Although there are many drugs available to treat major depression, the overall treatment outcome among depression patients is usually far from optimal. Regardless of the initial choice of antidepressant, about 30% to 50% of patients with a major depressive episode (MDE) will not respond sufficiently to adequately performed first-line treatment and will not return to premorbid levels of functioning (1). Various treatment strategies have been proposed for patients not responding or responding partially to a monotherapy trial with an antidepressant. The major strategies employed are as follows: 1) switching to a new antidepressant, either from within the same pharmacologic class or from a different class, 2) combining 2 antidepressants from different classes, 3) augmenting the antidepressant with other agents to enhance antidepressant efficacy, and 4) combining the antidepressant with a psychotherapeutic intervention (1).
These strategies have been studied with various agents and combinations, but most have not been subjected to rigorous scientific investigation or have only included small study groups (1,2). Currently, there is no consensus about which strategy should be favoured for nonresponding patients, since to date no rigorous trial with a randomized, double-blind design has been conducted to answer this question (3). Some authors have argued in favour of augmentation strategies because they eliminate the period of transition between antidepressants and build on the partial response. When they work, augmentation strategies can be rapidly effective. Further, patients who have had some response may be reluctant to risk losing that improvement, and in this situation, augmentation may be beneficial.
Lithium salts have been used to augment the efficacy of antidepressant medications for more than 20 years. The first study to test the hypothesis in patients with major depression was performed by de Montigny and associates in 1981 (4). The researchers reported a dramatic response—within 48 hours—when lithium was added to the regime of 8 patients who had not responded to at least 3 weeks of treatment with tricyclic antidepressants (TCAs) (4). The efficacy of the combination and the rapid response have since led many clinical research groups to study this treatment intervention further.
This article reviews the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depression. It also examines hypotheses regarding the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems.
Clinical Studies in Major Depression
We identified 27 studies and a total of 803 patients. Of these, 9 were randomized, double-blind, placebo-controlled studies (RCTs) in the acute-treatment phase (5–13). The remaining 18 trials included 13 open trials (4,14–25); 3 randomized, double-blind comparator trials (26–28), 1 randomized, open comparator trial (29), and 1 placebo-controlled trial in the continuation-treatment phase (30). In these studies, most patients (more than 90%) suffered from unipolar depression.
Acute-Treatment Phase: Randomized Placebo-Controlled Studies
Figure 1 Response rates in 9 placebo-controlled trials on the efficacy of
lithium augmentation of antidepressant medication in patients with major
The combined results of these 9 RCTs showed that lithium augmentation led to a higher response rate than was observed with the placebo (P < 0.001). When RCTs were entered into a cumulative metaanalysis in the order of increasing dosage, the effect was statistically significant at a lithium carbonate dosage of 600 to 800 mg daily, and results did not change with higher dosages. A cumulative metaanalysis of RCTs entered in the order of increasing treatment duration showed a statistically significant effect at 7 days (31).
There was a significant heterogeneity in the design and outcome of the studies. All studies presented some limitations in quality. Assuming a relation between quality and outcome, we performed a cumulative metaanalysis of studies arranged by descending quality scores (Figure 2). Study quality was evaluated independently by 2 investigators according to the Quality Assessment Scale (32). Differences in assessment were discussed and settled by consensus. Quality was expressed as a percentage of achievable scores. The cumulative metaanalysis allows an increasing estimate of treatment effects as studies with lower-quality scores are added to the previous higher-score studies. The analysis suggests that the benefit of lithium augmentation can still be demonstrated when studies of lesser quality are added to the pooled analysis (Figure 2).
Figure 2 Acute and continuation phases of a study on the effectiveness of lithium augmentation of antidepressant medication in patients with major depression
Acute-Treatment Phase: Open and Comparator Studies
Continuation-Treatment and Discontinuation Studies
Two controlled studies (34,35) examined the effects of gradually discontinued lithium augmentation therapy in elderly depression patients; both studies found high relapse rates after lithium discontinuation. In the first, Hardy and others conducted a placebo-controlled discontinuation study in 12 geriatric patients who had responded to lithium augmentation during their most recent refractory unipolar depressive episode (34). Patients were randomized to receive either continued lithium augmentation or matching placebo. In the lithium maintenance group, 2/6 patients had a recurrence of depression at 61 and 96 weeks, respectively, immediately after a stressful life event. Similarly, in the placebo group, 2/6 patients had a recurrence at 7 and 92 weeks, respectively, without any apparent changes in life stresses. In the second study, a naturalistic discontinuation study in a cohort of elderly patients with MDD, 11 patients (52%) relapsed following discontinuation of lithium augmentation (35).
