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The role of lithium in the treatment of bipolar depression
Clinical Neuroscience Research 2 (2002) 222–227 www.elsevier.com/locate/clires
The role of lithium in the treatment of bipolar depression Zubin Bhagwagar, Guy M. Goodwin* University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JK, UK
Abstract Bipolar depression is assuming increasing importance as perhaps the major challenge in the acute management of bipolar 1 disorder. Treatment guidelines suggest an overwhelming expert preference for the use of lithium as first line treatment rather than antidepressants. However, the actual evidence for acute efficacy of lithium in bipolar depression, either as a sole agent or in combination with other drugs, is disappointing. Lithium still has an important role in maintenance treatment and appears to reduce the incidence of suicide, but its efficacy specifically against depression is beginning to be questioned. It remains nevertheless a key comparator for new studies in bipolar disorder. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Lithium; Bipolar depression; Antidepressants; Efficacy
1. Introduction Depression is a central component of bipolar affective disorder. Indeed, it may be severe, chronic and potentially life-threatening. In bipolar 1 patients, we are familiar with depressive episodes that may be characterized acutely by marked retardation and even psychosis, and in more chronic conditions as a debilitating outcome of acute episodes of mania. In the past, little distinction was made between the severe depressive states that were associated with mania and those that were not. Kraepelin subsumed severe unipolar and bipolar illness together under the sobriquet of manic depressive insanity. Following the distinction between bipolar and unipolar illness, it was quickly understood that unipolar disorder in its less severe forms is common in General Practice and random community samples. Depression has become a major target for drug development and marketing since the introduction of fluoxetine and the other selective inhibitors of serotonin re-uptake. It has taken longer for the recognition that depression may be the presentation of less severe forms of bipolar disorder. Under-recognition of hypomanic episodes (usually associated with recurrent major depression) has led to an underestimation of the incidence and prevalence of bipolar disorder. The life time risk appears to be 0.5% for bipolar 1 disorder and about 3% for bipolar 2 disorder [1]. However, in out-patient settings, a relatively high fraction of apparent * Corresponding author. Tel.: 144-1865-226451; fax: 144-1865204198. E-mail address: [email protected] (G.M. Goodwin).
major depressions are claimed to belong to the bipolar spectrum [2–4]. Along with this slow recognition of the problem has followed an even slower recognition of the need for specific treatment. Therefore, the question of how we should we treat an episode of bipolar depression is easy to ask, but deceptively so. It is a remarkable fact, perhaps not fully recognized by either party, that the approaches to treatment for bipolar depression in Europe and North America have diverged widely in recent years. The difference is most unambiguously revealed in treatment guidelines, which will be reviewed below. There is a greater advocacy of mood stabilizers alone in North America while there is more confidence in the role of antidepressants in Europe. This has implications for the position of lithium. Such a divergence can only have arisen because of the relative dearth of compelling evidence for one approach over the other. Instead, it is a triumph of strong opinion, not always weakly held, primarily in the North American literature. Central to the North American approach is the potential for lithium and other so-called mood stabilizers to treat depressive episodes. Accordingly, it is to lithium, the oldest and most widely used drug for bipolar disorder, that we will turn in this article for a convincing answer to an apparently simple question. 2. Current status of lithium treatment of bipolar depression: evidence from treatment guidelines There are five sets of guidelines or recommendations for the treatment of bipolar depression which are the product of
1566-2772/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S15 66- 2772(02)0004 6-4
Z. Bhagwagar, G.M. Goodwin / Clinical Neuroscience Research 2 (2002) 222–227
