Expert Roundtable Supplement


An expert panel review of clinical challenges in psychiatry and primary care


Funding for this activity has been provided by an educational grant from Bristol-Myers Squibb.


Accreditation Statement

This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. 


Credit Designation

The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at the Mount Sinai School of Medicine. Review Date: November 9, 2007.


Statement of Need and Purpose

Major depressive disorder (MDD) is the fourth largest contributor to the worldwide burden of disease and is expected to be second only to ischemic heart disease by the year 2020. Over 60% of suicide deaths in the United States are directly attributable to MDD, and >300,000 people successfully commit suicide in the US annually. Despite its prevalence, 50% of MDD cases go undetected, undiagnosed, and untreated. The impairment of depression can lead to decreased productivity, alcohol and substance abuse, and an increased risk of suicide.  Treatment resistant depression (TRD) is frequently defined as depressive illness that does not fully remit after a single initial treatment failure. Patients who only achieve partial response or continue to experience residual symptoms are likely to show reduced functioning and an increased risk of relapse. Up to 50% of patients do not show a full response to their first antidepressant treatment. This has led to a re-emergence of interest in treatment augmentation research. There is a higher frequency of suicide in patients with TRD as opposed to those with treatment responsive MDD. Although the results of several open-label trials suggest a potential role of second-generation antipsychotics (SGAs) in TRD, there has been a paucity of double-blind, placebo-controlled studies confirming whether this treatment strategy is truly effective. New data continue to emerge and it is important to determine how these findings apply to each of the SGAs. It is also important to report on the safety, tolerability, and efficacy of augmenting with SGAs versus other augmentation or switching strategies for TRD.

Target Audience

This activity is designed to meet the educational needs of primary care physicians and psychiatrists.

Learning Objectives

• Recognize the efficacy, safety, and tolerability of augmenting pharmacologic treatment of major depressive disorder (MDD) with atypical antipsychotics.
• Discuss the challenges of limited response to MDD treatment and its impact on the course of illness.


Faculty Disclosures

Michael E. Thase, MD, is a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, sanofi-aventis, and Wyeth; has equity in MedAvant; and receives book royalties from American Psychiatric Publishing, Guilford Publications, and Herald House. Dr. Thase discloses that he will discuss investigational uses of older pharmacologic agents for the treatment of major depressive disorder (MDD).

J. Craig Nelson, MD, is a consultant to and/or on the advisory boards of Abbott, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Orexigen, Organon, and Pfizer. Dr. Nelson discloses that he will discuss unapproved/investigational uses of pharmacologic agents for the treatment of MDD.

George I. Papakostas, MD, has served as a consultant to Aphios, Bristol-Myers Squibb, GlaxoSmithKline, Evotec, Inflabloc, Jazz, PAMLAB, Pfizer, and Wyeth; has received honoraria from Bristol-Myers Squibb, Evotec, GlaxoSmithKline, Inflabloc, Jazz, Lundbeck, PAMLAB, Pfizer, Titan, and Wyeth; and has received research support from Bristol-Myers Squibb, PAMLAB, and Pfizer. Dr. Papakostas discloses that he will discuss unapproved/investigational uses of aripiprazole, buspirone, olanzapine, pindolol, quetiapine, risperidone, triiodothyronine, and ziprasidone for the treatment of MDD.

Michael J. Gitlin, MD, has received honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Pfizer, and Takeda. Dr. Gitlin discloses that he will discuss unapproved/investigational use of aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and ziprasidone for the treatment of MDD.

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Bristol-Myers Squibb.


Peer Reviewers

David L. Ginsberg, MD, receives honoraria from AstraZeneca and GlaxoSmithKline.

Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


To Receive Credit for this Activity

Read this expert roundtable supplement, reflect on the information presented, and complete the CME posttest and evaluation. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest by December 1, 2009 to be eligible for credit.

Release date: December 1, 2007
Termination date: December 31, 2009

The estimated time to complete this activity is 2 hours.


Under optimal circumstances, patients respond to treatments for major depression only 60% to 70% of the time. Therefore, there is a critical need for effective treatment strategies that augment available depression treatment. Currently, such strategies augment primary antidepressants with agents that increase the likelihood of treatment response. Augmentation agents include thyroid hormones, which are used to augment tricyclic antidepressants (TCAs); lithium, which also improves response to TCAs; and second-generation antipsychotics (SGAs), which are used to augment selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors. Other, less common, strategies include augmentation with stimulants, folate, and buspirone. Unfortunately, studies of augmentation efficacy are often limited or equivocal. Studies may overestimate the magnitude of effect, as augmentation may be attempted while patients still experience an initial response. Prescribers must be sure treatment strategies are not undermined by safety or tolerability concerns. Lithium, in particular, is not well tolerated by patients, and SGAs pose the risk of tardive dyskinesia, metabolic syndrome, and extrapyramidal symptoms. Clinicians must weigh these issues against a relatively limited base of knowledge.   

In this Expert Roundtable Supplement, Michael E. Thase, MD, discusses the history of augmentation strategies for depression. J. Craig Nelson, MD, reviews recent findings on augmentation with thyroid hormone, lithium, buspirone, and modafinil. George I. Papakostas, MD, reviews the efficacy of augmentation with SGAs. Finally, Michael J. Gitlin, MD, provides an overview of safety and tolerability issues.



Augmentation Strategies for Depression: History and Concepts

By Michael E. Thase, MD — Moderator

Dr. Thase is professor of psychiatry at the University of Pennsylvania School of Medicine in Philadelphia, the Philadelphia Veterans Affairs Medical Center and the University of Pittsburgh Medical Center.

Disclosures: Dr. Thase is a consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly, GlaxoSmithKline, Janssen, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire, Supernus, and Wyeth; is on the speaker’s bureaus of AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, GlaxoSmithKline, Organon, sanofi-aventis, and Wyeth; has equity in MedAvant; and receives book royalties from American Psychiatric Publishing, Guilford Publications, and Herald House.


Introduction: Need for Augmentation Strategies

Depression is one of the world’s great public health problems. As there are no perfect or uniformly effective treatments for depression, it is not surprising that treatment-resistant depression (TRD) is likewise an important public health problem. Although the potential benefits of antidepressants are now well documented, no widely used antidepressant can be expected to be effective in more than half the patients who begin to take it. Even under optimal circumstances (ie, a patient who is fully adherent to 12 weeks of treatment), there is only a 60% to 70% chance that the first choice of medication will be effective. The need for effective alternate strategies for TRD, as well as the need for innovations in service delivery systems to ensure those strategies are implemented in a timely manner, are foremost to fully realizing the potential benefits of antidepressant therapies.

Over the years, hierarchies of treatment strategies for TRD have been based on the widespread use of particular treatments, their ease of use, and their safety or complexity. One of the strategies consistently used since its introduction 20 years ago has been augmentation of the ineffective antidepressant by a second medication. The second agent may or may not have antidepressant effects of its own, but when used in combination with a primary antidepressant the agent reliably increases a patient’s likelihood of response and symptom remission.

When augmentation strategies were first implemented, only three classes of medication—the tricyclic antidepressants (TCAs), the heterocyclic alternatives to the TCAs (eg, trazodone, amoxapine, and maprotiline), and the monoamine oxidase inhibitors (MAOIs)—were available. These original antidepressants have since declined in use, largely replaced by a raft of newer antidepressants that, while no more effective on average, have more favorable profiles with respect to ease of use, tolerability, and safety in overdose. The number of options available to patients who do not respond to first-line treatments has thus also increased, multiplying the potential combinations of antidepressant medications and augmenting agents. Ironically, some of the most gratifying responses to pharmacotherapy observed among patients with TRD are observed with “old school” medications such as the TCA clomipramine and the MAOI tranylcypromine.


