A History of the Pharmacological Treatment of Bipolar Disorder.

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade's experiments with lithium and the beginning of the so-called "Psychopharmacological Revolution" in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed.

The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder.

The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients, caregivers, and society and accounts for the largest part of the morbidity-mortality of the illness. Lurasidone is an atypical antipsychotic with a potent binding affinity as antagonist for D2, 5-HT2A, 5-HT7, and partial agonist at 5-HT1A receptors. Affinity for other receptors as H1 and muscarinic were negligible. Lurasidone was approved in 2010 for the treatment of schizophrenia and recently, 2013, for bipolar depression in monotherapy and an adjunct to lithium or valproate. Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the QT interval. Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment, in patients with bipolar II disorders, and versus other antipsychotic agents.

[The historical background of the pineal gland: I. From a spiritual valve to the seat of the soul]. / El devenir histórico de la glándula pineal: I. De válvula espiritual a sede del alma.

INTRODUCTION: Throughout history, the special anatomical location of the pineal gland in the central nervous system has given rise to a number of physiological hypotheses regarding the functional role of this organ. DEVELOPMENT: In classical ancient times, the pineal body (conarium) was considered to be a sort of valve-like sphincter that regulated the flow of the spiritus animalis at the ventricular level. But it was not until the 17th century that the pineal gland finally reached its highest levels of physiological significance, when Rene Descartes considered it to be the anatomical structure that housed the seat of the soul. CONCLUSIONS: The Cartesian hypotheses regarding the pineal gland did not arouse much interest in the scientific community of the time, and attention to this organ dwindled from then until the 20th century, when its neuroendocrinological nature was finally confirmed.

The neurobiological interpretation of the mental functions in the work of Santiago Ramón y Cajal.

Cajal (1852-1934) first had contact with the fields of psychiatry and psychology through the experimental study of hypnotism. He interpreted this phenomenon as an aberrant failure of the machinery of the brain. It may be that Cajal's initial interest in the theory of hypnotic suggestion eventually led him to study the biological phenomena related to sleep and dreams, in the neurophysiological explanation of which he disagreed openly with Freud's postulates. Finally, Cajal studied the histophysiological mechanisms of the higher mentalfunctions (thought, intelligence, memory, perception, etc.). He proposed that the pyramidal cells of the cerebral cortex, which he called 'psychic cells', formed the substrate of these functions; he proposed the law of 'avalanche conduction', and he speculated on the possibility of a phenomenon of neuronal plasticity in relation to learning processes. After being awarded the Nobel Prize in 1906, Cajal's interests in psychological aspects began to decline.

Cajal y la psiquiatría biológica: actividades profesionales y trabajos científicos de Cajal en el campo de la psiquiatría / Cajal and biological psychiatry: professional activities and scientific works of Cajal in the psychiatry field

Santiago Ramón y Cajal dedicó parte de su actividad científica al estudio experimental de aspectos relacionados con la psiquiatría. El primer contacto de Cajal con estos temas tuvo lugar a través del estudio experimental del hipnotismo. Siguiendo la concepción psicoterápica de Bernkein. Cajal interpretó el fenómeno de la sugestión hipnótica como un fallo aberrante de la maquinaria cerebral. Posiblemente, el interés inicial de Cajal por la sugestión hipnótica dio paso, con los años, al estudio de los fenómenos biológicos relacionados con el sueño y el ensueño, en cuya explicación neurofisiológica discrepaba abiertamente con los postulados de Freud. Cajal se ocupó también del estudio de los mecanismos histofisiológicos de los procesos psíquicos superiores (pensamiento, inteligencia, memoria, percepción, etc.), según las corrientes científicas de la época, muy proclives a este tipo de interpretaciones. Cajal puso a las células piramidales de la corteza cerebral, a las que denominó “células psíquicas”, como las candidatas para asentar el sustrato de estas funciones psicológicas superiores, asignó algún papel a las células neurológicas de la sustancia gris, planteó, siguiendo las corrientes psicológicas del asociacionismo, su ley del “alud nervioso”, y especuló con la posibilidad de un fenómeno de plasticidad neuronal en relación con los procesos del aprendizaje. Finalmente, dedicó algunas publicaciones a la descripción de las alteraciones histopatológicas de los cerebros de pacientes esquizofrénicos. Desde el punto de vista clínico y anecdótico, Cajal fundó un Comité de Investigaciones Psicológicas en su época valenciana, en el que ejerció la terapéutica sofrológica, y abrió, durante algunos meses, una consulta de Neuropatología y Psiquiatría en su periodo madrileño

