Effects of aripiprazole combined with duloxetine on the treatment effect and VEGF level in patients with refractory depression / 中国临床药理学与治疗学

AIM: To explore the effects of aripiprazole and duloxetine on refractory depression and the change of VEGF concentration during treatment. METHODS: Ninety patients with refractory depression who were treated at the Fourth People's Hospital of Jiande from February 2017 to February 2019 were selected, and 40 healthy volunteers were recruited as healthy control groups. Random numbers table was used to divide patients into aripiprazole combined with duloxetine treatment group (combined treatment group) and duloxetine treatment group (monotherapy group). After 4 weeks of treatment, the differences in efficacy and adverse reactions between the two groups were evaluated. The difference of VEGF level between each group was compared. RESULTS: The effective rate was 88.8% in the combined treatment group and 80.0% in the monotherapy group. The effective rate between the two groups was not statistically significant (P<0.05). After 4 weeks of treatment, the HAMD score in the combined treatment group was lower than that in the monotherapy group, the difference was statistically significant (P<0.05). The difference in adverse reactions between the two groups was not statistically significant (R=0.641, P=0.624). The level of VEGF before treatment in the two treatment groups was higher than that in the healthy control group, and the difference was statistically significant (P<0.01). After treatment, the VEGF level of the two groups decreased compared with before treatment, and the difference was statistically significant (P<0.01). The level of VEGF in the combined treatment group was lower than that in the monotherapy group, and the difference was statistically significant (P<0.05). Pearson correlation analysis showed that the level of VEGF before treatment was positively correlated with the HAMD score (R=0.403, P<0.01), and VEGF decline level is positively correlated with HAMD score reduction rate (R=0.330, P<0.01). CONCLUSION: Aripiprazole combined with duloxetine has a better effect on refractory depression than duloxetine alone, and can significantly reduce the level of VEGF in peripheral blood.

Deep Brain Stimulation for the Treatment of Resistant Depression: Systematic Review of the Literature

Depression is the leading cause of disability worldwide, and it is related to high suicide rates. Furthermore, a great number of patients do not respond to any of the available treatments. Deep brain stimulation (DBS), a versatile technology with expanding indications, is considered a potential treatment for resistant depression. However, in over 10 years of clinical research, its efficacy has not been completely proven. Although new trials using DBS for treatment-resistant depression keep emerging, two of the three Level I evidence-based studies recently conducted have not provided conclusive data. Methodological limitations andmajor biases have compromised the obtention of clearer results. In this systematic review of the literature, we intend to critically assess the clinical trials performed in this field.

Ketamine use in Refractory Depression and Neuropathic Pain - A Case Report

Introduction: Depression is a common psychiatric illness inthe elderly. It often co-exists with chronic neuropathic pain inold age group.Case report: We present a case report of an elderly patientwho was successfully treated with subanaesthetic intravenousinfusion for severe depression with suicidal intention andchronic neuropathic pain.Conclusion: Ketamine has been reported to be used indepression with suicidal features as well as refractory pain.Depression is a common psychiatric problem across the agegroups. It occurs due to neurochemical imbalance in the brainnamely dopamine, norepinephrine serotonin.

The value of serum thyroid hormone levels in the treatment of patients with refractory depression / 中国生化药物杂志

