Treatment-Resistant Depression

July 27, 2009

The chances for full recovery from major depressive disorder diminish the longer a patient remains depressed-a fact that lends a sense of urgency for appropriate therapy.

Approximately 32 to 35 million adults in the United States have an episode of major depression sometime during their lifetime, and many of them do not respond to initial treatment.1 The results of an analysis undertaken by Fava and Davidson2 suggest that between 29% and 46% of depressed patients fail to respond fully to antidepressant treatment of adequate dose and duration; about 15% of patients fail to respond to multiple treatment trials.3 Fagiolini and Kupfer4 have suggested that patients with treatment-resistant depression (TRD) may represent a biologically unique subtype of depressed patients. Unfortunately, the chances for full recovery diminish the longer a patient remains depressed-a fact that lends a sense of urgency for appropriate therapy.5

MANAGEMENT STRATEGIES

Before discussing the effectiveness of individual agents in TRD, it is important to review recent evidence regarding the principles of using these agents to maximize the chance of a response.6-9 Some of the most salient findings from the STAR*D trial on this topic are summarized in Table 1.

The standard strategy for managing patients who are depressed includes an adequate clinical trial; when the response is unsatisfactory, the clinician’s options are:

• Switch to another antidepressant

• Combine a second antidepressant with the first

• Add a second drug that is not approved as an antidepressant

• Start psychotherapy

Antidepressants can be grouped into 6 major categories: tricyclic antidepressants (TCAs), SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), serotonin neurotransmitter (5-HT2)-receptor antagonists (eg, nefazodone, trazodone), and novel agents (eg, mirtazapine, bupropion). If a patient fails to respond to one antidepressant class, it makes sense (at least conceptually) to switch to another, although most guidelines acknowledge that 2 failed trials of SSRIs may be justifiable before switching classes.7,8 When examining switching studies, be certain that the reason for switching was a failure to respond to an adequate antidepressant trial rather than a lack of tolerability, as these are fundamentally different issues.

Switching

The concept of switching classes of antidepressants is only as valid as the theoretical basis by which the antidepressants are grouped. As noted, some treatment guidelines allow 2 SSRI trials before switching classes. For example, in a study by Thase and colleagues,10 58 patients failed

a trial of fluoxetine; however, there was a 76% response rate to citalopram among completers. Although this study was not blinded, it is interesting that citalopram (which is believed to be the most selective of the SSRIs) was effective when another SSRI was not. It is hoped that as our knowledge of the mechanism of action of antidepressants grows more sophisticated, methods of classifying these agents will evolve to better guide clinicians in switching and combination strategies.

The clinical trial data on switching are surprisingly sparse-a recent meta-analysis identified only 4 randomized controlled trials.11 These trials include data from level 2 of the STAR*D study in which patients who were switched from citalopram to sertraline, venlafaxine XR, or bupropion SR showed remission rates of 27%, 25%, and 26% (respectively) based on the Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR-16).12 The meta-analysis found a modest but statistically significant advantage in switching from SSRIs to non-SSRIs. Of the 5 comparisons, 3 used venlafaxine, which is predominately a serotonergic agent (the serotonin-norepinephrine Ki ratio is 30), although it is classified as an SNRI. This may account for the relative lack of separation. One wonders if duloxetine, with a Ki ratio of 9 and relatively greater noradrenergic potency, might show greater separation.13 However, only one open-label switching study with duloxetine has been published to date.14

In switching antidepressants, 2 pharmacokinetic issues are important:

• Drugs with potent cytochrome P-450 (CYP450) effects-particularly fluoxetine (because of its long half-life)-may produce toxic levels of medications taken concurrently, such as TCAs that are also metabolized by these systems. (This effect is even more of an issue with combinations.)

• Antidepressants that are associated with discontinuation symptoms (eg, paroxetine, venlafaxine, duloxetine) may produce discontinuation syndromes when stopped that can be erroneously attributed to adverse effects of the new drug, particularly if the new drug does not possess a significant degree of serotonin reuptake inhibition.

