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.     

The treatment of bipolar depression

Objectives: The treatment of the depressed phase of bipolar disorder is understudied and remains a common clinical dilemma for clinicians. Compared to the manic phases, episodes of bipolar depression are more frequent and of longer duration, yet the literature on this problem is minimal. The few methodologically sound studies find that treatment effective for unipolar depression are also efficacious for bipolar depression. However, standard antidepressant agents may cause acute mania or a long-term worsening of bipolar illness. This paper reviews the available literature on the treatment of bipolar depression and offers recommendations for clinical management.

Methods: A literature search was conducted using keywords 'bipolar disorder', 'depression', 'drug therapy', 'antidepressants', 'lithium', and 'anticonvulsants'.

Results: If effectively treated by lithium, patients are spared the risk of antidepressant-induced mania. If lithium is not sufficient treatment for acute depression, the combination of lithium and a standard antidepressant appears to reduce the risk of affective switch, as well as the induction of a long-term rapid-cycling course. Additionally, tapering antidepressant medication after periods of sustained remission can be beneficial in limiting the risk of affective switch and acceleration of the cycle rate.

Conclusions: Doctors must be cautious in prescribing antidepressants for bipolar depression. Use of antidepressants alone should be avoided.     

Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression

OBJECTIVE: Use of lithium to augment antidepressant medication has been shown to be beneficial in the acute treatment of depression. The authors examined the efficacy of lithium augmentation in the continuation treatment of unipolar major depressive disorder. METHOD: Thirty patients with a refractory major depressive episode who had responded to acute lithium augmentation during an open 6-week study participated in a randomized, parallel-group, double-blind, placebo-controlled trial of lithium augmentation during continuation treatment. After a 2-4-week stabilization period following remission, patients were randomly assigned to receive either lithium or placebo for a 4-month period. Antidepressant medication was continued throughout the study. RESULTS: Relapses (including one suicide) occurred in seven (47%) of the 15 patients who received placebo in addition to antidepressants. None (0%) of the 14 patients who received lithium augmentation with antidepressants suffered a relapse during the double-blind phase of the study. Five of the seven relapsing patients in the placebo group developed a depressive episode, and the other two experienced a manic episode. CONCLUSIONS: Lithium augmentation in the continuation phase of treatment of unipolar major depressive disorder effectively protects patients against a relapse. Patients who respond to lithium augmentation should be maintained on lithium augmentation for a minimum of 6 months or even longer.     

Newer treatment studies for bipolar depression

Objective:  Depressive symptoms of bipolar disorder have more negative impact on a patient's life than manic symptoms. This review focused on the emerging efficacy data for treatments in bipolar depression.
Methods:  English-language literature cited in Medline was searched with terms bipolar depression, clinical trial, and trial. Randomized, placebo-controlled trials of newer studies with older agents and all studies with newer or novel agents were prioritized. Open-label studies of novel agents presented at major scientific meetings were also included.
Results:  Olanzapine, olanzapine–fluoxetine combination (OFC), and quetiapine were superior to placebo in the acute treatment of bipolar depression. Lamotrigine only significantly reduced core symptoms of depression compared with placebo. Pramipexole, a dopamine D2/D3 receptor agonist and omega-3 fatty acids, a polyunsaturated fatty acid, augmentation to mood stabilizer (MS) had superiority to placebo in reducing depressive symptoms. Topiramate augmentation of an MS was equally as effective as Bupropion-SR. Patients treated with an MS responded well to the addition of agomelatine, a melatonin receptor agonist with 5-HT2C antagonist properties. However, inositol and repetitive transcranial magnetic stimulation did not separate from placebo. Lamotrigine and olanzapine, and to a lesser extent, divalproex, are superior to placebo in preventing depressive relapses. All agents were relatively well tolerated.
Conclusions:  Olanzapine, OFC, and quetiapine are effective in the acute treatment of bipolar depression. Compared with lithium and divalproex, lamotrigine is more effective in preventing bipolar depression. Larger controlled studies of the other agents in the acute and maintenance treatment of bipolar depression are warranted.     