Augmentation Strategies   

The earliest augmentation strategies were first employed in the 1960s, almost coincident with the introduction of the first antidepressants (Slide 1). For example, benzodiazepines were commonly used to enhance the anxiolytic or sedative hypnotic effects experienced by patients taking TCAs or MAOIs. Evidence from studies performed in the 1960s indicated that anxiolytic medications rapidly and reliably reduced anxiety symptoms and insomnia associated with depressive states and, when administered from the outset, might hasten treatment response.1-3 However, concomitant prescription of anxiolytics did not greatly increase the likelihood of patient response or symptom remission, and their longer-term utility (in combination with antidepressants) was never systematically confirmed. Although even greater use was limited by concerns about abuse liability, many experts believe that concerns about the risk of benzodiazepine addiction in this instance have been overstated4 and a large number of patients with difficult-to-treat forms of depression continue to receive palliative benefit from concomitant prescription of benzodiazapines.




First-Generation Antipsychotics
Combinations of antipsychotics and antidepressants were also fairly widely used in the 1960s and 1970s to treat more severe depressive episodes, particularly those characterized by agitation, anxiety, and of course psychosis (Slide 2).5,6 In fact, a proprietary combination of perphenazine and amitriptyline, the most prevalent such combination in the United States, remained in use well into the 1980s, although the fixed-dose combination formulation was more popular in primary care than psychiatric settings, perhaps because the specialists preferred to titrate the component medications separately. Other combinations were used both in the US and abroad, including the antipsychotic trifluperazine and the MAOI tranylcypromine.7 In retrospect, the amitriptyline plus perphenazine combination capitalized on pharmacokinetic interactions: perphenazine increased amitriptyline and, to a lesser extent, nortriptyline blood levels, functionally doubling the dose of the TCA for the average patient. However, with the growing recognition that first-generation antipsychotics conveyed the risk of tardive dyskinesia (TD), coupled with the still controversial observation that patients with mood disorders were even more likely to develop TD than patients with schizophrenia, these combinations were used with increasing reluctance. By the 1990s, this strategy was no longer widely used.



Psychiatrists thus have known for nearly 50 years that antipsychotics have the potential to enhance antidepressant effects, particularly for severely ill patients. This augmentation strategy was largely discontinued, partly because of the introduction of other options and partly for fear of TD. The availability of the second-generation (atypical) antipsychotics (SGAs) has, of course, changed the therapeutic landscape considerably. As is discussed in subsequent sections of this supplement, even though SGAs are less associated with TD in short- and intermediate-term studies of schizophrenia, there continues to be uncertainty about whether patients with resistant depression who respond to augmentation with SGAs will require long-term administration and, if so, whether they are indeed at greater risk for development of TD.


Thyroid Hormone Augmentation

Beginning in the 1960s, reports suggested that thyroid hormone, when added to a TCA at the beginning of a treatment regimen, could accelerate or increase the likelihood of response.8-10 Interestingly, the original observations suggested the strategy was more useful for depressed women, and efficacy specifically in depressed men was never established.11 As women are at higher risk for undetected thyroid disease, one parsimonious explanation for the therapeutic activity of adjunctive thyroid hormone was correction of “pre-clinical” hypothyroidism.12 Consistent with this view, the performance of thyroid augmentation has been disappointing in studies of euthyroid depressed patients.13

These observations reinforced a long-abiding interest in the role of the thyroid axis in the etiopathogenesis of mood disorders. One view is that the thyroid axis responds to the stress of an affective disorder with increased hypothalamic drive, ie, elevated levels of thyroid releasing hormone (TRH). This, over time, results in increased thyroid tone, ie, higher-than-usual levels of circulating thyroid hormone and blunted thyroid stimulating hormone response to TRH. As more recent observations suggest that even patients with low normal levels of thyroid hormone have greater rates of depression14 and slower or less robust responses to antidepressants (Slide 3),15,16 it has been speculated that depressed patients may require a higher-than-usual level of thyroid activity to benefit fully from antidepressant therapy. The efficacy of thyroid augmentation thus may be linked to induction of a higher-than-usual thyroid state, which in turn may selectively benefit patients with low-normal thyroid functions.



It remains unknown whether better results are obtained with triiodothyronine (T3), the centrally active form of thyroid hormone, or whether thyroxine (T4), the normal thyroid replacement hormone, is equally useful. More evidence exists indicating that T3 can be used to enhance an incompletely effective antidepressant, but only because T3 has been more extensively studied than T4.


Lithium Augmentation

Since the 1960s, lithium augmentation has been used to enhance the effects of antidepressants. One of the early case series reported on the utility of the combination of lithium with MAOIs in a group consisting predominantly of patients with bipolar disorder.17 On the basis of several studies in the early 1980s,18-20 lithium augmentation became the preferred augmentation strategy for unipolar patients not adequately responding to TCAs. Several initial reports suggested dramatic antidepressant effects within 24–72 hours.18,19 Results of subsequent studies, however, reported that this kind of rapid and dramatic augmentation response is less common than a slower emerging response over 4–6 weeks (Slide 4),21,22 which is certainly more suggestive of a primary antidepressant effect.22 As lithium salts have antidepressant effects for a subset of depressed people,23 it is difficult to say whether lithium’s therapeutic effects are actually due to augmentation of the antidepressant or a primary antidepressant effect.24 Unfortunately, despite more than 20 years of research, the proper experiment to answer this question still has not been undertaken.




The challenging problem of treating people who do not benefit from first-line antidepressant medications has not been solved by the availability of newer classes of drugs. Over the years one strategy used by physicians treating depressed people are not benefiting from antidepressant monotherapy has been to add a second medication thought to augment or enhance the actions of the primary medication. The concepts that guided selection of the first strategies used for this purpose—anxiolytics, antipsychotics, thyroid hormone, and lithium—continue to be relevant to the treatment of depression and guide clinicians’ choices of medications in an effort to enhance the effects of newer-generation antidepressants.



1. Blackman B. The adjunctive role of diazepam in the treatment of depression. Clin Med (Northfield Il). 1963;70:1495-500.
2. Hare HP Jr. Comparison of chlordiazepoxide-amitriptyline combination with amitriptyline alone in anxiety-depressive states. J Clin Pharmacol New Drugs. 1971;11(6):456-460.
3. Feighner JP, Brauzer B, Gelenberg AJ, et al. A placebo-controlled multicenter trial of Limbitrol versus its components (amitriptyline and chlordiazepoxide) in the symptomatic treatment of depressive illness. Psychopharmacology (Berl). 1979;61(2):217-225.
4. Shader RI, Greenblatt DJ. Benzodiazepine overuse-misuse. J Clin Psychopharmacol. 1984;4(3):123-124.
5. Robertson MM, Trimble MR. Major tranquillisers used as antidepressants. A review. J Affect Disord. 1982;4(3):173-193.
6. Spiker DG, Weiss JC, Dealy RS, et al. The pharmacological treatment of delusional depression. Am J Psychiatry. 1985;142(4):430-436.
7. Mena A, Heistad G, Schiele BC, Janecek J. A comparison of tranylcypromine alone with tranylcypromine plus trifluoperazine in the treatment of chronic outpatients: a double-blind controlled study. J Neuropsychiatr. 1964;5:542-550.
8. Prange AJ Jr, Wilson IC, Rabon AM, Lipton MA. Enhancement of imipramine antidepressant activity by thyroid hormone. Am J Psychiatry. 1969;126(4):457-469.
9. Prange AJ Jr, Wilson IC, Lipton MA, Rabon AM, McClae TK, Knox AE. Use of a thyroid hormone to accelerate the action of imipramine. Psychosomatics. 1970;11(5):442-444.
10. Wilson IC, Prange AJ Jr, McClane TK, Rabon AM, Lipton MA. Thyroid-hormone enhancement of imipramine in nonretarded depressions. N Engl J Med. 1970;282(19):1063-1067.
11. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
12. Haggerty JJ Jr, Stern RA, Mason GA, Beckwith J, Morey CE, Prange AJ Jr. Subclinical hypothyroidism: a modifiable risk factor for depression? Am J Psychiatry. 1993;150(3):508-510.
13. Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. J Clin Psychiatry. 1989;50(10):385-388.
14. Frye MA, Denicoff KD, Bryan AL, et al. Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients. Am J Psychiatry. 1999;156(12):1909-1914.
15. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
16. Gitlin M, Altshuler LL, Frye MA, et al. Peripheral thyroid hormones and response to selective serotonin reuptake inhibitors. J Psychiatry Neurosci. 2004;29(5):383-386.
17. Himmelhoch JM, Detre T, Kupfer DJ, Swartzburg M, Byck R. Treatment of previously intractable depressions with tranylcypromine and lithium. J Nerv Ment Dis. 1972; 155(3):216-220.
18. de Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
19. de Montigny C, Cournoyer G, Morissette R, Langlois R, Caille G. Lithium carbonate addition in tricyclic antidepressant-resistant unipolar depression. Correlations with the neurobiologic actions of tricyclic antidepressant drugs and lithium ion on the serotonin system. Arch Gen Psychiatry. 1983;40(12):1327-1334.
20. Heninger GR, Charney DS, Sternberg DE. Lithium carbonate augmentation of antidepressant treatment. An effective prescription for treatment-refractory depression. Arch Gen Psychiatry. 1983;40(12):1335-1342.
21. Price LH, Charney DS, Heninger GR. Variability of response to lithium augmentation in refractory depression. Am J Psychiatry. 1986;143(11):1387-1392.
22. Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of imipramine-resistant recurrent depression: II. An open clinical trial of lithium augmentation. J Clin Psychiatry. 1989b;50(11):413-417.
23. Kupfer DJ, Pickar D, Himmelhoch JM, Detre TP. Are there two types of unipolar depression? Arch Gen Psychiatry. 1975;32(7):866-871.
24. Thase ME, Howland RH, Friedman ES. Treating antidepressant nonresponders with augmentation strategies: an overview. J Clin Psychiatry. 1998;59(suppl 5):5-12.