Objective To investigate the value of serum thyroid hormone (Thyroid hormone, TH) levels on prognosis in patients with treatment-resistant depression ( Refractory depression, RD) .Methods 108 cases of RD patients collected in Hangzhou First People's hospital from March 2014 to February 2016 were divided into observation group and control group according to the method of random numbers, and each had 54 patients.Patients in the observation group were given antidepressant treatment program and the control group a placebo.Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA) score changes, and TSH, T3, T4, FT3, FT4 levels of two groups pre-and post-treatment were compared.Results After treatment, the HAMD and HAMA scores in observation group were (14.4 ±2.5) and (15.2 ±2.7) significantly lower than that in control group, which were (25.6 ±5.2) and (25.9 ±4.8),separately, the differences were significant(P<0.05);the TSH, T3, T4, FT3, FT4 levels in observation group post-treatment were (4.54 ±0.68) mIU/L, (1.21 ±0.56) nmol /L, (55.4 ±6.1) nmol/L, (3.16 ±0.42) pmol/L and (8.53 ±0.62) pmol/L, TSH decreased significantly, and T3, T4, FT3 , FT4 were significantly increased than pre-treatment(P<0.05); the indexes in control group were (5.16 ±0.62) mIU /L, (0.91 ±0.42) nmol/L, (51.9 ±3.2) nmol /L, (2.82 ±0.40) pmol/L and (7.76 ±0.64) pmol/L (P<0.05), the differences with observation group were significant ( P <0.05 ) .Conclusion The severity of the symptoms of patients is closely related with TH RD level, antidepressant therapy can improve TH, thereby improving the patient's symptoms, so it is important to pay attention to TH levels in the treatment process of RD.

Comparison of effect between duloxetine combined with small-dose of mirtazapine and duloxetine in treatment of refractory depression in elder patients / 中国生化药物杂志

Objective To compare effect and security between duloxetine combined with small-dose of mirtazapine and duloxetine alone in treatment of refractory depression in elder patients.Methods A total of 100 cases elder refractory depression patients were randamly divided into study group (duloxetine+mirtazapine, 50 cases) and control group(duloxetine, 50 cases).Compared HAMD,HAMA and CGI-SI between two groups, as well as the side reactions and TESS.Regression analysed mirtazapine blood concentration and HAMD subtraction rate.Results The effective rate of study group was 92.00%, while in control group was 76.00%, the difference was statistically significant(P<0.05).After treatment, the HAMD, HAMA and CGI-SI of each group significantly increased, and the difference of HAMD, HAMA and CGI-SI at 2w, 4w and 8w between two groups were statistically significant(P<0.05).The TESS and side reaction of two groups had no statistical difference.Conclusion Effect of duloxetine combined with small-dose of mirtazapine in treatment of refractory depression is better than duloxetine alone use, without significant side reaction.

Definición e impacto de las depresiones resistentes/refractarias al tratamiento / Definition and impact of treatment-resistant depression

Major depressive disorder (MDD) is characterized by high rates of medical morbidity, low productivity, low life expectancy, and high rates of suicide. Therefore, the treatment of depressed patients involves, among others, an early diagnosis and treatment of the disease. Although an increasing number of antidepressants to treat MDD are available, approximately half of the patients do not respond, and near of two-thirds do not achieve remission after a first treatment attempt. For this project, it was conducted a detailed review using several databases such as MEDLINE, PsycINFO, EMBASE, the Cochrane Library, and LILACS from 1949 to March 2011 crossing terms related to the diagnosis and impact of the DRT. Unfortunately, original publications on DRT in Latin America are scarce and the findings and conclusions of this review have been based almost entirely on Anglo-Saxon scientific evidence. In a similar manner as described by medical microbiology, a major depressive episode (MDE) can be considered refractory when it has not responded to an adequate treatment with an established therapy. What constitutes an inadequate treatment has been the subject of considerable debate, but most experts would probably say it is the failure to achieve remission. The rationale for this approach is that not achieving remission often results in changes in work performance, increased risk of recurrences, chronicity, suicide, and impaired social functioning. Before considering a patient as TRD, is necessary to confirm the diagnosis of unipolar MDD ruling out other psychiatric disorders such as bipolar disorder, or other non-psychiatric medical diseases. After clarifying the diagnosis, and in the absence of remission, the physician is confronted with a great diversity of definitions and clinical criteria suggested for DRT. This variety of diagnostic alternatives, rather than enrich the portfolio of treatment options for DRT, often leads to serious discrepancies that hinder the effective management of the DRT. Unfortunately, more than 50 years after the discovery of the first antidepressants and increased knowledge about the neurobiological mechanisms of MDD and their interactions with the environment, for now there are no uniform guidelines on the definition and treatment of patients with DRT. Perhaps, the most accepted definition of DRT in the literature is that in which an inadequate response after one or two courses of antidepressant treatment with dose optimization, appropriate time of administration (usually between 8 and 12 weeks) and high level of adherence and compliance can be assured. Among the models proposed for the diagnosis of the DRT, Thase and Rush developed a frequently used tool, although with a predictive value, regarding the outcome of treatment, not systematically evaluated. It is based on five steps or levels that arbitrarily assume that the lack of remission after one single trial with an appropriate treatment is just enough to make a diagnosis of DRT. In addition, certain interventions such as tricyclic antidepressants or monoamine oxidase inhibitors are considered superior to first-line strategies available today. This review also defines the differential diagnosis of DRT such as pseudo-resistance, chronic depression, bipolar depression and tachyphylaxis, and describes the costs and consequences of DRT with an inadequate intervention.

