Resumen de Tratamiento farmacológico de la fase depresiva del trastorno bipolar (depresión bipolar). Primera parte
- español
El trastorno bipolar es una enfermedad mental frecuente, severa y recurrente. La prevalencia de sus 2 variantes, el trastorno bipolar tipo I (con manía y depresión recurrentes) y el tipo II (episodios recurrentes de depresión e hipomanía) es, en los Estados Unidos de América, de 2.5%; la prevalencia del trastorno bipolar tipo I a lo largo de la vida es de 1%, aunque utilizando criterios más laxos de diagnóstico puede elevarse hasta 2- 5%. En la Encuesta Nacional de Epidemiología Psiquiátrica en México se encontró que la prevalencia del trastorno bipolar tipo I a lo largo de la vida es, en México, de 1.3 ± 0.2%, en el último año de 0.9 ± 0.1% y en el último mes de 0.4 ± 0.1%. En cuanto al género, la prevalencia es un poco mayor entre los hombres (1.6 ± 0.3) que entre las mujeres (1.1 ± 0.2) a lo largo de la vida, similar en el último año (0.9 ± 0.2 % vs. 0.8 ± 0.2% respectivamente) e igual en el último mes (0.4 ± 0.1%). Su inicio puede presentarse desde la niñez o la adolescencia y persistir a lo largo de la vida. La edad en que aparece el trastorno bipolar I, en México, oscila entre los 3 y los 47 años, y 21.36 años en promedio.
Objetivos. En este artículo se revisaron los distintos estudios relacionados con el tratamiento de la depresión del trastorno bipolar, poniendo énfasis en los ensayos clínicos controlados.
Método. Se llevó a cabo una búsqueda electrónica para obtener los estudios controlados acerca del tratamiento de la depresión bipolar, y se revisaron manualmente las referencias y procedimientos de las reuniones internacionales.
Resultados. Carbonato de litio: No existen estudios doble ciego controlados que examinen la efectividad del litio en la depresión bipolar. Los 3 estudios cruzados descritos demuestran su superioridad sobre el placebo. Valproato: Sólo existe un ensayo clínico controlado con placebo, en el que se observa que 43% de los sujetos asignados al azar remitieron con el uso de valproato, encambio sólo 27% remitieron con placebo. Sin embargo, al final del estudio los cambios observados en la Escala de Depresión de Hamilton (HAM-D) no favorecieron al valproato. Dado que es el único estudio con estas características y que la muestra es pequeña, se requieren estudios posteriores para definir la utilidad del valproato en la depresión bipolar. Carbamacepina: La carbamacepina ha demostrado alguna utilidad, sin embargo se requiere mayor estudio antes de establecer una conclusión definitiva acerca de ella. Lamotrigina: La lamotrigina a dosis de 200 mg/día resultó más efectiva que el placebo en la sintomatología depresiva, evaluada con la Escala de Calificación de la Depresión de Montgomery Asberg (MADRS) y con la Escala de Impresión Global Clínica (CGI-I). En otro estudio, demostró su utilidad, sólo en el tratamiento del trastorno bipolar tipo I, más no del tipo II. Su efectividad como tratamiento profiláctico se evaluó en 2 ensayos clínicos controlados. Los resultados indican claramente que la lamotrigina es efectiva para retrasar la aparición de las recaídas y las recurrencias depresivas, en pacientes con trastorno bipolar tipo I. Gabapentina: El estudio que compara a este medicamento con lamotrigina, en pacientes con trastornos del humor refractarios, señala que su efecto es similar al del placebo e inferior al de la lamotrigina. Topiramato: No existen ensayos clínicos controlados que estudien el efecto del topiramato en la depresión bipolar. Antidepresivos: El efecto de la imipramina es comparable al de la fluoxetina, pero significativamente menor que el de los inhibidores de la monoaminooxidasa (tranilcipromina). Antipsicóticos atípicos: La olanzapina es el único antipsicótico atípico que ha demostrado en ensayos clínicos controlados su utilidad en la fase depresiva del trastorno bipolar, donde la respuesta se observa en un 48.2% al administrarse como monoterapia y hasta de 64.8% cuando se administra conjuntamente con fluoxetina.
