Cytotoxicity evaluation of haloperidol, clozapine and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells

Abstract Schizophrenia is an illness that affects 26 million people worldwide. However, conventional antipsychotics present side effects and toxicity, highlighting the need for new antipsychotics. We aimed to evaluate the cytotoxicity of haloperidol (HAL), clozapine (CLO), and a new molecule with antipsychotic potential, PT-31, in NIH-3T3 cells. The neutral red uptake assay and the MTT assay were performed to evaluate cell viability and mitochondrial activity, morphological changes were assessed, and intracellular reactive oxygen species (ROS) detection was performed. HAL and CLO (0.1 µM) showed a decrease in cell viability in the neutral red uptake assay and in the MTT assay. In addition, cell detachment, content decrease, rounding and cell death were also observed at 0.1 µM for both antipsychotics. An increase in ROS was observed for HAL (0.001, 0.01 and 1 µM) and CLO (0.01 and 1 µM). PT-31 did not alter cell viability in any of the assays, although it increased ROS at 0.01 and 1 µM. HAL and CLO present cytotoxicity at 0.1 µM, possibly through apoptosis and necrosis. In contrast, PT-31 does not present cytotoxicity to NIH-3T3 cells. Further studies must be performed for a better understanding of these mechanisms and the potential risk of conventional antipsychotics

Bilateral ocular deposit of chlorpromazine / Depósito ocular bilateral de clorpromazina

ABSTRACT Chlorpromazine is a medication widely used in psychiatry for the treatment of psychoses, especially schizophrenia. Since 1964, published articles have been correlating this medication with the appearance of ocular alterations. In this paper, we report the case of a 65-year-old patient with ocular effects due to long-term therapy with chlorpromazine. Biomicroscopy of both eyes presented diffuse granular brown deposits, most prominent at the deep stroma and corneal endothelium level. Also showed anterior subcapsular brown deposits with a stellate pattern in the lens. The total amount exceeds 2.000g (significant for the ocular alterations described) considering the patient's daily dosage of chlorpromazine of 300mg for ten years. After performing complete ophthalmic evaluation and discarding other causes for the ocular deposits, we diagnosed a secondary corneal deposit and cataract due to the use of chlorpromazine. This case reinforces the importance of periodic follow-up with an ophthalmologist for chlorpromazine users to trace ocular changes, heeding the exposure time and its dosage.

RESUMO A clorpromazina é uma medicação muito empregada na psiquiatria para tratamento de psicoses, especialmente em casos de esquizofrenia. Desde 1964 existem artigos publicados que correlacionam o uso dessa medicação com o aparecimento de alterações oculares. Neste trabalho, relatamos o caso de um paciente de 65 anos com efeitos oculares devido à terapia de longo prazo com clorpromazina. A biomicroscopia de ambos os olhos apresentou depósitos granulares difusos e de cor marrom, mais proeminente ao nível do estroma profundo e do endotélio da córnea, além de depósitos castanhos subcapsulares anteriores centrais em um padrão estrelado no cristalino. Considerando a dose diária de clorpromazina de 300mg por 10 anos usada pelo paciente, a quantidade total ultrapassa 2.000g (dose considerada significativa para as alterações oculares descritas). Após avaliação oftalmológica completa e descartado outras causas desses depósitos oculares, foram diagnosticados depósito corneano e catarata secundários ao uso de clorpromazina. O caso apresentado reforça a importância do acompanhamento oftalmolÓgico periÓdico de usuários de clorpromazina para o rastreio de alteraçÕes oculares, atentando-se ao tempo de exposição à droga e à posologia da mesma.