Recent Findings and Current Status of Augmentation Strategies

By J. Craig Nelson, MD

Dr. Nelson is the Leon J. Epstein professor of psychiatry and director of geriatric psychiatry in the Department of Psychiatry at the University of California San Francisco.

Disclosures: Dr. Nelson is a consultant to and/or on the advisory boards of Abbott, Biovail, Bristol-Myers Squibb, Corcept, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Orexigen, Organon, and Pfizer.



Augmentation strategies have become popular in patients with a partial response or residual symptoms. In a survey conducted by the American Society of Consultant Pharmacists, 65% of 169 psychiatrists indicated that they would augment treatment as the next step in a partial responder in contrast to non-responders in whom they would switch to another drug (J.C. Nelson, unpublished data). This decision is based on common sense and practicality rather than empirical evidence. Many clinicians and patients think that if a patient achieves at least a partial response to a medication, it makes sense to continue that drug and add a second.  To some extent, the patient preferences for treatment shown in the Systematic Treatment Alternatives to Relieve Depression (STAR*D) study  reflect this approach.1 This discussion will update clinicians on the use of augmentation agents for the treatment of major depressive disorder (MDD).


Lithium Augmentation   

Lithium augmentation has been used since it was first described by de Montigny and colleagues2 in 1981. This strategy is based on a rational neurochemical hypothesis that lithium has a synergistic effect when added to a tricyclic antidepressant (TCA). Lithium increases serotonin turnover and the TCA increases postsynaptic serotonin receptor sensitivity.3 Recent debates have focused on whether lithium is as effective combined with selective serotonin reuptake inhibitors (SSRIs) as it is combined with a TCA. The rapid effects sometimes observed with lithium augmentation of TCAs does not seem to occur with SSRIs, conceivably because SSRIs do not increase postsynaptic serotonin receptor sensitivity.

A recent meta-analysis by Crossley and Bauer4 found  10 placebo-controlled lithium augmentation studies.  Augmentation with lithium was significantly more effective than augmentation with placebo. Forty percent of study participants on lithium responded versus 17% on placebo. However, many of the studies included in this meta-analysis were quite small. While one study had 61 patients, the other samples had ≤35 patients. Usual doses of lithium during augmentation were 600–900 mg/day, which translates into a lithium level of ≥0.4 mEq/L. Most recently, lithium augmentation was compared with triiodothyronine (T3) augmentation as a Level 3 strategy in the STAR*D study.5 Patients achieved a reasonable final lithium dose of about 900 mg/day; however, remission rates, while not significantly different, appeared to favor T3 (25% versus 13% to 16%) (Slide 1).6  Lithium was significantly less well tolerated than T3, with more patients discontinuing treatment.


Placebo-controlled study of the use of lithium for patients with treatment-resistant depression (TRD) is limited. Several early studies added lithium after 4 weeks of limited response to the initial antidepressant, and it is not clear that these patients were really treatment resistant. A recent study by Nierenberg and colleagues6 found lithium augmentation was not  more effective than placebo in a group of 35 patients who had failed a 6-week prospective nortriptyline trial.  

Another possible explanation of the apparent reduced effectiveness of lithium augmentation is the increased recognition of bipolar spectrum illness. We found, in patients with psychotic depression, that lithium was particularly effective for augmentation in patients with first-degree relatives with bipolar illness or probable histories of hypomania.7 It is possible that as clinicians have become more alert to the diagnosis of bipolar disorder and exclude these patients from studies, the efficacy of lithium augmentation has declined. 


Thyroid Augmentation   

Thyroid augmentation is another commonly employed augmentation strategy. Several controlled studies have suggested this strategy may accelerate response. Altshuler and colleagues8 performed a meta-analysis of six studies using T3 to accelerate response. Five of these showed a significant effect in increasing the speed of response. The effect was particularly notable in women. Three placebo-controlled studies subsequent to the meta-analysis have examined acceleration of response with T3, with two finding an advantage for T3.9,10 

The evidence for the effectiveness of T3 in patients with TRD is less clear. Aronson and colleagues11 performed a meta-analysis of eight controlled studies of T3 augmentation (Slide 2). Four of the studies were placebo-controlled, and those that were not used other controls or comparisons. For example, one study compared T3 and T4, and three of the other studies used a historical control for comparison. Overall, the studies indicated that T3 had a significant effect, with an odds ratio of 2 in 292 patients. However, in the four placebo-controlled trials, T3 was not superior to placebo. The placebo-controlled studies included 75 patients, and the odds ratio was 1.5 with a wide confidence interval.


The nature of the thyroid trials varied widely, and there are limitations to the studies. A small placebo-controlled trial reported by Gitlin and colleagues12 used a crossover design after randomizing patients to T3 or placebo. Crossover designs in depression are limited by the lingering effects of the prior treatment. Goodwin and colleagues13 substituted T3 for placebo in a blinded fashion, but without randomization to a parallel comparison. Arguably the best designed study was conducted by Joffe and colleagues.14 This was a placebo-controlled parallel comparison of T3, lithium and placebo in 50 patients receiving TCAs. Both T3 and lithium were more effective than placebo but augmentation occurred after only 5 weeks of failure to respond to the first antidepressant. The use of T3 in patients we would now consider treatment resistant is limited. There are no placebo-controlled studies of T3 in SSRI-resistant patients. The best evidence for the efficacy of T3 augmentation of SSRIs in TRD comes from STAR*D which found that ~25% of patients who had failed two prior antidepressant trials, remitted with T3.5 Forty-seven of the 70 patients receiving T3 were taking citalopram or sertraline.  

The dose of T3 for thyroid augmentation is typically 25–50 μg/day. T3 has relatively few side effects. As is the case with almost all augmentation strategies, it is unknown how long thyroid augmentation should be continued. Although no significant problems have yet been identified with long-term treatment, this has not been well studied in depression.


Stimulant Augmentation   

Stimulants are also commonly used to augment antidepressants but this strategy is not as well studied as lithium or thyroid augmentation. Several open studies, previously reviewed,15 with <100 total patients reported that the addition of methylphenidate or dextroamphetamine to a TCA or MAOI could be useful in the addressing TRD. Stimulants were usually employed in patients who were anergic or fatigued.  A recent study by Patkar and colleagues16 examined methylphenidate augmentation in 60 patients with MDD who had been resistant to at least one trial with various antidepressants, primarily SSRIs (Slide 3). These patients were randomly assigned to extended-release methylphenidate, 18–54 mg/day, or to placebo for a duration of 4 weeks. The response rates were 40% with methylphenidate and 23% with placebo, but this difference was not significant. Of note, the sample of 60 patients may have been too small to  detect subtle differences.


