Resumen de Estudio controlado doble-ciego con clonazepam y placebo en pacientes con trastorno de ansiedad social
José Alfonso Ontiveros Sánchez de la Barquera
- español
Introducción El trastorno de ansiedad social o fobia social afecta a 4.7% de la población, de acuerdo con reportes epidemiológicos de México y otros países. Los síntomas de este trastorno son más frecuentes en la mujer (5.4%) que en el hombre (3.8%) y en personas jóvenes (18 a 29 años) con una edad de inicio de 13 años. El tratamiento de la fobia social es importante ya que este padecimiento se asocia con comorbilidad psiquiátrica, abuso y dependencia de sustancias, mayor incidencia de intentos suicidas y dependencia financiera. Entre los tratamientos farmacológicos para este trastorno contamos con antidepresivos del tipo ISRS e IMAO y benzodiacepinas. En 1993 Davidson et al. publicaron el primer estudio doble–ciego controlado con placebo y clonazepam en el tratamiento de la fobia social. Los autores encontraron que el clonazepam mejoraba a los pacientes desde la primera semana de tratamiento. Nosotros estudiamos la efectividad y tolerabilidad del clonazepam en pacientes con fobia social en un estudio de 24 semanas, doble–ciego con asignación al azar, controlado contra placebo. Este estudio incluyó una fase simple–ciego de tratamiento con placebo de una semana, 16 semanas de tratamiento doble–ciego con clonazepam o placebo y una fase final de discontinuación con placebo simple–ciego.
Material y métodos El diagnóstico de fobia social se estableció de acuerdo con la sección de trastornos de ansiedad del SCID–I para establecer el diagnóstico de acuerdo a los criterios del DSM–III–R. Se incluyeron 62 pacientes en la fase simple–ciego, 53 de los cuales ingresaron a la fase doble–ciego del estudio por no haber mejorado. Las evaluaciones clínicas se realizaron con las escalas ICG de severidad y de mejoría de 8 puntos para la Enfermedad global, Ansiedad anticipatoria y Evitación fóbica, las escalas HamA y Covi, Liebowitz Social Phobic Disorder Rating Form (LSPD), HamD y de Raskin. Los pacientes completaron la ICG–S y la ICG–M de 8 puntos, la escala de Liebowitz para ansiedad social (LSAS), la escala de miedos de Marks y la escala de incapacidad.
Resultados En la fase doble–ciego del estudio 27 pacientes recibieron placebo y 26, clonazepam. A la fase de seguimiento doble–ciego de 10 semanas entraron sólo los pacientes que mejoraron, 20 en clonazepam (73%) y siete en placebo (25.9%). Las evaluaciones clínicas fueron realizadas cada semana durante las primeras cuatro semanas y cada dos semanas posteriormente. El análisis de las evaluaciones clínicas al punto final del tratamiento mostró un mayor beneficio en los pacientes que recibieron clonazepam que aquellos que estuvieron con placebo (ANOVA p=.001). En la escala ICG de mejoría las respuestas «muy mejorado» y «mucho muy mejorado» al final del tratamiento se observaron en 65.3% (N=17) de los pacientes con clonazepam y en 29.6% (N=8) de pacientes con placebo. Con clonazepam se observó mejoría desde la segunda semana del tratamiento (ANOVA p=.001). La razón más frecuente para no completar el estudio fue la respuesta clínica insuficiente (19% en clonazepam n=5 y 66.6% en placebo n=18; P=.001), abandono del tratamiento (NS) y experiencias adversas (NS). La dosis final de clonazepam fue de 3.4±DS 2.27 mg/día. Se presentaron más eventos adversos con clonazepam (3.85 ± 3.13) que con placebo (0.81 ± 1.08) (p<.0001). Cuatro pacientes de 16 (25%) en clonazepam que iniciaron la fase de supresión abandonaron el estudio por síndromes de supresión del medicamento.