What we need are agents with novel mechanisms of action. As indicated in Table 2, there is a rich pipeline of candidates. Some of these agents, such as agomelatine, are relatively far along in the clinical trial process with human subjects. Others, such as amibegron and sipatrigine, have been shown to be efficacious only in animal models of depression and their benefit is therefore highly speculative.15-17 Some of the drugs have been tried as augmentation agents as well (eg, riluzole). Agents such as pramipexole, memantine, riluzole, and ketoconazole are already available in the United States.

Proposed mechanisms of action vary widely, but 2 development strategies are generating a great deal of activity:

• Agents are being developed that affect corticosteroid function at various levels. (Glucocorticoids have figured prominently in recent theories as major agents in stress-induced neuronal injury and cell death leading to depression.18)

• Compounds are being developed that induce the synthesis of brain-derived neurotrophic factor (BDNF), particularly through their effects on glutamate receptors.

In a sense, these 2 strategies are related: it has been proposed that BDNF acts as a modulator of neuronal repair and even neurogenesis in response to cortisol-induced brain injury. The findings with ketamine are particularly exciting. A recent study reported that ketamine, through its activity as an N-methyl-D-aspartate (NMDA)-receptor antagonist, increases synaptic glutamate and therefore stimulates a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (both NMDA and AMPA receptors are subtypes of glutamate receptors).19 AMPA potentiators are known to induce BDNF production more rapidly than current antidepressants.20 It has been hypothesized that a more rapid induction of BDNF would lead to a faster onset of antidepressant action. In a study by Zarate and colleagues,21 the onset of the antidepressant effect of ketamine occurred within 2 hours. Unfortunately, the drug must be given by intravenous infusion, but because the effect persisted for 7 days, ketamine treatment may be useful if given as a series.

Another NMDA-receptor antagonist now available in the United States is memantine (FDA-approved for Alzheimer disease). Memantine was shown to be effective in an open-label study in major depression. In a double-blind, randomized trial it showed comparable effects to escitalopram in patients with major depression and alcohol dependence.22,23 However memantine failed to separate from placebo in a double-blind, placebo-controlled study in major depression.24 The less robust antidepressant properties of memantine when compared with those of ketamine may be due to differing NMDA receptor binding properties between the 2 compounds.21

Combining agents

In this category there are 2 similar strategies: (1) combination, that is, combining 2 FDA-approved antidepressants with presumably complementary mechanisms of action; and (2) augmentation, in which a drug not approved as an antidepressant is used with an FDA-approved antidepressant. Such pairings can be used either at the beginning of therapy to speed the response (an accelerator strategy) or to improve the overall response, thereby enhancing the odds of achieving remission. As noted, when combining agents, one must be aware of possible CYP450-based pharmocokinetic interactions or other pharmacological interactions, such as the risk of serotonin syndrome when an SSRI is combined with an MAOI.

Combination strategies. Of the 2 strategies, the addition of a second antidepressant is the more intuitively obvious. Randomized controlled trials have supported the superior efficacy of a TCA/SSRI combination, as well as a mirtazapine/SSRI combination; open studies have done the same for TCA/MAOI and SSRI/bupropion combinations.25 A positive retrospective chart review of 10 patients treated with a combination of duloxetine and bupropion has also been published.26

These findings raise the question of whether combining antidepressants is superior to switching. For example, an open-label, nonrandomized study by Lam and colleagues27 found that when 61 patients who were taking citalopram or bupropion SR for TRD were either switched to the other drug or given the combination, the combination group showed statistically greater rates of response and remission. At a minimum, combination treatments ensure that a partial response to the first agent will not be lost.

Augmentation strategies. If the switching and combination literature is conspicuous by its paucity, the augmentation literature is abundant-but the quality of evidence varies tremendously and the reader must maintain a “buyer beware” approach. One recent review concluded that although studies of augmentation were abundant, many were underpowered and uncontrolled.28 Several comprehensive reviews have been published.28-31

Evaluation strategies have been suggested to assess the quality of evidence.28,32 In general, augmentation strategies are recommended in the event of a partial response to an antidepressant. Switching is preferred in the event of a nonresponse.25 One of the few studies to examine this issue systematically found numerically higher response rates among partial responders compared with nonresponders when lithium or desipramine was added to fluoxetine, but these differences were not statistically significant.33Table 3 presents a summary of agents that may be effective. Although the amount and quality of evidence about the agents in category A is meaningful, the differentiation of groups B and C is somewhat arbitrary.