Lithium augmentation increases post-dexamethasone cortisol in the dexamethasone suppression test in unipolar major depression

Although considerable evidence exists on the efficacy of lithium as an augmenting agent in refractory depression, the underlying neurobiology of this phenomenon is unknown. In patients with major depression, changes of the hypothalamic-pituitary-adrenocortical (HPA) system have been detected by means of the dexamethasone suppression test (DST), when administered during treatment with tricyclic antidepressants. We investigated whether the DST also reveals alterations of the HPA system during lithium augmentation. We also sought to identify whether response to lithium augmentation can be predicted with the DST. Twenty-five patients with unipolar major depression, who did not respond to an adequate antidepressant monotherapy of at least 4 weeks, were measured for basal (pre-dexamethasone, 0800h) cortisol and ACTH levels and were administered the DST the day before initiation of lithium augmentation treatment. The same neuroendocrine procedures were repeated after 3 to 4 weeks. Criteria of response to lithium augmentation, defined as a reduction of the Hamilton Depression Rating Scale (HDRS17) score by > or =50% and an end point score of 9 or less, were determined by weekly HDRS ratings. The DST revealed a statistically significant increase of the post-dexamethasone cortisol values (P = 0.021) and an increase in the post-dexamethasone ACTH values (P = 0.051) during lithium augmentation as compared to pre-treatment baseline evaluations. The pre-dexamethasone hormone values were unchanged. The number of non-suppressors at baseline was one and increased to three at follow-up. Results of DST did not predict response to lithium augmentation, which occurred in 40% of subjects. Results suggest that lithium augmentation increases HPA system activity, as indicated by the increase of post-dexamethasone cortisol and ACTH levels measured by the DST. This is in contrast to the established decline of HPA system activity during treatment with tricyclic antidepressants.     

Antidepressant efficacy of venlafaxine

Venlafaxine is a unique antidepressant medication with well documented efficacy and safety in the acute treatment of major depressive disorder. Reports suggest that it may also be effective in the treatment of dysthymic disorder and bipolar II depression, but the available data for these conditions are more limited compared to major depressive disorder. Several studies suggest that there may be a more rapid onset of action for venlafaxine in the treatment of major depression compared to other antidepressant pharmacotherapies, but this has not been fully established. Venlafaxine is also effective in the important long term continuation and maintenance phases of the treatment of depression.     

Lithium in depression: a review of the antidepressant and prophylactic effects of lithium

The therapeutic effects of lithium in depression are reviewed. The acute antidepressant effect of lithium alone is neither as impressive nor as predictable as its antimanic action, nor is it equivalent to that of tricyclic antidepressants. In patients who are 'refractory' to tricyclics or monoamine oxidase inhibitors, combined treatment with lithium may augment antidepressant response. Lithium is an effective prophylactic treatment in both unipolar and bipolar disorder and in the latter is the drug of choice. Aspects of monitoring, such as range of therapeutic plasma levels, dosage regimen and adverse effects, are discussed. Current evidence suggests that, in patients who fail to respond to lithium or are unable to tolerate side-effects, carbamazepine should be considered.     

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.     

Rapid response to the addition of lithium in iprindole-resistant unipolar depression: a pilot study

The authors administered lithium carbonate, 900 mg/day, in an open study to seven patients with a major unipolar depression refractory to 3-week treatment with iprindole, 90 mg/day, a tricyclic antidepressant devoid of any action on monoaminergic reuptake. All patients showed clinically significant improvement within 48 hours. Since iprindole induces in the animal a sensitization of forebrain neurons to serotonin (5-HT), as do other tricyclic antidepressants, and lithium enhances the activity of 5-HT neurons, the authors propose that an enhanced release of 5-HT on sensitized target neurons might underlie the rapid antidepressant effect in tricyclic-refractory depression when lithium is added to the treatment regimen.     

Antidepressants in bipolar disorder: the case for caution

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15–20% of bipolar depressed patients).     

Lithium carbonate augmentation of desipramine in refractory depression

An open clinical study with 20 consecutive outpatients suffering from major depression with melancholia (DSM-III) was carried out. All patients were resistant to desipramine after at least six weeks of treatment. A significant improvement was found in 13 of the 20 patients when lithium carbonate was added. Among the responder patients, five improved in the first week of lithium augmentation, while eight others improved after one week of lithium. The mechanism of action of the lithium augmentation effect in tricyclic-resistant depressed patients is discussed in view of our findings. We suggest that the unified 5-HT/NE hypothesis used in affective disorder could be applied in drug refractory depression.     

