Maprotiline

Abstract: A meta-analysis of the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) against nonselective and noradrenergic reuptake inhibitors (mainly tricyclic antidepressants, TCAs) in depressed inpatients was carried out. Twenty-five double-blind studies provided data on relative efficacy which was determined by a summary variance-weighted mean effect size calculated from the difference in the reduction in mean Hamilton Depression Rating Scale (HDRS) scores for the two antidepressants in each study. Twenty-three studies provided data on dropouts and relative tolerability which was determined as the variance-weighted pooling of the relative risk (RR) of dropout for all reasons and for adverse effects from each study. TCAs were significantly more effective than SSRIs (effect size = -0.23, 95% CI -0.40 to -0.05, P = 0.011), although sensitivity analyses by analysing larger studies (> 100 patients) and those providing complete data reduced the advantage to TCAs to a trend (P < 0.10). When the TCAs were grouped into those with dual action on 5-hydroxytryptamine (HT) and noradrenaline reuptake (clomipramine and amitriptyline) and those with predominantly noradrenaline reuptake (imipramine, desipramine and maprotiline), only the dual action TCAs had greater efficacy than SSRIs (effect size = -0.30, 95% CI -0.54 to -0.05, P = 0.017). When TCAs were considered individually, only amitriptyline was significantly more effective than comparator SSRIs (effect size = -0.37, 95% CI -0.67 to -0.07, P = 0.015). More patients overall discontinued treatment on TCAs than on SSRIs (29.0% vs. 25.5%), although this did not reach statistical significance (RR = 0.88, 95% CI 0.75 to 1.03, P = 0.121). However, significantly more patients stopped treatment due to adverse effects on TCAs compared to SSRIs (14.2% vs. 9.1%, RR = 0.66, 95% CI 0.50 to 0.87, P = 0.003) with no difference in discontinuations due to treatment failure (10% vs. 11.6%, RR = 1.13, 95% CI 0.84 to 1.51, P = 0.42). This meta-analysis suggests that at least some TCAs may be more effective than SSRIs in depressed inpatients, with there being the strongest evidence for amitriptyline. A possible explanation is that this is related to a dual action in inhibiting both 5-HT and noradrenaline reuptake. In agreement with previous meta-analyses, TCAs appear less well tolerated than SSRIs, although the absolute risk difference for discontinuation due to adverse effects (4.9%, 95% CI -8.1 to -1.7%) is of uncertain clinical significance.

Abstract: The dopamine theory of depression was studied by assessing the effect of antidepressant drugs on uptake of dopamine, noradrenaline, and serotonin in synaptosomes from rat brain. Five newer drugs—butriptyline, maprotiline, trimipramine, iprindole, and mianserine—exhibited rather potent inhibition of 3H-dopamine uptake in corpus striatum, as their IC50 values, which were in the order of 10-6–10-5 M, were only about 50 times higher than for nomifensine (IC50=10-7 M). The five drugs were weak, compared to chlorimipramine, on 14C-serotonin uptake in the whole forebrain, as their IC50 were about 10-5 M. Butriptyline, trimipramine, and iprindole were very weak uptake inhibitors of 3H-noradrenaline in the occipital cortex. Their IC50 values were about 10-6 M, which is almost 1000 times higher than for desmethylimipramine. These results are discussed in relation to comprehensive recent literature as further indicating a link between dopamine and depression.

Abstract: OBJECTIVE Late-life depression is an important public health issue, given the growing proportion of the elderly relative to the general population in the developed world. The purpose of this study was to examine the efficacy of antidepressants for the treatment of major depressive disorder (MDD) in elderly patients. DATA SOURCES PubMed/MEDLINE was searched for randomized, double-blind, placebo-controlled trials of antidepressants for treatment of both adult (nonelderly) MDD (patients aged < 65 years) and late-life MDD (patients aged ≥ 55 years). The search was limited to articles published between January 1, 1980, and March 3, 2010 (inclusive). The year 1980 was used as a cutoff in our search to decrease diagnostic variability, since the DSM-III was introduced in 1980. Our search cross-referenced the term placebo with each of the following antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine, trimipramine, protriptyline, dothiepin, doxepin, lofepramine, amoxapine, maprotiline, amineptine, nomifensine, bupropion, phenelzine, tranylcypromine, isocarboxazid, moclobemide, brofaromine, fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine, zimelidine, tianeptine, trazodone, nefazodone, agomelatine, venlafaxine, desvenlafaxine, duloxetine, milnacipran, reboxetine, mirtazapine, and mianserin. We also reviewed the reference lists of all studies identified through the PubMed/MEDLINE search. STUDY SELECTION Articles were selected that reported on randomized, double-blind, placebo-controlled trials of antidepressants used as monotherapy for treatment of MDD and that met numerous a priori criteria pertaining to MDD diagnosis criteria, study duration, study design, drug formulation, original data, age thresholds, primary and secondary outcome measures, and exclusions of other disorders. Final inclusion of articles was determined by consensus between the authors. Seventy-four articles were found eligible for inclusion in our analysis (15 late-life MDD trials and 59 adult MDD trials). RESULTS Antidepressants were found to be efficacious for late-life MDD (age 55 and older; P < .0001), although there was evidence for heterogeneity across studies (Q22 = 67.302, P < .001). However, antidepressants were not found to be efficacious in the subset of studies using age thresholds of 65 years or older (older late-life MDD) (P = .265). Finally, when we controlled for study design characteristics, antidepressant but not placebo response rates were lower among late-life MDD patients than among adult MDD patients. CONCLUSIONS The present meta-analysis suggests that antidepressants are efficacious in late-life MDD, but significant study heterogeneity suggests that other factors may contribute to these findings. A secondary analysis raises the possibility that efficacy of these agents may be reduced in trials involving patients aged 65 years or older. Why antidepressants may be less efficacious in elderly versus younger subjects remains unclear.