official organizations with an interest in the area, and all originate in North America. Lithium plays a central part in the treatment of bipolar depression in all of them. The American Psychiatric Association guidelines of 1994 [5] recommended that a mood stabilizer should be the first line of treatment for bipolar depression with psychotherapy and/or antidepressants as the next option. Clinical Practice Guidelines for Bipolar Disorders from the Department of Veterans Affairs [6] were formulated after a literature review followed by input from focus groups. A 14-member workgroup summarized the initial recommendations, which were critiqued by ten non-Veteran’s Administration experts along with other experts and general practitioners. The recommendations for the treatment of bipolar depression were to initiate/optimize a mood stabilizer with a strong preference for lithium followed by antidepressants subsequently. The Expert Consensus Guidelines Treatment of Bipolar Disorder was based on aggregate opinions from survey results among 68 identified experts in the treatment of bipolar illness in response to specific clinical situations [7]. The suggestion is for a mood stabilizer with lithium again as the favoured agent. The Texas Medication Algorithm Project was a Randstyle survey of academicians and clinicians followed by a consensus conference leading to the formulation of a multistep algorithm [8]. Here too the suggestion is for lithium treatment to be initiated in the first instance with added antidepressants being the second option. A group of clinicians and researchers from Canada who methodologically incorporated a large-scale review and classification of the quality of existing evidence developed the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines (http://www.canmat.org/psychs/ index.html). A total of 206 psychiatrists and 91 GPs reviewed initial recommendations with further critique by clinicians from Canada and USA. Here again there is a strong recommendation for the use of lithium as a first line treatment for bipolar depression with antidepressants as a second line option. The near consensus view appears to be that the first step in managing depression should be to initiate or ‘optimize’ treatment with a mood stabilizer, usually lithium, and the second should be to combine an antidepressant with the mood stabilizer. With the weight of current opinion so firmly favouring lithium as a first line option for the treatment of bipolar depression, one might expect the evidence for lithium’s efficacy as a single treatment or when combined with another agent to be overwhelming. In fact, quite simply, it is not.
3. Lithium as monotherapy There are few trials comparing lithium with placebo for the treatment of patients with bipolar depression and all but
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one of them were conducted more than 20 years ago. Only controlled trials with a minimum of ten patients with bipolar depression are discussed here. These numbers may not be the total number of patients in the trial. Seven controlled trials were published in the 10 year period between 1968 and 1978. All employed a crossover design rather than a parallel group comparison, which would now be preferred, and most of these trials were no more than 4 weeks in duration and some were as short as a week. Fieve et al. [9] studied 29 acutely depressed inpatients with bipolar disorder (retrospectively reported as Bipolar I), all of whom had a history of one or more affective episodes in each of the previous 2 years or two episodes in the last year. All patients were treated with placebo for a varying period of 2–4 weeks (exact duration and reason for variability was unspecified) and were subsequently randomly assigned to imipramine or lithium for 3 weeks. No details were provided on lithium dose or serum levels. Compared with the placebo run-in period, patients treated with lithium experienced a 32% reduction in depressive symptoms after 4 weeks of treatment: imipramine-treated patients in fact did slightly better. The trial was viewed as convincing because a flat placebo run-in was followed by apparent acute response. The response to lithium may have been less than that to imipramine, but the study was of course underpowered and the interval over which responses occurred was not placebo-controlled. Goodwin et al. [10] studied 12 inpatients with bipolar depression, six with previous manic episodes, the others with previous hypomanic episodes. Some form of response was seen in ten patients started on lithium after a placebo run-in but only five had a complete response and the others had a partial response. The dose of lithium carbonate used was 900–1800 mg per day with serum levels of 0.8–1.3 mEq/l. Goodwin et al. [11] reported a further cohort of 40 acutely depressed bipolar patients (it is unclear if the sample included the 12 patients reported previously). The design again involved an initial placebo period of at least 6 days followed by lithium for at least 2 weeks. An unequivocal response was seen in 12 patients, an equivocal response in 20, while eight did not respond or worsened. No details were provided regarding dosage, plasma lithium levels or numbers of bipolar I or II patients. Stokes et al. [12] reported a study of 18 patients with bipolar I disorder treated with lithium for 7–10 days following placebo. No advantage of lithium over placebo over this short period could be detected. Mendels reported a placebo-controlled study in a group of 13 moderately to severely depressed bipolar patients [13]. All patients had a 1–2 week period on placebo followed by 3 weeks on lithium and finally a 1–3 week period on placebo. He reported an improvement in nine patients on lithium followed by a relapse in six on placebo substitution. Remarkably, this trial may be the best evidence we have for lithium’s efficacy since we have data on the postresponse interval.