Figure 3 Lithium augmentation in refractory depression: metaanalysis of placebo-controlled trials
Mechanisms of Action of Lithium Augmentation: Neurobiological Basis
Treatment strategies for major depression that show well-documented effects on the outcome of patients have heuristic value for the investigation of the disorder’s pathophysiology. There is strong evidence that the serotonergic (5-HTergic) system plays a key role in mood regulation (36,37), and studies indicate that lithium has a net enhancing effect on the 5-HT function (38,39). Neurochemical and neuroendocrine research based on studies in animals and humans has provided hypotheses for the mechanisms involved in lithium augmentation therapy. Arguments for a true augmentation effect result from both animal and human studies. Animal studies show that a potentiation of antidepressant treatment by lithium may be mediated through enhanced 5-HT neurotransmission. Neuroendocrine studies in humans also demonstrate that lithium augments the function of the 5-HTergic system. We outline these 2 lines of experimental evidence below.
Effects of Lithium on the 5-HT System in Animals
Subsequently, it was postulated that a pharmacodynamic action mediated via the 5-HTergic systems may account for the synergistic effect of lithium added to a TCA (14). This hypothesis was based on several observations of the neurobiological effects of TCAs in combination with the above-described lithium effects on the 5-HT system. Initially, de Montigny and Aghajanian demonstrated that long-term TCA treatment induced a selective increase in the responsiveness to 5-HT in rats’ dorsal hippocampus (46); this was later shown to be mediated by postsynaptic 5-HT1A receptors (47). If also true for humans, this would mean that, in patients who fail to respond to an antidepressant, chronic TCA use may induce postsynaptic sensitization to 5-HT, as seen in animals. Second, if lithium has similar effects on 5-HT turnover in humans, lithium augmentation of antidepressant therapy may alter 5-HT neurotransmission (14,48).
Further evidence for a true augmentation effect, derived from animal studies, showed that, in contrast to lithium alone, lithium added to antidepressant treatment with an SSRI (citalopram) potentiated presynaptic 5-HTergic function in rats (49). A subchronic lithium dosage added to chronic citalopram therapy, using microdialysis techniques, further elevated basal levels of 5-HT in the rat ventral hippocampus (50).
Another endocrine system that has been studied during lithium augmentation is the hypothalamo–pituitary– adrenocortical (HPA) system (53,54). The dexamethasone suppression–corticotropin-releasing hormone stimulating test (DEX–CRH test) is a sensitive neuroendocrinological challenge test to investigate HPA system function (55). A significant proportion of patients with major depression show an overstimulation in the DEX–CRH test (55).
The combined DEX–CRH test was given to 30 subjects with unipolar depression who had not responded to an antidepressant treatment trial of at least 4 weeks. The test was performed directly before and—depending on the response status—2 to 4 weeks after the initiation of lithium augmentation therapy (n = 24 for the second test). In contrast to results from studies in depression patients treated with TCAs (56,57), where a decline was found, the cortisol and adrenocorticotropic hormone (ACTH) response to CRH stimulation after dexamethasone pretreatment displayed a significant rise under lithium augmentation, compared with the baseline (58,59). Eleven patients responded according to the criteria applied (based on weekly ratings with the Hamilton Depression Rating Scale [HDRS]), and it is noteworthy that both responders and nonresponders demonstrated the increase. This led to the assumption that stimulation of the HPA system may be a direct effect of the lithium ion, probably mediated by the 5-HTergic actions of the pharmacon (58). Early studies in patients (60,61), as well as in animals and cell cultures (62–64), had already demonstrated a stimulating effect of lithium on cortisol or ACTH production.
In depression patients treated with antidepressants, a significant association has been demonstrated between a high cortisol reaction in the combined DEX–CRH test at admission from hospital and a depressive relapse in the continuation- treatment phase (69,70). However, after lithium augmentation, a follow-up study detected no correlation between the DEX–CRH test results and a depressive relapse. The mean follow-up interval was 18 months (range 12 to 28 months). Only 48% of the 23 patients studied had a favourable follow-up, defined as no occurrence of a major depressive syndrome. Favourable or unfavourable course was not correlated to any demographic, clinical, or therapeutic variable (Bschor and others, unpublished observation).
This review revealed substantial evidence for the efficacy of lithium augmentation therapy in the treatment of MDEs. It has been well established in controlled trials that approximately one-half of all treatment-refractory depression patients respond when lithium is added to their ongoing antidepressant regimen. The level of evidence for the efficacy of lithium augmentation is higher than that for other augmentation strategies (1). Therefore, lithium augmentation should be considered a first-line treatment strategy in patients with an MDE that does not adequately respond to standard antidepressant treatment. In responders, lithium augmentation should be continued for a minimum of 12 months (32,33).