The current understanding of lamotrigine as a mood stabilizer

OBJECTIVE: To examine whether lamotrigine has a unique role in the treatment of bipolar disorder, we evaluated the results of recent clinical trials and molecular and cell biological studies on lamotrigine. DATA SOURCES: Using keywords such as bipolar disorder, lamotrigine, clinical trial, outcomes studies, and mechanisms, we conducted a search for English-language articles on MEDLINE and Index Medicus and also on abstracts presented in recent research conferences. DATA SYNTHESIS: Several studies have strongly suggested that lamotrigine is effective for the acute treatment of bipolar depression as well as for long-term maintenance treatment of bipolar disorder. Stevens-Johnson syndrome is a concern, but the incidence of this side effect may not be as high as previously believed, if dosing is slowly titrated. The action mechanisms underlying the mood-stabilizing effects of lamotrigine are unknown at present but recent studies have produced interesting leads. Lamotrigine modulates various ion channels, altering neuronal excitability. The use-dependent inhibition of neuronal firing by lamotrigine is potentially important because it could result in attenuating supranormal neuronal activities that are possibly associated with bipolar disorder. Lamotrigine inhibits the release of glutamate, similarly to lithium, and its possible association with mood-stabilizing or antidepressant effects needs to be further examined. Unlike lithium or valproic acid, however, lamotrigine does not down-regulate the expression of protein kinase C or MARCKS, suggesting that lamotrigine employs different intracellular mechanisms for long-term changes in neuro-biology from those of lithium or valproic acid. CONCLUSION: The efficacy of lamotrigine for bipolar depression may provide us with new options in the treatment of bipolar disorder. Examining the effects of lamotrigine on various molecular mechanisms in correlation with its unique efficacy on bipolar depression may enhance our understanding of action mechanisms of the mood stabilizers.     

Atypical antipsychotics for bipolar disorder.

Atypical antipsychotic agents have been widely investigated for their efficacy in acute mania. The data to date suggest that olanzapine,risperidone, quetiapine, aripiprazole, and ziprasidone are effective, with no significant differences in antimanic efficacy among these agents. These agents are effective as an alternative to lithium or divalproex as monotherapy or in combination with these mood stabilizers. The data concerning their utility in acute bipolar depression and maintenance treatment of bipolar disorder are limited. The studies to date suggest that olanzapine has modest acute antidepressant properties but probably has efficacy comparable to lithium and divalproex in preventing manic and depressive episodes. Quetiapine seems to have robust antidepressant properties, but these data need to be replicated in further trials before quetiapine can be recommended as a first-line agent for acute bipolar depression. Aripiprazole has shown promise in preventing manic episodes in one 6-month study, but further studies with at least 1-year duration and larger sample sizes are needed before this agent can be recommended as a monotherapy for prophylaxis of bipolar disorder. It is currently unknown if risperidone, aripiprazole, and ziprasidone have any efficacy in treating acute bipolar depression. Similarly, long-term studies are needed to ascertain the role of risperidone, quetiapine, and ziprasidone in the maintenance treatment of bipolar disorder. Overall, the atypical antipsychotic agents as a group represent an effective and relatively safe addition to the armamentarium for the treatment of bipolar disorder.     

Lithium: still a major option in the management of bipolar disorder

Still after more than 50 years, lithium is a major treatment of bipolar disorder, even though it has not been promoted by the pharmaceutical industry over the last decades. In recent years the evidence base on lithium for bipolar disorder has substantially increased due to results from a number of trials. Therefore, a review of this evidence is timely. The efficacy of lithium as an acute treatment and as a maintenance treatment of bipolar disorder was evaluated through a review of the evidence, focusing on modern, randomized, parallel-group designed trials. Additionally, the evidence was sought translated into the proper use of lithium in clinical practice. Lithium's antimanic efficacy has been convincingly demonstrated. However, as blood monitoring due to the risk of toxicity is required and due to an insufficient response in highly agitated patients, lithium monotherapy has a limited place in the acute treatment of severe manic states. For acute bipolar depression, results are conflicting. Recent maintenance trials have added substantially to the documentation of lithium's long-term stabilizing properties in bipolar disorder, and these properties have been demonstrated independently of any acute response to lithium. Finally, it is now beyond doubt that not only does lithium prevent mania, but also depression in bipolar disorder. Lithium is still to be considered a major if not the most important mood- stabilizer, at least for maintaining long-term stability in patients with bipolar disorder. The potential risks of lithium should be weighed up against its benefits and the fact that serious adverse effects are usually avoidable.     

