Update on augmentation of antidepressant response in resistant depression

Most patients in acute depression trials fail to achieve remission with antidepressant monotherapy. Many patients seem to require more than one medication to achieve remission or adequate response. Augmentation strategies are commonly used in clinical practice, but most have been poorly studied. In addition, better-studied strategies, such as the use of lithium and thyroid augmentation, have not been well investigated in combination with newer antidepressants. Various novel strategies are being investigated as augmenting agents, including selective dopamine agonists, sex steroids, norepinephrine reuptake inhibitors, glucocorticoid-specific agents, and newer anticonvulsants. We review the status of augmentation strategies in the treatment of depression.     

Augmentation strategies in patients with refractory depression

In the evaluation of treatment-resistant or treatment-refractory depression (TRD), true resistance to antidepressant therapy must be distinguished from inadequate dose, duration, or compliance with past antidepressant therapy. Reassessment of the diagnosis may reveal psychiatric comorbidity, the presence of depressive subtypes, or the possibility of a medical etiology. Management of TRD should consider patient-specific factors; drug therapy may be directed by depressive subtype or the presence of psychiatric comorbidity. Increasing the dose or duration of current antidepressant therapy is appropriate for patients who have received inadequate therapy in the past. Augmentation of tricyclic antidepressant (TCA) or selective serotonin reuptake inhibitor (SSRI) therapy with thyroid hormone (T₃) or lithium has been shown to be effective in open and controlled trials. Efficacy of other strategies such as higher-dose antidepressant treatment, venlafaxine therapy, combined antidepressant therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or augmentation with pindolol or buspirone has been less well established, but emerging data from open studies and case reports are encouraging. Depression and Anxiety 4:169–181, 1996/1997. © 1997 Wiley-Liss, Inc.     

Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms.

OBJECTIVE: This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research. METHOD: We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin. RESULTS: Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. CONCLUSIONS: Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression. Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium.     

Discontinuation of lithium augmentation in geriatric patients with unipolar depression: a systematic review.

OBJECTIVE: Lithium is an augmentation strategy for unipolar depression in geriatric populations. This review outlines the evidence in the literature regarding risk of relapse when lithium is discontinued in geriatric patients. METHOD: Articles were selected based on selection criteria for relevance and design quality (original studies, French or English, patients older than 65 years, patients with an episode of major depressive disorder, meeting DSM-III or greater criteria, and patients who had been successfully treated to remission with lithium augmentation of an antidepressant, then withdrawn from lithium augmentation treatment). RESULTS: Three articles were found. Overall rate of relapse could not be clearly established but a rate of 50% relapse over about 6 months follow-up could be surmised from the study results. CONCLUSIONS: There is a risk of relapse in elderly patients whose lithium augmentation treatment for unipolar depression is discontinued. More studies with a randomized control trial design are required to provide more definitive information on this topic.     

Lithium augmentation therapy in refractory depression—Update 2002

Lithium has been used to augment the efficacy of antidepressant medications for more than 20 years. The present study examines whether evidence exists to support the clinical efficacy of lithium augmentation in refractory, treatment resistant depression. Studies were identified by searching Medline (1980 to August 2002) and by scanning the references of published reviews and standard textbooks. Studies were selected if they were open-labeled or double-blind, placebo-controlled or comparator trials that involved patients who had not responded to conventional antidepressants. 27 prospective studies were identified that included a total of 803 depressed patients displaying the following designs: 10 double-blind, placebo-controlled trials, 2 randomized, double-blind comparator trials, 2 randomized, open comparator trials, and 13 open-label trials. The majority of randomized controlled trials has demonstrated substantial efficacy of lithium augmentation in partial and non responders to antidepressant treatment. In the placebo-controlled trials, the response rate in the lithium group was 45% and in the placebo group 18% (p<0.001). Summarizing all open and controlled studies, approximately 50% of patients responded to lithium augmentation within 4 weeks. In conclusion, lithium is the foremost and most well-documented augmentation strategy in refractory depression.Therefore, it should be considered a first-line treatment strategy in patients with major depression who do not adequately respond to standard antidepressants.     

Augmentation Strategies for Inadequate Antidepressant Response: A Review of Placebo-Controlled Studies

Uncontrolled trials of strategies directed at inadequate antidepressant response are prone to falsely positive results. Most of those studies which have used placebo control have assessed augmentation and the addition of lithium to tricyclic antidepressants or serotonin reuptake inhibitors has so far received the most support. A smaller literature shows promise for augmentation with triiodothyronine, pindolol and dehydroepiandrosterone.     

