Needs Assessment: Despite numerous published efficacy studies, use of lithium augmentation for the treatment of refractory depression has declined markedly among clinicians. This paper critically reviews the literature in order to clarify the current role of this strategy in light of emerging trends and findings in managing treatment-resistant depressed patients.

Learning Objectives:
• Be familiar with the controlled and large-scale uncontrolled acute efficacy studies on lithium augmentation.
• Be aware of data concerning the effects of lithium augmentation on long-term outcome.
• Understand the strengths and limitations of the clinical database on lithium augmentation.
• Appreciate the role of lithium augmentation in contemporary practice.

Target Audience: Primary care physicians and psychiatrists.

CME 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 3 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 James C.-Y. Chou, MD, associate professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: October 6, 2008.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Chou receives honoraria from AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Pfizer.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by November 1, 2010 to be eligible for credit. Release date: November 1, 2008. Termination date: November 30, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Return

Primary Psychiatry. 2008;15(11):35-42

 

Dr. Price is professor of psychiatry and human behavior, Dr. Carpenter is associate professor of psychiatry and human behavior, and Dr. Tyrka is assistant professor of psychiatry and human behavior, all at the Warren Alpert Medical School of Brown University in Providence, Rhode Island. Dr. Price is director of research and clinical director, Dr. Carpenter is chief, and Dr. Tyrka is associate chief of the Mood Disorders Research program, all at Butler Hospital in Providence.

Disclosures: Dr. Price is consultant to Gerson Lehrman, Oxford University Press, Springer, and Wiley; serves on the speaker’s bureau for Jazz; and receives research support from Cyberonics, the National Institutes of Health (NIH), Sepracor, UCB Pharma, and the United States Department of Defense. Dr. Carpenter is consultant to AstraZeneca, Cyberonics, Novartis, and Wyeth; is on the speaker’s bureau for Cyberonics; and receives research support from Cyberonics, National Alliance for Research on Schizophrenia and Depression, the NIH, Sepracor, and UCB Pharma. Dr. Tyrka receives research support from Cyberonics, Sepracor, UCB Pharma, and the US Department of Defense.

Please direct all correspondence to: Lawrence H. Price, MD, Butler Hospital, 345 Blackstone Blvd, Providence, RI 02906; Tel:  401-455-6533; Fax: 401-455-6534;  E-mail: Lawrence_Price_MD@Brown.edu.


 
Abstract

Lithium augmentation, first described in 1981, is considered one of the best-supported strategies for treating refractory depression. However, clinical use of this approach has fallen dramatically in recent years, and some recent studies have cast doubt over its efficacy. This article reviews published findings in order to clarify the current role of lithium augmentation in treating refractory depression. Ten placebo-controlled studies, eight comparator-controlled studies, and 13 uncontrolled large-scale prospective studies of acute efficacy were reviewed in addition to six studies of effects on long-term outcome. Detailed examination found that controlled studies of lithium augmentation suffer from inadequate criteria for refractoriness, marked variability in duration of augmentation, variability in lithium levels, inadequate criteria for evaluating response, and idiosyncratic designs. Even more recent studies, while methodologically superior to earlier trials, have significant limitations, especially with respect to variability in lithium levels. “True” response rates to lithium augmentation are likely between 30% to 40%, rather than the 50% assumed by clinicians. A more balanced appraisal of the benefits and risks of this underutilized approach might encourage its wider use by clinicians.

Introduction

Numerous groups in the 1970s studied the effects of combining lithium with tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs),1,2 but broad interest in this approach developed after an open-label report by De Montigny and colleagues in 1981.3 The researchers described dramatic improvement in eight inpatients with unipolar depression within 48 hours of adding lithium 900 mg/day to an ongoing ineffective TCA regimen. Early investigators hypothesized that a specific pharmacodynamic interaction between the TCAs and lithium accounted for such effects, so that lithium acted to “augment” the effects of the TCA rather than exerting independent antidepressant effects of its own.4 This interpretation is complicated; lithium alone does appear to have some antidepressant efficacy.5 Lithium augmentation has come to mean the addition of lithium to a primary antidepressant in order to increase efficacy over what might be obtained with the primary antidepressant alone.6