Modafinil has also been used to improve alertness or energy in targeted populations of sedated or fatigued patients. Several open trials support the use of modafinil as an augmentation agent. A double-blind study by Fava and colleagues17 looked at patients with MDD who experienced a partial response to 8 weeks of SSRI monotherapy and had residual fatigue or sleepiness (Slide 4). The study also implemented scales for sleepiness and fatigue. The patients were randomized to modafinil or placebo for 8 weeks. Approximately 150 patients participated in each arm of the study. Patients receiving modafinil showed significantly greater improvement on the Clinical Global Impression (CGI) scale.



Thase and colleagues18 performed a 12-week, open-label, dose-titration extension study of the study by Fava and colleagues.17 Patients who had received placebo in the randomized phase had the option to switch to modafinil. The response was sustained in patients, and some patients who had failed to respond to modafinil during the initial 8-week trial responded during the 12-week treatment with modafinil.

The mechanism of action for modafinil is less clear than that of other stimulants, and some clinicians have limited experience with this agent. It has thus far been used to treat specific residual symptoms. The usual dose has been 200–300 mg/day. A randomized trial by Fava and colleagues17  is one of the largest augmentation studies conducted and showed modafinil to be quite effective in treating patients with specific residual symptoms. 


Buspirone Augmentation   

Buspirone was the first augmentation strategy proposed for use with the SSRIs in 1991.19,20 Several previously reviewed15 open studies, with samples ranging up to 30 patients, suggested efficacy. However, a controlled study by Landen and colleagues21 found that buspirone augmentation was not more effective than placebo after 4 weeks of SSRI treatment failure in 119 patients. The high placebo response rate of 47% suggested that patients were continuing to improve with the initial SSRI. 

Buspirone augmentation was employed in Level 2 of the STAR*D study.1 While the overall remission rate, 32.9%, looked promising, patients who  elected to receive augmentation had fewer symptoms at the start of Level 2 treatment than the patients who elected or were randomized to switch.  The ultimate efficacy of buspirone for augmentation has yet to be determined.


Other Augmentation Strategies

Although pindolol has shown efficacy when used to accelerate initial SSRI treatment,15 it has not been effective in patients with TRD. In two studies of TRD patients, particularly the larger study by Perez and colleagues,22 augmentation with pindolol was no more effective than augmentation with placebo.

An emerging body of evidence suggests lamotrigine may be useful as an augmentation strategy. In addition to case reports, three retrospective series of cases (N=14, 34, and 37) suggest the value of the addition of lamotrigine to an ongoing antidepressant in unipolar patients who have been resistant to treatment.23-25 In addition, one placebo-controlled trial in 23 patients, who had failed at least one prior antidepressant, randomly assigned patients to the addition of lamotrigine or placebo to fluoxetine 20 mg/day.26 The sample included 8 patients with bipolar II depression and 15 patients with unipolar MDD.  In both groups lamotrigine failed to show superiority on the primary outcome measure, the Hamilton Rating Scale for Depression, but did show an advantage on the CGI scale. Lamotrigine would appear to be a promising but not established strategy.  

Several studies have examined the use of testosterone in depressed men. A report of five cases suggested testosterone replacement therapy might be useful in hypogonadal men with SSRI-resistant depression.27 The results of placebo-controlled studies have been mixed. Pope and colleagues28 randomly assigned 22 depressed men who had failed 4 weeks of antidepressant treatment and had low or borderline testosterone levels, to the addition of either testosterone gel or placebo to their ongoing antidepressant and found this strategy effective. The authors noted that the effect was only observed in patients whose serum testosterone levels rose appreciably.  A second randomized controlled trial (RCT) in 18 hypogonadal depressed men who were partial responders to prior treatment added testosterone gel or placebo to the continuing antidepressant. The study employed a 12-week trial followed by a crossover. No advantage for testosterone was observed.29 The third RCT examined intramuscular testosterone or placebo in 26 depressed subjects who had failed two prior antidepressant trials and were now receiving an SSRI.30 Again testosterone augmentation was not found to be superior to placebo. At this point, the usefulness of testosterone in depressed men with either low or adequate testosterone levels remains unclear.

Estrogen has been examined as a potential augmentation agent in women. Various comparisons have been performed with monotherapy, augmentation, estrogen versus an antidepressant, and in peri- and post-menopausal women. Two large retrospective analyses of SSRI trials found that postmenopausal women receiving hormone replacement therapy were more likely to respond to the SSRI.31,32 However, results of prospective studies have been mixed.  A small (N=16) study of perimenopausal women, who were partial responders and who were experiencing other perimenopausal symptoms, found that adding estrogen to antidepressant treatment elicited a better response than adding placebo.33 Two other placebo-controlled studies, however, in postmenopausal women, found no advantage of augmenting sertraline with an estrogen patch (N=22)34 or adding an estrogen/progesterone combination to venlafaxine (N=56).35 These studies illustrate the need for a placebo control as all groups in both studies improved. The controlled data to date suggest that estrogen augmentation in postmenopausal women is not effective but may be useful in symptomatic perimenopausal women who are depressed. 

Several studies have indicated that high homocysteine levels and low B12 and folate levels are associated with depression. Papakostas and colleagues36 found that low folate serum levels were associated with reduced response to fluoxetine. In a 10-week RCT by Coppen and Bailey,37 127 subjects with MDD who were receiving fluoxetine but were not treatment resistant were randomly assigned to folate 500 μg or placebo (Slide 5). Female patients taking folate were more likely to respond than those taking placebo. This effect was not observed in men and it was suggested this dose may be too low in men. Although the value of folate has not been established in TRD, given the minimal side effects observed, this simple strategy ought to be considered in women. Alternatively it is not clear if this effect is limited to women with low folate or if additional folate would be useful to women already taking multi-vitamins that often contain about 400 μg of folic acid.




Currently several augmentation strategies have been described for use in patients with TRD. Unfortunately, with the exception of STAR*D, almost all of these studies have been conducted in samples of <100 subjects. Only recently have studies employed designs that more carefully assure that patients have received adequate prior treatment and are in fact treatment resistant. Seldom have two augmentation strategies been compared with each other under similar conditions, thus the relative magnitude of their effects is largely unknown.  The lack of large comparison studies also limits what is known about predictors of response to these treatments. Thus selection of a particular agent is based more on clinical experience than empirical data. Some strategies—augmentation with T3, estrogen, testosterone, and folate—would appear to make sense in patients deficient in that substance, but that rational hypothesis has not been confirmed. Finally, the following question remains: If the patient responds to augmentation, should the augmenting agent be continued? This question has seldom been studied.