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Given the relative weakness of the efficacy data, it would be surprising if we had any subsidiary information on who responds best to lithium. Donnelly et al. attempted to evaluate possible associations between pre-treatment measures on the Minnesota Multiphasic Personality Inventory (MMPI) and behaviourally rated responses to lithium in bipolar depression [14]. The group included 17 patients with bipolar disorder I and 16 with bipolar II (14 men, 19 women). A total of 11/17 bipolar I patients and 10/17 bipolar patients responded to a 4 week trial of lithium (median 1500 mg/day; 0.9–1.3 mEq/l) after a 5 day placebo washout period. Lithium response was tentatively associated with some items on the MMPI. The only recent acute study that employed lithium compared it as monotherapy with the combination of lithium plus paroxetine or imipramine in bipolar depression [15]. This trial recruited 117 patients who were randomly allocated treatments across 19 participating centres. The main finding was negative: no difference between the different treatment arms. However, in an attempt to make sense of the findings a post-hoc secondary analysis of the data suggested that a positive treatment response was associated with serum lithium levels greater than 0.08 mEq/l. This supports a lithium treatment effect. However, the result is open to other interpretation: for example, high lithium levels may only be achieved by healthy compliers, who tend to do well in all trials. The evidence barely supports the basic claim that lithium is superior to placebo in the treatment of bipolar depression. Patients were on varying durations of placebo treatment prior to crossing over to lithium with consequences that are at best unclear and may make interpretation difficult. Crossover methodology is susceptible to carry-over effects of lithium and the rate of relapse in placebo withdrawal phases might be inflated because of abrupt discontinuation of lithium [16]. Furthermore, no distinction is possible between bipolar I and II nor is there an adequate comparison with a unipolar group treated with lithium monotherapy. Thus, there is almost no reliable basis other than clinical experience and habit for the usual advice to treat acute bipolar depression preferentially with lithium.
4. Continuation and maintenance treatment with lithium Given the inadequacy of the acute treatment data, the evidence from patients randomized to receive long-term lithium is of considerable interest. This is probably appropriate because episodes of depression in bipolar patients tend to be shorter than for unipolars and spontaneous recovery may be more likely. Maintenance of effect is anyway more important in a highly recurrent condition. A systematic review of the placebo-controlled maintenance data suggests that lithium is effective in preventing recurrence to both mania and depression in bipolar and unipolar patients [17]. While it cannot prove acute efficacy one
way or the other, it has undoubtedly influenced practice because of the strength of the evidence. It also justifies the assumption that patients with bipolar depression will be at a reduced risk of switching to mania when treated with lithium. The original maintenance studies used hard outcomes such as hospital admission or new episodes. More recent relapse prevention studies with lamotrigine, lithium and placebo arms in patients with an index episode of depression or mania have used a lower threshold (time to intervene for a mood episode) for ethical and practical reasons. Two large new landmark studies have been completed and suggest that lithium has a greater potential to prevent manic relapse than depressive relapse [18,19]. Some action against depression in these studies compared to placebo appears likely but power to detect the size of effect present was limited. However, these studies may have important negative implications for how lithium is viewed in the future.