Using adjunctive treatments when first-line antidepressants fail

Treatment-resistant depression is a common challenge for clinicians, as the majority of patients with depression do not achieve remission after an initial antidepressant trial. Major strategies for managing treatment-resistant depression include switching to another antidepressant or augmenting the initial antidepressant with another medication. Switching may be appropriate for patients experiencing little or no symptom relief or intolerable side effects with the initial antidepressant. For patients who experience partial response from the first-line antidepressant, adjunctive therapies avoid the loss of this response and the wash-out and cross-titration that are required when switching antidepressants. Several effective antidepressant augmentation agents are available, including lithium, thyroid hormone, anti-anxiety medications, and atypical antipsychotics. The evidence for the efficacy and risks of these strategies is discussed.     

The pharmacological treatment of tricyclic-resistant depression: review and management guidelines

Despite the introduction of a wide range of antidepressant drugs since the late 1950s, approximately 30-50% of depressed subjects do not respond to these agents. Various treatment strategies, both pharmacological and non-pharmacological, have been proposed for treatment-resistant depression. This paper critically reviews the studies of single and combined pharmacological treatments for tricyclic-resistant patients, with a particular discussion of lithium augmentation. The major inadequacies of these studies have been the frequent lack of definitions of treatment resistance, the heterogeneity of the depressed samples, and the infrequent use of double-blind, placebo-controlled designs. Two central issues, definition of treatment resistance and clinical predictors of response to pharmacological treatments, are discussed in detail. Finally, a suggested guideline for the management of tricyclic-resistant depression is proposed.     

Antidepressant augmentation and combinations.

A significant proportion of patients with MDD are treatment resistant or only partial responders to adequate therapy with a single agent. In this situation, one must consider augmentation with another agent. Lithium and thyroid augmentation have been investigated for many years. In a meta-analysis of double-blind studies involving augmentation with lithium or placebo after nonresponse to conventional antidepressants, lithium augmentation was concluded to be the first-line therapy for depressed patients who failed to respond to monotherapy. One important study reported no significant difference in response rates between T3 and lithium as augmentation agents in patients who had failed to respond to TCAs. Very few controlled, double-blind trials show consistently positive results for the other augmentation strategies, although some open-labeled trials and case reports are promising. Additional placebo-controlled, double-blind studies are needed to assess the efficacy and tolerability of all of these agents, especially in combination with the newer classes of antidepressants.     

Antidepressant studies in Parkinson's disease: a review and meta-analysis.

The objective of this study was to determine effect sizes for both antidepressant treatment and placebo for depression in Parkinson's disease (PD), and to compare the findings with those reported in elderly depressed patients without PD. Recent reviews have concluded that there is little empiric evidence to support the use of antidepressants in PD; however, available data has not been analyzed to determine the effect size for antidepressant treatment in PD depression. A literature review identified antidepressant studies in PD. Suitable studies were analyzed using meta-analytic techniques, and effect sizes were compared with those from antidepressant studies in elderly patients without PD. Large effect sizes were found for both active treatment and placebo in PD, but there was no difference between the two groups. In contrast, active treatment was superior to placebo in depressed elderly patients without PD. In PD, increasing age and a diagnosis of major depression were associated with better treatment response. Results also suggest that newer antidepressants are well tolerated in PD. Despite the high prevalence of depression and antidepressant use in PD, controlled treatment research has been almost nonexistent. Meta-analysis results suggest a large but nonspecific effect for depression treatment in PD. In addition, PD patients may benefit less from antidepressant treatment, particularly selective serotonin reuptake inhibitors, than do elderly patients without PD.     

Lithium augmentation in depressive patients not responding to selective serotonin reuptake inhibitors

This communication reviews current literature on lithium augmentation in patients not responding to SSRIs, giving some recommendations at the end. A significant proportion of depressive patients do not respond to a first antidepressive treatment independently of the class of drugs used. During the last 10 years, there have been several case reports published about open and controlled studies on the use of lithium augmentation in patients who were non-responders to SSRIs, including citalopram, fluoxetine, paroxetine and sertraline. The main underlying hypothesis is a synergistic effect between SSRIs and lithium, which both act on serotonergic neurotransmission. The available studies vary considerably in methodology. There are insufficient results available to confirm a rapid improvement (within 24-48h) after introduction of lithium, but most studies show substantial effects after 1 - 2 weeks, and some after 6 weeks. There is as yet no more clear evidence for a pharmacokinetic interaction between lithium and SSRIs with pharmacodynamic consequences. In conclusion, present evidence suggests that a lithium augmentation in depressive patients who do not respond to SSRIs may be an efficacious and generally well tolerated treatment, with a response rate of at least 50% after a period lasting 1 - 2 weeks. However, special care is indicated when treating elderly patients, where the risk of adverse effects is higher.     