Santiago Ramón y Cajal dedicated part of his scientific work to the experimentl study of aspects related to psychiatry. Cajal´s first contact with these subjects took place through experimental study of hypnotism. Following the psychotherapeutical approach of Bernheim. Cajal interpreted the phenomenon of hypnotic suggestion as an aberrant failure of the cerebral machinery. Possibly, Cajalñs initial interest in hypnotic suggestion gave way over the years to the study of the biological phenomena related to sleep and dreams, in whose neurophysiological explanation he differed apenly with the postulates of Freud. Cajal also studied the histophysiological mechanisms of the higher mental functions (thought, intelligence, memory, perception, etc.), on which the scientific thinking of the tima was greatly inclined to this type of interpretation. Cajal proposed the pyramidal cells of the cerebral cortex, which he called “physic cells”, as the possible seat of the substrate of these superior psychological functions. He assigned certain roles to the neuroglial cells of grey matter. In accordance with the psychological trend of association, he proposed his “law of avalanche conduction”. He speculated on the possibility of a phenomenon of neuron plasticity in relation to the learning processes. Finally, he dedicated some publications to the description of the histopathological alterations of the brains of schizophrenia patients. From the clinical and anecdotal point of view. Cajal founded a Committee of Psychological Research during his time in Valencia, when he practiced relaxation therapy, and for a few months during his time in Madrid, he opened a Neuropathology practice

Cajal y la psiquiatría biológica: influencias procedentes del ámbito psiquiátrico en la trayectoria científica de Cajal / Cajal and biological psychiatry: influences coming from the psychiatric scope in the scientific career of Cajal

La trayectoria científica y la vocación neurohistológica de Santiago Ramón y Cajal, sobre todo en su primera época como investigador, estuvieron moduladas por influencias procedentes desde el ámbito de la psiquiatría. Entre éstas cabe resaltar el contacto mantenido con el neuropsiquiatra Luis Simarro, quien le enseñó el método argéntico de Golgi, decisivo para sus futuros descubrimientos, o las corrientes psiquiátricas asociadas al fenómeno de la sugestión hipnótica, que ejercieron algún papel en las interpretaciones psico-fisiológicas del histólogo. La psicoterapia hipnótica gozaba de gran actualidad internacional cuando Cajal era catedrático de Anatomía en Valencia, gracias a la polémica confrontación científica mantenida durante la década de 1880 entre la denominada Escuala de París, encabezada por Charcot, de carácter más experimental y vinculada al estudio de las neurosis histéricas, y la Escuela de Nancy, representada por Bernheim y Liébault, que concedía más protagonismo a la sugestión terapéutica. Cajal se decantó por esta última y fundó un Comité de Investigaciones Psicológicas para profundizar en el conocimiento de la sugestión hipnótica. Simarro, tras un periodo de formación en París de varios años, creó en 1887 un pequeño laboratorio privado en Madrid, donde desarrolló todas las técnicas histológicas aprendidas en Francia. Ese año Cajal fue nombrado juez de oposiciones a cátedras, por loq ue hubo de trasladarse a Madrid, y para aprovechar su estancia en dicha ciudad efectuó una serie de visitas a distintos centros donde se practicaban los estudios micrográficos, entre ellos el de Simarro. En esta visita, Cajal tomó contacto con el proceder argéntico de Golgi, tan decisivo para su futura carrera histológica

The scientific trajectory and the neurohistological vocation of Santiago Ramón y Cajal, mainly in his first time as researcher, were modulated by originating influences from the scope of psychiatry. Between these, it is possible to emphasize the contact maintained with the neuropsychiatrist Luis Simarro, who taught the Golgi´s silverchromate method to him, decisive for its future discoveries, or the psychiatric currents associated to the phenomenon of the hypnotic suggestion, that they exerted certain roles in the psycho-physiological interpretations of Cajal. The hypnotic psychotherapy enjoyed the great international actually when Cajal was professor of Anatomy in Valencia University, thanks to the controversial scientific confrontation maintained during the decade of 1880 between the denominated School of Paris, headed by Charcot, of more experimental character and tie to the study of the hysterical neurosis, and the School of Nancy, represented by Bernheim and Liébault, that it granted more protagonism to the therapeutic suggestion. Cajal showed preference for this last one and founded a Committee of Psychological Investigations to deepen in the knowledge of the hypnotic suggestion. Simarro, after a period of formation in Paris of several years, created in 1887 a small private laboratory in Madrid, where he developed all the histological techniques learned in France. That year, Cajal was assigned to the professorial appointments committee, reason why he had to be travelled to Madrid, and to take advantage of its stay in this city, he carried out a series of visits to different centres where the micrographical studies practiced, among them the one of Simarro laboratory. In this visit, Cajal took contact with the Golgi´s silver-chromate procedure, so decisive for its future histological career

Risperidone versus zuclopenthixol in the treatment of schizophrenia with substance abuse comorbidity: a long-term randomized, controlled, crossover study

