Do antidepressant combinations work? Jl of affective disorders:Oct 2012

18.10.2012

Antidepressant combination has been suggested as a strategy to increase treatment efficacy in resistant depression. In incomplete responders to one antidepressant, adding another antidepressant  is  often tried. Do we have enough evidence to support this?

Rocha and team reports on a meta analysis using data published up to Feb 2012. Randomized controlled trials that had two phases (first phase: antidepressant mono- therapy of patients with major depression. The second phase:  only patients who persisted with major depression and compared two arms: continuation of monotherapy versus the addition of a second antidepressant to the first on) were included in this analysis. The mono- therapy dosage could be kept the same or be increased. Remission and response rates were the primary outcomes. Remission defined as a score of 7 or less on the Hamilton 17-Item Depression Rating Scale (HDRS) or a score of 10 or less on the Montgomery–Asberg Depression Rating Scale (MADRS). Response was defined as a reduction of at least 50% in baseline symptoms on a depression scale

Results:

Only five trials satisfied the  inclusion criteria (Fava et al. 1994; Ferreri et al., 2001; Carpenter, et al. 2002; Fava et al., 2002; Licht and Qvitzau 2002) with a combined total of 565 patients.

Carpenter et al 2002 :  26 patients: AD plus Mirt (15-30 mg) vs AD plus Placebo :Remission 46% (active) vs 13% ( placebo).Difference was statistically significant.

Ferreri et al 2001: 104 patients: Fluoxetine 20mg+ Mianserine 60 mg Vs Fluoxetine 20mg + Placebo Vs Mianserine 60mg :  Remission :44% (Both Antidep)  18% ( placebo) , 36% (Add on antidep alone): difference was statistically significant.

Licht & Qvitzau 2002 : 293 patients: Sertraline 100mg + Mianserine 10-30mg Vs Sertraline 100mg + placebo vs Ser 200 + Placebo :  Remission 44% ( both antidep) , 38%(same dose antidep + placebo)  , 29 (high dose antidep).Difference was significant.

Fava et al 1994: 41 patients: Fluoxetine 20 + Desipramine 25-50 Vs Fluoxetine 40-60mg + Placebo vs Fluoxetine 20 + Lithium 300-600:  Response 25% ( Both antidep) , 53 (High dose antidep) ,29%  (Li aug): No statistically significant difference was found.

Fava et al 2002: 101 patients: Flu 20+ Des 25-50 Vs Flu 40-60 + placebo Vs Flu 20 + Lithium 300-600     response 29% ( both antidep) , 42 (higher dose antidep) ,23% (Li aug): No statistically significant difference was found.

With the exception of Ferreri et al., (2002), studies did not include a third arm with monotherapy using the second antidepressant. Thus, it was not possible to evaluate the efficacy of the added antidepressant alone.

With the exception of Ferreri et al., (2002), studies did not include a third arm with monotherapy using the second antidepressant. Thus, it was not possible to evaluate the efficacy of the added antidepressant alone.

Conclusions:

There is very little good quality evidence in this area. Only two small trials reported benefits with antidepressant combination (Ferreri et al., 2001; Carpenter et al. 2002).In both studies, the combination arm was compared to the monotherapy arm in which the dosage of the initial antidepressant was kept the same. (This is usually not the clinical practice ie dose increase is the usual option). The largest study (Licht) found no evidence to support combination.Side effects that led to dropouts were not specified in three studies (Ferreri et al., 2001; Fava et al., 2002; Licht and Qvitzau, 2002).All included studies were short term, with a combination period of 4 to 6 weeks.

Only  Ferreri et al., (2002), included a third arm with monotherapy using the second antidepressant. ( this is key to evaluate the efficacy of the added antidepressant alone).

Comment: Resistant depression is quite difficult to treat. Combination of antidepressant is one strategy we use. Many cocktails are used in secondary and tertiary referral units.  Even small response or remission rates is a welcome one when refractory depression ruins the life. Good quality larger trials are required in this area.

Summary of article:

Antidepressant combination for major depression in incomplete responders-a systematic review.

Lopes Rocha F, Fuzikawa C, Riera R, Ramos MG, Hara C. J Affect Disord. 2012

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