Different Clinical Outcomes in Bipolar Depression Based on Dosage

Antidepressants Can Worsen Rapid Cycling in Bipolar Depression
Antidepressants Can Worsen Rapid Cycling in Bipolar Depression
There are clear disadvantages to prescribing higher rather than lower doses of SGAs.

There are clear disadvantages to prescribing higher rather than lower doses of selected second-generation antipsychotics (SGAs), a study published in Journal of Psychiatric Research concluded.1

Researchers from the Department of Medicine and Surgery at the University of Milano Bicocca in Monza, Italy, conducted a systematic review and meta-analysis to test the differences in clinical harms and benefits for low vs high doses of SGAs in acute treatment of bipolar depression (BD). This study represented the first meta-analysis performing a systematic evaluation of data on efficacy and tolerability of different doses of selected SGAs.

They compared different doses of the same SGA monotherapy using randomized, double-blind clinical trials on adults with BD in a current major depressive episode, basing a dosage of 3 mg/day as the threshold to define low and high doses for cariprazine. Four different clinical outcomes were tested: improvement, response, remission, and discontinuation. Improvement, response, and remission were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS).2 Discontinuation was determined by the number of participants who left the study.

Data from the meta-analysis, including 7 randomized, double-blind clinical trials for 2834 patients, yielded 2 main findings. First, there was no significant difference between lower and higher doses of SGA monotherapy in terms of clinical efficacy, defined as decrease of depressive symptoms, remission, response, and discontinuation because of inefficacy rates.

Second, lower doses of selected SGAs yielded better tolerability compared with higher ones. “Indeed, we found a significantly favorable profile for lower versus higher doses of SGAs in terms of all-cause discontinuation rates,” the researchers said. In addition, lower doses were associated with a lower likelihood of adverse effect-related discontinuation compared with higher ones.

The researchers also acknowledged several limitations. Trials assessing lurasidone and ziprasidone tested low- and high-dose ranges with flexible, rather than fixed, doses and included 2 different dosages (0.75 and 1.5 mg) in the low-dose group of cariprazine.

“Therefore, despite the high statistical consistency, the interpretation of our results needs to take into account this potential source of methodological heterogeneity,” the authors wrote, adding: “we tested SGA monotherapy, but we could not exclude that there might be a dose-effect relationship, in terms of efficacy and tolerability, if SGA were used as add-on treatment to mood stabilizers and/or antidepressants…. [F]uture research should explore the dose effect of SGAs not only in monotherapy but also as adjunctive/combination treatments.”

They concluded, “[B]ased on high quality evidence, we found that low and high doses of selected SGAs had consistent comparability, in terms of efficacy-related outcomes.” However, “lower doses were associated with more favorable tolerability-related outcomes…. Establishing the optimal therapeutic dosage range for SGAs, reaching the minimum effective and maximum tolerated doses, needs to be carefully considered also for bipolar depression treatment…. [C]linicians should seriously consider the tolerability advantages of using lower doses of approved SGA monotherapy for acute bipolar depression, particularly in patients with non-urgent mood symptoms and/or substantial tolerability concerns.”

The authors emphasized the need for attentiveness to specific populations of patients, including those with treatment-resistant depression, high suicide risk, and other psychiatric comorbidities. 

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  1. Bartoli F, Dell’Osso B, Crocamo C, Fiorillo A, et al. Benefits and harms of low and high second-generation antipsychotics doses for bipolar depression: A meta-analysis [published online December 31, 2016]. J Psychiatr Res. doi: 10.1016/j.jpsychires.2016.12.021
  2. Montgomery, S.A., Asberg, M. 1979. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-389. doi: 10.1192/bjp.134.4.382