However, it remains to be examined whether the response to lithium augmentation represents true augmentation resulting from synergistic effects or whether the response is simply owing to the antidepressant effect of lithium itself. Arguments for a true augmentation effect derive from a controlled clinical trial showing that the antidepressant effects of lithium addition were significantly higher in amitriptyline-pretreated depression patients, compared with placebo-pretreated patients, who showed no improvement after a 3-week treatment (14). Conversely, it has been well documented in a series of controlled studies undertaken in the 1970s that lithium alone exerts antidepressant effects (71,72). Therefore, a randomized, double-blind study that controls for the effects of lithium alone, compared with lithium in combination with an antidepressant, is warranted.
Previous placebo-controlled studies used either various antidepressants with different pharmacologic profiles or SSRIs. None of the prior studies exclusively used a selective norepinephrine inhibitor. Postulating that lithium augmentation has a 5-HTergic mode of action (14,48), one may speculate that lithium augmentation does preferentially work with 5-HTergic antidepressants but that it does not work, or works insufficiently, with antidepressants acting mainly on the noradrenergic system. Therefore, a controlled lithium augmentation study using a highly selective norepinephrine inhibitor (for example, reboxetine) and including a placebo or an SSRI, or both, as a comparator drug would be of great theoretical and clinical interest.
Neuroendocrine studies of the effects of lithium augmentation on the HPA system showed an unexpected and marked increase in the ACTH and cortisol response in the combined DEX–CRH test (58,59). These results contrast with the established decline of HPA-system activity during treatment with TCAs and, therefore, question the paradigm that in major depression the normalization of HPA-system overstimulation in the combined DEX–CRH test is a necessary prerequisite for recovery (57). To elucidate lithium’s effects on the HPA system, studies are needed to investigate the effects of lithium monotherapy on the HPA system in healthy control subjects, as well as in subjects with major depression during the acute depressed state and during remission.
The lithium augmentation strategy is derived from de Montigny’s heuristic proposal that the enhancement of ascending presynaptic 5-HTergic function would translate into the potentiation of antidepressant efficacy (14). Evidence from both basic and clinical studies clearly demonstrates that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the anti- depressant on brain 5-HT pathways. However, it remains to be seen whether enhanced 5-HT neurotransmission is the major mechanism by which lithium acts to potentiate the effects of antidepressants (73).
Over the past decade, studies of lithium’s action in receptor- mediated phosphoinositide signalling in the brain have opened up new lines of investigation that derive from lithium’s inhibition of the enzyme inositol monophophatase (74). Considerable recent basic research has shown that lithium can affect neurotrophic signalling cascades, and it has been suggested that these effects may also underlie its efficacy in potentiating the efficacy of various classes of antidepressants (73). Specifically, lithium acts upon various neurotransmitter systems at multiple signalling levels in the brain—for example, by altering neurotransmitter receptor regulation, second messenger generating systems, protein kinase C (PKC) regulation, and gene expression (reviewed in 73,75). Among the most recent discoveries in this new area of research are findings that lithium markedly increased the levels of the neuroprotective protein, bcl-2, in rat frontal cortex and hippocampus and also increased the expression of the major PKC substrate, myristoylated alanine-rich C-kinase substrate (MARCKS) (76). Beyond these neuroprotective effects, it has recently been demonstrated that lithium also exerts regenerative effects on axons of retinal ganglion cells, enhances hippocampal neurogenesis, and protects neurons from proapoptotic stimuli (77–79). In summary, these molecular studies have demonstrated that lithium’s action has novel cellular target sites; they may therefore have a major impact on our understanding of the pathophysiology of affective illness.
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Manuscript received and accepted June 2003.
1. Associate Professor, Department of Psychiatry and Psychotherapy, Charité, Humboldt-University at Berlin, Berlin, Germany.
2. Research Fellow, Department of Psychiatry and Psychotherapy, Charité, Humboldt-University at Berlin, Berlin, Germany.
3. Research Fellow, Consolidated Department of Psychiatry, Harvard Medical School, the Bipolar and Psychotic Disorders Program, McLean Division of Massachusetts General Hospital, Belmont, Massachusetts.
4. Assistant Professor, Institute for Social Medicine, Epidemiology and Health Economics, Charité, Humboldt-Universität zu Berlin, Berlin, Germany.
5. Resident, Department of Psychiatry and Psychotherapy, Charité, Humboldt-University at Berlin, Berlin, Germany.
6. Professor, Department of Psychiatry and Psychotherapy, Charité, Humboldt-University at Berlin, Berlin, Germany.
7. Assistant Professor, Department of Psychiatry, Technische Universität Dresden, Dresden, Germany.
Address for correspondence: Dr M Bauer, Department of Psychiatry and Psychotherapy, Charité University Hospital, Humboldt-University at Berlin, Schumannstr. 20/21, 10117 Berlin, Germany.
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