Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder.

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and "Z drugs") has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile.

Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and “Z drugs”) has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile. (AU)

Extrapyramidal adverse events and anticholinergics use after the long-term treatment of patients with schizophrenia with the new long-acting antipsychotic Risperidone ISM®: results from matching-adjusted indirect comparisons versus once-monthly formulations of Paliperidone palmitate and Aripiprazole monohydrate in 52-week studies.

BACKGROUND: Risperidone ISM® is a newly developed long-acting injectable (LAI) treatment for schizophrenia in adults. In the absence of head-to-head comparisons with other similar antipsychotics, the objective of this study was to generate indirect evidence of some aspects of the safety and tolerability of Risperidone ISM compared to other LAI antipsychotics for treatment of patients with schizophrenia in the maintenance treatment setting. METHODS: A literature review was conducted systematically to identify maintenance treatment studies reporting safety and tolerability outcomes for LAI antipsychotic therapies. Following an assessment of between-trial heterogeneity, a matching-adjusted indirect comparison (MAIC) was performed to account for between-trial imbalances in patient characteristics and to generate comparative evidence for safety and tolerability endpoints. RESULTS: The analysis showed that incidence of extrapyramidal symptoms (EPS) was found to be numerically, but not statistically significantly, lower in patients receiving Risperidone ISM than in those receiving Paliperidone palmitate (PP) (OR [95% CI] 0.63 [0.29, 1.38], p = 0.253) and statistically significantly lower than with Aripiprazole monohydrate once-monthly (AOM) (OR [95% CI] 0.25 [0.12, 0.53], p < 0.001). Use of anticholinergic agents for the alleviation of EPS was also shown to be significantly lower in Risperidone ISM patients than in those receiving PP (OR [95% CI] 0.29 [0.10, 0.83], p = 0.021) or AOM (OR [95% CI] 0.01 [0.003, 0.06], p < 0.001), suggesting a superior tolerability profile for clinically relevant EPS. Results from the sensitivity analyses comparing stabilized and stable patients receiving Risperidone ISM to those receiving AOM yielded similarly favorable conclusions in line with the base case analyses. CONCLUSIONS: This MAIC is consistent with the safety and tolerability results obtained during the PRISMA-3 clinical trial in the long-term treatment of schizophrenia and suggests a favorable safety and tolerability profile in terms of EPS incidence and anticholinergic agent use, relative to other antipsychotic therapies used for treatment of patients with schizophrenia in the maintenance setting.

Depression in Major Neurodegenerative Diseases and Strokes: A Critical Review of Similarities and Differences among Neurological Disorders.

Depression and anxiety are highly prevalent in most neurological disorders and can have a major impact on the patient's disability and quality of life. However, mostly due to the heterogeneity of symptoms and the complexity of the underlying comorbidities, depression can be difficult to diagnose, resulting in limited recognition and in undertreatment. The early detection and treatment of depression simultaneously with the neurological disorder is key to avoiding deterioration and further disability. Although the neurologist should be able to identify and treat depression initially, a neuropsychiatry team should be available for severe cases and those who are unresponsive to treatment. Neurologists should be also aware that in neurodegenerative diseases, such as Alzheimer's or Parkinson's, different depression symptoms could develop at different stages of the disease. The treatment options for depression in neurological diseases include drugs, cognitive-behavioral therapy, and somatic interventions, among others, but often, the evidence-based efficacy is limited and the results are highly variable. Here, we review recent research on the diagnosis and treatment of depression in the context of Alzheimer's disease, Parkinson's disease, and strokes, with the aim of identifying common approaches and solutions for its initial management by the neurologist.

Aripiprazole for the treatment of schizophrenia: Recommendations of a panel of Spanish experts on its use in clinical practice.