1. 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.
2. Dé Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
3. Nelson JC. Lithium augmentation in refractory depression. In: Roose SP, Glassman.AH. Treatment Strategies for Refractory Depression. Washington, DC: American Psychiatric Press, Inc; 1990:35-49.
4. 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.
5. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519-1530.
6. Nierenberg AA, Papakostas GI, Petersen T, et al. Lithium augmentation of nortriptyline for subjects resistant to multiple antidepressants. J Clin Psychopharmacol.2003;23:92-95.
7. Nelson J C, Mazure C. Lithium augmentation in psychotic depression refractory to combined drug treatment. Am J Psychiatry. 1986;143:363-366.
8. Altshuler LL, Bauer M, Frye MA, et al. Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158(10):1617-1622.
9. Posternak M, Novak S, Stern R, et al. A pilot effectiveness study: placebo-controlled trial of adjunctive L-triiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacol. 2007;13:1-11.
10. Cooper-Kazaz R, Apter JT, Cohen R, et al. Combined treatment with sertraline and liothyronine in major depression: a randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2007;64:679-688.
11. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation in the treatment of refractory depression. A meta-analysis. Arch Gen Psychiatry. 1996;53(9):842-848.
12. Gitlin MJ, Weiner H, Fairbanks L, Hershman JM, Friedfeld N. Failure of T3 to potentiate tricyclic antidepressant response. J Affect Disord. 1987;13(3):267-272.
13. Goodwin FK, Prange AJ Jr, Post RM, Muscettola G, Lipton MA. Potentiation of antidepressant effects by L-triiodothyronine in tricyclic nonresponders. Am J Psychiatry. 1982;139(1):34-38.
14. Joffe RT, Singer W, Levitt AJ, MacDonald C. A placebo-controlled comparison of lithium and triiodothyronine augmentation of tricyclic antidepressants in unipolar refractory depression. Arch Gen Psychiatry. 1993;50:387-393.
15. Nelson JC. Augmentation strategies in depression 2000. J Clin Psychiatry. 2000;61(suppl 2):13-19.
16. Patkar AA, Masand PS, Pae CU, et al. A randomized, double-blind, placebo-controlled trial of augmentation with an extended release formulation of methylphenidate in outpatients with treatment-resistant depression. J Clin Psychopharmacol. 2006;26(6):653-656.
17. Fava M, Thase ME, DeBattista C. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry. 2005;66(1):85-93.
18. Thase ME, Fava M, DeBattista C, Arora S, Hughes RJ. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label, extension study. CNS Spectr. 2006;11(2):93-102.
19. Jacobsen FM.  Possible augmentation of antidepressant response by buspirone. J Clin Psychiatry. 1991;52:217-220.
20. Bakish D. Fluoxetine potentiation by buspirone: Three case histories. Can J Psychiatry. 1991;36:749-750.
21. 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(12):664-668.
22. Pérez V, Soler J, Puigdemont D, Alvarez E, Artigas F, Grup de Recerca en Trastorns Afectius. A double-blind, randomized, placebo-controlled trial of pindolol augmentation in depressive patients resistant to serotonin reuptake inhibitors. Arch Gen Psychiatry. 1999;56(4):375-379.
23. Gabriel A. Lamotrigine adjunctive treatment in resistant unipolar depression: an open, descriptive study. Depress Anxiety. 2006;23:485-488.
24. Gutierrez RL, McKercher RM, Galea J, Jamison KL. Lamotrigine augmentation strategy for patients with treatment-resistant depression. CNS Spectr. 2005;10:800-805.
25. Barbee JG, Jamhour NJ. Lamotrigine as an augmentation agent in treatment-resistant depression. J Clin Psychiatry. 2002;63:737-741.
26. Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry. 2003;64:403-407.
27. Seidman SN, Rabkin JG. Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression. J Affect Disord. 1998;48:157-161.
28. Pope HG, 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.
29. Orengo CA, Fullerton L, Kunik ME. Safety and efficacy of testosterone gel 1% augmentation in depressed men with partial response to antidepressant therapy. J Geriatr Psychiatry Neurol. 2005;18:20-24.
30. Seidman SN, Miyazaki M, Roose SP. Intramuscular testosterone supplementation to selective serotonin reuptake inhibitor in treatment-resistant depressed men: randomized placebo-controlled clinical trial. J Clin Psychopharmacol. 2005;25:584-588.
31. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine Collaborative Study Group. Am J Geriatr Psychiatry. 1997;5:97-106.
32. 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.
33. Morgan ML,Cook IA, Rapkin AJ, Leuchter AF. Estrogen augmentation of antidepressant in perimenopausal depression: a pilot study. J Clin Psychiatry. 2005;66:774-780.
34. Rasgon NL, Altshuler LL, Fairbanks LA, et al. Estrogen replacement therapy in the treatment of major depressive disorder in perimenopausal women. J Clin Psychiatry. 2002;63(suppl 7):45-48.
35. Dias RS, Kerr-Correa F, Moreno RA, et al. Efficacy of hormone therapy with and without methyltestosterone augmentation ov venlafaxine in the treatment of postmenopausal depression: a double-blind controlled pilot study. Menopause. 2006;13:202-211.
36. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-reistant depression. J Clin Psychiatry. 2004;65:1090-1095.
37. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60(2):121-130.


Examining the Evidence on Augmentation with Atypical Antipsychotics

By George I. Papakostas, MD

Dr. Papakostas is assistant professor of psychiatry at Harvard Medical School, and staff psychiatrist in the Department of Psychiatry at Massachusetts General Hospital in Boston.

Disclosures: Dr. Papakostas has served as a consultant to Aphios, Bristol-Myers Squibb, GlaxoSmithKline, Evotec, Inflabloc, Jazz, PAMLAB, Pfizer, and Wyeth; has received honoraria from Bristol-Myers Squibb, Evotec, GlaxoSmithKline, Inflabloc, Jazz, Lundbeck, PAMLAB, Pfizer, Titan, and Wyeth; and has received research support from Bristol-Myers Squibb, PAMLAB, and Pfizer.


Introduction: Efficacy of Current Treatment Strategies for Depression   

There is mounting evidence to suggest that the efficacy of all available antidepressants when used as monotherapy to treat major depressive disorder (MDD) is, at best, modest. For example, a meta-analysis1 of all double-blind placebo-controlled studies of antidepressants published since 1980 revealed response rates of 53% for antidepressants versus 36% for placebo (difference in response rate of 16.8%) (Slide 1). To make matters worse, if one is to assume that “negative trials” (ie, trials which do not demonstrate the superiority of a drug over placebo) are less likely to be published than “positive trials” (trials which demonstrate the superiority of a drug versus placebo), it is quite possible that the margin of efficacy of antidepressants when compared to placebo is <16.8%. Thus, if one were to include all unpublished along with published double-blind, placebo-controlled trials of antidepressants for MDD, this efficacy margin could be <10%.


At the present time, it is unclear to what extent conclusions drawn from randomized, double-blind, placebo-controlled trials (ie, efficacy studies) also apply to “real-world” treatment settings. However, preliminary studies focusing on the use of antidepressants in “real-world” clinical settings present discouraging results. For example, Petersen and colleagues2 report remission rates as low as 20% to 23% following each successive treatment among patients with MDD enrolled in one of two academically-affiliated, depression-specialty clinic (Slide 2). In fact, only ~50% of patients enrolled achieved full remission of their depression. Similarly, only about one in three patients with MDD experienced a remission of their depression following treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram during the first-level of the large, multicenter, Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.3 Clearly, there is an urgent need to develop safer, better tolerated, and more effective treatments for MDD.



Augmentation of Antidepressants with Second-Generation Antipsychotics: A Novel Approach

There are three major “paths” toward the development of novel pharmacotherapeutic strategies for MDD (Slide 3). The first approach involves developing new drugs. The second approach involves identifying subpopulations of depressed patients that are more likely to experience the benefits of a given treatment versus placebo. Attempts have been made to identify such “subpopulations” with the use of either biological markers (ie, genetic markers), or clinical markers (ie, the presence of symptoms, symptoms clusters, or comorbid disorders). Finally, a third approach involves combining two pharmacologic treatments: either two antidepressants or an antidepressant with a novel agent. The case of augmenting antidepressants with second-generation (atypical) antipsychotics (SGAs) for treatment-resistant depression (TRD) falls under the third “path” of treatment development. Other examples which also fall under this category include the combination of SSRIs or serotonin norepinephrine reuptake inhibitors (SNRI) with other antidepressants including mirtazapine (a 5-HT2 receptor antagonist and α2-adrenergic receptor antagonist), bupropion (a norepinephrine dopamine reuptake inhibitor), tricyclic antidepressants, or with non-antidepressant agents including lithium, triiodothyronine (T3), pindolol, or buspirone.4


The preclinical rationale for the use of the SGAs in MDD derives from their complex neuropharmacologic effects at various monoaminergic receptors and transporters.4 Specifically, all SGAs appear to be 5-HT2 receptor antagonists.4 SGAs also vary in terms of neuropharmacologic effects. Ziprasidone and aripiprazole possess affinity for the 5-HT1A receptor, while ziprasidone and risperidone possess affinity for the 5-HT1D receptor.4 Ziprasidone has also been shown to inhibit the reuptake of serotonin and norepinephrine, while aripiprazole has been shown to possess mixed agonist and antagonist effects at various dopamine receptors.4 These effects were thought to be suggestive of antidepressant activity.4

Early clinical studies focusing on augmentation with SGAs in depression demonstrated mixed findings. The first clinical report ever to be published focusing on this treatment strategy was a case series describing eight patients with SSRI-resistant depression who experienced remission of symptoms following the addition of low doses of risperidone (0.5–1 mg).5 What was also notable in that report was that all patients achieved remission of symptoms of depression quite rapidly (within 1 week of combined treatment). This preliminary report was soon followed by a double-blind placebo-controlled study that focused on adding olanzapine to fluoxetine among fluoxetine nonresponders.6 A greater improvement in depressive symptoms was reported among patients treated with the combination of these two agents than either agent alone.6 

However, soon thereafter, doubt was cast on the potential utility of this treatment strategy when two subsequent studies combining olanzapine with fluoxetine for nortriptyline- or venlafaxine-resistant MDD failed to show that combining olanzapine with fluoxetine was more effective than monotherapy with either venlafaxine, fluoxetine, or nortriptyline.7,8 More recently, however, several double-blind, placebo-controlled studies focusing on augmenting antidepressants with either risperidone,9,10 quetiapine,11-13 or olanzapine14 for TRD re-kindled clinicians interest in this treatment strategy. Specifically, six of these seven trials9,10,12-14 demonstrated greater efficacy in TRD among patients treated with adjunctive SGAs than placebo (Thase and colleagues14 reported two separate but identical trials of olanzapine augmentation of fluoxetine, and found olanzapine augmentation to be effective in the first but not the second study). 