Since De Montigny and colleagues’ initial report,3 1,263 patients have been described in 31 published prospective studies of lithium augmentation. Attention to the problem of treatment-resistant or refractory depression has expanded greatly, and articles on the topic have generally identified lithium augmentation as one of the best-substantiated pharmacologic approaches to treatment.7-10 Despite the extent of the supporting evidence base, several observers have noted that use of lithium augmentation in general psychiatric practice has declined markedly in recent years.7,9

This article reviews published findings on the efficacy of lithium augmentation in refractory depression, focusing on acute-controlled and large-scale prospective studies and long-term outcome studies. Based on this article, and in light of evolving trends and emerging findings, the current role of lithium augmentation in treating refractory depression should be reconsidered.

Efficacy in Acute Treatment

Placebo-controlled Studies

Ten studies, comprising a total of 269 patients, have evaluated lithium augmentation in the context of a placebo-controlled, double-blind design (Table 1).11-20 Six of these11,14,16-19 containing 194 patients supported the efficacy of the intervention; 4 studies12,13,15,20 with 75 patients did not. A recent meta-analysis21 of these studies demonstrated superiority of lithium augmentation over placebo. The cumulative response rates in these studies, omitting three reports in which categorical response under double-blind conditions was not clearly reported,11,14,17 are 42% for lithium augmentation and 20% for placebo. Including two reports in which single-blind categorical response was reported,14,17 cumulative response rates for lithium augmentation yielded 41% and 21% for placebo.

 

Nine studies reported complete diagnostic data on 194 of 208 patients who had unipolar illness; one study involving 61 patients included both unipolar and bipolar patients without providing a breakdown.18 All studies utilized validated criteria for depression as defined by either the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III)22 or its successors, or the Research Diagnostic Criteria. All studies provided data on the severity of depression at entry to lithium augmentation based on the Hamilton Rating Scale for Depression (HAM-D), with minimum scores ranging from >12 to >18; two studies19,20 required a <50% decrease from pre-antidepressant baseline but did not specify a minimum score. Primary antidepressant treatment in most of the studies involved TCAs; one study19 of 24 patients, used a selective serotonin reuptake inhibitor (SSRI) exclusively, while another with 61 patients, treated 50% of patients with an SSRI and 50% with a TCA.18 Only a few patients were treated with an MAOI or trazodone. Antidepressant doses (or plasma levels) were generally adequate when reported.

Duration of primary antidepressant treatment was ≥21 days in all studies, and ≥28 days in six studies collectively comprising 186 patients.13,15,16,18-20 Although some data support the use of 28 days as a benchmark for adequacy of antidepressant trial duration,23 several authorities recommend 4–8 weeks.24,25 Experts on refractory depression advise a duration of at least 6 weeks,26,27 and there is empirical support for trials of 8–10 weeks.28 Studies in Table 1 meeting a criterion of 6 weeks comprised only 112 of 269 patients,13,18,20 meaning that a large proportion of patients participating in these studies might not meet current criteria for refractoriness. However, use of the parallel-group design for the augmentation component of these trials would mitigate this limitation, since patients treated with placebo would be as likely to have a delayed response to the primary antidepressant as patients treated with lithium. These factors might lead to an underestimate of lithium augmentation’s efficacy. The same could not be said of open-label trials, in which enrollment of patients insufficiently treated with a primary antidepressant would be expected to inflate the apparent response to augmentation.

