Vol. 22, No. 4 / November 2010

Switching, combination, and augmentation strategies for major depressive disorder

• TREATMENT - RESISTANT MAJOR DEPRESSIVE DISORDER • AUGMENTATION STRATEGIES • AUGMENTATION/COMBINATION THERAPY VS SWITCHING • SUMMARY

Director, Treatment-Resistant Depression Studies, Massachusetts General Hospital, Boston, Massachusetts; Associate Professor of Psychiatry, Harvard Medical School, Boston, Massachusetts 

Dr Papakostas has disclosed that he has received grants or research support from Bristol-Myers Squibb Company; Forest Laboratories, Inc; Pamlab LLC; Pfizer Inc; and Precision Human Biosystems. He is a retained consultant for AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Pamlab LLC, and Wyeth Pharmaceuticals and has received honoraria for non–speakers bureau presentations from AstraZeneca, Bristol-Myers Squibb Company, GlaxoSmithKline, Lundbeck Inc, and Otsuka America Pharmaceutical, Inc.

TREATMENT - RESISTANT MAJOR DEPRESSIVE DISORDER

Treatment of major depressive disorder (MDD) often requires multiple treatment steps to achieve remission, or the complete absence of depressive symptoms, which is the ultimate goal of therapy. Approximately one-third of patients treated for MDD do not respond fully to the first antidepressant prescribed, and up to 15% of patients continue to have significant depressive symptoms, despite being prescribed multiple pharmacologic agents.¹ Treatment nonresponse to an antidepressant agent is typically defined as failure to adequately respond to therapy after 6 or more weeks of treatment at an appropriate dose. An alternatively defined use of the term “treatment-resistant depression,” however, has been proposed: nonresponse to at least 2 trials of antidepressants with at least 2 different classes of medication.²

Multiple treatment options are available to patients who do not respond fully to the first antidepressant agent prescribed. Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the norepinephrine-dopamine reuptake inhibitor bupropion (BUP) are common first steps. As was shown in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only about 30% of patients achieve remission after 12 weeks of therapy with the SSRI citalopram (CIT).³ For patients who have not had adequate response to a first-line antidepressant, 4 broad pharmacologic approaches are available: 1) increase the dose of the current antidepressant; 2) switch to a different antidepressant; 3) combine the initial antidepressant prescribed with a second antidepressant; or 4) augment the current antidepressant with a nonantidepressant agent.⁴

Although multiple treatment strategies exist for treatment-resistant MDD, there is little consensus regarding optimizing patients who have incomplete response to therapy.⁵ Because of this lack of consensus and adequate comparator studies, the weight of existing randomized, placebo-controlled trials should be used in conjunction with practical advantages and disadvantages of each agent or strategy. Factors that need to be considered when addressing advantages and disadvantages of agents are efficacy, tolerability, drug–drug interactions, dosing convenience, treatment history, patient preference, and cost.^4,6

AUGMENTATION STRATEGIES

Atypical antipsychotic agents. Since 2006, the number of studies on the use of atypical antipsychotics as augmentation agents for medication-resistant MDD has increased. A 2007 meta-analysis pooled results of 10 randomized, double-blind, placebo-controlled trials that examined the efficacy and tolerability of augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant MDD. The studies looked at 1500 patients treated with risperidone, olanzapine, or quetiapine vs placebo.⁵ The remission rate for augmentation with antipsychotic agents was high: approximately 47%, compared with 22% for the placebo group (FIGURE 1). The majority of these patients were treatment-resistant patients who had already failed 2 or more antidepressant agents. By STAR*D categorization, these patients would be at Level 3, where remission rates were relatively low, yet they had high remission rates with the antipsychotic agents. These agents, however, were found to be less tolerable than adjunctive placebo. The rate of discontinuation due to adverse effects was lower among the placebo group (RR=3.38; 95% CI=1.98-5.76; P<.0001). The efficacy of augmentation with atypical antipsychotic agents that was demonstrated by the 10 studies led to further trials on their use for treatment-resistant MDD.⁵

Three randomized, double-blind, placebo-controlled trials compared augmentation of aripiprazole with placebo in patients who did not respond to 2, 3, or 4 adequate treatment trials. The evidence from these trials led to Food and Drug Administration (FDA) approval of the use of aripiprazole as adjunctive treatment for patients with antidepressant-resistant MDD.^7-10 In all 3 trials, remission rates were significantly higher with aripiprazole than with placebo (FIGURE 2). Discontinuation rates due to adverse events were low (<10% of total sample).⁴