In order to reconcile the discrepancy in results between “positive” and “negative” studies, we conducted a random-effects model meta-analysis pooling all 10 randomized, double-blind, placebo-controlled clinical trials focusing on augmentation of antidepressants with SGAs for TRD.15 In that meta-analysis, the difference in remission rates between the SGAs and placebo was found to be statistically significant, with a 47.4% remission rate for augmentation with SGAs versus a 37% remission rate for augmentation with placebo (Slide 4). Though the difference in efficacy in favor of this augmentation strategy over placebo was pronounced, tolerability appeared to be a considerable limitation. Specifically, the difference in the rates of discontinuation due to intolerance for patients treated with SGAs compared to placebo was also statistically significant (22.3% for the SGAs and 12% for placebo, respectively).




Second-Generation Antipsychotic Augmentation for MDD: Questions Unanswered

Although the results of our meta-analysis provided evidence in support of the use of SGAs as adjuncts for TRD, two major questions remain: (A) is this evidence generalizeable to all SGAs; and (B) is there evidence supporting the long-term efficacy for this treatment strategy as there is for standard antidepressants?

Regarding the issue of generalizability, it is important to note that at the time the meta-analysis was conducted, evidence supporting the use of adjunctive ziprasidone in MDD derived exclusively from open-label, but not placebo-controlled trials. In one such study, Papakostas and colleagues16 treated 20 patients with SSRI-resistant MDD with adjunctive ziprasidone. Twenty-five percent of patients remitted during the trial and 50% experienced a clinical response (Slide 5).


However, more recently, two positive, double-blind, placebo-controlled trials investigating the use of adjunctive aripiprazole in MDD were either been published17 or presented at major scientific meetings (Slide 6).18 In the first study, Berman and colleagues17 focused on the use of aripiprazole augmentation for patients resistant to up to 1–3 retrospective antidepressant trials. To confirm treatment resistance, those patients underwent an 8-week, open-label trial with an SSRI (fluoxetine, sertraline, paroxetine or escitalopram) or an SNRI (venlafaxine). The patients who made insufficient symptom improvement had either aripiprazole or placebo added to their SSRI or SNRI regimen, under double-blind conditions for 6 weeks. A statistically significant difference in remission rates was observed, with 26% remission for aripiprazole versus 15.7% remission for placebo (P<.05). This study also reported relatively low rates of discontinuation due to intolerance in the treatment groups (2% for aripiprazole and 1.7% for placebo [P>.05]). The results of a separate study of identical design also demonstrated greater remission rates for adjunctive aripiprazole- than placebo-treated patients.18


Much less is know regarding long-term efficacy.  Rapaport and colleagues19 examined 386 MDD patients who failed to experience sufficient symptom improvement following treatment with citalopram. These patients then received adjunctive treatment (open-label) with risperidone for 4–6 weeks. Of these patients, 241 (63%) experienced significant symptom improvement. These patients were randomized under double-blind conditions to continue to receive the combination of risperidone and citalopram or to continue with citalopram but to undergo a substitution of risperidone for placebo (double-blind) for 24 weeks. Relapse rates between the two groups were not statistically significant (Slide 7).





From the evidence available to date, it appears that augmentation of standard, first-line antidepressants with SGAs is effective in some cases of TRD, at least during the acute phase of treatment. However, there are limitations in the tolerability of this combination strategy, while the long-term efficacy, tolerability, and safety of this treatment are not yet understood. Further research is required into how this compares with other augmentation strategies and other strategies for addressing TRD.



1. Papakostas GI, Fava M. Does the probability of receiving placebo influence the likelihood of responding to placebo or clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Neuropsychopharmacology. 2006;31(suppl 1):s158.
2. Petersen T, Papakostas GI, Posternak MA, et al. Empirical testing of two models for staging antidepressant treatment resistance. J Clin Psychopharmacol. 2005;25(4):336-341.
3. Trivedi MH, Rush AJ, Wisniewski SR, et al; STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
4. Papakostas GI. Augmentation of standard antidepressants with atypical antipsychotic agents for treatment-resistant major depressive disorder. Essent Psychopharmacol. 2005;6(4):209-220.
5. Ostroff RB, Nelson JC. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression. J Clin Psychiatry. 1999;60(4):256-259.
6. Shelton RC, Tollefson GD, Tohen M, et al. A novel augmentation strategy for treating resistant major depression. Am J Psychiatry. 2001;158(1):131-134.
7. Shelton RC, Williamson DJ, Corya SA, et al. Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance. J Clin Psychiatry. 2005;66(10):1289-1297.
8. Corya SA, Williamson D, Sanger TM, Briggs SD, Case M, Tollefson G. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression. Depress Anxiety. 2006;23(6):364-372.
9. Keitner GI, Garlow SJ, Ryan CE, et al. Risperidone augmentation for patients with difficult-to-treat major depression. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
10. Gharabawi G, Canuso C, Pandina G, et al. A double-blind, placebo-controlled trial of adjunctive risperidone for treatment-resistant major depressive disorder. Poster presented at: 25th Collegium Internationale Neuropsychopharmacologicum; July 9-13, 2006; Chicago, Illinois.
11. Khullar A, Chokka P, Fullerton D, McKenna S, Blackman A. Quetiapine as treatment of non-psychotic unipolar depression with residual symptoms: double blind, randomized, placebo controlled study. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
12. Mattingly G, Ilivicky H, Canale J, Anderson R. Quetiapine augmentation for treatment-resistant depression. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
13. McIntyre AW, Gendron A, Mcintyre A. Quetiapine augmentation of SSRIs/SNRIs in major depression with anxiety. Poster presented at: 159th Annual Meeting of the American Psychiatric Association; May 20-26, 2006; Toronto, Canada.
14. Thase ME, Corya SA, Osuntokun O, et al. A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder. J Clin Psychiatry. 2007;68(2):224-236.
15. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.
16. Papakostas GI, Petersen TJ, Nierenberg AA, et al. Ziprasidone augmentation of selective serotonin reuptake inhibitors (SSRIs) for SSRI-resistant major depressive disorder. J Clin Psychiatry. 2004;65(2):217-221.
17. 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(6):843-583.
18. Thase ME, Marcus RN, Hennicken D, et al. Efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled study (Study CN 138-163). Poster presented at: 61st Annual Convention of the Society of Biological Psychiatry; May 18-20, 2006; San Diego, California.
19. Rapaport MH, Gharabawi GM, Canuso CM, et al. Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation. Neuropsychopharmacology. 2006;31(11):2505-2513.


Clinical Considerations with Atypical Antipsychotic Augmentation

By Michael J. Gitlin, MD

Dr. Gitlin is professor of clinical psychiatry at the University of California, Los Angeles (UCLA) School of Medicine and director of the Mood Disorders Clinic at the Neuropsychiatric Clinic at UCLA.

Disclosures: Dr. Gitlin has received honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, GlaxoSmithKline, Pfizer, and Takeda.


