Treatment-resistant depression represents a common problem, with the vast majority of depressed patients showing incomplete response to antidepressant trials. Augmentation and combination strategies are commonly employed to address this problem, but there are few randomized, controlled studies to guide treatment choice. Indeed, some of the most common augmentation strategies in depression are those with the least controlled evidence. The popularity of bupropion, psychostimulants and atypical antipsychotics as augmentors may not be warranted by existing controlled studies, whereas two less commonly used augmentors-lithium and thyroid hormone- have substantial controlled evidence to support their use. This paper summarizes the state of the evidence for commonly used augmenting strategies and explores preliminary findings for more investigational approaches.
"Therefore, " augmentation strategies " (addition of one or more nonantidepressant drugs to an existing antidepressant regimen to enhance mood and overall antidepressant response), " adjunctive therapies " (addition of one or more agents to target specific symptoms of depression) (DeBattista, 2006) or " combination treatments " (augmentations made using two or more drugs from the same class, e.g., two antidepressants) (Papakostas, 2009) represent popular treatment strategies for TRD. While some augmentation strategies for standard antidepressants , including atypical antipsychotics (Nelson and Papakostas, 2009) and lithium or thyroid hormones (DeBattista, 2006), have consistent and/or increasing levels of evidence of support, the actual usefulness of most antidepressant within-or across-class combinations vs. monotherapy remains substantially not supported by existing studies, at least for melancholic cases of TRD or moderately to severe nonpsychotic chronic and/or recurrent MDD according to the acute and long-term outcomes reported by the single-blind randomized " Combining Medications to Enhance Depression Outcomes (CO-MED) " study (Rush et al., 2011), despite the popularity of this practice among clinicians (Bares et al., 2013; Gaynes et al., 2012; Souery et al., 2011). This issue could also affect TRD cases with atypical features, which apart from nosological revisions (Fornaro and Giosue, 2010; Perugi et al., 2011; Stewart et al., 2009; Thase, 2009), require further controlled studies on the matter compared with " typical " (melancholic) TRD. "
[Show abstract][Hide abstract] ABSTRACT: The efficacy, safety, and tolerability of combined bupropion versus placebo using duloxetine as active reference drug, in patients with a DSM-IV diagnosis of major depression with atypical features and a history of treatment resistance, were evaluated in this preliminary six-week study. Patients (n=46) had a baseline Hamilton Depression Scale (HAM-D) ≥14 and were randomly assigned to 150/300 mg/day bupropion vs. placebo, which was added to 60 to 120 mg/day duloxetine depending on baseline depression severity. Atypical features of depression were assessed using the additional eight-item module of the Structured Interview Guide for the HAM-D with the Atypical Depression Supplement. By week 6, only five (21.7%) patients receiving duloxetine+placebo vs. six (26.1%) patients on the bupropion combination achieved response. No significant difference in final HAM-D scores between the two groups was observed between those patients achieving response. The presence of a higher number of atypical features significantly predicted non-response, with the relevant binary logistic regression model correctly classifying 17 out 22 (77.3%) of non-responders [Exp(B)=0.294; p=.016] vs. 17 out 23 (73.9%) [Exp(B)=0.353; p=.028] non-responder cases in the “+placebo” and “+bupropion” groups, respectively. In those patients receiving bupropion, treatment-emergent adverse events leading to withdrawal were more common among those receiving lower doses of the combination drug, and no life-threating dangers were noted. Additional studies, including an adequate course of duloxetine trial, are nonetheless aimed to allow a firm conclusion about the usefulness of the combination of duloxetine and bupropion for treatment-resistant cases of major depression with atypical features.