OBJECTIVES: Aripiprazole is an antipsychotic with a partial agonism of dopamine D2 and D3 receptors. This differential mechanism implies a rigorous appraisal of the appropriate therapeutic strategies in certain situations. To answer currently unsolved clinical questions about the use of oral and long-acting injectable (LAI) aripiprazole, we present here an expert consensus from 12 Spanish psychiatrists and a pharmacologist with extensive experience in the use of this antipsychotic. METHODS: Through one face-to-face session and online collaboration, we reached consensus and established practical recommendations based on scientific evidence and clinical experience. We classified the available scientific literature according to SIGN system and attributed a level of evidence to each reviewed article. RESULTS: The recommendations were divided according to (i) chronological dimension (based on previous treatments, including patients naïve or not to antipsychotic treatment and maintenance regimen), and (ii) dimension related to therapeutic options, comprising switches to aripiprazole and the most used combinations with this antipsychotic. CONCLUSIONS: We recommend considering aripiprazole as first treatment option in the early stages of schizophrenia and in patients with affective symptoms and contemplating a switch to aripiprazole LAI in all candidate patients. Importantly, switches from other antipsychotics should consider previous antipsychotic history and exposure to aripiprazole. KEYPOINTSAripiprazole can be considered as first treatment option in early stages of schizophrenia and in patients with significant affective symptoms.Aripiprazole LAI shows better adherence than oral aripiprazole and could be considered in all candidate patients.Before switching to aripiprazole, detailed information about previous antipsychotic history should be gathered.Switch to aripiprazole should be managed differently for aripiprazole naïve and non-naïve patients.Rigorous and controlled studies on antipsychotics in real clinical practice should be carried out.

Risperidone ISM as a New Option in the Clinical Management of Schizophrenia: A Narrative Review.

Antipsychotics are the cornerstone of schizophrenia treatment. Lack of treatment adherence encouraged the development of injectable long-acting antipsychotics. However, second-generation or atypical antipsychotics require a loading dose at the start of treatment and eventually oral supplementation to achieve therapeutic plasma levels. This review discusses the evidence emerging from studies evaluating the pharmacokinetics, efficacy and safety of the intramuscular formulation of risperidone based on in situ microparticles (ISM). ISM® technology applied to risperidone allows therapeutic levels of the active moiety to be achieved within 2 h of intramuscular administration without the need for loading doses or oral supplementation, leading to a constant release over the whole dosing period. Risperidone ISM showed significant antipsychotic efficacy versus placebo in the Positive and Negative Syndrome Scale (PANSS) total score (p < 0.0001) and on the subscales of positive symptoms after 8 days, negative symptoms in 8 weeks, and general psychopathology during the 12 weeks of treatment. The improvement was also statistically significant (p < 0.0001) against placebo in the Clinical Global Impressions-Severity of Illness scale (CGI-S) score at the end of the treatment. Risperidone ISM was generally well tolerated and the most frequently reported adverse events were similar to those observed with other risperidone formulations. There is clinical evidence that these results are maintained in the long term. In conclusion, four-weekly risperidone ISM (75 mg and 100 mg) is an adequate antipsychotic for treating schizophrenia, both in the short term when an exacerbation has recently occurred and for long-term maintenance, since it provides rapid onset of action and sustained efficacy, as well as being safe and well tolerated.

Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder characterised by persistent inattention, hyperactivity and impulsivity. Moreover, ADHD is commonly associated with other comorbid diseases (depression, anxiety, bipolar disorder, etc.). The ADHD symptomatology interferes with subject function and development. The treatment of ADHD requires a multidisciplinary approach based on a combination of non-pharmacological and pharmacological treatments with the aim of ameliorating the symptomatology; among first-line pharmacological treatments are stimulants [such as methylphenidate (MPH) and lisdexamfetamine dimesylate (LDX)]. In this review we explored recent ADHD- and stimulants-related literature, with the aim of compiling available descriptions of molecular pathways altered in ADHD, and molecular mechanisms of current first-line stimulants MPH and LDX. While conducting the narrative review, we applied structured search strategies covering PubMed/MEDLINE database and performed handsearching of reference lists on the results of those searches. The aetiology and pathophysiology of ADHD are incompletely understood; both genetic and environmental factors have been associated with the disorder and its grade of burden, and also the relationship between the molecular mechanisms of pharmacological treatments and their clinical implications. The lack of comprehensive understanding of the underlying molecular pathology makes both the diagnosis and treatment difficult. Few published studies evaluating molecular data on the mechanism of action (MoA) of MPH and LDX on ADHD are available and most of them are based on animal models. Further studies are necessary to improve the knowledge of ADHD pathophysiology and how the MoAs of MPH and LDX differentially modulate ADHD pathophysiology and control ADHD symptomatology.

Role of serendipity in the discovery of classical antidepressant drugs: Applying operational criteria and patterns of discovery.

