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World J Psychiatry. 2015 Sep 22;5(3):330-41. doi: 10.5498/wjp.v5.i3.330.

Pharmacologic approaches to treatment resistant depression: Evidences and personal experience.

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Antonio Tundo, Rocco de Filippis, Luca Proietti, Istituto di Psicopatologia, Private Outpatients Clinic, 00196 Roma, Italy.



To review evidence supporting pharmacological treatments for treatment-resistant depression (TRD) and to discuss them according to personal clinical experience.


Original studies, clinical trials, systematic reviews, and meta-analyses addressing pharmacological treatment for TRD in adult patients published from 1990 to 2013 were identified by data base queries (PubMed, Google Scholar e Quertle Searches) using terms: "treatment resistant depression", "treatment refractory depression", "partial response depression", "non responder depression", "optimization strategy", "switching strategy", "combination strategy", "augmentation strategy", selective serotonin reuptake inhibitors antidepressants (SSRI), tricyclic antidepressants (TCA), serotonin norepinephrine reuptake inhibitors antidepressants, mirtazapine, mianserine, bupropione, monoamine oxidase inhibitor antidepressant (MAOI), lithium, thyroid hormones, second generation antipsychotics (SGA), dopamine agonists, lamotrigine, psychostimulants, dextromethorphan, dextrorphan, ketamine, omega-3 fatty acids, S-adenosil-L-metionine, methylfolat, pindolol, sex steroids, glucocorticoid agents. Other citations of interest were further identified from references reported in the accessed articles. Selected publications were grouped by treatment strategy: (1) switching from an ineffective antidepressant (AD) to a new AD from a similar or different class; (2) combining the current AD regimen with a second AD from a different class; and (3) augmenting the current AD regimen with a second agent not thought to be an antidepressant itself.


Switching from a TCA to another TCA provides only a modest advantage (response rate 9%-27%), while switching from a SSRI to another SSRI is more advantageous (response rate up to 75%). Evidence supports the usefulness of switching from SSRI to venlafaxine (5 positive trials out 6), TCA (2 positive trials out 3), and MAOI (2 positive trials out 2) but not from SSRI to bupropione, duloxetine and mirtazapine. Three reviews demonstrated that the benefits of intra- and cross-class switch do not significantly differ. Data on combination strategy are controversial regarding TCA-SSRI combination (positive results in old studies, negative in more recent study) and bupropion-SSRI combination (three open series studies but not three controlled trails support the useful of this combination) and positive regard mirtazapine (or its analogue mianserine) combination with ADs of different classes. As regards the augmentation strategy, available evidences supported the efficacy of TCA augmentation with lithium salts and thyroid hormone (T3), but are conflicting regard the SSRI augmentation with these two drugs (1 positive trial out of 4 for lithium and 3 out of 5 for thyroid hormone). Double-blind controlled studies showed the efficacy of AD augmentation with aripiprazole (5 positive trials out 5), quetiapine (3 positive trials out 3) and, at less extent, of fluoxetine augmentation with olanzapine (3 positive trials out 6), so these drugs received the FDA indication for the acute treatment of TRD. Results on AD augmentation with risperidone are conflicting (2 short term positive trials, 1 short-term and 1 long-term negative trials). Case series and open-label trials showed that AD augmentation with pramipexole or ropinirole, two dopamine agonists, could be an effective treatment for TRD (response rate to pramipexole 48%-74%, to ropinirole 40%-44%) although one recent double-blind placebo-controlled study does not support the superiority of pramipexole over placebo. Evidences do not justify the use of psychostimulants, omega-3 fatty acids, S-adenosil-L-metionine, methylfolate, pindolol, lamotrigine, and sex hormone as AD augmentation for TRD. Combining the available evidences with our experience we suggest treating non-responders to one SSRI bupropion or mirtazapine trial by switching to venlafaxine, and non-responders to one venlafaxine trial by switching to a TCA or, if TCA are not tolerated, combining mirtazapine with SSRI or venlafaxine. In non-responders to two or more ADs (including at least one TCA if tolerated) current AD regimen could be augmented with lithium salts (mainly in patients with bipolar depression or suicidality), SGAs (mostly aripiprazole) or DA-agonists (mostly pramipexole). In patients with severe TRD, i.e., non-responders to combination and augmentation strategies as well as to electroconvulsive therapy if workable, we suggest to try a combination plus augmentation strategy.


Our study identifies alternative effective treatment strategies for TRD. Further studies are needed to compare the efficacy of different strategies in more homogeneous subpopulations.


Antidepressants; Augmentation; Combination; Dopamine-agonists; Major depressive disorder; Non responder depression; Partial response depression; Second generation antipsychotics; Switching; Treatment resistant depression

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