El trastorno depresivo mayor (TDM) se acompaña de altas tasas de morbilidad médica, baja productividad, disminución de la esperanza de vida, altas tasas de suicidio y ha sido considerado como la primera causa de discapacidad laboral en las Américas. Por ello, la atención al paciente deprimido implica, entre otras cosas, el diagnóstico oportuno y el tratamiento adecuado del padecimiento. Aunque un número creciente de agentes antidepresivos está disponible para tratar la depresión, aproximadamente la mitad de los pacientes no responden y hasta dos tercios no logran la remisión después del tratamiento de primera línea. Para este proyecto se llevó a cabo una revisión detallada utilizando varias bases de datos como MEDLINE, PsycINFO, EMBASE, the Cochrane Library y LILACS, desde 1949 hasta marzo 2011, cruzando términos por medio de un sistema de búsqueda predefinido que permitió incluir artículos relevantes en relación al diagnóstico e impacto de las DRT. Desafortunadamente, las publicaciones originales en América Latina sobre DRT son escasas y los resultados y conclusiones de esta revisión han debido basarse casi en su totalidad en la producción científica anglosajona. En forma análoga a lo descrito por la microbiología médica, un episodio depresivo mayor (EDM) puede ser considerado como resistente al tratamiento cuando no ha respondido a un tratamiento adecuado con una terapia establecida. Lo que constituye una respuesta inadecuada ha sido objeto de considerable debate, pero la mayoría de los expertos hoy en día probablemente dirían que es el fracaso en el logro de la remisión. La justificación de este enfoque es que no conseguir la remisión, a pesar del tratamiento sugerido, suele dar lugar a la presencia de síntomas depresivos residuales (como insomnio, fatiga, dolores y ansiedad), que se han asociado de manera consistente con un peor efecto antidepresivo, alteraciones en el rendimiento laboral y un mayor riesgo de recurrencias, cronicidad, suicidio y deterioro del funcionamiento social en comparación con los pacientes cuya depresión está totalmente en remisión. Cuando se inicia una terapia con antidepresivos, los clínicos deben mantener la prudencia terapéutica para no sobre-estimarla. Los pacientes deben saber que la mayoría de las personas no alcanzan la remisión con rapidez y que los síntomas residuales son comunes. Según la intensidad de los síntomas residuales y otros factores, como la comorbilidad y el número de ensayos antes del fracaso terapéutico, una estrategia tan simple como la continuación del tratamiento con antidepresivos por algunas semanas más puede ser suficiente para alcanzar la remisión. En muchos casos, sin embargo, puede ser necesario el cambio a otro antidepresivo, la adición de otros medicamentos o la combinación con otro antidepresivo. Un artículo publicado en este número de la revista describe en detalle las estrategias terapéuticas para pacientes con depresión refractaria/ resistente al tratamiento (DRT) (Tamayo et al., 2011). Antes de proceder a clasificar un paciente deprimido como refractario/resistente al tratamiento es necesario confirmar el diagnóstico de TDM unipolar, descartando otros trastornos psiquiátricos como el trastorno bipolar u otras enfermedades médicas no psiquiátricas. Luego de la aclaración diagnóstica, y ante la ausencia de remisión, el médico se ve enfrentado a una gran diversidad en las definiciones y criterios clínicos sugeridos para las DRT. Esta variedad de alternativas diagnósticas, antes que enriquecer el portafolio de opciones terapéuticas, suele llevar a serias discrepancias que entorpecen la eficacia de su manejo, especialmente en países como los latinoamericanos donde los consensos basados en las necesidades regionales son escasos. Desafortunadamente, a más de 50 años del descubrimiento de los primeros antidepresivos y de un mayor conocimiento sobre los mecanismos neurobiológicos del TDM y sus interacciones con el entorno, no existen por ahora directrices uniformes sobre la definición y tratamiento de los pacientes con DRT. En la última década se ha publicado un número creciente de estudios de intervención en pacientes con este diagnóstico pero sin criterios operacionales consensuados y con más de 10 definiciones dispares. Quizá la definición más utilizada en la literatura médica es la de una respuesta insuficiente posterior a uno o dos esquemas de tratamiento antidepresivo que ha sido optimizado en dosis, administrado por un tiempo adecuado (usualmente entre ocho y 12 semanas) y en el que se tiene un nivel de certeza elevado sobre la adherencia y cumplimiento del mismo por parte del paciente. Las dosis subterapéuticas de los antidepresivos han sido reconocidas como una de las principales causas de la falta de remisión al tratamiento. Con el transcurso del tiempo la recomendación de dosis adecuadas ha aumentado de 150 mg/día a 250-300 mg/día de imipramina o su equivalente. La mayoría de los estudios, o bien no proporcionan la dosis máxima que se necesita para describir un tratamiento previo como un fracaso o un éxito, o sólo se refieren a ellas de forma genérica con frases como <

