Abstract
Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.
Highlights
Major depressive disorder (MDD) is one of the most common psychiatric disorders and is associated with work/social dysfunction, accounting for a significant financial burden worldwide [1]
Four-hundred-ninety studies were discarded because, after reviewing the abstracts, the papers dealt with another topic, and 52 studies were discarded because they were written in a different language
The full texts of the remaining 342 citations were examined in more detail, concluding that 235 studies did not meet the inclusion criteria because: one-hundred-twenty-four did not accurately define treatment resistance; forty-nine studies included mixed samples; forty-one articles were about neuromodulation; thirteen were pooled analyses; four were study protocols; four were duplicates
Summary
Major depressive disorder (MDD) is one of the most common psychiatric disorders and is associated with work/social dysfunction, accounting for a significant financial burden worldwide [1]. According to the European Medicine Agency, TRD patients are those who fail to show clinically meaningful improvement after treatment with at least two antidepressant (AD) agents of different classes, prescribed in adequate dosages for an appropriate period of time and with adequate affirmation of treatment adherence [4]. This definition is in agreement with the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines [5] about unipolar depressive disorder. Despite the assessment of TRD having improved over the last few years, the lack of consensus may limit the ability of researchers to generalize the findings on this topic
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