Assignment to lithium or placebo augmentation was randomized in all but two studies, one of which was alternating11 and in the other unreported.12 Duration of lithium augmentation was extremely variable, ranging from 2–42 days, with 123 patients in six studies11,12,14-16,19 treated for ≤14 days; 75 patients in four studies were treated for only ≤7 days.12,14,15,19 The reason many investigators used such short treatment durations derives from the initial understanding of lithium augmentation as a synergistic pharmacodynamic interaction between acutely administered lithium and chronic primary antidepressant treatment.4 In that conceptualization, the behavioral (ie, therapeutic) effects of adding lithium were expected to occur almost immediately, and early uncontrolled reports supported that expectation.4,29 Other investigators, conceptualizing lithium augmentation from a more clinical perspective, utilized longer trial durations more in keeping with standard pharmacologic approaches to depression. In their cumulative meta-analysis of the first nine studies in Table 1, Bauer and Döpfmer30 found that significant effects of lithium augmentation were first evident at the point of including studies lasting ≥7 days. While this is reassuring regarding the sensitivity of these short-term trials in detecting the positive effects of lithium augmentation, it does not mitigate the fact that such studies provide no information on the duration of any sustained benefit.

Dosing of lithium ranged from 250–1,200 mg/day; plasma levels reported in all but one study18 ranged from 0.3–1.1 mmol/L. In general, no relationship between dose or plasma level and clinical outcome was observed within studies. The exception to this was the study by Stein and Bernadt,17 which was specifically designed to evaluate this issue. These investigators found that low-dose lithium (250 mg/day; mean ± SD plasma level=0.3±0.1 mmole/L) was no better than placebo, whereas intermediate-dose lithium (750 mg/day; mean ± SD plasma level=0.8±0.5 mmole/L) was superior to the low dose. In their meta-analysis, Bauer and Döpfmer30 observed a significant effect of lithium augmentation beginning with studies dosing ≥600–800 mg/day.

The HAM-D was used to evaluate outcome in all but one study, which used the nurse-rated Short Clinical Rating Scale (SCRS).11 Most studies categorized response as a >50% decrease in the HAM-D. Exceptions to this were two studies in which a maximum final HAM-D score was required (ie, either <713 or <1,018). One was a study11 in which response criteria were not clearly specified, and the other was a study in which response criteria were not specified but a single responder was identified based on a >50% decrease in the HAM-D and final score <7.12 One study specified the criterion of a >50% decrease plus a final score of <10.16 Categorical response rates to double-blind treatment were available for all but three studies. In one study, the HAM-D was not used,11 and in the other two studies, the data were not reported, although single-blind categorical outcome was presented.14,17 Aggregate response was evaluated in all studies. Most of these studies would not meet current standards for evaluating response or remission.31

Comparator-controlled Studies

Eight studies, collectively comprising a total of 469 patients, have evaluated lithium augmentation in the context of a comparator-controlled design (Table 2).16,32-38 One of these studies included a placebo comparison group in addition to an active comparator16 and was included in the discussion of placebo-controlled studies mentioned above. The cumulative response rates in these studies are 30% for lithium augmentation and 38% for the active comparators. In general, these studies show no significant differences in response rates between lithium and the comparators used. However, in all but one study,33 lithium augmentation was numerically less effective than the comparator. In another study, lithium was significantly less effective than quetiapine augmentation based on continuous but not categorical measures of outcome.38

 

All but one patient in these studies were unipolar,32 and all studies used validated diagnostic criteria for depression. Most studies provided data on the severity of depression at entry to augmentation based on the HAM-D, with minimum scores ranging from >10 to >20. One study used an entry criterion of >5 on the Quick Inventory of Depressive Symptomatology-Clinician Rating.36 Three studies required a <50% decrease from pre-antidepressant baseline in addition to a minimum score.34,35,37 Primary antidepressant treatment involved a mix of TCAs, SSRIs, and other second-generation agents (eg, bupropion,36,38 mirtazapine,37,38 venlafaxine36-38). In contrast to the placebo-controlled studies, only 114 of 469 patients in these studies had primary treatment with a TCA.16,32,33 This reflects the fact that the comparator studies tend to be more recent than placebo-controlled studies, during which time usage of TCAs has declined.16,32,33 Primary antidepressant doses were adequate.

Duration (≥28 days) of primary antidepressant treatment in all studies was longer than that of placebo-controlled trials; 369 of  452 patients had ≥6 weeks of treatment,33,37 and 284 had ≥8 weeks.34-36 These durations meet stringent current criteria for trial adequacy.