5. Lithium and active comparators or in combination treatment While the evidence reviewed above suggests that lithium is only possibly superior to placebo in the treatment of bipolar depression, evidence of superiority to an active comparator or in the presence of another agent would be equally convincing and clinically reassuring. In fact, there appears to be little to suggest the superiority of one treatment over another alone or in combination for bipolar depression. In the study already mentioned above [9], after 3 weeks of active treatment with imipramine or lithium, the patients on lithium were regarded as improved with a 32% decrease in depressive symptom score while the imipramine group had a 58% reduction in depressive symptom scores. Watanabe et al. [20] similarly compared lithium with imipramine. In 64 patients with depression (of whom only five had a bipolar disorder; depressed state, circular type) no significant differences were found between the two treatments in the rate of response, depression scale scores or clinical effects. The results for the five bipolar patients are not given separately. However, the average lithium levels reported were low: 0.41–0.45 mEq/l. Trials describing responses to antidepressants co-administered with lithium or other mood stabilizers have been inconsistent. Cohn et al. [21] conducted a 6 week, doubleblind comparison of fluoxetine, imipramine, and placebo in 89 patients with bipolar depression. Importantly there was a response to fluoxetine (and imipramine compared with placebo). Of the patients who completed the trial, a number were also on lithium [21]: 4/17 fluoxetine subjects, 1/14 imipramine subjects and 2/10 subjects treated with placebo. The numbers were insufficient to allow any comment about the value of combination treatment. There are two studies which have examined the efficacy
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of paroxetine in combination with lithium. Despite some initial concern that it might produce a serotonin syndrome, the combination has been reported to be safe [22,23]. Bauer et al. [24] reported a trial of lithium-maintained patients suffering from a breakthrough episode of major depression who were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (n ¼ 19) or amitriptyline 75 mg/day (n ¼ 23). After 4 weeks, a significantly greater proportion of patients in the paroxetine group had achieved a 50% reduction in baseline Hamilton Rating Scale for Depression scores, and the mean improvement in Clinical Global Impression severity of illness was significantly greater in the paroxetine group at weeks 3 and 5. Serum lithium levels were not affected by either antidepressant. The authors proposed that the more rapid improvement demonstrated by the group receiving the combination of lithium and paroxetine may be due to the synergistic serotonergic effects of these two medications. This finding contrasts with that of the largest study to compare the combination of lithium and paroxetine or imipramine which showed no difference from lithium plus placebo in the treatment of patients with bipolar depression [15]. As already noticed this may be a failed rather than a negative trial. In a randomized, double-blind, parallel group, multicentre study of moclobemide (450–750 mg daily) and imipramine (150–250 mg daily) in 156 patients with bipolar disorder there were no statistically significant differences between the two groups on any efficacy measures [25]. Though this trial was not designed to study the efficacy of combined treatment with lithium, the proportion of patients on lithium was broadly similar in the moclobemide (n ¼ 37; 46%) and imipramine (n ¼ 37; 49%) groups. The similar efficacy of the two antidepressants may also translate to similar efficacy of the combination of lithium plus imipramine and lithium plus moclobemide. A recent underpowered study compared the efficacy of combined mood stabilizer treatment against mood stabilizer with an antidepressant in 27 patients with bipolar disorder [26]. There were no differences in the efficacy of the two treatments. Nineteen of the 27 patients in the trial were on lithium.
6. Lithium and suicide Suicide is a tragic consequence of the depressive pole of bipolar disorder [27]. In a meta-analysis of suicide risk among patients with a mental illness, Harris and Barraclough [28] demonstrated that patients with bipolar disorder had a risk of suicide 15 times greater than the expected value though there was considerable variability between studies. Given that depression is usually the final common pathway to suicide, it follows that better treatment of and protection against bipolar depression might be the key to a reduction in the suicide rates in bipolar disorder.