Necrólisis epidérmica tóxica en una adolescente diagnosticada de trastorno bipolar II y tratada con lamotrigina / Toxic epidermal necrolysis in an adolescent with Bipolar Disorder II and treated with Lamotrigine

Resumen La necrólisis epidérmica tóxica es una enfermedad cutánea severa, la mayoría de las veces desencadenada como reacción adversa a medicamentos, con alta morbilidad y mortalidad. La lamotrigina, junto a otros medicamentos estabilizadores del ánimo, constituye la causa medicamentosa más frecuente de esta complicación, consistente en necrosis y esfacelo de la epidermis y mucosas en más del 30 % de la superficie corporal, con la consecuente pérdida de líquidos y electrolitos, respuesta inflamatoria sistémica, susceptibilidad a infecciones y hasta sepsis, además de posibles secuelas ominosas. En la actualidad, el diagnóstico de trastorno bipolar se hace con mayor frecuencia, incluyendo al grupo etario de niños y adolescentes, pero tal proceso diagnóstico se caracteriza por dificultades y controversias en mayor cuantía que otros diagnósticos psiquiátricos. Ello obliga a una meticulosa elucubración diagnóstica y selección farmacológica, con pleno conocimiento de las moléculas del arsenal medicamentoso para, en caso de prescripción de lamotrigina, establecer una escrupulosa psicoeducación al paciente y sus familiares además de un seguimiento estricto y cercano. A propósito del caso de una adolescente diagnosticada de trastorno bipolar II, que recibió lamotrigina durante un episodio depresivo pero con un esquema posológico inadecuado, y desarrolló necrólisis epidérmica tóxica, revisamos y comentamos la literatura correspondiente. Concluimos en que es preciso extremar las precauciones al decidir el uso de lamotrigina para minimizar el riesgo de este severo efecto adverso.

Toxic epidermal necrolysis is a severe skin disease, most often triggered as an adverse drug reaction, with high morbidity and mortality. Lamotrigine, together with other mood stabilizer drugs, constitutes the most frequent drug that causes this complication, which consists of necrosis and detachment of the epidermis and mucosa in more than 30% of the body surface, with the consequent loss of water and electrolytes, systemic inflammatory response, susceptibility to infections and even sepsis, in addition to other possible ominous sequelae. Currently, the diagnosis of bipolar disorder is made more frequently, including the age group of children and adolescents, but such a diagnostic process is characterized by difficulties and controversies to a greater extent than other psychiatric diagnoses. This requires meticulous diagnostic process and pharmacological selection, with full knowledge of the molecules in the drug arsenal so, in case of lamotrigine prescription, it should be established scrupulous psychoeducation to the patient and their family members, as well as strict and close follow-up. A propos of the case of an adolescent girl diagnosed with bipolar II disorder, who received lamotrigine during a depressive episode but with an inappropriate posology, and developed toxic epidermal necrolysis, we reviewed and commented on the corresponding literature. We conclude that extreme caution is necessary when deciding the use of lamotrigine to minimize the risk of this severe adverse effect.

Acatisia inducida por antipsicóticos: recomendaciones para la práctica clínica / Antipsychotic-induced akathisia: recommendations for clinical practice

La acatisia es uno de los eventos adversos inducidos por antipsicóticos más prevalentes y puede generar severa angustia en quien lo experimente. Se caracteriza por inquietud psicomotora objetiva y subjetiva. Pertenece al gran paraguas de los "síntomas extrapiramidales", sin embargo, tiene sus particularidades clínicas lo que representa un desafío clínico, tanto en su diagnóstico como en su manejo específico. La presente revisión sintetiza la información disponible a la fecha y ofrece al clínico recomendaciones para prevenir, reconocer y manejar esta complicación frecuente de una de las familias de psicofármacos de mayor prescripción clínica en la actualidad.

Abstract. Akathisia is one of the most prevalent antipsychotic-induced adverse events and causes severe distress in those who experience it. It is characterized by objective and subjective psychomotor restlessness. Usually classified under the great umbrella of extrapyramidal symptoms; however, it has its own clinical peculiarities, which might represent a challenge for the clinician in diagnosis as well as specific management. This review synthesizes the information available to date on antipsychotic-induced akathisia and offers the clinician recommendations to prevent, recognize and treat this prevalent complication of one of the most widely prescribed psychotropic medications today.

Pathological Gambling Due to Aripiprazole: Two Cases

ABSTRACT Aripiprazole is an atypical antipsychotic agent which has a partial agonistic effect on dopamine D2 and D3 receptors. It is effective in the treatment of schizophrenia and bipolar disorder. Owing to its partial agonistic effect, hyperactivity of dopamine may occur in the mesolimbic pathway. In the literature, there are few case reports about pathological gambling due to aripiprazole. In this article, there are two case reports of patients who showed pathological gambling behaviour and alcohol abuse and who were under treatment with aripiprazole. The patient had a history of gambling in the past. With the use of aripiprazole, pathological gambling behaviour occurred quickly and with discontinuation of aripiprazole it ended completely. Aripiprazole causes pathological gambling by forming a hyperdopaminergic condition in the mesolimbic dopaminergic pathway. Aripiprazole should be recommended cautiously and carefully to patients who are impulsive and have a history of alcohol/substance abuse.