Lithium augmentation in treatment-resistant depression: clinical evidence, serotonergic and endocrine mechanisms

For now more than 50 years, lithium has been the gold standard for the pharmacologic treatment of bipolar disorder. However, its utility is not restricted to acute mania and prophylactic treatment of bipolar disorder. A relatively new indication for its use is the addition to an antidepressant in the acute treatment phase of unipolar major depression. To date, this treatment approach called lithium augmentation is the best-documented approach in the treatment of refractory depression. In international treatment guidelines and algorithms, lithium augmentation is considered a first-line treatment strategy for patients with a major depressive episode who do not adequately respond to standard antidepressant treatment. In a recent double-blind, placebo-controlled trial, lithium augmentation has demonstrated to also be effective in the continuation treatment phase to prevent early relapses. From animal studies there is robust evidence that lithium augmentation increases serotonin (5-HT) neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. In contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants, neuroendocrine studies on 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. Here we review new data on the efficacy and mechanism of action of lithium augmentation.     

Fünfundzwanzig Jahre Lithiumaugmentation

Twenty-five years ago the research group of the Canadian psychiatrist de Montigny reported treating antidepressant-refractory depressive patients successfully by adding lithium to their antidepressant. The report, published in 1981 as an open-label uncontrolled observation of only eight patients, falls short of today's methodological standards, but the treatment method, subsequently known as lithium augmentation, nonetheless was to change profoundly the pharmacological strategies for depressive disorders. The story of its development is remarkable, starting with a strictly theoretical idea conceived by Montigny and his colleagues after animal experiments in the 1970s had revealed that pretreatment with an antidepressant over several weeks led to sensitization of central nervous serotonin receptors. The team postulated that the proserotonergic characteristics of lithium, which had been systematically used as a psychotropic drug since 1949, could thus be used specifically to stimulate these receptors. Lithium augmentation demonstrated its effectiveness in the 1980s and 1990s, first in open-label and later in randomized and placebo-controlled studies. In the late 1990s studies aimed at optimizing its clinical application indicated that lithium augmentation must be administered for at least 2 weeks, with lithium serum levels within the range established for prophylactic treatment and assuming patient response, and that the combination of lithium and antidepressant must be continued as a maintenance therapy for 6 to 12 months. Research has yet to clarify how lithium augmentation actually works. Current results show that in addition to the idea postulated by Montigny, lithium could also have an activating effect on the cortisol axis. Thanks to the sound body of evidence which has accrued in the meantime, lithium augmentation is recommended in most guidelines and treatment algorithms as a main strategy for patients who do not respond to antidepressant monotherapy.     

Enhancing outcomes in the management of treatment resistant depression: a focus on atypical antipsychotics

Abstract:  Clinical trials indicate that over 50% of depressed patients show an inadequate response to antidepressant therapy, and that incomplete recovery from major depressive disorder (MDD) increases the risk of chronicity and recurrence. Recovery, complete remission of symptoms, and a return to baseline psychosocial function, should be the goal of therapy. Poor response to adequate antidepressant treatment has been termed treatment resistant depression (TRD). Issues such as adherence, missed diagnosis of psychotic depression, bipolar disorder, or comorbid anxiety must be investigated as reasons why patients have not responded to initial therapeutic strategies. Beyond ensuring optimal use of the index antidepressant, treatment strategies for TRD include switching to another antidepressant, and augmentation or combination with two or more agents. Since little comparative data exist it is important to consider side-effect burden, partial response, and previous medication history when deciding between strategies. In patients with TRD, adding or augmenting with lithium, tri-iodothyronine or atypical antipsychotics have demonstrated benefits. Augmentation with atypical antipsychotics, including risperidone, olanzapine, ziprasidone, and quetiapine, show promising results in terms of improving remission rates. Other interventions, including non-pharmacologic strategies and investigational physical treatments, have demonstrated some benefits, but availability and patient preference should also be considered. With today's therapeutic alternatives, full remission of depression is an attainable goal. For some patients, combination and augmentation strategies earlier in treatment may increase the likelihood of remission.     

Le lithium dans la dépression unipolaire

Although poorly used as an augmentation strategy in resistant depression, the association of lithium is a good therapeutic option to consider in case of partial or insufficient response to the initial antidepressant. Various studies show significant efficacy of this treatment in combination with antidepressants: the practical aspects of implementation and monitoring are also discussed in this paper.     