Bipolar depression: pharmacotherapy and related therapeutic strategies.

The depressed phase of bipolar affective disorder is a significant cause of suffering, disability, and mortality and represents a major challenge to treating clinicians. This article first briefly reviews the phenomenology and clinical correlates of bipolar depression and then focuses on the major pharmacological treatment options. We strongly recommend use of mood stabilizers as the first-line treatment for the type I form of bipolar depression, largely because longer-term preventative therapy with these agents almost certainly will be indicated. Depressive episodes that do not respond to lithium, divalproex, or another mood stabilizer, or episodes that "breakthrough" despite preventive treatment, often warrant treatment with an antidepressant or electroconvulsive therapy. The necessity of mood stabilizers in the type II form of bipolar depression is less certain, aside from the rapid cycling presentation. Both experts and practicing clinicians recommend bupropion and the selective serotonin reuptake inhibitors as coequal initial choices, with venlafaxine and monoamine oxidase inhibitors, such as tranylcypromine, preferred for more resistant cases. The risk of antidepressant-induced hypomania or mania with concomitant mood stabilizer therapy is low, on the order of 5% to 10% during acute phase therapy. Additional therapeutic options and optimal durations of therapy also are discussed.     

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.     

Lithium - a continuing story in the treatment of bipolar disorder

OBJECTIVE: To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety. METHOD: A selective literature review. RESULTS: Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies. CONCLUSION: Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use.     

Prednisone augmentation in treatment-resistant depression with fatigue and hypocortisolaemia: a case series

Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have long been implicated in major depression with hypercortisolaemia reported in typical depression and hypocortisolaemia in some studies of atypical depression. We report on the use of prednisone in treatment-resistant depressed patients with reduced plasma cortisol concentrations. Six patients with treatment-resistant major depression were found to complain of severe fatigue, consistent with major depression, atypical subtype, and to demonstrate low plasma cortisol levels. Prednisone 7.5 mg daily was added to the antidepressant regime. Five of six patients demonstrated significant improvement in depression on prednisone augmentation of antidepressant therapy. Although hypercortisolaemia has been implicated in some patients with depression, our findings suggest that hypocortisolaemia may also play a role in some subtypes of this disorder. In treatment-resistant depressed patients with fatigue and hypocortisolaemia, prednisone augmentation may be useful.     

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.     

Mirtazapine monotherapy versus combination therapy with mirtazapine and aripiprazole in depressed patients without psychotic features: a 4-week open-label parallel-group study.

BACKGROUND: There is preliminary evidence that the atypical antipsychotic aripiprazole, which is a partial agonist at D(2) and 5-HT(1A) receptors and a potent antagonist at 5-HT(2A) receptors, may be useful as an augmentation strategy in treatment-resistant depression. METHOD: In this 4-week open-label non-randomized parallel-group study, the safety and efficacy of aripiprazole as add-on treatment strategy in patients suffering from non-delusional depression was investigated. Forty drug-free depressed inpatients without psychotic symptoms (13 men, 27 women), suffering from a major depressive episode or bipolar disorder, depressive state (DSM-IV criteria), were included in the study. The patients were treated either with mirtazapine monotherapy (45 mg/day) or combination therapy (mirtazapine 45 mg/day plus aripiprazole 15 mg/day) for 4 weeks. Safety and efficacy were assessed weekly using the Hamilton Depression Rating Scale, the Simpson-Angus Scale and the Barnes Akathisia Scale. RESULTS: Mirtazapine monotherapy and combined treatment with mirtazapine and aripiprazole showed comparable antidepressant effects as assessed at the endpoint of the study period. However, additional administration of aripiprazole accelerated the onset of antidepressant action in patients suffering from treatment-resistant depression. Additive use of aripiprazole reduced the mirtazapine-induced increase in the body mass index. Moreover, mirtazapine had favourable effects on aripiprazole-induced akathisia. No other extrapyramidal side effects were seen in the combination therapy group. CONCLUSION: Combined therapy with mirtazapine and aripiprazole is a safe and well-tolerated treatment option which may be useful especially in treatment-resistant depression. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole in depressed patients.