Assignment to lithium augmentation or comparator was randomized in all of these studies, but assessment of outcome was conducted on a double-blind basis in only half.16,33-35 This constitutes a significant limitation of these studies in comparison with the placebo-controlled trials, all of which were double-blind. Comparators used included electroconvulsive therapy,32 switch to an alternative full-dose antidepressant (reversible MAO-A inhibitor brofaromine),33 dose escalation of the primary antidepressant (fluoxetine increased from 20 mg/day to 40–60 mg/day),34,35 and augmentation with an agent other than lithium (triiodothyronine,16,36 low-dose desipramine,34,35 full-dose lamotrigine,37 and quetiapine38).

Duration of lithium augmentation or comparator was ≤14 days in all studies, and in most studies, it was ≥4 weeks; two studies specified minimum durations of <4 weeks,16,32 while one study, which did not establish a minimum, reported a mean lithium augmentation duration of 9.3±5.4 weeks.36 This constitutes a major strength of these studies in comparison with the placebo-controlled trials, in 50% of which lithium augmentation lasted ≤14 days. Again, this reflects the more recent provenance of these studies and evolution in the management of refractory depression in the 25 years since the first reports on lithium augmentation.

Dosing of lithium, reported in all but one study,37 ranged from 300–1,200 mg/day while plasma levels ranged from 0.1–1.1 mmol/L. Three studies employed low doses of lithium (300–600 mg/day). The first had a range of levels between 0.1–0.8 mmol/L (mean=0.4±0.2),35 the second reported only mean level (0.2±0.1 mmol/L),34 and the third reported titration to an unspecified dose range with a mean level of 0.7 mmol/L (no SD reported).38 A fourth study reported mean dosage of 860±373 mg/day and a median level of 0.6 mmol/L.36 Based on the meta-analysis of Bauer and Döpfmer,30 efficacy of lithium augmentation might be attenuated at these low doses and levels, which appears to be the case in all four reports.

The HAM-D was used to evaluate outcome in all studies, and criteria for categorical response were notably more stringent than in the placebo-controlled studies. In those trials, the most common criterion for response was a >50% decrease in the HAM-D scores, but this was used as a criterion in 4 of the 8 comparator trials. It was the sole criterion in only one study.33 In one of the remaining three, it was combined with a maximum final HAM-D score of <10,16 while in the other two a maximum final HAM-D score of <7 was set to define a more stringent criterion of remission.37 All other comparator trials used the more stringent requirement of a maximum final HAM-D score to define response, either <734-36 or <10.32

The STAR*D study39 is the largest and most widely publicized study of refractory depression. The component of this study examining lithium augmentation36 included the largest sample by far (N=142) of any controlled or uncontrolled lithium augmentation trial reported in the literature. Major strengths of this study included a form of randomized assignment, stringent criteria for refractoriness and response, prolonged primary antidepressant and augmentation treatment duration, and an overall meticulous attention to standardization of methods, as well as the broad generalizability deriving from its design as an effectiveness trial. Major limitations, however, are the modest mean doses (860±373 mg/day) and median levels (0.6 mmol/L) of lithium achieved, coupled with significant findings of poor tolerability. These features raise questions as to the impact the open-label nature of this study, using non-expert clinicians, may have had on its outcome. In this sense, the generalizability of the study as an effectiveness trial may have come at the expense of a more accurate assessment of the efficacy of lithium augmentation as implemented by experts.

Uncontrolled Studies

There are scores of uncontrolled, open-label reports on lithium augmentation. In an effort to minimize the effects of ascertainment bias, reporting bias, and inter-study variability in this literature, the authors of this article identified studies meeting the following three criteria. First, the study had to be of prospective design. Second, the sample size had to be larger (N≥15). Last, a categorical assessment of outcome had to be conducted. Thirteen studies collectively comprising a total of 525 patients, met these criteria (Table 3).29,40-51 In keeping with current standards on outcome assessment,31 and in contrast to previous reviews,6 the authors of this article classified patients as “responders” only if they met the study’s criteria for response or remission; “partial responders” were classified as nonresponders.