Introduction: Practical Clinical Applications

In spite of the tremendous advances made in developing antidepressant treatments and exploring augmentation with second-generation antipsychotics (SGAs), significant obstacles remain for psychiatrists: How should clinicians make use of cutting-edge augmentation studies? How should they use the antipsychotics in their treatment algorithm? How should they think about dosing and side effects?

The first major problem is there have been no great algorithmic studies on adjunctive strategies. In fact, the most useful algorithmic study was the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, from which SGAs were entirely absent. The second problem is that STAR*D showed a clear pattern in which the efficacy of an augmentation agent depended on its placement in the algorithm. Those agents occurring later in the algorithm, such as monoamine oxidase inhibitors (MAOIs), adjunctive triiodothyronine (T3), and adjunctive lithium, appeared to be less effective than adjunctive buspirone, which occurred earlier in the algorithm. This was not the result of a direct comparison. Because of these two problems, it is therefore difficult to determine how to rank the efficacy of SGAs among the agents investigated by the STAR*D study. Among clinical treatment strategies, SGAs might appear toward the end of first-line strategies, perhaps after combinations and stimulants but before buspirone.

As a field, we also know very little about optimal dosing of SGAs when used as adjunctive treatments for depression. In general, however, doses used in adjunctive strategies are lower than those used for either acute mania or acute psychotic states. These are usually dosed in the range of 2.5–10 mg for aripiprazole, 20–60 mg for ziprasidone, 2.5–10 mg for olanzapine, 0.5–3 mg for risperidone, and 50–200 mg for quetiapine. However, these doses are based more on clinical experience than evidence-based data.


Side-Effect Concerns

Considering what is currently known about augmentation with SGAs, clinicians must consider how to make decisions within a relatively limited base of knowledge. Another factor to consider in making these decisions are side effects. There are class concerns, such as tardive dyskinesia (TD), and concerns that differ across agents, such as weight gain and propensity for metabolic syndrome. Many of these side-effect concerns have caused hesitation among clinicians regarding the use of SGAs earlier in the algorithm of treatment-resistant depression (TRD).

It is clear that SGAs are less associated with TD than first-generation antipsychotics (FGAs). In the best meta-analysis conducted on the subject thus far, the occurence of TD with SGAs was one seventh its occurence with FGAs.1 However, this study was conducted several years ago, and therefore did not include more recent medications such as ziprasidone and aripiprazole. In addition, TD studies are conducted with schizophrenia patients who have received full doses of antipsychotics. It is not known how relevant those data are to low-dose strategies in mood disorders patients. While it seems likely that TD risk is reduced with low-dose strategies, it has not yet been proven. It is also unknown whether rates of TD vary across SGAs. In theory, quetiapine, with its fast dopamine (D)2 dissociation; aripiprazole, with its D2 partial agonism; and clozapine should have the lowest risks of TD. However, there is not enough data to show that these agents are less likely to be associated with TD than any other SGA.

Prolactin is another concern for clinicians. It is clear that risperidone has a unique propensity to increase prolactin levels, whereas other SGAs increase prolactin rarely, if at all. Clinicians prescribing SGAs should look for side effects such as menstrual abnormalities in women; galactorrhea and gynecomastia in both men and women; and certainly sexual dysfunction in men.

Risperidone is far more likely to cause extrapyramidal symptoms (EPS) than the other SGAs, for all symptoms except agitation. Quetiapine seldom causes EPS, and clozapine is not associated with EPS at all. Ziprasidone and aripiprazole are most linked to agitation. A restlessness syndrome, often diagnosed as agitation or akathisia, occurs in ~10% of people taking ziprasidone or aripiprazole.


Metabolic Syndrome and Weight Gain

Even though medications that increase weight have existed since the beginning of modern psychopharmacology, starting with chlorpromazine and amitriptyline, it has become a greater concern in recent years. This is especially true with SGAs. The definition of metabolic syndrome is polythetic; it must meet three of five criteria (Slide 1).2 No one criterion is weighted more than another. Other risk factors for cardiovascular disease, such as cigarette smoking, are not typically included in the definition of metabolic syndrome but are considered additive risk factors. Obesity is clearly a strong mediating variable for a number of these factors, but it is not the only one. Some patients have suddenly and dramatically developed diabetic ketoacidosis early in the course of treatment with an SGA (specifically clozapine, olanzapine, or quetiapine) without gaining any weight at all. Treatment with SGAs causes both obesity-mediated metabolic syndrome and non-obesity–related concerns.



Metabolic syndrome in psychiatrically ill patients mirrors epidemiologic trends in society at large, where rates of type 2 diabetes among children and adults have increased markedly over the past 20 years. It is widely presumed that this is related to dietary factors, although a concrete cause has not yet been established. Clinicians must also remember that chronically psychiatrically ill patients, whether afflicted with schizophrenia, bipolar disorder, or major depressive disorder, tend to have very unhealthy habits. These habits may contribute to, or even cause, patients’ metabolic disturbances. It is also significant to note that abdominal obesity, not simple weight gain, is the relevant criterion. Truncal weight gain correlates with cardiovascular risk more than fat deposits elsewhere, making this specific type of obesity of greater concern.

A study by Allison and colleagues3 showed differential weight gain across antipsychotics (Slide 2). Aripiprazole was not included in the study because data were not available at the time, though its weight gain effects might be similar to those of ziprasidone and fluphenazine. It is clear, in any case, that weight gain is not uniform across agents.



The Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes investigated the differential concern for weight gain, risk for diabetes, and worsening lipid profile.4 These can be divided into three groups: the clozapine-olanzapine group, which clearly has the highest propensity toward metabolic syndrome; the risperidone-quetiapine group, which has a medium propensity; and the ziprasidone-aripiprazole group, which has the lowest propensity (Slide 3).



Analyses of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study also demonstrated that olanzapine has the greatest weight gain concern (Slides 4 and 5) and is associated with the highest glucose levels (Slide 6).5 Clinicians might be disinclined to use agents with greater weight gain propensity and metabolic syndrome concerns. However, they must bear in mind that some patients do much better on olanzapine, and some patients experience the most symptom improvement with clozapine.




Recommendations for Monitoring

Clinicians must be vigilant about monitoring patients taking antipsychotics as adjunctive antidepressants. The Consensus Development Conference recommended monitoring for a number of risk factors, such as family history, waist circumference, fasting plasma glucose, and fasting lipid glucose (Slide 7).4 Unfortunately, many clinicians do not rigorously follow these guidelines. Clinicians in institutional settings, with ample assistance from nurses and ancillary personnel, may have less difficulty drawing blood and following these extensive guidelines. However, clinicians in smaller practices face obstacles to carrying out the recommendations, both because they often lack the infrastructure to obtain frequent lab tests and because because they simply do not have a tradition of doing them. The formal recommendations are lofty but burdensome, and because the majority of clinicians in the community may not follow them, those doctors are left without practicable guidelines.


Should clinicians receive a second set of guidelines? It seems that there are practical measures clinicians can take to monitor their patients without undue burden. Though they will miss some rare diabetic ketoacidoses without consistently monitoring weight gain or other laboratory parameters, clinicians can safely assume that patients who have experienced significant weight gain—≥7% of baseline body weight, or ≥10 pounds for a 150-pound person—belong to a higher-risk group. When using SGAs as adjunctive antidepressants, identifying high-risk groups might best involve monitoring weight gain and testing glucose, lipid profiles, and blood pressure for those patients who have gained ≥7% of their baseline body weight.

Clinicians should be reminded that using lower doses of the SGAs does not mean they can be dismissive about weight gain. While there are some data indicating that weight gain is dose-related, at least for olanzapine and quetiapine, there has been no conclusive evidence. However, adjunctive therapy with an SGA does utilize relatively low doses of SGAs, which may give clinicians some peace of mind. This is a topic that clinicians will have to address more in the future as SGAs are increasingly used as adjunctive antidepressants.



In summary, the use of SGAs as adjunctive antidepressants has increased substantially. At this point, the data has not kept up with the clinical interest but we can anticipate a number of controlled studies in this area emerging over the next few years. With the use of these medications for depression comes the obligation to carefully consider side effect issues in choosing specific agents.



