Treatment-Resistant Depression: Page 4 of 4

Treatment-Resistant Depression: Page 4 of 4

By contrast to these relatively small studies with classical augmentation agents, there are a number of large, randomized, placebo-controlled trials of atypical antipsychotics in nonpsychotic, unipolar depression in combination with antidepressants. These studies culminated in the first-ever FDA approval of an agent specifically for antidepressant augmentation—aripiprazole. In their meta-analysis, Papakostas and colleagues38 conclude that the results support the utility of atypical augmentation, even in the absence of double-blind, placebo-controlled trials with aripiprazole (now available) and ziprasidone. Virtually all of the studies to date of atypical augmentation have been conducted with SSRIs, although there are reports that aripiprazole was effective with bupropion, tranylcypromine, and mirtazapine.39-41

The study of tranylcypromine (an MAOI) with aripiprazole suggests the need for cautious use of some combinations. As noted in the package insert, tranylcypromine should not be coadministered with dibenzazepine-related entities because of the risk of severe interactions, including hypertensive crises and seizures.42 Some of the atypical antipsychotics (eg, aripiprazole, ziprasidone) have a high affinity at the 5-HT1A-receptor; agents such as buspirone, which also binds at this receptor site, are not recommended for use with MAOIs. Ziprasidone also has a similar potency to imipramine in terms of blocking norepinephrine and serotonin reuptake (imipramine is al-so relatively contraindicated with MAOIs).43 There is a report of 5 patients treated safely with risperidone and MAOIs, and another of 12 patients exposed to olanzapine with the selegiline patch.44,45

In general, the effective dosage of atypical antipsychotics in this role seems to be lower than that used in psychosis. Data on the long-term risks in depressed patients, including tardive dyskinesia and metabolic syndrome, are urgently needed. The recent FDA approval of quetiapine as monotherapy in bipolar depression raises questions as to whether some of the atypical antipsychotics may be effective (and perhaps better tolerated) when given as a single agent for unipolar TRD.

In regard to the value of switching atypicals, if one agent fails, is it worth attempting trials of another? There are limited data that show that switching to another atypical is worthwhile.46,47 However, results from randomized controlled trials are still needed.


Each of the agents listed in Table 3 may be most effective when used for augmentation purposes. The quality of the evidence varies widely, particularly in the second and third categories of the table. For example, in a pooled analysis, estrogen was effective when added to sertraline in a group of depressed women over 60 years; however, the total sample size was only 127.48 There are small, positive, double-blind studies for agents such as testosterone, L-tryptophan, and omega-3-fatty acids.49-51 In the case of pindolol, there are negative studies as well, and in a recent review, the evidence supporting its efficacy was rated as a “C” (the lowest rating).28,32

Open-label reports for buspirone were positive, but 2 randomized controlled trials were negative.52,53 Buspirone was used as an augmentation agent for citalopram in level 2 of STAR*D: remission rates were 33% by the QIDS-SR compared to 39% with bupropion at the same stage. Although the remission rates between the 2 drugs did not differ significantly, the bupropion group had a significantly greater reduction in depression scores.54

Despite reports that suggest the efficacy of lamotrigine, this agent did not separate significantly from placebo in the only large, multicenter, double-blind, placebo-controlled trial to date.55 Modafinil, used in 2 randomized, placebo-controlled trials did not show significant placebo separation on most mood-scale scores, but it did reduce sleepiness and fatigue.56,57

The unfortunate reality is that conducting large, double-blind, placebo-controlled trials is extremely expensive and time consuming. Definitive evidence of the efficacy of these agents is likely to accrue slowly. Negative studies may not prove that a drug is ineffective because of factors such as high placebo response rates, or the more subtle reality that there may be meaningful subgroups of patients with TRD that we are currently unable to identify.



Drugs Mentioned in This Article

Agomelatine (Valdoxan, Melitor)
Amantadine (Symmetrel)
Aminoglutethimide (Cytadren)
Aripiprazole (Abilify)
Atomoxetine (Strattera)
Bromocriptine (Parlodel)
Bupropion (Wellbutrin, Zyban)
Bupropion SR (Wellbutrin SR)
Buspirone (BuSpar)
Carbamazepine (Carbatrol, Tegretol, others)
Celecoxib (Celebrex)
Citalopram (Celexa)
Desipramine (Norpramin; Pertofrane)
Dexamethasone (Decadron, others)
Duloxetine (Cymbalta)
Escitalopram (Lexapro)
Fluoxetine (Prozac, Sarafem)
Folic acid (Folacin, Folate, Pteroylglutamic acid, Vitamin B9)
Gabapentin (Neurontin)
Imipramine (Tofranil)
Ketoconazole (Nizoral)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
Melatonin (Bevitamel)
Memantine (Namenda)
Metyrapone (Metopirone)
Mifepristone (Mifeprex)
Mirtazapine (Remeron)
Modafinil (Provigil)
Nefazodone (Serzone)
Olanzapine (Zyprexa)
Omega-3-acid ethyl esters (Lovaza)
Paroxetine (Paxil)
Pergolide (Permax)
Pindolol (Visken)
Quetiapine (Seroquel)
Risperidone (Risperdal)
Ropinorole (Requip)
S-adenosyl-l-methionine (SAMe)
Selegiline (Emsam, Atrapryl, Carbex, others)
Sertraline (Zoloft)
Topiramate (Topamax)
Tranylcypromine (Parnate)
Trazodone (Desyrel)
Valproate/valproic acid (Depakote, others)
Venlafaxine (Effexor)
Yohimbine (Procomil)
Ziprasidone (Geodon)


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Evidence-Based References

Barowsky J, Schwartz TL. Part 1: An evidence-based approach to augmentation and combination strategies for treatment-resistant depression. Psychiatry 2008. 2006;3:42-61.
Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.

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