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There is good evidence for an association between lithium treatment and lowered suicide rates. It is based on a number of careful naturalistic studies [29–34]. In a recent meta-analysis of the effect of long-term lithium treatment on suicide rates in 5647 patients with a major affective illness, the number of suicides by patients on lithium was 0.159 per 100 patient years compared with 0.875 per 100 patient years in patients off lithium [35]. In a sub-analysis of 12 studies reporting observations with and without lithium and also rates of suicide greater than 0 in the untreated condition, the overall risk ratio of 8.85 (95% confidence intervals 4.14–19.1) favoured lithium and was highly statistically significant (P ¼ 0:0001). This reduction of suicide rates by lithium of slightly more than 82% was seen in a population where the main diagnosis was bipolar disorder, although patients with schizoaffective disorder were also included in the study. The beneficial effect of lithium also seems to extend to attempted suicide with good evidence for a reduction in suicidal behaviour while on lithium [36]. Interpretation of these studies is constrained by a number of factors that may bias the results. None are randomized studies, so all rely on naturalistic comparisons. The most convincing are studies where the same patient populations contribute estimates of rates on and off lithium. The least convincing are those where a clinic population treated with lithium can sometimes be shown to have a mortality rate from suicide lower than the general population. In the latter studies, the most important confound is the healthy compliance factor of good clinic attenders.
7. Conclusion Lithium is a widely used treatment for patients with bipolar depression. Its use is strongly promoted by guidelines dominated by North American opinion. It is the weight of opinion and not evidence that shapes practice at present. Indeed, it would be difficult, actually impossible, to imagine a drug with lithium’s portfolio surviving contemporary regulatory scrutiny for acute treatment of depressive episodes in bipolar disorder. There is almost no evidence that lithium has been shown to be superior to placebo or any active comparator in randomized controlled trials. Randomized trials are not the only kind of evidence, however: clinical experience counts and if guidelines were followed they should show low rates of antidepressant use in North America. In fact, even pragmatic surveys suggest that the recourse to antidepressants by clinicians is common and probably necessary. Audit suggests that antidepressants are compatible with satisfactory outcomes [37]. Thus, lithium’s promotion as an acute antidepressant agent is not entirely at one either with the evidence base or clinical practice. It is unclear whether lithium in combination with an antidepressant offers particular advantages for the treatment of bipolar depression. It has long been thought to augment the actions of antidepressants in the treatment of unipolar states [38].
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The evidence for lithium as an effective maintenance treatment in bipolar disorder is good, if not overwhelming, given the extent of its use. There is a reasonable basis for saying that lithium prevents both manic and depressive relapse when these are severe, but recent trials suggest that it may be more effective in preventing the return of manic than depressive symptoms. It is also widely accepted that lithium seems to have a beneficial effect on the rate of suicide and deliberate self-harm in patients with affective disorders. This may be via its effects upon bipolar depression, or conceivably by an independent anti-suicidal action. Lithium remains of central importance for maintenance treatment. That its use is often neglected in North America in favour of other compounds of less certain efficacy is a matter of regret. However, its position as an acute treatment for bipolar depression merits greater scepticism and may currently be overstated. It is, however, a key reference compound for comparator studies in all phases of bipolar illness. With the rising interest in treating bipolar depression, it will be essential for lithium to be included as an active comparator. Only then, and very belatedly, are we likely to discover how efficacious it really is, and whether we should promote its use in acute bipolar depression.