1. Correll Cu, Leucht S, Kane JM. Lower risk for tardive dyskinesia associated with second-generation antipsychotics: a systematic review of 1-year studies. Am J Psychiatry. 2004;161(3):414-425.
2. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA. 2002;287(3):356-359
3. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696.
4. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596-601.
5. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209-1223.


Question-and-Answer Session

Q: I have long been interested in using thyroid hormone as adjunctive treatment for depression, but I am consistently disappointed with the results in my patients. What has your experience been?

Dr. Thase: In my clinical experience, thyroid augmentation is the treatment of choice for a depressed patient with an underfunctioning thyroid gland, but it is not high on my list for anyone else with refractory depression. Simply said, I believe this treatment works by enhancing thyroid function and patients who have high normal thyroid function to begin with do not benefit. In a study of bipolar depression,1 the cutoff for thyroid-stimulating hormone (TSH) was ~2.5 and a below 50 percentile value for the free thyroxin index (FTI). Patients with one or both of these were less likely to respond to antidepressants. Since that time I have since been targeting those patients with a slightly higher-than-average TSH and a slightly lower than average FTI for thyroid augmentation.

Dr. Nelson: Many studies have looked at augmentation very early in the course of treatment, at ~4 weeks. This may overestimate the effect of augmentation since patients may still be in the midst of responding to initial treatment. Not many studies have carefully selected patients who are truly refractory to initial treatment. A study by Thase and colleagues2 was one of the only studies that incorporated a 12-week period of treatment with imipramine and psychotherapy. Augmentation with thyroid did not seem to add efficacy. In my own experience, I have been similarly disappointed with thyroid augmentation for people who are really treatment resistant.


Q: Have the studies focusing on augmenting tricyclic antidepressants (TCAs)  with first-generation (conventional) antipsychotics (FGAs) for major depressive disorder largely evaluated them as first-line treatments?

Dr. Thase: The original set of studies looked at FGAs as first-line treatments. In that era, FGAs were often used as augmentation agents because psychiatrists did not want to use benzodiazepines. Lower doses of FGAs showed good anxiolytic effects as long as they did not induce akathisia. The evidence of FGA efficacy in depression primarily comes from studies of their first-line use, not their use as augmentation strategies.

Dr. Nelson: There are several positive studies showing that FGAs have an advantage over placebo in the treatment of depression, especially with severely ill patients. The reason they are not considered “antidepressants,” however, is because they were less effective than imipramine for treating loss of interest or motor retardation—symptoms the field considers to be central to the concept of depression.3 However, antipsychotics are useful for treating many other symptoms of depression such as feelings of guilt, anxiety-tension, sleep disturbance, and of course, depressive delusions.3 Hollister and Overall4 argued that some depressed patients have a complete response to antipsychotics alone.


Q: Consider a hypothetical patient with moderately severe nonpsychotic depression, with no clear family history or worrisome historical factors suggestive of bipolar disorder, who has not responded to a second-line antidepressant. The clinician has tried one monotherapy after another, and the patient has experienced a 25% to 30% symptom reduction. The clinician now has decided to augment rather than go to a third favorite monotherapy. Given the state of the evidence, which strategy would you pick?   

Dr. Nelson: That is a difficult question at this point. Should one pick an augmentation strategy or a combination treatment strategy? If the patient remained generally depressed, I would use an antidepressant combination. I would use augmentation agents for specific prominent residual symptoms such as lack of energy and fatigue, or insomnia, or anxiety and agitation and select the agent most likely to help with those symptoms.   
Dr. Gitlin: There is a reasonable amount of positive data for lithium augmentation, most of it with tricyclic antidepressants (TCAs), but clinician and patient acceptance of lithium augmentation is very poor. There are also stimulants for which we do not have any supportive double-blind evidence, yet stimulant augmentation is the single most common augmenting technique clinicians use. It is quite difficult to make research-informed decisions when the findings do not translate into practices acceptable to clinicians and patients.    

Dr. Nelson: It would be nice to have a study similar to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, with a more extensive comparison of common augmentation and combination strategies, as well as a placebo arm. This kind of study would allow psychiatrists to compare the efficacy of these strategies. 


Q: The findings of the meta-analysis by Crossley and Baur5 favor lithium augmentation. However, the authors do not highlight the discrepancies in study durations. Many of these durations are ≤2 weeks. Clinical effects of lithium appear very early, but are not very apparent later. Might this meta-analysis indicate an early acceleration effect which might not appear as robust at week 2?  

Dr. Nelson: There are two duration issues that are variable and limited. One is the duration of prior treatment, which often was only 4 weeks. The other is the duration of the augmentation phase, which in some studies was only 48 hours. The short duration of these studies was based on de Montigny’s6 report of rapid response. There may indeed have been a rapid effect (acceleration) independent of long-term efficacy. Alternatively, Dr. Thase’s historical comparison7 had a longer duration of treatment (6 weeks) during which patients continued to improve.   
Dr. Thase: It is important to keep in mind the source of the patients in the study. Ours was part of a study of highly recurrent depression, and our patients had an average of seven prior episodes. The clinic was strict in its definition of bipolar disorder, and many of our patients would today be said to fall in the bipolar spectrum. Of the lithium responders, 20% to 30% had relatively fast responses, while the other lithium responders experienced slow, gradual, 4–6-week responses.7 For patients with difficult-to-treat depression, lithium can enhance antidepressant effect. This seems more likely to occur with a TCA than with a selective serotonin reuptake inhibitor (SSRI) because TCAs are primarily noradrenergic medications and lithium is a relatively weak serotonergic enhancer.

Q: Is there evidence of an advantage for the use of second-generation (atypical) antipsychotics (SGAs) as an adjunct in more severely depressed patients? It is my impression that severely ill patients are usually more willing to tolerate side effects.

Dr. Papakostas: Unfortunately, in our meta-analysis8 we did not have data that would allow us to look at whether the treatment difference is more robust in patients with severe depression versus those with mild depression. It would be interesting as a post-hoc analysis. However, in my clinical practice, when a patient has very severe depression with suicidal ideation or with irritability, using SGAs certainly comes to mind sooner than it would for a patient who is nearly remitted, whose initial treatment had a low side-effect burden.
Dr. Gitlin: I agree. We have difficulty telling patients with significant residual symptoms, but without severe depression, that we want to put them on antipsychotics. That can be quite jarring for patients. In the less severe patients who presumably have less agitation, we must be careful about using more sedating agents, such as quetiapine and olanzapine. A moderately residually depressed patient might prefer to try aripiprazole or ziprasidone than more sedating and weight-gaining agents.    
Dr. Nelson: It is still quite difficult to determine which augmentation agents will work best with which patients. The data on predictors of response to augmentation are very limited. These decisions are currently based on clinical experience.  It does seem that depression severity interacts with ability to tolerate side effects. Early studies of lithium augmentation were primarily done in more severely ill inpatients who were started on lithium 900 mg/day (300 mg TID). In these hospitalized patients, lithium was relatively well tolerated. In the STAR*D sample, however, which consisted of outpatients who were less ill, lithium was considered quite problematic in terms of patient tolerability.   



1. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry. 2002;159(1):116-121.
2. Thase ME, Kupfer DJ, Jarrett DB. Treatment of imipramine-resistant recurrent depression: I. An open clinical trial of adjunctive L-triiodothyronine. J Clin Psychiatry. 1989;50(10):385-388. 
3. Raskin A, Schulterbrandt JG, Reatig N, McKeon. Differential response to chlorpromazine, imipramine, and placebo. Arch Gen Psychiatry. 1970;23:164-173.
4. Hollister LE, Overall JE. Reflections on the specificity of action of anti-depressants. Psychosomatics. 1965;6(5):361-365.
5. 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(6):935-940.
6. Dé Montigny C, Grunberg F, Mayer A, Deschenes JP. Lithium induces rapid relief of depression in tricyclic antidepressant drug non-responders. Br J Psychiatry. 1981;138:252-256.
7. Thase ME, Kupfer DJ, Frank E, Jarrett DB. Treatment of imipramine-resistant recurrent depression: II. An open clinical trial of lithium augmentation. J Clin Psychiatry. 1989;50(11):413-417.
8. Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007;68(6):826-831.