The role played by serendipity in the origin of modern psychopharmacology has proven to be controversial in scientific literature. In its original meaning (Walpole), serendipity refers to discoveries made through a combination of accidents and sagacity. We have implemented an operational definition of serendipity based on finding something unexpected or unintended, regardless of the systematic process that led to the accidental observation, and we have established four different patterns of serendipitous attributability. In this paper, we have analyzed the role of serendipity in the discovery and development of classical antidepressant drugs, tricyclic antidepressants and monoamine oxidase inhibitors as well as heterocyclic, "atypical" or "second generation" antidepressants. The discovery of the antidepressant properties of imipramine and iproniazid, the prototypes of tricyclic antidepressants and monoamine oxidase inhibitors, respectively, fits the mixed type II pattern; initial serendipitous discoveries (imipramine was an antipsychotic and iproniazid was an anti-tuberculosis agent) led secondarily to non-serendipitous discoveries. But the other components of these two families of drugs were developed specifically as antidepressants, modifying the chemical structure of the series leaders, thereby allowing all of them to be included in the type IV pattern, characterized by the complete absence of serendipity. Among the heterocyclic drugs, mianserin (originally developed as an antihistamine) also falls into the type II pattern.

Tianeptina, un abordaje farmacológico atípico de la depresión / Tianeptine, an atypical pharmacological approach to depression

La introducción de los primeros antidepresivos en la década de los cincuenta del sigloxx modificó de forma radical el tratamiento de la depresión, a la vez que aportó información sobre aspectos fisiopatológicos de esta enfermedad. Los nuevos fármacos antidepresivos (agomelatina, tianeptina, vortioxetina) están aportando datos que dan lugar a hipótesis fisiopatológicas de la depresión que difieren de la clásica teoría monoaminérgica. En este sentido, la tianeptina, un fármaco atípico por su mecanismo de acción diferencial, contribuye a clarificar que en la fisiopatología de la depresión hay algo más que monoaminas. Así, la tianeptina no modifica la tasa de serotonina extracelular, por lo que no aumenta ni disminuye la recaptación de serotonina. La administración crónica de tianeptina no altera la densidad ni la afinidad de más de un centenar de receptores clásicos relacionados con la depresión. Recientemente se ha descrito una acción débil de la tianeptina sobre receptores opioidesMu que podría explicar la liberación de dopamina en el sistema límbico y su participación en la modulación de mecanismos glutamatérgicos. Estos mecanismos sustentan la hipótesis del posible mecanismo de acción de este antidepresivo. La tianeptina es un antidepresivo con propiedades ansiolíticas que puede mejorar síntomas somáticos. La tianeptina como modulador glutamatérgico, entre otros mecanismos, permite abordar la depresión desde un punto de vista diferente al del resto de antidepresivos

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants

Tratamiento farmacológico del trastorno obsesivo-compulsivo en adultos: una guía de práctica clínica basada en el método ADAPTE / Pharmacological treatment of obsessive compulsive disorder in adults: a clinical practice guideline based on the ADAPTE methodology

A pesar de la existencia de tratamientos efectivos basados en la evidencia para el tratamiento del trastorno obsesivo-compulsivo (TOC), el abordaje de esta enfermedad sigue siendo subóptimo. Disponer de una guía terapéutica farmacológica del TOC puede ayudar a mejorar el manejo de la enfermedad en nuestro entorno y contribuir a reducir la carga de la enfermedad para el paciente. Con el patrocinio de la Sociedad Española de Psiquiatría un grupo de expertos ha desarrollado una guía para el tratamiento farmacológico del TOC a partir de algunas guías existentes siguiendo la metodología de la ADAPTE Collaboration. En este artículo se resume el proceso de elaboración de esta guía y las recomendaciones adoptadas por consenso por el grupo elaborador de las guías agrupadas en 5 áreas de interés: tratamiento agudo, duración del tratamiento, predictores de respuesta y síntomas especiales, respuesta parcial a falta de respuesta al tratamiento y poblaciones especiales

Despite the existence of effective evidence-based treatments for the management of obsessive-compulsive disorder (OCD), the therapeutic approach to this disease remains suboptimal. The availability of a therapeutic pharmacological guideline for OCD could help to improve the management of the disease in our setting and to reduce the burden of disease for the patient. With the sponsorship of the Spanish Society of Psychiatry, a group of experts has developed a guideline for the pharmacological treatment of OCD based on the recommendations of existing guidelines and following the methodology of the ADAPTE Collaboration. This article summarises the process of preparing this guideline and the recommendations adopted by consensus by a guideline panel grouped into five areas of interest: acute treatment, duration of treatment, predictors of response and special symptoms, partial response to lack of response to treatment, and special populations

Pharmacological treatment of obsessive compulsive disorder in adults: A clinical practice guideline based on the ADAPTE methodology. / Tratamiento farmacológico del trastorno obsesivo-compulsivo en adultos: una guía de práctica clínica basada en el método ADAPTE.