The results of 2 published studies that looked at augmentation with quetiapine in nonresponders with MDD led to FDA approval of the use of adjunctive quetiapine for partial nonresponse to antidepressants in patients with MDD.¹¹ Patients who had failed to respond to exactly 1 and no more than 1 prior adequate treatment trial with antidepressants were randomized to augmentation with a target daily dose of quetiapine 150 mg, quetiapine 300 mg, or placebo (FIGURE 3). In both studies, patients on quetiapine 300 mg had a significant reduction in depressive symptoms compared with those on placebo.^12,13 Only 1 study, however, demonstrated a statistically significant reduction in depressive symptoms with quetiapine 150 mg compared with placebo.^12,13 Another antipsychotic agent, olanzapine, was approved in 2009 for adjunctive use in patients who fail to respond to ≥2 adequate treatment trials with antidepressants. Because the studies on which this decision was based used olanzapine as adjunctive treatment with fluoxetine, however, the approval was only for use of olanzapine with fluoxetine.¹⁴

Three studies investigated risperidone augmentation in nonresponders with MDD^15-17; in all 3, remission rates were higher with risperidone than with placebo, but the smallest study did not reach statistical significance.¹⁶ Risperidone is not approved in the US for treatment of MDD. Randomized, double-blind, placebo-controlled studies involving ziprasidone, paliperidone, asenapine, iloperidone, or clozapine for treatment-resistant MDD have not been conducted or published to date.

Augmentation with atypical antipsychotics currently is the best-studied augmentation strategy for antidepressant nonresponders with MDD. Atypical antipsychotics can have a number of potential side effects, however, that should be taken into consideration when deciding on treatment strategies for nonresponders with MDD. The side-effect profile of each antipsychotic agent is different and should be considered when choosing treatment for individual patients. Adverse effects associated with atypical antipsychotic agents include hyperprolactinemia; metabolic abnormalities such as weight gain, dyslipidemia, and glucose dysregulation (especially seen with olanzapine); leucopenia; sedation/ somnolence; anticholinergic effects; and extrapyramidal adverse effects. There is also the small risk of tardive dyskinesia and neuroleptic malignant syndrome.^4,18

Lithium (Li). Before the studies involving augmentation with antipsychotic agents were published, Li was the best-studied augmentation agent for use with antidepressants in nonresponders with MDD. Seven randomized, double-blind, placebo-controlled studies looked at the use of Li as adjunctive therapy with tricyclic antidepressants (TCAs) compared with placebo. Three of these studies showed that Li augmentation was superior to placebo, and 4 showed equivalent efficacy.^19-25 A meta-analysis of the 7 studies demonstrated greater antidepressant efficacy with Li than with placebo.²⁶

The studies showing that Li augmentation was superior to placebo, however, were short in duration (1 to 3 weeks). The question remains, “Would Li be effective as an augmentation agent when used for longer duration?” Also, these 7 studies used TCAs as the antidepressant agents. There is a paucity of evidence regarding the use of Li with agents that are commonly used now as first-, second-, or third-line antidepressant therapy (eg, SSRIs, SNRIs, or BUP).⁴ Only 2 randomized, double-blind, placebo-controlled studies have used Li for augmentation with SSRIs.^27,28 One showed that Li augmentation was superior to placebo, and one found no differences in efficacy. There is also a paucity of data comparing Li with alternative treatment strategies.⁴ Two identical, randomized, double-blind studies compared Li augmentation or desipramine combination therapy with increasing the fluoxetine dose for fluoxetine nonresponders with MDD.^29,30 Pooled results of these studies revealed that patients whose SSRI dose was increased had greater resolution of depressive symptoms than did patients who received either Li augmentation or desipramine combination therapy (FIGURE 4).⁴ Adverse effects of Li may include cardiotoxicity, nephrotoxicity, thyrotoxicity, and weight gain. Also, there is a need for periodic blood-level monitoring because of Li’s narrow therapeutic index, which patients may find sufficiently inconvenient to make them resist this choice of drug.⁴

Mirtazapine (MIRT)/mianserin. Four studies have looked at the use of the antidepressants MIRT or mianserin in combination with an SSRI. Both agents are antagonists of the serotonin-2 and serotonin-3 receptors and of the alpha-2 adrenergic inhibitory autoreceptor; mianserin is not available in the United States.⁴ Three of the 4 studies showed that combination therapy with these agents was superior to placebo for antidepressant nonresponders with MDD.^31-34 An advantage of these drugs is that they can cause sedation, which may help with the residual depressive symptom of insomnia in some patients. Disadvantages of using these agents in combination with other antidepressants include the risk of antihistaminic side effects, such as weight gain and sedation; anticholinergic side effects, such as impaired concentration and confusion; and the rare risk of agranulocytosis.^4,35