Revisión de la literatura médica sobre el manejo de las depresiones resistentes/refractarias al tratamiento / Literature review on management of treatment-resistant depression

Major depressive disorder (MDD) is a prevalent and costly disease that is usually associated with high rates of disability. The target for the treatment of MDD is to achieve and maintain remission or complete control of depressive symptoms by the choice of an effective antidepressant. Sometimes, despite evidence based-treatment, it is possible that the patient does not have a favorable response. Although there is an increasing number of antidepressants available to treat depression, approximately half of the patients do not respond and two-thirds do not achieve remission after first-line treatment. In these cases we refer to treatment-resistant depression (TRD) as is defined in an article in this issue of Salud Mental. The TRD is one of the most complex conditions in psychiatry from the therapeutic point of view due to different definitions, algorithms, and response criteria, especially in Latin America where the procedures based on regional needs and consensus are scarce and not always based on evidence. It was conducted a systematic review using several databases such as MEDLINE, PsycINFO, EMBASE, the Cochrane Library and LILACS from 1949 to March 2011 crossing terms which allowed the inclusion of relevant articles in the management of the TRD. Unfortunately, the original publications in Latin America are often based on TRD case report, so the results and conclusions of this review have been based entirely on Anglo-Saxon scientific production. The therapeutic strategies used in the TRD are many, and include combinations of antidepressants or other psychotropic agents, in some cases addition of psychotherapy and, in extreme cases, neurostimulation techniques such as electroconvulsive therapy (ECT). The study Sequenced Treatment Alternatives to Relieve Depression (STAR-D) is the largest trial of treatment for MDD conducted in real practice settings, and the first to study remission as a measure of pre-defined primary outcome. It consists of four different stages of resistance. It is clear that there are diminishing remission rates as the number of treatment trials increases. The strategies include: antidepressant dose optimization, addition of medications like thyroid hormone, lithium, or nutritional supplements, a combination of antidepressants, and addition of second-generation antipsychotics (SGAs). Evidence suggests that remission rates can be from 25% to 50%, although with some differences among the drugs recommended. Evidence supports the use of SGAs for increasing the level of remission of new-generation antidepressants, although neither the profit nor the long-term benefits of this strategy have been well established. Neuro-modulation techniques include ECT, repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS). ECT remains a first line option for the treatment of DRT with response rates ranging from 50% to 89%. Finally, the effectiveness of cognitive-behavioral therapy (CBT) in the management of the DRT could be a useful alternative when practiced in conjunction with any of the pharmacological strategies. However, further studies are needed to recommend it as first line treatment.