Hyperprolactinemia associated with psychiatric disorders / Hiperprolactinemia asociada con trastornos psiquiátricos

Abstract Hyperprolactinemia may be associated with psychiatric disorders in the context of two scenarios: antipsychotic-induced hyperprolactinemia and psychiatric disorders arising from the medical treatment of hyperprolactinemia. Both situations are particularly common in psychiatric and endocrine clinical practice, albeit generally underestimated or unrecognized. The aim of this article is to provide tools for the diagnosis and treatment of hyperprolactinemia associated with psychiatric disorders to raise awareness, especially among psychiatrists and endocrinologists, so that these professionals can jointly focus on the appropriate management of this clinical entity.

Resumen La hiperprolactinemia puede asociarse con trastornos psiquiátricos en el contexto de dos escenarios: la hiperprolactinemia inducida por antipsicóticos y trastornos psiquiátricos surgidos por el tratamiento médico de la hiperprolactinemia. Ambas situaciones son particularmente comunes en la práctica clínica psiquiátrica y endocrinológica, aunque generalmente subestimadas o inadvertidas. El objetivo de este artículo es proporcionar herramientas de diagnóstico y tratamiento de la hiperprolactinemia asociada a trastornos psiquiátricos, para concientizar particularmente a psiquiatras y endocrinólogos a enfocar en conjunto el manejo apropiado de esta entidad.

Combined influence of illness duration and medication type on visual sensitivity in schizophrenia

Objective: Patients with schizophrenia have visual processing impairments. The main findings from the literature indicate that these deficits may be related to differences in paradigms, medications, and illness duration. This study is part of a large-scale study investigating visual sensitivity in schizophrenia. Here we aimed to investigate the combined effects of illness duration and antipsychotic use on contrast sensitivity function. Methods: Data were collected from 50 healthy controls and 50 outpatients with schizophrenia (classified according to illness duration and medication type) aged 20-45 years old. The contrast sensitivity function was measured for spatial frequencies ranging from 0.2 to 20 cycles per degree using linear sine-wave gratings. Results: Patients with an illness duration > 5 years had more pronounced deficits. Differences in the combined effects of illness duration and antipsychotic use were marked in patients on typical antipsychotics who had been ill > 10 years. No significant differences were found between typical and atypical antipsychotics in patients with an illness duration < 5 years. Conclusion: Visual impairment was related to both long illness duration and medication type. These results should be tested in further studies to investigate pharmacological mechanisms.

Terapia Electroconvulsiva y Estimulación Magnética Transcraneal Repetitiva en pacientes con esquizofrenia: una revisión sistemática / Electroconvulsive Therapy and Repetitive Transcranial Magnetic Stimulation in patients with schizophrenia: a systematic review

Cuando la esquizofrenia no responde satisfactoriamente a tratamiento farmacológico, alcanzar una terapia efectiva para el paciente es una tarea bastante frustrante para el médico psiquiatra. Es en este contexto que la terapia electroconvulsiva y la estimulación magnética transcraneal repetitiva han tomado fuerza en la investigación clínica, a pesar de los grandes cuestionamientos sobre su efectividad y mala reputación. Se realizó una revisión sistemática de la literatura en las principales bases de datos disponibles. Concluyendo que ambas terapias demuestran ser herramientas útiles en el tratamiento de la esquizofrenia resistente a tratamiento farmacológico, así como también complementarias a los antipsicóticos

When schizophrenia does not respond satisfactorily to pharmacological treatment, achieving effective therapy for the patient is quite a frustrating task for the psychiatrist. It is in this context that electroconvulsive therapy and repetitive transcranial magnetic stimulation have gained strength in clinical research, despite huge questions about its success and bad reputation. A systematic review of the literature was conducted in the main available databases. Concluding that both specific therapies will be useful tools in the treatment of schizophrenia resistant to pharmacological treatment, as well as complementary to antipsychotics.