Pindolol. Four randomized, double-blind, placebo-controlled studies have looked at the use of pindolol, a ß-blocker and serotonin-1A receptor antagonist, for antidepressant nonresponders with MDD.^31,36-38 Two of these studies performed in the Netherlands showed that pindolol was more effective than placebo^31,36; a criticism of the 2 studies, however, was that they enrolled both treatment-naive and treatment-resistant patients. Two later studies using pindolol focused exclusively on pindolol augmentation in patients who were treatment-resistant.^37,38 These 2 studies did not demonstrate superiority of pindolol over placebo. In a meta-analysis pooling results of the 4 studies, pindolol showed increased efficacy over placebo early in treatment but had no effect after Week 2.³⁹ Side effects reported with pindolol include somnolence, nausea, bradycardia, postural hypotension, sweating, and dry mouth.^4,39

Omega-3 fatty acids. Three randomized, double-blind, placebo-controlled studies support the use of adjunctive omega-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) for nonresponders to antidepressants with MDD.^40-42 These essential fatty acids are very well tolerated and acceptable to patients, and may provide other health benefits, such as promotion of cardiovascular health. However, because studies show different efficacy data for different doses, an optimal dose has not been established. Moreover, this use of adjunctive omega-3 fatty acids typically is not covered by insurance companies, and thus can be costly for patients.⁴

Triiodothyronine (T₃). Three randomized controlled trials have examined use of adjunctive T₃, which is the active form of thyroid hormone. These studies looked at augmentation of TCAs with T₃ in people with MDD who did not respond to TCAs. Two of the 3 studies demonstrated that T₃ was superior to placebo; the third study did not. The studies were of relatively short duration, eg, 2 weeks.^24,43,44 A meta-analysis pooling results of the trials of adjunctive T₃ for antidepressant nonresponders did not show a clinically significant advantage over placebo. Over 1- and 2-week periods, T₃ did show increased efficacy over placebo; the single study with an end point beyond Week 2, however, did not show a clinically significant difference between T₃ and placebo.⁴⁵ Longer studies of the efficacy of T₃ used adjunctively with newer antidepressants are needed, as are data on the long-term effect of T₃ on bone density in women.⁴

Modafinil. Two randomized, double-blind, placebo-controlled trials examined adjunctive use of modafinil for antidepressant nonresponders with MDD who had hypersomnia and fatigue. The mechanism of action of modafinil in MDD is unknown, although it may work by potentiating histaminergic tone in the brain.⁴ These studies demonstrated that modafinil was not superior to placebo at resolving residual depressive symptoms of sleepiness and fatigue.^46,47 A pooled analysis of data from patients who met certain criteria (eg, somnolence score, using the Epworth Sleepiness Scale), however, demonstrated that modafinil augmentation of SSRIs is superior to placebo for improving wakefulness and depressive symptoms.⁴ It is unclear whether modafinil is effective for antidepressant nonresponders who do not have sleepiness and for those who exhibit insomnia as a feature of their depression. Adverse effects from modafinil can include headache, nervousness, irritability, nausea, insomnia, diarrhea, dizziness, and dry mouth.⁴

Buspirone (BUS). BUS is a serotonin-1A agonist approved by the FDA for anxiety.⁴⁸ Two randomized, placebo-controlled studies failed to demonstrate that augmentation with BUS was superior to placebo for alleviating depressive symptoms in antidepressant nonresponders with MDD.^49,50

BUP. In STAR*D, Level 2 involved adding BUP vs BUS to CIT in CIT nonresponders.⁵¹ Patients treated with adjunctive BUP had lower depressive symptom scores than did patients treated with adjunctive BUS. There was also a numerical but not statistically significant increased remission rate for BUP compared with BUS (39% vs 33%). Also, BUP had a significantly lower dropout rate due to intolerance than did BUS (13% vs 21%). Adverse effects with BUS can include somnolence, headache, nausea, and sweating. BUP is contraindicated in patients with eating disorders, epilepsy, or a history of head injury.⁴

Methylphenidate. Methylphenidate is a psychostimulant approved for treatment of attention-deficit/hyperactivity disorder (ADHD). Two randomized, double-blind, placebo-controlled trials looked at adjunctive use of osmotic-release oral system (OROS) methylphenidate for antidepressant nonresponders with MDD. Neither showed that augmentation with methylphenidate was superior to placebo for depression overall; 1 study, however, demonstrated that apathy and fatigue were more likely to be reduced with methylphenidate than with placebo.^52,53 Besides being helpful for these symptoms associated with depression, methylphenidate may also be helpful for the ADHD that is often comorbid with depression. Methylphenidate does have the potential for dependence and abuse.⁴