New approaches to the treatment of refractory depression

Although the majority of patients with depression respond well to their initial pharmacologic treatment, as many as 30% to 45% fail to achieve an adequate response. In addition to the more traditional lithium and thyroid hormone augmentation strategies, a number of new pharmacotherapeutic approaches are currently being used to help manage refractory depression, including the addition of another agent or a switch to another antidepressant. Augmentation and switching strategies are often selected in order to obtain a different neurochemical effect (e.g., adding a relatively noradrenergic agent to a relatively serotonergic antidepressant). In particular, several studies have suggested that depressed patients refractory to treatment with selective serotonin reuptake inhibitors (SSRIs) may show a good response to newer agents that have a pharmacologic profile distinct from the SSRIs. Furthermore, preliminary studies have shown that the addition of SSRIs to either noradrenergic drugs such as the tricyclic antidepressants (TCAs) or dopaminergic agents may be efficacious, even though concerns about drug-drug interactions and tricyclic cardiac toxicity have limited the use of TCA-SSRI combinations. The introduction of reboxetine, a relatively selective norepinephrine reuptake inhibitor, may increase the use of the latter therapeutic approach because of its improved safety profile compared with the TCAs. The review of treatment options for refractory depression that follows will outline the advantages, disadvantages, and level of support for a number of new treatment strategies.     

Thyroid function and affective illness: a reappraisal

It has been generally accepted that increased thyroid function facilitates treatment response in depression. Recent data show that response to several antidepressant treatments, particularly lithium and carbamazepine, are associated with decreased thyroid hormone levels. An alternative hypothesis that decreased thyroid indices are related to antidepressant response is proposed and clinical and research implications are discussed.     

The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression

The addition of lithium carbonate to various antidepressant agents, including heterocyclics and monoamine oxidase inhibitors, has been reported to rapidly effect an antidepressant response in otherwise treatment-unresponsive depressed patients. Fifteen depressed patients diagnosed by DSM-III criteria who had not responded to double-blind treatment with carbamazepine were treated with the blind addition of lithium to carbamazepine. Eight patients (53%) responded with a moderate to marked improvement. The time to onset of substantial clinical improvement was rapid; ie, the mean (+/- SD) was 4.1 +/- 2.4 days for lithium potentiation compared with 9.7 +/- 4.1 days in a separate group of depressed patients responding to lithium alone. Side effects during carbamazepine-lithium combination therapy were minimal. The mechanisms by which lithium appears to rapidly potentiate the effects of carbamazepine in treatment-resistant depression are discussed.     

Augmentation of antidepressants with atypical antipsychotics: a review of the current literature

Studies have found that a large percentage of depressed patients may have limited response and remission rates when treated with traditional antidepressants. Options for augmenting antidepressant treatment include buspirone, lithium, and triiodothyronine. There are also increasing data concerning the use of atypical antipsychotics as augmenting agents in the treatment of unipolar, nonpsychotic, treatment-resistant depression. Aripiprazole has recently received an indication from the U.S. Food and Drug Administration (FDA) for adjunctive treatment in unipolar, nonpsychotic depression, the first indication of its kind, after two double-blind trials; doses were slightly lower than those recommended for monotherapy in schizophrenia or bipolar disorder. Olanzapine and risperidone have several controlled clinical trials indicating the efficacy of both of these agents, generally at low doses. One trial of quetiapine suggested that it may not be effective in the treatment of unipolar, nonpsychotic depression. One open-label trial of ziprasidone indicated some efficacy. According to these results, aripiprazole, olanzapine, and risperidone are reasonable choices as augmentation agents, with only aripiprazole currently having an FDA indication for this use. Given the preliminary results, double-blind, placebo-controlled trials with quetiapine and ziprasidone are needed, as well as studies comparing atypical antipsychotic agents with traditional augmentation agents in the treatment of depression.     

Are atypical antipsychotic drugs also atypical antidepressants?

OBJECTIVE: To report a case series and review the psychopharmacology of the neuroleptic drugs to suggest that the atypical antipsychotic drugs may have an antidepressant action, at least for those patients with the melancholic subtype. METHOD: We note the literature suggesting that the older (or typical) antipsychotic drugs were established as having antidepressant activity, describe an open study of some two dozen patients with a treatment-resistant melancholic depression, describe rapid resolution of depression and augmentation benefits associated with commencing an atypical antipsychotic drug in a percentage of subjects, and then review relevant psychopharmacological studies to consider whether there is a rationale for use of antipsychotic drugs to treat depression. RESULTS: Of some two dozen patients treated with an atypical antipsychotic drug, almost immediate improvement was noted in four patients, and evidence of augmentation benefit obtained in another three patients. CONCLUSIONS: Impressions from this case series are encouraging. However, as open clinical observational studies are problematic, controlled studies are required to establish whether the atypical antipsychotic drugs have a role in the management of certain expressions of depression, and, in particular, treatment-resistant melancholic depression.