Innovations In Clinical Neuroscience

MAR-APR 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 3 – 4 , M A R C H – A P R I L 2 0 1 7 ] 25 releasing factor, and brain derived neurotrophic factor. 6–8 There are changes in sensitivity and transcription of serotonin (5-HT) receptors and possibly a net increase in serotonin signaling after T3 administration. 9,10 Administration of T3 has also led to increased basal 5- HT levels in the frontal cortex. 11 There is a possible but unclear association between T3 and adrenergic transmission and activity of second-messenger systems. 10 It has not been demonstrated to increase concentrations of monoamine metabolites, even in patients whose depression improved after treatment with T3. 12 METHODS Ovid Medline and PubMed databases were used to search for original studies, reviews, and meta-analyses in English published in journals or books from 1966 to June 2016 using search terms depression, augmentation, antidepressant, and liothyronine. We included open-label studies, randomized, placebo-controlled trials, meta-analyses, case reports, and case series; however, we focused on randomized, placebo- controlled or open-label trials given their higher evidence base compared to case reports or case series. Our searches yielded a total of 26 articles: six open- label trials with TCAs, nine randomized trials with TCAs, three open-label reports with SSRIs, three randomized studies with SSRIs, four reports utilizing other antidepressants, and one meta-analysis. TCAs AND T3 The use of T3 in combination with TCAs for the treatment of MDD has been evaluated as a method to enhance or accelerate a treatment response (both agents initiated simultaneously) or as augmentation after an adequate trial of TCA monotherapy. Controlled trials rated depression severity using the Hamilton Rating Scale for Depression (HRSD) 13 and defined response to treatment as a 50 percent or greater reduction in HRSD score. A meta-analysis of six placebo- controlled, double-blind studies evaluating the effects of T3 enhancement found T3 to be significantly more effective compared to placebo, and that the effects of T3 enhancement were greater with the larger percentage of women subjects. 14 In the individual studies, doses of T3 ranged from 25mcg daily to 62.5mcg daily; however, some T3 toxicity was noted after a few days of 62.5mcg daily dose. Four of these six trials found a significantly quicker time to response and/or greater response rate with T3 enhancement. 15–20 Additional details of the individual enhancement studies are noted in Table 1. In regard to augmentation studies, uncontrolled, open-label trials in outpatients have suggested that T3 is an efficacious augmentation strategy as well with response rates of greater than 50 percent. 21–25 A small number of controlled trials in subjects without a full response to adequate trials of TCAs for the treatment of unipolar depression followed these previous findings (Table 1). 26–29 Doses of T3 ranged from 25mcg daily to 37.5mcg daily; however, only the 37.5mcg daily dose showed greater response rates compared to controls. Two of these four trials found a significantly greater response rate with T3 augmentation. Additional details of controlled augmentation studies are noted in Table 1. SSRIs AND T3 The combination of SSRIs and T3 has also been studied in both open-label and randomized, placebo-controlled trials either as enhancement or as augmentation (Table 2). An enhancement study demonstrated a response rate of 70 percent when T3 was initiated with sertraline in patients with non-treatment- resistant MDD compared with a 50- percent response in participants that received sertraline alone; improvement in HRSD by 50 percent or greater was considered a response. 30 This study utilized a maximum dose of 100mg/day for the sertraline group, and thus possible underdosing of this SSRI may have occurred. Two additional enhancement studies did not find a significant difference in response rates when T3 was added to paroxetine or sertraline compared to paroxetine or sertraline monotherapy. 31,32 In three augmentation studies, T3 doses of 25- to 50mcg/day led to response and remission in patients that had an inadequate response to SSRI treatment. 33–35 However, the studies utilized an uncontrolled, open-label design, which does not adequately evaluate the true efficacy of T3 augmentation. This highlights the need for randomized, placebo-controlled trials. OTHER ANTIDEPRESSANTS AND T3 The Sequenced Alternatives to Relieve Depression (STAR*D) study 36 compared T3 to lithium for augmentation in patients receiving sustained-release bupropion or extended-release venlafaxine. Subjects were randomly assigned to T3 25mcg/day for one week then increased to 50mcg/day (mean exit dose 45.2mcg/day), compared to lithium up to 900mg/day for 14 weeks. Approximately 23 percent of subjects who received T3 augmentation achieved a response, and close to 25 percent of the subjects received remission. Overall, T3 was better tolerated than lithium as an augmentation strategy. The same year the STAR*D trial was published, Joffe et al 27 also reported data comparing T3 and lithium augmentation in a small randomized, double-blind, placebo-controlled study. All subjects (N=36) had received a trial of an antidepressant for at least five weeks and received augmentation with T3 37.5mcg/day, lithium up to 900mg/day, T3 plus lithium, or placebo for two weeks. Antidepressants other than SSRIs and TCAs included moclobamide 600- to 750mg/day, nefazodone 150- to 300mg/day, or venlafaxine 187.5- to 375mg/day. No significant difference was found in change in HDRS scores between groups. However, it is difficult to determine the efficacy of T3 with these antidepressants, as a majority of the subjects were receiving SSRIs, not other antidepressants. All subjects that received T3 alone as augmentation were taking SSRIs, and more than 60 percent of the subjects that received T3 plus lithium or placebo were taking SSRIs. The addition of T3 to the MAO-I phenelzine has been described in three case reports. The first case report noted significant improvement in depressive symptoms after augmenting with T3

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