The presumed mechanism of action of augmentation agents varies tremendously and is generally believed to complement the action of the primary antidepressant in some predictable theoretical manner. Questions remain about the validity of our current classification systems for grouping augmentation agents-an issue of crucial importance for clinicians who need to pair them with antidepressants for maximum benefit.

Lithium, the classic augmentation agent, has been the subject of the greatest number of studies. A recent meta-analysis identified 10 randomized, placebo-controlled trials, all of which were relatively small (the largest included 61 subjects).34 The authors of these studies concluded that lithium was significantly more effective than placebo. The vast majority of the studies with lithium did not include SSRIs but instead used TCAs. Remission rates from level 3 of the STAR*D trial using lithium as an augmentation agent with citalopram were only 13.2% (measured by QIDS-SR), whereas T3 augmentation remission rates at this same step were 24.7%.35 Although these differences were not statistically different, there was a significantly higher dropout rate in the lithium group.

As with lithium, a recent review concluded that the trial data that support the efficacy of T3 augmentation are of better quality with TCAs than with SSRIs.32 Although it has been reported that approximately 50% of patients with unipolar depression given thyroid augmentation show a response, a pooled analysis of 4 randomized double-blind studies of T3 augmentation revealed nonsignificant effects, but the results of 1 of the 4 studies may have accounted for this finding.36,37

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.

SUMMARY

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.

References:

Drugs Mentioned in This Article

Agomelatine (Valdoxan, Melitor)
Amantadine (Symmetrel)
Amibegron
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)
Dehydroepiandrosterone
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)
Inositol
Ketamine
Ketoconazole (Nizoral)
Lamotrigine (Lamictal)
Lithium (Eskalith, Lithane, Lithobid)
L-tryptophan
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)
Pramipexole
Quetiapine (Seroquel)
Riluzole
Risperidone (Risperdal)
Ropinorole (Requip)
S-adenosyl-l-methionine (SAMe)
Selegiline (Emsam, Atrapryl, Carbex, others)
Sertraline (Zoloft)
Sipatrigine
Topiramate (Topamax)
Tranylcypromine (Parnate)
Trazodone (Desyrel)
Valproate/valproic acid (Depakote, others)
Venlafaxine (Effexor)
Yohimbine (Procomil)
Ziprasidone (Geodon)