Schizophrenia: effects of aripiprazole in metabolic syndrome

Schizophrenia, in general, is characterized by severe and disabling mental alterations, characterized by the impairment of one's mental, behavioral and social activities, developing certain clinical symptoms, relevant to the diagnosis. The drugs used for the reversion of the symptoms cause several adverse effects that affect the patient's health and well-being, such as motor, endocrine and cardiovascular damages. For a long time, little was known about the origin and the treatment of schizophrenia, which has become a curiosity for science, originating countless researches and theories that are background for several treatments. It is known that alterations in dopaminergic pathways are related to the development of the symptoms of the disease, and evaluating these symptoms, the diagnosis is made and the treatment is initiated. The insertion of new drugs with different characteristics and mechanisms tends to be an advance in the treatment of schizophrenia, as well as reducing the occurence of adverse effects or not worsening already existing cases. Aripiprazole is an innovative atypical antipsychotic employed in the pharmacotherapy of schizophrenia, which tends to attenuate the symptoms, inducing few adverse effects compared to other drugs that are already used, and promotes better quality of life to patients.

Metabolic dysregulation in early onset psychiatric disorder before and after exposure to antipsychotic drugs

Antipsychotic Drugs (APDs) are being widely prescribed to treat various disorders, including schizophrenia and bipolar disorder; however, abnormal glucose metabolism and weight gain have been reported with Atypical Anti-Psychotic drugs (AAPDs) that can lead to insulin-resistance and type 2 diabetes mellitus. The study was designed to assess various biochemical parameters including insulin and blood sugar before and after exposure to APDs in order to exclude the involvement of psychiatric disorders and certain other factors in metabolic dysregulations. Fifty seven APDs-naïve patients with first episode psychosis were divided into six groups who received olanzapine, quetiapine, risperidone, aripiprazole, haloperidol or combination of olanzapine with escitalopram and haloperidol. The serum samples were taken before the intake of the first dose and then on follow-up. Decrease in the level of elevated insulin and glucose was observed post-treatment in some patients, while others were observed whose insulin and glucose levels increased post-treatment, yet some patients did not show any disturbance in the insulin and glucose levels. It is concluded that psychiatric disorders by itself, narcotics, cigarette smoking and use of oral snuff may be also be implicated in metabolic dysregulations. The effects of APDs on insulin and glucose in healthy volunteers might be different than in patients with psychiatric disorders.

Manejo perioperatorio de nuevos fármacos psiquiátricos / Perioperative management of new psychiatric drugs

Psychoactive drugs, including antidepressants and antipsychotics, are currently one of the most commonly used drugs, so we often find patients who consume them during the perioperative period. Historically, they have been associated with multiple and serious adverse effects, such as serotonin syndrome, but nowadays these are infrequent, especially due to the good safety profile of the new drugs most commonly used. Therefore, it is recommended to keep these drugs in the perioperative period, to avoid adverse effects related to their suspension. Among the novel and most used antidepressants are the so-called duals, such as venlafaxine, desvenlafaxine and duloxetine, these are safe and it is recommended to maintain their use. The same is recommended with drugs such as trazodone, bupropion and mirtazapine. Another antidepressant, vortioxetine, has not reported significant adverse effects in the perioperative period, so it is recommended to maintain its use. Agomelatine, derived from melatonin, is considered safe to maintain and could have beneficial effects by reducing preoperative anxiety and eventually reducing the incidence of postoperative delirium in susceptible patients. Antipsychotics are safe in the perioperative period and, in general, it is recommended to maintain their use.