Discusión Nuestro estudio corrobora los hallazgos del primer estudio controlado de Davidson et al., de 1993, y datos de numerosos estudios abiertos en el sentido de que el clonazepam es un tratamiento rápido y eficaz para el trastorno de ansiedad social. Nuestro estudio aporta también datos sobre la prevalencia de sucesos adversos y síntomas de supresión y recaídas tempranas al retirar el clonazepam hasta en 25% de pacientes. Las benzodiacepinas pueden estar contraindicadas en grupos de pacientes con patología comórbida y aquellos que abusan o son adictos al alcohol y las drogas. En tales casos la terapia cognoscitivo–conductual acompañada de medicamentos antidepresivos del tipo ISRS o IMAO puede ser una mejor opción de tratamiento primario para la fobia social.
- English
Introduction Social anxiety disorder or social phobia affects approximately 4.7% of the general population as shown in Mexican epidemiological studies and studies done in other countries. The symptoms of this disorder are more frequent in women (5.4%) than in men (3.8%) and younger people (18 to 29 years), with an average onset age of 13 years. The main clinical characteristic of social phobia is an intense and irrational fear to be exposed to social situations. Social phobia emerges to anticipate or be submitted into situations where the subject could be evaluated or be observed by others. Treatment of social phobia is important because this disorder has been associated with an increase rate of suicidal intents, financial dependency and psychiatric comorbidity.
Pharmacological treatment of social phobia includes SSRI and MAOI antidepressants and benzodiacepines. For the treatment of social phobia, potent benzodiacepines, such as alprazolam and clonazepam, have showed efficacy in several studies. In 1993 Davidson et al. published the first double–blind controlled study with clonazepam in patients with social phobia. They found that patients using clonazepam showed an improvement from the first week of treatment and that improvement persisted during the study and was superior to placebo.
The objective of the present study was to improve our knowledge about the efficacy and tolerability of clonazepam in patients with social phobia. We studied a group of social phobic patients during 24 weeks in a double–blind treatment study with clonazepam and placebo. Patients took one week single–blind of placebo, followed by 16 weeks of double–blind treatment with clonazepam or placebo. During the first six weeks of the double–blind treatment, dosage was adjusted looking for maximal improvement and tolerability. After this phase we selected only those patients who improved and they were treated double–blind for 10 more weeks with clonazepam or placebo. Discontinuation of treatment was done in a period of two weeks during which clonazepam was changed to placebo and then patients followed with a four weeks of single–blind treatment with placebo.
Methods All patients signed consent forms for the study which was approved by our hospital Ethical Committee. Patients were selected from those who looked for help in our Anxiety and Depression Research Clinic or by newspaper advertising. All candidate patients were interviewed with the SCID–I Anxiety Disorders section for DSM–III–R diagnosis of social phobia. Also, patients had to rank in the PARS scale a higher score in the Social phobia section than in the Separation phobia section. Also, patients included had to have at least a moderate severity of social anxiety disorder. Exclusion criteria required that patients had not had any other psychiatric disorders, including psychotic disorders, bipolar disorder, major depression, history of abuse or addiction to alcohol or drugs, eating disorders and anxiety disorders as panic disorder, generalized anxiety disorder, obsessive–compulsive disorder and post–traumatic stress disorder. Also, patients needed to be free of any psychotropic medication. A two week of discontinuation phase was conducted with patients receiving benzodiacepines or antidepressants (six weeks for fluoxetine).
From a total of 85 patients (78% males and 22% females), 62 were admitted in the fist single–blind week of placebo. Mean age of patients included (± DS) was 28.17 (8.95) years (79 % male and 79% single). Of them, nine patients (14.5%) showed a placebo response and were not admitted to the double–blind treatment phase.