References

1. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder. results from the National Comorbidity Survey replication (NCS-R). JAMA. 2003:289:3095-3105.
2. Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200.
3. Berlim MT, Turecki G. Definition, assessment and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Can J Psychiatry. 2007;52:46-54.
4. Fagiolini A, Kupfer DJ. Is treatment-resistant depression a unique subtype of depression? Biol Psychiatry. 2003;53:640-648.
5. Keller MB, Shapiro RW, Lavori PW, Wolfe N. Recovery in major depression disorder: analysis with the life table and regression models. Arch Gen Psychiatry. 1982;39:905-910.
6. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. World J Biol Psychiatry. 2007;8:67-104.
7. Crismon ML, Trivedi M, Pigott TA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry. 1999;60:142-156.
8. Kennedy SH, Lam RW, Cohen NL, et al. Clinical guidelines for the treatment of depressive disorders IV. Medications and other biological treatments. Can J Psychiatry. 2001;46(suppl 1):38S-58S.
9. American Psychiatric Association. Practice guidelines for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4 suppl):1-45.
10. Thase ME, Feighner JP, Lydiard RB. Citalopram treatment of fluoxetine nonresponders. J Clin Psychiatry. 2001;62:683-687.
11. Papakostas GI, Fava M, Thase ME. Treatment of SSRI-resistant depression: A meta-analysis comparing within- versus across-class switches. Biol Psychiatry. 2008;63:699-704.
12. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. 2006;354:1231-1242.
13. Koch S, Hemrick-Luecke SK, Thompson LK, et al. Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats. Neuropharmacology. 2003;45:935-944.
14. Karp JF, Whyte EM, Lenze EJ, et al. Rescue pharmacotherapy with duloxetine for selective serotonin reuptake inhibitor nonresponders in late-life depression: outcome and tolerability. J Clin Psychiatry. 2008;69:457-463.
15. Norman TR, Burrows GD. Emerging treatments for major depression. Expert Rev Neurotherapeutics. 2007;7:203-213.
16. Overstreet DH, Stemmelin J, Griebel G. Confirmation of antidepressant potential of the selective b3 adrenoreceptor agonist amibegron in an animal model of depression. Pharmacol Biochem Behav. 2008; 89:623-626.
17. Tsai SJ. Sipatrigine could have therapeutic potential for major depression and bipolar depression through antagonism of the two-pore-domain K+ channel TREK-1. Med Hypotheses. 2008;70:548-550.
18. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature. 2008;455:894-902.
19. Maeng S, Zarate CA Jr, Du J, et al. Cellular mechanisms underlying the antidepressant effects of ke-tamine: role of a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors. Biol Psychiatry. 2008;63:349-352.
20. Skolnick P. AMPA receptors: a target for novel antidepressants? Biol Psychiatry. 2008:63:347-348.
21. Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
22. Ferguson JM, Shingleton RN. An open-label, flexible-dose study of memantine in major depressive disorder. Clin Neuropharmacolgy. 2007;30:136-144.
23. Muhonen LH, Lönngvist J, Juva K, Alho H. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry. 2008;69:392-399.
24. Zarate CA, Singh JB, Quiroz JA, et al. A double-blind placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry. 2006;163:153-155.
25. Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resis-tant/refractory major depression: an overview. Ann Med. 2008:40:149-159.
26. Papkostas GI, Worthington JJ, Iosifescu DV, et al. The combination of duloxetine and bupropion for treatment-resistant major depressive disorder. Depress Anxiety. 2006;23:178-181.
27. Lam RW, Hossie H, Solomons K, Yatham LN. Citalopram and bupropion SR: combining versus switching in patients with treatment-resistant depression. J Clin Psychiatry. 2004;65:337-340.
28. 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.
29. Carvalho AF, Cavalcante JL, Castelo MS, Lima MC. Augmentation strategies for treatment-resistant depression: a literature review. J Clin Pharm Ther. 2007;32:415-428.
30. DeBattista C, Lembke A. Update on augmentation of antidepressant response in resistant depression. Curr Psychiatry Rep. 2005;7:435-440.
31. Nierenberg AA, Katz J, Fava M. A critical overview of the pharmacologic management of treatment-resistant depression. Psychiatr Clin North Am. 2007;30:13-29.
32. Thase ME. Pharmacologic strategies for treatment-resistant depression. Psychiatr Ann. 2005;35: 970-978.
33. Fava M, Alpert J, Nierenberg A, et al. Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine. J Clin Psychopharmacol. 2002;22:379-387.
34. Crossley NA, Bauer M. Acceleration and augmentation of antidepressants with lithium for depressive disorders: two meta-analyses of randomized, placebo-controlled trials. J Clin Psychiatry. 2007;68:935-940.
35. Gaynes BN, Rush AJ, Trivedi MH, et al. The STAR*D study: treating depression in the real world. Cleve Clin J Med. 2008;75:57-66.
36. Joffe RT, Sokolov ST. Thyroid hormone treatment of primary unipolar depression: a review. Int J Neuro-psychopharmacol. 2000;3:143-147.
37. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53:842-848.
38. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotics for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68: 826-831.
39. Sokolski KN. Adjunctive aripiprazole for bupropion-resistant major depression. Ann Pharmacother. 2008;42:1124-1129.
40. Goforth HW, Carroll BT. Aripiprazole augmentation of tranylcypromine in treatment-resistant major depression. J Clin Psychopharmacol. 2007;27:216-217.
41. Schüle C, Baghai TC, Eser D, et al. Mirtazapine monontherapy versus combination therapy with mirtazapine and aripiprazole in depressed patients without psychotic features: a 4-week open-label parallel-group study. World J Biol Psychiatry. 2007;8:112-122.
42.Physicians’ Desk Reference. 61st ed. Montvale, NJ: Thompson PDR; 2007:1527-1529.
43. Schmidt AW, Lebel LA, Johnson CG, et al. The novel antipsychotic ziprasidone has a unique human receptor binding profile compared to other agents. SocNeurosci Abstr. 1998;24:2177.
44. Stoll AL, Haura G. Tranylcypromine plus risperidone for treatment-refractory major depression. J Clin Psychopharmacol. 2000;20:495-496.
45. Azzaro AJ, Ziemniak J, Kemper E, et al. Selegiline transdermal system: an examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications. J Clin Pharmacol. 2007;47:146-158.
46. Barbee JG, Conrad EJ, Jamhour NJ. The effectiveness of olanzapine, risperidone, quetiapine, and ziprasidone as augmentation agents in treatment-resistant major depressive disorder. J Clin Psychiatry. 2004;65:975-981.
47. Barbee JG, Conrad EJ, Jamhour NJ. Aripiprazole augmentation in treatment-resistant depression. Ann Clin Psychiatry. 2004;16:189-194.
48. Schneider LS, Small GW, Clary CM. Estrogen replacement therapy and antidepressant response to sertraline in older depressed women. Am J Geriatr Psychiatry. 2001;9:393-399.
49. Pope HG Jr, Cohane GH, Kanayama G, et al. Testosterone gel supplementation for men with refractory depression. A randomized, placebo-controlled trial. Am J Psychiatry. 2003;160:105-111.
50. Levitan RD, Shen JH, Jindal R, et al. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci. 2000;25:337-346.
51. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477-479.
52. Appelberg BG, Syvälahti EK, Koskinen TE, et al. Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: results from a placebo-controlled, randomized, double-blind, placebo wash-in study. J Clin Psychiatry. 2001;62:448-452.
53. Landén M, Björling G, Agren H, Fahlén T. A randomized, double-blind placebo-controlled trial of buspirone in combination with an SSRI in patients with treatment-refractory depression. J Clin Psychiatry. 1998;59:664-668.
54. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Eng J Med. 2006;354:1243-1252.
55. Barbee JG, Jamhour NJ, Stewart JS, et al. La-motrigine as an antidepressant augmentation agent in treatment refractory unipolar depression. Presented at: Annual Meeting of the American Psychiatric Association; May 19-24, 2007; San Diego.
56. DeBattista C, Doghramji K, Menza MA, et al. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64:1057-1064.
57. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafanil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66:85-93.
58. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluations of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28-40.
59. 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.
60. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcomes in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165:342-351.
61. Zarate CA Jr, Payne JL, Quiroz J, et al. An open-label trial of riluzole in patients with treatment-resis-tant major depression. Am J Psychiatry. 2004;161: 171-174.
62. Binneman B, Feltner D, Kolluri S, et al. A 6-week randomized placebo-controlled trial of CP-316, 311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry. 2008;165:617-620.
63. Berman RM, Marcus RN, Swanink R, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:843-853.
64. Marcus RN, McQuade RD, Carson WH, et al. The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder. A second multicenter, randomized, double-blind placebo-controlled study. J Clin Psychopharmacol. 2008;28:156-165.
65. Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder. A randomized trial. Ann Intern Med. 2007;147: 593-602.
66. Dunner DL, Amsterdam JD, Shelton RC, et al. Efficacy and tolerability of adjunctive ziprasidone in treatment-resistant depression: a randomized, open-label, pilot study. J Clin Psychiatry. 2007;68:1071-1077.
67. Pilhatsch MK, Burghardt R, Wandinger KP, et al. Augmentation with atomoxetine in treatment-resis-tant depression with psychotic features. A case report. Pharmacopsychiatry. 2006;39:79-80.
68. Carpenter LL, Milosavljevic N, Schechter JM, et al. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66:1234-1238.
69. Sanacora G, Kendell SF, Levin Y, et al. Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms. Biol Psychiatry. 2007;61:822-825.
70. Müller N, Schwarz MJ, Dehning S, et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry. 2006;11:680-684.
71. Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: a preliminary study. Bipolar Disord. 2007;9:754-758.


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.