 

The cumulative response rate in these reports is 49%; in trials restricted to unique clinical subgroups (ie, adolescent46 and geriatric43,47 patients) in which response rates to antidepressants might be lower or lithium is less tolerable, the cumulative response rate is 52%. This is substantially higher than the 42% response rate observed in the placebo-controlled trials and the 30% response rate in the comparator-controlled studies. Interestingly, response rates of approximately 50% for lithium augmentation are most commonly cited in reviews on the treatment of refractory depression.7,9,52

Effects on Long-term Outcome

Data concerning the impact of lithium augmentation on long-term outcome in depression are still limited. One study has examined the efficacy of continued lithium augmentation in preventing the return of depressive symptoms following an acute positive response. In a randomized, placebo-controlled, double-blind trial of 29 unipolar depressed patients, Bauer and colleagues53 found relapse rates of 47% with placebo, including two patients who became manic, and 0% with lithium during a 4-month continuation period following 8–10 weeks of acute treatment and stabilization. During a subsequent open-label, 6-month follow up after taper and discontinuation of all medications, five of 14 lithium- and two of eight placebo-augmented patients relapsed.54

Three studies, all in unipolar depressed geriatric patients, examined the effects of lithium discontinuation following successful augmentation.55 In the only randomized, double-blind trial involving 12 patients maintained on lithium augmentation for a mean 5.8 years, Hardy and colleagues56 observed relapse rates of 33% in the group randomized to placebo and 33% in those continuing on lithium over a 2-year period. Reynolds and colleagues57 reported a relapse rate of 46% over an unspecified follow-up period in 11 patients discontinued from a median 10 weeks of lithium augmentation, while Fahy and colleagues58 observed a relapse rate of 52% over a mean 19.5-month follow up in 21 patients tapered from maintenance lithium augmentation. In the study by Fahy and colleagues,58 likelihood of relapse correlated with duration of lithium maintenance.

Finally, Nierenberg and colleagues59 studied 66 depressed patients (60 unipolar, 6 bipolar) who had undergone an acute trial of lithium augmentation. In this retrospective study, 63% of acute responders had a good outcome during a mean 29-month follow-up period; there was only 40% of partial or non-responders.

Conclusion

This critical reevaluation of evidence supporting lithium augmentation reveals serious deficiencies in the current database. Taken together, these deficiencies are sufficiently fundamental and pervasive to limit the usefulness of formal meta-analytic approaches to literature review. The placebo-controlled trials suffer from inadequate criteria for refractoriness, marked variability in duration of augmentation, variability in lithium levels, inadequate criteria for evaluating response, and idiosyncratic designs. The comparator trials, as a group newer than the placebo-controlled studies, improve upon numerous methodologic flaws of the older work, albeit with even more variability in lithium levels. However, the lack of placebo controls in the comparator studies is a fundamental limitation that is not readily mitigated. The large-scale prospective uncontrolled trials suffer from the usual constraints of such studies, including an overly generous evaluation of responses to the intervention. Again, early enthusiasm for lithium augmentation must be considered in light of the looser methodologic practices, more modest expectations of benefit, and dearth of alternatives that characterized the field 20 years ago.

While the “true” response rate to lithium augmentation is still unclear, it is certainly less than the 50% assumed by many clinicians and closer to 30% to 40%. It is increasingly problematic to consider this approach a “gold standard” in treating refractory depression given emerging large-scale controlled trials of other interventions employing superior designs and methodologies.60,61 At the same time, its current underutilization by clinicians in the United States,62,63 is highly unfortunate, given its supporting database and the limited number of studies supporting newer approaches. In addition to the efficacy studies discussed here, that database includes extensive preclinical64 and clinical10 research on its mechanism of action, such research on basic mechanisms being fairly unique among augmentation strategies. Particularly promising are recent findings on potential genetic markers for response.65,66 Consideration of these factors might help promote a more balanced appraisal of the benefits and risks of this neglected approach. PP

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