Lamotrigine. Two randomized controlled trials that looked at the use of lamotrigine, an anticonvulsant also used in maintenance therapy for bipolar I disorder, showed no increased efficacy for lamotrigine vs placebo for treatment of antidepressant nonresponders with MDD.^54,55 Slow titration is required for lamotrigine because of a small risk of Stevens-Johnson syndrome.⁴

Cognitive-behavioral therapy (CBT). Data from Level 2 of STAR*D suggest that augmentation of CIT with CBT or with BUP or BUS results in comparable patient outcomes, although augmentation with BUP or BUS is more rapidly effective.⁵⁶

AUGMENTATION/COMBINATION THERAPY VS SWITCHING

Augmentation and combination regimens for antidepressant nonresponders with MDD, as have been discussed, have certain advantages over switching strategies. With augmentation and combination strategies, therapeutic benefits that patients may have experienced with the first-line agent can be maintained, and the potential for withdrawal symptoms related to discontinuation of the first-line agent can be avoided. Also, the augmentation or combination agent can target and minimize adverse effects of the first-line treatment. A disadvantage of augmentation/combination strategies is that any side effect associated with the first-line agent could persist or even be compounded by the augmentation or combination agent, which might have a different or overlapping pharmacologic profile. Other disadvantages could include increased cost and lower patient adherence due to the need to take multiple medications.⁴

Switching consists of discontinuing one medication and starting another in its place. Switching may be the preferred method for patients with MDD who experience intolerable side effects from first-line antidepressant medication, with little or no symptom improvement. Other advantages of switching over augmentation and combination strategies are the lower risk of drug–drug interactions, potentially better patient adherence with taking fewer medications, and possibly a lower prescription cost.⁴

Regarding switch strategies, certain questions should be examined:

• If a patient is an SSRI nonresponder, is it better to switch to another SSRI (within-class) or to a newer non-SSRI (across-class) such as venlafaxine (VEN) or BUP?

STAR*D suggested that there is no difference between these strategies.⁵⁷ A meta-analysis that pooled results of studies that looked at this question, however, found a statistically significant yet numerically small advantage in remission rates when SSRI nonresponders were switched to a non-SSRI as opposed to a second SSRI (FIGURE 5).⁵⁸ Given how small this difference was, if a patient is not responsive to an SSRI, switching to another SSRI or to a newer non-SSRI both seem like reasonable strategies that most likely would differ little clinically in efficacy.

• Should patients be switched to another antidepressant agent besides an SSRI?

Crossover studies switching TCA (imipramine) nonresponders to the monoamine oxidase inhibitor (MAOI) phenelzine showed better response rates than when phenelzine nonresponders were switched to imipramine.^59,60 Imipramine and sertraline (SERT) also were compared in a crossover study; in this case, SSRI nonresponders switched to the TCA showed lower response rates than TCA nonresponders switched to the SSRI.⁶¹ In addition, based on STAR*D results from Level 3, switching antidepressant nonresponders to either nortriptyline or MIRT after ≥2 previous treatment failures showed response rates of around 8% to 12%.⁶² All this taken together suggests that a TCA is less efficacious as a switch option than either an MAOI or another SSRI.

• And as topics for future studies on treatment strategy in antidepressant nonresponders with MDD:

– What treatment is most efficacious in patients who have failed 2 SSRI regimens?

– Should these patients be prescribed a third SSRI or a different class of treatment?

CBT. Results from STAR*D Level 2 suggest that switching from CIT to CBT generally is as effective as switching from CIT to VEN, BUP, or SERT.⁵⁶

SUMMARY

Many pharmacologic agents and multiple treatment strategies are available for treatment-resistant MDD. When choosing among them, the weight of evidence behind the efficacy of agents or combinations of agents should be considered along with their relative advantages and disadvantages. The most thoroughly studied treatment strategy for treatment-resistant MDD is augmentation with atypical antipsychotics. Augmentation and combination with other agents, however, have shown efficacy as well. MIRT, mianserin (not available in the United States), and omega-3 fatty acids all have reasonable data to support their use. Li, modafinil, T₃, and BUP have mixed results and should be used only after considering advantages and disadvantages for individual patients. Switching SSRI nonresponders to a different SSRI and switching them to newer non-SSRI antidepressants both have shown efficacy and are seemingly clinically equivalent strategies; switching to TCAs, however, has mixed data, and should be considered only after other options have failed.

It is important to use existing data in combination with advantages and disadvantages for individual patients when considering augmentation or combination therapy as well as other treatment strategies for antidepressant nonresponders with MDD. Although antidepressant nonresponders with MDD continue to be a difficult-to-treat patient group, multiple agents and strategies exist for their treatment. Persistence and open communication between providers and patients are essential to achieving adequate response and remission.

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Annals of Clinical Psychiatry ©2010 Quadrant HealthCom Inc.