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Background: Substance use disorders (SUDs) are present in more than 50 percents of subjects diagnosed with schizophrenia. However, there are no controlled studies assessing the efficacy of antipsychotic drugs in this subgroup of patients. The aim of the present work was to compare the efficacy of risperidone and zuclopenthixol in a sample of schizophrenic subjects with dual diagnosis. Method: Thirty-three male were selected for treatment with risperidone, while another 33 were treated with zuclopenthixol. Substances most commonly used were alcohol, cannabis (both 82 percents) and cocaine (32 percents). Patients were randomized and treated for the first six months with one antipsychotic and the second six months with the other antipsychotic. Psychopathological and clinical scales were used every two months. Participants received training on how to reduce their consumption of substances (Substance Abuse Management Module, SAMM). Results: During the first six months risperidone group patients presented fewer positive urine tests and showed better compliance with the SAMM programme. In the second period the patients treated with risperidone significantly improved their scores on the PANSS-negative subscale. Differences between the CGIs indicated that the subjects who moved from risperidone to zuclopenthixol worsened, while those who moved from zuclopenthixol to risperidone significantly improved. Conclusions: Risperidone was more effective than zuclopenthixol in improving the symptoms of schizophrenia and substance use (AU)

"The herbs that have the property of healing...,": the phytotherapy in Don Quixote.

Don Quixote, the most outstanding novel of the Spanish literature, represents a documentary source widely used among those specialists who intend to deepen in the knowledge of the late Renaissance society. In this sense, Don Quixote has been also studied from a medical perspective, including a general therapeutical view (oils, ointments, balms, poultices, syrups and other pharmacy preparations). We have tackled Don Quixote from the phytotherapeutic and ethnopharmacological perspective, a barely explored field. In this work, we intend to study the medicinal plants used during the Cervantine time for the treatment de multiples diseases (sedatives like opium, laxatives and emetics like hellebore, tonics and irritants) and we analyze the specific herbal therapies (balms, purgatives and emetics, ointments and poultices), which Cervantes reveals to us in his novel. Among them, the rhubarb root (Rheum spp. or Rumex spp.) should be highlighted, as well as the seeds of gopher spurge (Euphorbia lathyris), chicory (Cichorium intybus) and rosemary (Rosmarinus officinalis), primary component of the famous Balsam of Fierabras. Also, we have examined the possible scientific influences, which might have inspired Cervantes in this field, mainly the work of Andrés Laguna (Dioscorides' Materia Medica).

Management of depression in primary care: a survey of general practitioners in Spain.

OBJECTIVE: The objective of this study was to analyze the current situation of health care for depression in Spain according to general practitioners' (GPs') opinion and how it has evolved over the last 20 years on the basis of comparisons with the results of two previous social-health studies (published in 1997 and 1982). METHOD: Throughout 2002, we recorded the opinions of 238 GPs after asking them to fill up structured questionnaires in which they rated care, clinical, therapeutic and care quality aspects. RESULTS: Only 40% of patients with depression visit a doctor, implying a very high level of "concealed epidemiology." The diagnostic instruments most commonly used are assessment of symptoms and patient interview. Pharmacological treatment is the option GPs most commonly choose once a depression diagnosis is established (80% vs. 50% in 1997; P<.001). Selective serotonin reuptake inhibitors (SSRIs), together with anxiolytics, are the drugs most commonly used in the treatment of depression. SSRIs are the first choice drugs, being preferred to tricyclic antidepressants and anxiolytics, which were the most popular options for GPs in the 1997 survey. Areas where there is a need for improvement are time devoted to consultation, coordination between GPs and psychiatrists and waiting lists. CONCLUSIONS: The quality of health care for depression has improved in recent years, thanks to changes in the attitudes of GPs and the evolution of pharmacological treatment.

Abordaje farmacológico de las recaídas en las adicciones / Pharmacological therapy of the reapses in the opiate addiction

La adicción es una enfermedad crónica, que requiere tratamiento durante la mayor parte de la vida del paciente y como tal, las recaídas y el incumplimiento terapéutico son hechos habituales. En las dos últimas décadas se ha avanzado notablemente en el conocimiento de las bases neuropsicobiológicas y farmacológicas de las adicciones, lo que ha permitido concluir que estamos ante una patología tratable. En la actualidad, se acepta que la fase más importante en la farmacoterapia de la dependencia es la que la que corresponde a la prevención de las recaídas. En este sentido, los antagonistas de los receptores opiáceos, en especial la naltrexona, constituye el avance más importante en esta fase preventiva. Su utilidad se ha demostrado en la prevención de la recaída a opiáceos y, más recientemente, en pacientes alcohólicos. De hecho, la naltrexona reduce en un 50 por ciento la tasa de recaídas y los individuos permanecen más tiempo abstinentes. Otros agentes utilizados en este campo son el acamprosato y los fármacos moduladores de la transmisión serotoninérgica, como la buspirona o los inhibidores selectivos de la recaptación de serotonina, fluoxetina y citalopram. Desafortunadamente, para otras dependencias (cocaína, cánnabis, anfetaminas, éxtasis, etc.) no existe un abordaje farmacológico específico, si bien se han empleado algunos de los fármacos comentados, así como antagonistas dopaminérgicos, con resultados poco significativos (AU)