Despite the existence of effective evidence-based treatments for the management of obsessive-compulsive disorder (OCD), the therapeutic approach to this disease remains suboptimal. The availability of a therapeutic pharmacological guideline for OCD could help to improve the management of the disease in our setting and to reduce the burden of disease for the patient. With the sponsorship of the Spanish Society of Psychiatry, a group of experts has developed a guideline for the pharmacological treatment of OCD based on the recommendations of existing guidelines and following the methodology of the ADAPTE Collaboration. This article summarises the process of preparing this guideline and the recommendations adopted by consensus by a guideline panel grouped into five areas of interest: acute treatment, duration of treatment, predictors of response and special symptoms, partial response to lack of response to treatment, and special populations.

Trends in the scientific literature on atypical antipsychotic drugs in the United Kingdom: a bibliometric study.

OBJECTIVE: A bibliometric study was undertaken of peer-reviewed publications on atypical antipsychotic drugs (AADs) from the United Kingdom and the findings are presented herein. METHODS: We selected the documents from the Scopus database. We applied several production and dispersion bibliometric indicators, including Price's law on the growth of the scientific literature, and Bradford's law. We also calculated a so-called 'participation index' across different countries. The bibliometric data were thereafter correlated with social and health data from the UK, including total per capita expenditure on health and gross domestic expenditure. RESULTS: A total of 4156 original manuscripts were published within the timeframe 1967-2015. Our results are in accord with Price's law, with scientific output demonstrating exponential growth (r = 0.9227, as against an r = 0.8766 after adjustment). The drugs most widely evaluated were clozapine (465 documents), olanzapine (263) and risperidone (248). Stratification into Bradford zones produced a nucleus represented by the Journal of Psychopharmacology (168 articles) and British Journal of Psychiatry (159 articles). A total of 1250 different journals were evaluated. CONCLUSIONS: Publications on AADs in the UK have shown exponential growth across the studied period, which is in line with the progressively burgeoning novel AAD releases. No evidence of a saturation point was observed.

Proyecto adapta: adecuación del tratamiento en dolor irruptivo oncológico / Adapta project: adequacy of treatment in breakthrough cancer pain

Introducción: El fentanilo de administración transmucosa tiene características específicas que lo convierten en el fármaco adecuado para el tratamiento del dolor irruptivo oncológico (DIO). Aunque en España existe un amplio consenso sobre la idoneidad de la administración de fentanilo transmucoso para el DIO, es relevante conocer cómo los oncólogos adecuan su prescripción al paciente y cuáles son los factores determinantes de la elección de las diferentes formas farmacéuticas. Objetivos: El objetivo principal de este proyecto fue identificar y priorizar los atributos que los oncólogos médicos españoles tienen en cuenta cuando valoran las opciones de tratamiento con fentanilo transmucoso en pacientes con DIO. Métodos: Un comité científico realizó una tipificación de 14 atributos relevantes en la prescripción de fentanilo transmucoso para el DIO. Posteriormente se generó un dossier de evidencia científica comparando estos 14 atributos entre los distintos fentanilos transmucosos disponibles, que se compartió con el panel de expertos (115 oncólogos médicos). Tras una exhaustiva revisión del documento, los participantes realizaron una votación online de priorización de los atributos. Resultados: De catorce atributos analizados, siete consiguieron un consenso de ≥ 50 % de los participantes: el inicio de la acción analgésica (84 %), la adecuación del efecto del fentanilo al perfil del episodio de DIO (72 %), la facilidad de uso por los pacientes y cuidadores (69 %), la duración del efecto (58 %), la presencia de mucositis (57 %),la facilidad de titulación de la dosis óptima (57 %) y las presentaciones y dosis disponibles (59 %). Conclusiones: Los atributos más valorados fueron los relativos a la rapidez de acción del tratamiento analgésico y su adaptación al perfil del DIO, algo esperable dadas las características clínicas del episodio de DIO. Como atributos menos valorados aparecen el riesgo de abuso o conductas aberrantes y la presencia de rinitis para su administración, lo que indica que la existencia de estos factores no tiene tanta influencia en la elección del tratamiento para el abordaje del DIO. Estos resultados permitirán a los oncólogos médicos conocer qué atributos deben ser tenidos en cuenta a la hora de personalizar los tratamientos del paciente con DIO con el objetivo de mejorar la adecuación de la analgesia de rescate