El trastorno depresivo mayor (TDM) es una enfermedad costosa y prevalente que suele asociarse con altas tasas de discapacidad funcional. La meta para el tratamiento del TDM es lograr y mantener la remisión o el control completo de los síntomas depresivos por medio de la elección de un antidepresivo efectivo. Entre los factores a considerar para el logro de la remisión en pacientes deprimidos con los diferentes tratamientos disponibles, se incluyen su mecanismo de acción, el nivel de tolerabilidad, su facilidad de uso, su costo (directo e indirecto), la historia del tratamiento del paciente y su familia y algunas peculiaridades culturales que influyen en la adhesión al tratamiento y en la patoplastia clínica. En ocasiones, a pesar de un tratamiento ceñido a la evidencia, cabe la posibilidad de que el paciente no tenga una respuesta favorable al mismo. Aunque un número creciente de agentes antidepresivos está disponible para tratar la depresión, aproximadamente la mitad de los pacientes no responden y hasta dos tercios no logran la remisión después del tratamiento de primera línea. En estos casos nos referimos a la depresión refractaria/ resistente al tratamiento (DRT) tal como es definida en un artículo publicado en este número de la revista (Tamayo JM et al., 2011). La DRT es una de las condiciones más complejas en psiquiatría desde el punto de vista terapéutico debido a diferentes definiciones, algoritmos y criterios de respuesta que hacen difícil ofrecer alternativas eficaces, especialmente en América Latina donde los procedimientos basados en las necesidades regionales o el consenso son escasos y no siempre basados en la evidencia. Para este proyecto se llevó a cabo una revisión sistematizada utilizando varias bases de datos como MEDLINE, PsycINFO, EMBASE, the Cochrane Library y LILACS desde 1949 hasta marzo de 2011, cruzando términos por medio de un sistema de búsqueda predefinido que permitió incluir artículos relevantes en relación al manejo de las DRT. Desafortunadamente, las publicaciones originales en América Latina sobre la DRT suelen basarse en el reporte de casos por lo que los resultados y conclusiones de esta revisión han debido basarse en su totalidad en la producción científica anglosajona. Las estrategias terapéuticas utilizadas para la DRT son múltiples e incluyen combinaciones entre antidepresivos o con otros agentes psicotrópicos, en algunos casos adición de psicoterapia y en casos extremos técnicas de neuroestimulación como la TEC. El Estudio Secuenciado de Alternativas de Tratamiento para Aliviar la Depresión (STAR-D, por sus siglas en inglés) es el mayor ensayo de tratamiento del TDM llevado a cabo en entornos de práctica real, y el primero en estudiar la remisión como una medida de resultado primaria y predefinida. Está conformado por cuatro etapas diferentes de resistencia/refractariedad. Queda claro que hay rendimientos decrecientes a medida que el número de intentos de tratamiento aumenta. Pero cuando los pacientes siguen en tratamiento durante las cuatro fases que componen el STAR-D, aproximadamente el 67% alcanza la remisión. Las estrategias psicofarmacológicas incluyen cambio de antidepresivo en respondedores parciales luego de optimización de dosis, adición de medicamentos no antidepresivos como hormona tiroidea, litio o suplementos nutricionales, combinación de antidepresivos y adición de antipsicóticos de segunda generación (ASG). En general, se puede afirmar que los diversos estudios tienden a corroborar un incremento de las tasas de mejorías y remisiones después de seguir alguna de las estrategias terapéuticas mencionadas. Sin embargo, ningún estudio ha evaluado adecuadamente a los pacientes que no han respondido a múltiples cursos y combinaciones de terapias de medicamentos. En particular, respecto a las terapias de aumento, la evidencia sugiere que se pueden lograr tasas de remisión entre 25% y 50%, aunque con algunas diferencias entre los medicamentos recomendados. El uso del litio y de la hormona tiroidea, por ejemplo, si bien se basa en niveles de evidencia aceptables, se apoya en estudios pequeños, con diseños objetables y en pacientes menos refractarios que los que suelen incluirse en los estudios actuales. De todas las estrategias farmacológicas para aumentar la respuesta a los antidepresivos de nueva generación, la evidencia apoya con más frecuencia el uso de los ASG, aunque ni la rentabilidad ni el beneficio a largo plazo de esta estrategia han sido bien establecidos. Las técnicas de neuromodulación incluyen la TEC, la estimulación magnética transcraneana repetitiva (EMTr), la estimulación cerebral profunda (ECP) y la terapia de estimulación del nervio vago (ENV). La TEC sigue siendo una opción de primera línea para el tratamiento de la DRT con tasas de respuesta que van desde el 50% al 89%. Desafortunadamente, las estrategias de neuroestimulación, si bien suelen ser eficaces, especialmente la TEC y la ECP, son invasivas, costosas y deben relegarse como segunda línea de tratamiento en pacientes que no responden a las estrategias farmacológicas para la DRT. Finalmente, la eficacia de la terapia cognitivo-comportamental (TCC) en el manejo de las DRT podría ser una alternativa útil cuando se practica conjuntamente con alguna de las estrategias farmacológicas. Sin embargo, la eficacia de la psicoterapia en pacientes con DRT no ha sido fehacientemente demostrada y se requieren más estudios para recomendarla como primera línea de tratamiento. En cuanto al manejo a largo plazo de pacientes con DRT, el estudio STAR-D muestra que las tasas de remisión, cercanas al 67% luego de varias estrategias, se reducen al 45% cuando se incluyen en el análisis los pacientes que abandonan el estudio. Esto sugiere que el orden de administración de las alternativas terapéuticas aconsejadas hasta hoy necesita ser revaluado. Se requiere, pues, encontrar un tratamiento más rápido y más eficaz en el logro de la remisión en pacientes con TDM y estudios preliminares propenden por el uso temprano de la combinación de antidepresivos desde el inicio en pacientes con depresiones graves y caractersticas que sugieran un alto riesgo de resistencia/refractariedad.