Los fármacos psiquiátricos, entre los que se encuentran los antidepresivos y antipsicóticos, son de los fármacos más utilizados en la actualidad, por lo que con frecuencia nos encontramos con pacientes que los consumen en el perioperatorio. Históricamente se han relacionado con múltiples y graves efectos adversos, como el síndrome serotoninérgico, pero hoy en día estos son infrecuentes, sobre todo por el buen perfil de seguridad que presentan los nuevos fármacos más utilizados. Por lo anterior, es que en general se recomienda mantener estas drogas en el perioperatorio, para evitar efectos adversos relacionados con su suspensión. Entre los antidepresivos más utilizados se encuentran los denominados duales, como venlafaxina, desvenlafaxina y duloxetina, estos son seguros y se recomienda mantener su uso. Lo mismo se recomienda con drogas como trazodona, bupropión y mirtazapina. Otro más novedoso, la vortioxetina, hasta el día de hoy no ha reportado efectos adversos relevantes en el perioperatorio, por lo que se recomienda mantener su uso. La agomelatina, derivada de la melatonina, se considera segura de mantener y podrían tener efectos beneficiosos al reducir la ansiedad preoperatoria y eventualmente reducir la incidencia de delirium postoperatorio en los pacientes susceptibles. Los antipsicóticos son seguros en el perioperatorio y en general se recomienda mantener su uso.

Síndrome de piernas inquietas/Willis Ekbom desde la mirada del psiquiatra / Restless legs syndrome from the perspective of psychiatry

Restless Legs Syndrome (RLS) or Willis-Ekbom Disease is an under-diagnosed chronic and progressive primary sensory-motor disorder. It can lead to severe sleep disturbances, a usual cause of consultation. It is characterized by an urgent need to move the legs in resting situations, a cardinal symptom that is usually accompanied by an unpleasant sensation in legs. These symptoms appear or aggravate at the end of the day and in resting situations and are alleviated with movement. Based on these clinical characteristics, it has been defined as a quiescegenic focal akathisia. The diagnosis is essentially clinical. As a guide, there are five cardinal diagnostic criteria. The treatment consists of non-pharmacological measures and the use of medications such as dopamine agonists. Despite the treatment, the symptoms persist in 40% of patients. Psychiatrists should be aware of the syndrome since many drugs used by them such as antipsychotics, antidepressants and anxiolytics can worsen the symptoms. Moreover, the syndrome may be associated with depressive and anxiety diseases.

Evaluación de síndrome metabólico en varones hospitalizados en Unidad de Corta Estadía Psiquiátrica Marzo 2017 / Evaluation of metabolic syndrome in Hospitalized Men in the Short Stay Psychiatric Unit. March 2017

El síndrome metabólico (SM) corresponde a un conjunto de factores de riesgo derivados de la obesidad visceral e insulinoresistencia. 35.3% de la población adulta chilena presentó SM en el período 2009 - 2010, con diferencia significativa entre hombres y mujeres (41.6% vs 30.9%, respectivamente). En Estados Unidos se ha calculado que la media de años potencialmente perdidos en pacientes con enfermedades mentales va de 25 a 30, comparada con la población general. La principal causa de muerte es la enfermedad coronaria. La mayoría de los pacientes en tratamiento neuroléptico en hospitales psiquiátricos no reciben control de factores de riesgo metabólicos. La evidencia señala que los pacientes esquizofrénicos no son adecuadamente pesquisados ni tratados por Dislipidemia (hasta un 88% de estos pacientes siguen sin tratamiento) ni por hipertensión (hasta un 62%). El objetivo de este trabajo es evaluar factores de riesgo cardiovascular en varones hospitalizados en unidad de corta estadía psiquiátrica del Instituto Psiquiátrico Dr. José Horwitz Barak. Se evaluó a 35 pacientes varones, de los cuales un 37% presentó SM, un 45.3% presentó sobrepeso.

The metabolic syndrome (MS) corresponds to a set of risk factors derived from visceral obesity and insulin resistance. 35.3% of the Chilean adult population had MS in the 2009-2010 period, with a significant difference between men and women (41.6% vs 30.9%, respectively). In the United States, it has been estimated that the average number of years potentially lost in patients with mental illness ranges from 25 to 30, compared with the general population. The main cause of death is coronary heart disease. Most patients on neuroleptic treatment in psychiatric hospitals do not receive control of metabolic risk factors. The evidence indicates that schizophrenic patients are not adequately researched or treated for dyslipidemia (up to 88% of these patients remain untreated) or hypertension (up to 62%). OBJECTIVE: To evaluate cardiovascular risk factors in hospitalized men in a short stay psychiatric unit of the Psychiatric Institute Dr. José Horwitz Barak. Thirty-five male patients were evaluated, of which 37% had MS, and 45.3% were overweight.