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[13] Mendels J. Lithium in the treatment of depression. Am J Psychiatry 1976;133(4):373–378. [14] Donnelly EF, Goodwin FK, Waldman IN, Murphy DL. Prediction of antidepressant responses to lithium. Am J Psychiatry 1978;135(5):552–556. [15] Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebocontrolled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001;158(6):906–912. [16] Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991;48(12):1082–1088. [17] Burgess S, Geddes J, Hawton K, Townsend E, Jamison K, Goodwin G. Lithium for maintenance treatment of mood disorders, Cochrane Database Syst Rev 2001(2):CD003013. [18] Bowden C, Calabrese J, Akthar S, et al. Lamotrigine demonstrates long-term mood stabilisation in manic patients. Bipolar Disord 2001;3(Suppl 1):27–28. [19] Calabrese J, Bowden C, Akthar S, et al. Lamotrigine: evidence for mood stabilisation in bipolar 1 depression. Bipolar Disord 2001;3(Suppl 1):29. [20] Watanabe S, Ishino H, Otsuki S. Double-blind comparison of lithium carbonate and imipramine in treatment of depression. Arch Gen Psychiatry 1975;32(5):659–668. [21] Cohn JB, Collins G, Ashbrook E, Wernicke JF. A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 1989;4(4):313–322. [22] Zornberg GL, Pope Jr. HG. Treatment of depression in bipolar disorder: new directions for research. J Clin Psychopharmacol 1993;13(6):397–408. [23] Fagiolini A, Buysse DJ, Frank E, Houck PR, Luther JF, Kupfer DJ. Tolerability of combined treatment with lithium and paroxetine in patients with bipolar disorder and depression. J Clin Psychopharmacol 2001;21(5):474–478. [24] Bauer M, Zaninelli R, Muller-Oerlinghausen B, Meister W. Paroxetine and amitriptyline augmentation of lithium in the treatment of major depression: a double-blind study. J Clin Psychopharmacol 1999;19(2):164–171. [25] Silverstone T. Moclobemide vs. imipramine in bipolar depression: a multicentre double-blind clinical trial. Acta Psychiatr Scand 2001;104(2):104–109. [26] Young LT, Joffe RT, Robb JC, MacQueen GM, Marriott M, PatelisSiotis I. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry 2000;157(1):124–126. [27] Jamison KR. Suicide and bipolar disorder. J Clin Psychiatry 2000;61(Suppl 9):47–51. [28] Harris EC, Barraclough B. Suicide as an outcome for mental disorders: a meta-analysis. Br J Psychiatry 1997;170:205–228. [29] Tondo L, Baldessarini RJ, Hennen J, Floris G, Silvetti F, Tohen M. Lithium treatment and risk of suicidal behavior in bipolar disorder patients. J Clin Psychiatry 1998;59(8):405–414. [30] Sharma R, Markar HR. Mortality in affective disorder. J Affect Disord 1994;31(2):91–96. [31] Nilsson A. Mortality in recurrent mood disorders during periods on and off lithium. A complete population study in 362 patients. Pharmacopsychiatry 1995;28(1):8–13. [32] Thies-Flechtner K, Muller-Oerlinghausen B, Seibert W, Walther A, Greil W. Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Pharmacopsychiatry 1996;29(3):103–107. [33] Coppen A, Farmer R. Suicide mortality in patients on lithium maintenance therapy. J Affect Disord 1998;50(2–3):261–267. [34] Bocchetta A, Ardau R, Burrai C, Chillotti C, Quesada G, Del Zompo M. Suicidal behavior on and off lithium prophylaxis in a group of patients with prior suicide attempts. J Clin Psychopharmacol 1998;18(5):384–389.
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The role of lithium in the treatment of bipolar depression Zubin Bhagwagar, Guy M. Goodwin* University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JK, UK
Abstract Bipolar depression is assuming increasing importance as perhaps the major challenge in the acute management of bipolar 1 disorder. Treatment guidelines suggest an overwhelming expert preference for the use of lithium as first line treatment rather than antidepressants. However, the actual evidence for acute efficacy of lithium in bipolar depression, either as a sole agent or in combination with other drugs, is disappointing. Lithium still has an important role in maintenance treatment and appears to reduce the incidence of suicide, but its efficacy specifically against depression is beginning to be questioned. It remains nevertheless a key comparator for new studies in bipolar disorder. q 2002 Elsevier Science B.V. All rights reserved. Keywords: Lithium; Bipolar depression; Antidepressants; Efficacy
1. Introduction Depression is a central component of bipolar affective disorder. Indeed, it may be severe, chronic and potentially life-threatening. In bipolar 1 patients, we are familiar with depressive episodes that may be characterized acutely by marked retardation and even psychosis, and in more chronic conditions as a debilitating outcome of acute episodes of mania. In the past, little distinction was made between the severe depressive states that were associated with mania and those that were not. Kraepelin subsumed severe unipolar and bipolar illness together under the sobriquet of manic depressive insanity. Following the distinction between bipolar and unipolar illness, it was quickly understood that unipolar disorder in its less severe forms is common in General Practice and random community samples. Depression has become a major target for drug development and marketing since the introduction of fluoxetine and the other selective inhibitors of serotonin re-uptake. It has taken longer for the recognition that depression may be the presentation of less severe forms of bipolar disorder. Under-recognition of hypomanic episodes (usually associated with recurrent major depression) has led to an underestimation of the incidence and prevalence of bipolar disorder. The life time risk appears to be 0.5% for bipolar 1 disorder and about 3% for bipolar 2 disorder [1]. However, in out-patient settings, a relatively high fraction of apparent * Corresponding author. Tel.: 144-1865-226451; fax: 144-1865204198. E-mail address: [email protected] (G.M. Goodwin).
