamental contributions to the development of psychiatry: one of a social-health nature, consisting in an authentic change in the psychiatric care of depressive patients; and the other of a purely pharmacological nature, since these agents have constituted an indispensable research tool for neurobiology and psychopharmacology, permitting, among other things, the postulation of the first aetiopathogenic hypotheses of depressive disorders. The clinical introduction of fluoxetine, a selective serotonin reuptake inhibitor, in the late 1980s, once again revolutionized therapy for depression, opening the way for new families of antidepressants. The present work reviews, from a historical perspective, the entire process that led to the discovery of these drugs, as well as their contribution to the development of the neuroscientific disciplines. However, all of these antidepressants, like the rest of those currently available for clinical practice, share the same action mechanism, which involves the modulation of monoaminergic neurotransmission at a synaptic level, so that the future of antidepressant therapy would seem to revolve around the search for extraneuronal non-aminergic mechanisms or mechanisms that modulate the intraneuronal biochemical pathways.

/pdf/monoaminergic-neurotransmission-the-history-of-the-discovery-5eej6keyor.pdf

Monoaminergic Neurotransmission: The History of the Discovery of Antidepressants from 1950s Until Today

D-Amino acid oxidase (DAAO) is a FAD-containing flavoenzyme that catalyzes the oxidative deamination of D-isomers of neutral and polar amino acids. This enzymatic activity has been identified in most eukaryotic organisms, the only exception being plants. In the various organisms in which it does occur, DAAO fulfills distinct physiological functions: from a catabolic role in yeast cells, which allows them to grow on D-amino acids as carbon and energy sources, to a regulatory role in the human brain, where it controls the levels of the neuromodulator D-serine. Since 1935, DAAO has been the object of an astonishing number of investigations and has become a model for the dehydrogenase-oxidase class of flavoproteins. Structural and functional studies have suggested that specific physiological functions are implemented through the use of different structural elements that control access to the active site and substrate/product exchange. Current research is attempting to delineate the regulation of DAAO functions in the contest of complex biochemical and physiological networks.

Physiological functions of D-amino acid oxidases: from yeast to humans

Background. 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.Methods. 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.Results. 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 Rhone-Poulenc Laboratories (Charpentier, Courvoisier, Koetschet) in December 1950. Its introduction in anaesthes...

History of the discovery and clinical introduction of chlorpromazine

We performed a bibliometric study of the scientific publications referring to selective serotonin reuptake inhibitors (SSRIs). The database used was EMBASE: Psychiatry. We applied the principal bibliometric indicators: Price's and Bradford's laws on the increase or dispersion of scientific literature, Lotka's law on the productivity of authors, the participation index (PaI) of countries, the productivity index (PI) of authors, and the collaboration index. By means of manual coding, documents were classified according to type of study and to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) or nonpsychiatric categories. We analysed 3,622 original documents published between 1980 and 2000. Our results show nonfulfilment of Price's law because production on SSRIs does not grow exponentially (r=0.937 vs. r = 0.946, after linear adjustment). The journal most employed is the Journal of Clinical Psychiatry (Bradford's first zone). The United States is the most productive country (PaI=41.50). The documents were distributed in four groups: experimental pharmacology (8.38%), tolerance and safety (34.94%), clinical efficacy (49.11%), and not specified (7.56%). The drug most studied was fluoxetine (1,745 articles), followed by paroxetine (659). The DSM-IV diagnostic categories most studied were depression (834), obsessive-compulsive disorder (171), and panic disorder (75). The control antidepressants most used in comparative clinical studies were amitriptyline (51) and imipramine (42). The results of the present study show that the SSRIs are not solely antidepressant drugs, but also have a wide range of uses both within the psychiatric sphere (especially in the field of anxiety) and outside it, which explains the considerable scientific production generated in relation to these drugs.

Bibliometric analysis of biomedical publications on SSRI during 1980-2000.

Effects of yohimbine on morphine analgesia and physical dependence in the rat.

The clinical introduction of chlorpromazine in 1952 constitutes one of the greatest advances of 20th century medicine. This paper traces the historic process of its discovery and its introduction to the psychiatric practice as well as the role played by different researches and clinics (Laborit, Delay, Deniker, etc.). The chlorpromazine inaugurated a new era in the therapeutic treatment of mental patients, revolutionizing the psychiatric assistance and being the starting point of the modern psychopharmacology, of which half a century has been reached.

Half a century since the clinical introduction of chlorpromazine and the birth of modern psychopharmacology.

Durante la decada de los 50 tiene lugar, en el ambito de la psicofarmacologia, una autentica "revolucion", pues supone, por primera vez en la historia, la introduccion en clinica de herramientas terapeuticas realmente eficaces en el manejo del paciente psiquiatrico Con anterioridad, los medicos apenas contaban con tratamientos de contrastada eficacia para manejar las enfermedades mentales graves Entre ellos, destacaba unicamente la electroconvulsivoterapia (Ugo Cerletti) Otras terapeuticas fisicas o biologicas, ampliamente utilizadas aun durante los anos 40, como los comas insulinicos de Sackel, la convulsoterapia cardiazolica de Von Meduna, la piretoterapia de Von Jauregg, o la hidroterapia, no habian demostrado una eficacia relevante Tampoco lo habian hecho las terapias psicologicas, incluido el psicoanalisis, ni los procedimientos quirurgicos postulados por Egas Moniz (leucotomias prefrontales)

Eduardo Cuenca

Papers

History of the discovery and clinical introduction of chlorpromazine

Bibliometric analysis of biomedical publications on SSRI during 1980-2000.

Effects of yohimbine on morphine analgesia and physical dependence in the rat.

Half a century since the clinical introduction of chlorpromazine and the birth of modern psychopharmacology.

La "Década de oro" de la psicofarmacología (1950-1960): trascendencia histórica de la introducción clínica de los psicofármacos clásicos.