European Neuropsychopharmacology 08/2014; DOI:10.1016/j.euroneuro.2014.04.004 · 4.37 Impact Factor
"interventions are being developed. New pharmacologic interventions include NMDA antagonists, as zinc (Nowak et al., 2003a), and the addition of one or more agents to an existing antidepressant regimen (DeBattista, 2006). Our results show, to our knowledge for the first time, that ZnCl 2 given systemically by p.o. route (10 and 30 mg/kg) is effective in reducing the immobility time in the TST, consistent with an antidepressant-like effect in this predictive test of antidepressant action (Steru et al., 1985). "
[Show abstract][Hide abstract] ABSTRACT: The antidepressant-like activity of creatine in the tail suspension test (TST) was demonstrated previously by our group. In this study we investigated the involvement of the noradrenergic system in the antidepressant-like effect of creatine in the mouse TST. In the first set of experiments, creatine administered by i.c.v. route (1 μg/site) decreased the immobility time in the TST, suggesting the central effect of this compound. The anti-immobility effect of peripheral administration of creatine (1 mg/kg, p.o.) was prevented by the pretreatment of mice with α-methyl-p-tyrosine (100 mg/kg, i.p., inhibitor of tyrosine hydroxylase), prazosin (1 mg/kg, i.p., α1-adrenoceptor antagonist), but not by yohimbine (1 mg/kg, i.p., α2-adrenoceptor antagonist). Creatine (0.01 mg/kg, subeffective dose) in combination with subeffective doses of amitriptyline (1 mg/kg, p.o., tricyclic antidepressant), imipramine (0.1 mg/kg, p.o., tricyclic antidepressant), reboxetine (2 mg/kg, p.o., selective noradrenaline reuptake inhibitor) or phenylephrine (0.4 μg/site, i.c.v., α1-adrenoceptor agonist) reduced the immobility time in the TST as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an activation of α1-adrenoceptor and that creatine produces synergistic effects in the TST with antidepressants that modulate noradrenaline transporter, suggesting that an improvement in the response to the antidepressant therapy may occur when creatine is combined with these antidepressants. Furthermore, the synergistic effect of creatine (0.01 mg/kg, p.o.) and reboxetine (2 mg/kg, p.o.) combination was abolished by the α1-adrenoceptor antagonist prazosin, indicating that the antidepressant-like effect of combined therapy is likely mediated by an activation of α1-adrenoceptor.
Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2013; DOI:10.1016/j.pnpbp.2013.01.014 · 3.69 Impact Factor
"Pindolol (7.5 mg daily) augmentation of SSRIs is probably not effective in treatment-resistant depression; two small studies were positive (Maes, et al., 1999; Sokolski, et al., 2004) but three, including the two largest were not (Moreno, et al., 1997; Perez, et al., 1999; Perry, et al., 2004). Manipulation of the glucocorticoid system may be of benefit in treatment-resistant depression but somewhat confusingly both antiglucocorticoid treatment and steroid agonists may have some efficacy (DeBattista, 2006). An RCT in nonresistant patients of 3-weeks treatment with the steroid synthesis inhibitor metyrapone added to nefazodone or fluvoxamine found better response at 5 weeks compared with placebo (58% versus 33%, NNT 4) (Jahn, et al., 2004) and a small RCT of predominantly treatment-resistant patients found an advantage over placebo to the addition of dehydroepiandrosterone (DHEA) to ongoing treatment (Wolkowitz, et al., 1999). "
[Show abstract][Hide abstract] ABSTRACT: A revision of the 2000 British Association for Psychopharmacology evidence-based guidelines for treating depressive disorders with antidepressants was undertaken to incorporate new evidence and to update the recommendations where appropriate. A consensus meeting involving experts in depressive disorders and their management was held in May 2006. Key areas in treating depression were reviewed, and the strength of evidence and clinical implications were considered. The guidelines were drawn up after extensive feedback from participants and interested parties. A literature review is provided, which identifies the quality of evidence to inform the recommendations, the strength of which are based on the level of evidence. These guidelines cover the nature and detection of depressive disorders, acute treatment with antidepressant drugs, choice of drug versus alternative treatment, practical issues in prescribing and management, next-step treatment, relapse prevention, treatment of relapse, and stopping treatment.
Journal of Psychopharmacology 07/2008; 22(4):343-96. DOI:10.1177/0269881107088441 · 3.59 Impact Factor
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