A clinical evaluation of the patients was carried out on each visit with the Clinical Global Impression of severity and improvement of eight points for the Global severity of social phobia, Anticipatory anxiety and Phobic avoidance, the Hamilton anxiety and COVI scales, the Liebowitz Social Phobic Disorder Rating Form (LSPD) and the Hamilton depression and Raskin scales. Also, patients completed on each visit the Global impression of severity and improvement of 8 points, the Liebowitz social anxiety scale (LSAS), the Marks' fear questionnaire and an Incapacity score. Patients were evaluated each week for the first four weeks of double–blind treatment and later each two weeks.
Results We did not found any demographic differences in groups of patients who received clonazepam or placebo for age, sex distribution, marital status, occupation, years of study and social economic level. Likewise, patients were similar in basal weight, arterial tension and cardiac frequency. We did not found any differences in mean onset age of social phobia (14 years old) and length of disease. Most of the patients had a generalized social anxiety disorder, 61.5% (n=16) in clonazepam, and 74.1% (n=20) in placebo (z=.98, p>.10). Of 53 patients who entered the double–blind phase of the study, 27 received placebo and 26 clonazepam. On placebo, 85% of the patients (n=23) completed the first six weeks of double–blind treatment, while on clonazepam it occurred in 92.3% (n=24) of the patients. Patients who showed an improvement at the end of the first six weeks of the double–blind treatment continued the study. There were 20 patients in clonazepam (73%) and seven patients in placebo (25.9%). Mean time (± DS) in the study was longer for those patients who received clonazepam, 16.6 (±8.32) weeks, and nine (±7.52) weeks (t=3.52, gl=51, P=.001) for patients in placebo. The main reason for dropout was lack of efficacy: 19% in clonazepam (N=5) and 66.6% in placebo (N=18) (Fisher Exact Test, p=.001), abandon of treatment (3.8% in clonazepam N=1 and 14.8% N=4 in placebo; Fisher Exact Test, p=0.35) and adverse events (11.53% N=3 in clonazepam and 0% in placebo; two–tailed Fisher Exact test, p=0.1). Analysis of clinical evaluations on each visit showed that the general benefits of clonazepam were different and higher than those obtained with placebo since the second week of treatment (ANOVA p=.001). CGI of improvement responses of «better» and «much better» at the end point of treatment was obtained in 65.3% (N=17) of patients in clonazepam and in 29.6% (N=8) of patients in placebo. Improvement on clonazepam was observed not only in the anxiety and social phobic scales, but also in the depression scales. The mean ± SD dose of clonazepam was 3.4 ±DS 2.27 mg/day. Mean number (±SD) of adverse events per patient was reported higher in the group of patients who received clonazepam (3.85 ± 3.13) than in those who received placebo (0.81 ± 1.08) (t=4.762, df=51, P<.0001), with a higher incidence of somnolence and memory disturbances. In three patients the cause to discontinue the treatment was adverse events added to a lack of efficacy. The discontinuation phase of the double–blind treatment was followed by 16 (61.5%) patients treated with clonazepam and five (18.5%) patients on placebo. Of them, 25% patients (four of 16) on clonazepam and all on placebo completed the discontinuation phase. Relapse of phobic social symptoms and adverse event were related to discontinuation treatment in this phase.
Discussion Our study showed corroborated data observed in the first double–blind treatment study of Davidson et al. (1993) and those observed in several open studies showing efficacy and a fast improvement of social phobia symptoms with clonazepam. The efficacy results observed in our study are similar to those reported with paroxetine, an SSRI antidepressant extensively studied in social anxiety disorder with a 50% to 60% efficacy. We also observed a higher incidence of somnolence and memory troubles while patients were taking clonazepam and insomnia and nervousness when this drug was stopped. Our study showed a 25% prevalence of adverse events, suppression and early relapses when clonazepam was discontinued after 16 weeks for continue treatment. Dependency, abstinence and adverse events which included lack of concentration, loss of fine motor coordination and memory troubles could prevent the use of clonazepam in groups of patients with social phobia including those with comorbidity as depression, abuse or dependency of substance. In these, SSRI antidepressants could be a better first choice of treatment. More controlled studies with a longer duration of treatment and comparison with antidepressants are needed in social phobic patients.