Conclusiones: La revisión realizada indica que el carbonato de litio es el único estabilizador del ánimo que es efectivo en la depresión bipolar, pues controla la sintomatología depresiva aguda, previene nuevos episodios y no predispone al paciente a desarrollar manía, por lo que debe considerarse el tratamiento de primera elección para estos casos. La lamotrigina también resultó efectiva para la depresión bipolar aguda, así como en la prevención de nuevos episodios, pero no se ha comprobado que pueda evitar los episodios maníacos. La magnitud del efecto antidepresivo de la olanzapina parece ser menor que el de los antidepresivos convencionales y que el de la lamotrigina. Otros anticonvulsivantes, los antidepresivos u otras antipsicóticos atípicos no se recomiendan como tratamiento de primera elección. A partir de las observaciones realizadas, se describen dos algoritmos de tratamiento, que pueden utilizarse si el paciente ha recibido o no tratamiento previo con estabilizadores del ánimo. Aunque es relativamente escasa la cantidad de ensayos clínicos controlados, los datos obtenidos a partir de ellos, pueden utilizarse para proveer las alternativas de tratamiento para los pacientes que cursan con episodios depresivos, a lo largo de la evolución del trastorno bipolar. Sin embargo, es necesario un mayor número de estudios para terminar de definir las opciones de tratamiento más apropiadas para los distintos tipos de pacientes.
- English
Bipolar disorder is a major public health problem, affecting approximately 1.3 ± 0.2 % of the Mexican population. In addition to the subjects personal suffering, bipolar disorders places substantial burdens on health care services, families, caregivers and employers. In the World Health Organization’s Global Burden of Disease study, bipolar disorder ranked sixth among all medical disorders in years of life lost to death or disability.
Bipolar depression, or the depressive phase of bipolar disorder, represents a difficult- to- treat and disabling form of depression.
However, in regard to its impact, an insufficient number of studies have explored its treatment. Studies indicate that patients with bipolar disorder spend more time in treatment and take longer to recover from the depressive phase that from the manic phase.
Patients with bipolar disorder, experience depressive symptoms more than 3 times more longer than they experience manic symptoms. The median time to recovery from the depressive phase is 9 weeks but from the manic phase is 5 weeks; 22 % of the patients in the depressive phase and only 7 % in the manic phase remained ill for at least 1 year. The median time to full remission is 16.8 weeks for a manic episode but 40 weeks for a depressive episode. In addition to being longer and more persistent, the depressive phase of bipolar disorder is associated with higher rates of morbidity and mortality. The relative risk of suicide among patients with bipolar depression is 34.9 times greater than that among patients with pure mania. Despite the clear clinical implications of these findings, treatment of bipolar depression remains an understudied area, as clinicians and researchers have historically focused on treatment of mania. Although a wide range of mood-stabilizing medications is available, treatment options for bipolar depression remain more limited. The 2002 treatment guidelines from the American Psychiatric Association recommended either lithium or lamotrigine as first-line treatment.
Although reviews of clinical trials have concluded that there is evidence of lithium’s acute efficacy for bipolar depression, anticonvulsants such as lamotrigine and valproate have also been used to treat bipolar depression. However, lamotrigine requires a slow upward titration to avoid the risk of rash. Other treatments include the adjunctive use of antidepressants with a mood stabilizer. However, antidepressants, may cause problems due to their potential to induce mania or hypomania or to accelerate cycling.
This paper reviews controlled studies of bipolar depression, outlines criteria for choosing treatment, and provides options for treatment of refractory bipolar depression. The author conducted a comprehensive review of English-language literature describing peer- reviewed and quality class A controlled trials in order to identify agents used for bipolar disorder. Controlled studies to examine the efficacy of treatments for acute bipolar depression were located through electronic searches of several databases and by manual cross search of references and proceedings of international meetings. Lithium: There are no double-blind, parallel-design, placebo-controlled studies that have examined the efficacy of lithium monotherapy in comparison with placebo in acute bipolar depression. However, the efficacy of lithium was examined in three placebo-controlled cross-over studies and all of them showed lithium’s superiority over placebo. Available data supports the efficacy of lithium in acute bipolar depression.