A comparative study of escitalopram angumentation with psychoanalysis in the treatment of refractory depression / 中华行为医学与脑科学杂志

Objective To investigate the efficacy of escitalopram combined with psychoanalysis in the treatment of refractory depression. Methods A total of 63 patients were randomly divided into escitalopram group ( n = 32) and escitalopram combined with psychoanalysis group( n = 31 ). All patients were evaluated with Hamilton depression Rating Scale(HAMD). Results After treatment,the scores of HAMD in two groups were both significantly lower than those before treatment. In the 8th ( ( HAMD ( 17.35 ± 2.98 ) ), 12th ( ( HAMD (9. 26 ±3.46) )weekend of treatment, the scores of HAMD in study group were significanlly lower than those in control group(8 th:21.97 ± 3.26; 12 th: 15.28 ± 3. 18 ). There were no significant differences in side effects between study group and control group. Conclusion Escitalopram angumented with psychoanalysis takes effects better than escitalopram single and doesn't increase side effects in the treatment of refractory depression.

Left Vagus Nerve Stimulation (VNS) for the Treatment of Depression / 대한정신약물학회지

Depressive disorder is one of the very serious mental diseases in terms of personal, social, economical losses. It is not clear for the pathogenesis of the depression, however, even though decreased 5-HT and NE may be the biological causing factors in the neuronal synapses. Moreover, there are many depressive patients who are treatment resistant or partial responders. Thus, we have been needed the other therapeutic methods for those cases. Repeated transcranial magnetic stimulation (rTMS) & VNS are the newly introduced methods for the treatment of refractory or partial responders with depression, which nature of therapeutic effect is the stimulation of the CNS. VNS has been used to treat the refractory epilepsy patients. Despite of numerous empirical and preclinical data, although VNS may be effective for the treatment of depression, the parameters for the treatment of depression using the VNS device have not been confirmed yet. However, from the several reports clinical effectiveness were described about 40%, thus, it is interested that VNS will be able to use for the treatment of depression in a future.