Introduction: Transmucosal fentanyl has specific properties which make it ideal for the treatment of breakthrough cancer pain (BTCP). Although there is a broad consensus for the administration of transmucosal fentanyl for BTCP in Spain, there is uncertainty as to the way oncologists adjust their prescription to the patient and what are the determinants of the choice of different pharmaceutical forms. Objectives: The main objective of this study was to analyze and prioritize the attributes that Spanish oncologists consider when assessing treatment options with transmucosal fentanyl in patients with BTCP. Methods: A Scientific Committee performed a classification of 14 relevant attributes in the prescription of transmucosal fentanyl for BTCP. Subsequently, a dossier of scientific evidence was generated comparing these 14 attributes among the different available transmucosal fentanyl formulations, which was shared with the panel of experts (115 Medical Oncologists). After a thorough review of the document, the participants carried out an online vote for the prioritization of the attributes. Results: Out of fourteen attributes analyzed, seven achieved a consensus of ≥ 50 % of the participants: the start of the analgesic action (84 %), the adequacy of the effect of fentanyl to the BTCP episode (72 %), the ease of use (58 %), the presence of mucositis (57 %), the ease of titration of the optimal dose (57%), and the variety of presentations and doses available (59 %). Conclusions: The most valued attributes were those related to the speed of action of the analgesic treatment and its adaptation to the BTCP profile, something to be expected given the spontaneous, unpredictable, and transitory nature of BTCP. As less valued attributes appear the risk of abuse or aberrant behavior and the presence of rhinitis for its administration, which indicates that the existence of these factors do not influence the choice of treatment for BTCP. These results will allow medical oncologists to know what attributes should be taken into account when customizing the patient's treatment of BTCP in order to improve the adequacy of rescue analgesia

Tianeptine, an atypical pharmacological approach to depression. / Tianeptina, un abordaje farmacológico atípico de la depresión.

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant. Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants.

A survey of perceptions, attitudes, knowledge and practices of medical oncologists about cancer pain management in Spain

Purpose: To monitor oncologists’ perspective on cancer pain management. Methods: An anonymized survey was conducted in two waves. First, over a convenience sample of oncologists known to be particularly concerned with the management of pain. Second, using a random sample of oncologists. Results: In total, 73 and 82 oncologists participated in the first and second wave, respectively. Many oncologists reported to have good knowledge of analgesic drugs (95.9%), the mechanism of action of opioids (79.5%), and good skills to manage opioid-related bowel dysfunction (76.7%). Appropriate adjustment of background medication to manage breakthrough pain was reported by 95.5% of oncologists. Additionally, 87.7% (68.3% in the second wave, p = 0.035) of oncologists reported suitable opioid titration practices, and 90.4% reported to use co-adjuvant medications for neuropathic pain confidently. On the other hand, just 9.6% of oncologists participated in multidisciplinary pain management teams, and merely 30.3 and 27.1% reported to routinely collaborate with the Pain Clinics or involve other staff, respectively. Only 26.4% of the oncologists of the second wave gave priority to pain pathophysiology to decide therapies, and up to 75.6% reported difficulties in treating neuropathic pain. Significantly less oncologists of the second wave (82.9 vs. 94.5%, p = 0.001) used opioid rotation routinely. Conclusions: Unlike in previous surveys, medical oncologists reported in general good knowledge and few perceived limitations and barriers for pain management. However, multi-disciplinary management and collaboration with other specialists are still uncommon. Oncologists’ commitment to optimize pain management seems important to improve and maintain good practices

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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.

A survey of perceptions, attitudes, knowledge and practices of medical oncologists about cancer pain management in Spain.