Valproate: A recent placebo-controlled, parallel-design study, examined the efficacy of valproate monotherapy. Intent-to-treat analysis indicated that 43 % of the subjects randomized to valproate and 27 % randomized to placebo met criteria for recovery (p= .04), but mean change from baseline in HAM-D scores were similar at the end-point to the placebo group. The negative findings in this study could be due to a smaller sample size, so this suggests the efficacy of valproate in acute bipolar depression but this needs to be verified in further larger- scale double- blind trials. Carbamazepine: Carbamazepine has some efficacy, but further studies are needed before firm conclusions can be drown. Lamotrigine: In the largest double-blind, placebocontrolled, parallel study of bipolar depression to date, the lamotrigine 200 mg/day group showed a significantly greater improvement compared with the placebo group on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression-Improvement (CGI-I) scale. In another 10-weekdouble-blind trial in bipolar I and bipolar II depressed patients, above all, no significant differences were noted using last observation carried forward (LOCF). However, a subgroup analysis revealed significant differences favoring lamotrigine in bipolar I but not in bipolar II depressed patients. The efficacy of lamotrigine in preventing depressive episodes in bipolar I disorder was examined in two recent double-blind placebo-controlled studies. In one of the studies, patients with bipolar I disorder who were currently or recently in a manic or hypomanic phase were treated with lamotrigine monotherapy or add on therapy to other psychotropic medications. Survival analysis showed that lamotrigine was significantly superior to placebo in time, for any mood episode or depressive episode. In the other study, bipolar I depressed patients were treated in an open-label design with lamotrigine monotherapy or add on therapy and those meeting the stabilization criteria were randomized to double-blind treatment with one of three fixed doses of lamotrigine monotherapy, lithium monotherapy or placebo for 18 months.
Results using survival analysis indicated that lamotrigine was significantly superior to placebo in delaying time of intervention for any mood episode or a depressive episode. The results of these two double-blind trials clearly indicate that lamotrigine is effective in delaying depressive relapses and recurrences in bipolar I patients.
There is no evidence to indicate that lamotrigine induces rapid cycling in bipolar patients. Gabapentine: The efficacy of gabapentine monotherapy in comparison with lamotrigine or placebo was examined over a 6-week period in patients with refractory mood disorders. The results of this study indicate that lamotrigine is effective in 45 % of the patients, and gabapentine is no more effective than placebo in treating depressive symptoms. Topiramate:
No double-blind studies have been reported on the efficacy of topiramate monotherapy in bipolar depression. Antidepressants: In double-blind active comparator studies, response rates to imipramina were comparable with the response rates to fluoxetine through significantly lower when compared with tranylcypromine.
Atypical antipsychotics: Olanzapine is the only atypical antipsychotic that has been tested for its efficacy in a double-blind, placebocontrolled trial in bipolar depression. Response rates were 48.2 % in the olanzapine group, 64.8 % in the olanzapine plus fluoxetine group, and 36.1 % in the placebo group. The results of this study indicate olanzapine’s monotherapy efficacy in treating acute bipolar depression.
Conclusions: The literature reviewed above indicates that lithium is the only efficient medication in acute bipolar depression and in preventing depressive episodes, and that it has no propensity to induce a manic switch or rapid cycling; also, it should be the firstline treatment for bipolar depression. Lamotrigine is also efficient in acute bipolar depression, and in preventing depressive episodes, but its efficacy in preventing manic episodes has not been proven.
The magnitude of the antidepressant effect of olanzapine appears to be somewhat smaller than other established antidepressant medications as well as lamotrigine. The other anticonvulsants, antidepressants, or atypical antipsychotics cannot be recommended as first-line treatments for bipolar depression.