PURPOSE: To monitor oncologists' perspective on cancer pain management. METHODS: An anonymized survey was conducted in two waves. First, over a convenience sample of oncologists known to be particularly concerned with the management of pain. Second, using a random sample of oncologists. RESULTS: In total, 73 and 82 oncologists participated in the first and second wave, respectively. Many oncologists reported to have good knowledge of analgesic drugs (95.9%), the mechanism of action of opioids (79.5%), and good skills to manage opioid-related bowel dysfunction (76.7%). Appropriate adjustment of background medication to manage breakthrough pain was reported by 95.5% of oncologists. Additionally, 87.7% (68.3% in the second wave, p = 0.035) of oncologists reported suitable opioid titration practices, and 90.4% reported to use co-adjuvant medications for neuropathic pain confidently. On the other hand, just 9.6% of oncologists participated in multidisciplinary pain management teams, and merely 30.3 and 27.1% reported to routinely collaborate with the Pain Clinics or involve other staff, respectively. Only 26.4% of the oncologists of the second wave gave priority to pain pathophysiology to decide therapies, and up to 75.6% reported difficulties in treating neuropathic pain. Significantly less oncologists of the second wave (82.9 vs. 94.5%, p = 0.001) used opioid rotation routinely. CONCLUSIONS: Unlike in previous surveys, medical oncologists reported in general good knowledge and few perceived limitations and barriers for pain management. However, multi-disciplinary management and collaboration with other specialists are still uncommon. Oncologists' commitment to optimize pain management seems important to improve and maintain good practices.

A Bibliometric Analysis of Scientific Production on Second-Generation Anti-Psychotic Drugs in Malaysia.

OBJECTIVE: We carried out a bibliometric study on the scientific papers related to second-generation antipsychotic drugs (SGAs) in Malaysia. METHODS: With the SCOPUS database, we selected those documents made in Malaysia whose title included descriptors related to SGAs. We applied bibliometric indicators of production and dispersion, as Price's law and Bradford's law, respectively. We also calculated the participation index of the different countries. The bibliometric data were also been correlated with some social and health data from Malaysia (total per capita expenditure on health and gross domestic expenditure on R&D). RESULTS: We found 105 original documents published between 2004 and 2016. Our results fulfilled Price's law, with scientific production on SGAs showing exponential growth (r = 0.401, vs. r = 0.260 after linear adjustment). The drugs most studied are olanzapine (9 documents), clozapine (7), and risperidone (7). Division into Bradford zones yields a nucleus occupied by the Medical Journal of Malaysia, Singapore Medical Journal, Australian and New Zealand Journal of Psychiatry, and Pharmacogenomics. Totally, 63 different journals were used, but only one in the top four journals had an impact factor being greater than 3. CONCLUSION: The publications on SGAs in Malaysia have undergone exponential growth, without evidence a saturation point.

A bibliometric analysis of scientific production on atypical antipsychotic drugs from Italy

Objective: A bibliometric study of peer-reviewed scientific publications on atypical antipsychotic drugs (AADs) from Italy is herein presented. Methods: We selected the documents from Scopus database. We applied several bibliometric indicators of production and dispersion, including Price's Law about the increase of scientific literature, and Bradford's Law. We also calculated the participation index across different countries. The bibliometric data have also been correlated with some social and health data sourcing in Italy, such as total per capita expenditure on health and gross domestic expenditure. Results: A total of 2949 original documents were published within the period 1972-2015. Our results state fulfilment of Price's Law, with scientific production showing exponential growth (r=0.901, as against an r=0.838 after linear adjustment). The drugs most widely studied were clozapine (257 documents), risperidone (179), and olanzapine (172). Stratification into Bradford zones yielded a nucleus represented by the Journal of Clinical Psychopharmacology and Rivista di Psichiatria (58 articles, each one). A total of 1091 different journals were evaluated. Conclusions: The publications on AADs in Italy have undergone exponential growth over the studied period, which is in line with the progressively burgeoning on novel AAD releases. No evidence of saturation point was observed.

Mechanism of action of guanfacine: a postsynaptic differential approach to the treatment of attention deficit hyperactivity disorder (adhd).

The treatment of ADHD has focused on the use of psychostimulants drugs such as methylphenidate or amphetamine and derivatives, or not stimulants agents, such as atomoxetine. These agents act mainly on catecholaminergic presynaptic mechanisms. Recently the European Medicines Agency (EMA) has approved another not psychostimulant drug, guanfacine extended release (ER), as a new option to the treatment of ADHD, which acts at postsynaptic level. Guanfacine stimulates postsynaptic alfa-2A adrenergic receptors so it inhibits the production of cAMP and closes HCN channels enhancing the effectiveness of the signal of the pyramidal neurons of the prefrontal cortex (PFC), thus improving working memory and attention. In addition, stimulation of the alpha-2A receptors promotes growth and maturation of the dendritic spines of pyramidal neurons of the medial PFc, that are associated with brain function such as learning and memory. In contrast with psychostimulants or atomoxetine, guanfacine mimics noradrenaline stimulation of postsynaptic receptors alfa-2A on the PFC.