major depressions are claimed to belong to the bipolar spectrum [2–4]. Along with this slow recognition of the problem has followed an even slower recognition of the need for specific treatment. Therefore, the question of how we should we treat an episode of bipolar depression is easy to ask, but deceptively so. It is a remarkable fact, perhaps not fully recognized by either party, that the approaches to treatment for bipolar depression in Europe and North America have diverged widely in recent years. The difference is most unambiguously revealed in treatment guidelines, which will be reviewed below. There is a greater advocacy of mood stabilizers alone in North America while there is more confidence in the role of antidepressants in Europe. This has implications for the position of lithium. Such a divergence can only have arisen because of the relative dearth of compelling evidence for one approach over the other. Instead, it is a triumph of strong opinion, not always weakly held, primarily in the North American literature. Central to the North American approach is the potential for lithium and other so-called mood stabilizers to treat depressive episodes. Accordingly, it is to lithium, the oldest and most widely used drug for bipolar disorder, that we will turn in this article for a convincing answer to an apparently simple question. 2. Current status of lithium treatment of bipolar depression: evidence from treatment guidelines There are five sets of guidelines or recommendations for the treatment of bipolar depression which are the product of
1566-2772/02/$ - see front matter q 2002 Elsevier Science B.V. All rights reserved. PII: S15 66- 2772(02)0004 6-4
Z. Bhagwagar, G.M. Goodwin / Clinical Neuroscience Research 2 (2002) 222–227
official organizations with an interest in the area, and all originate in North America. Lithium plays a central part in the treatment of bipolar depression in all of them. The American Psychiatric Association guidelines of 1994 [5] recommended that a mood stabilizer should be the first line of treatment for bipolar depression with psychotherapy and/or antidepressants as the next option. Clinical Practice Guidelines for Bipolar Disorders from the Department of Veterans Affairs [6] were formulated after a literature review followed by input from focus groups. A 14-member workgroup summarized the initial recommendations, which were critiqued by ten non-Veteran’s Administration experts along with other experts and general practitioners. The recommendations for the treatment of bipolar depression were to initiate/optimize a mood stabilizer with a strong preference for lithium followed by antidepressants subsequently. The Expert Consensus Guidelines Treatment of Bipolar Disorder was based on aggregate opinions from survey results among 68 identified experts in the treatment of bipolar illness in response to specific clinical situations [7]. The suggestion is for a mood stabilizer with lithium again as the favoured agent. The Texas Medication Algorithm Project was a Randstyle survey of academicians and clinicians followed by a consensus conference leading to the formulation of a multistep algorithm [8]. Here too the suggestion is for lithium treatment to be initiated in the first instance with added antidepressants being the second option. A group of clinicians and researchers from Canada who methodologically incorporated a large-scale review and classification of the quality of existing evidence developed the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines (http://www.canmat.org/psychs/ index.html). A total of 206 psychiatrists and 91 GPs reviewed initial recommendations with further critique by clinicians from Canada and USA. Here again there is a strong recommendation for the use of lithium as a first line treatment for bipolar depression with antidepressants as a second line option. The near consensus view appears to be that the first step in managing depression should be to initiate or ‘optimize’ treatment with a mood stabilizer, usually lithium, and the second should be to combine an antidepressant with the mood stabilizer. With the weight of current opinion so firmly favouring lithium as a first line option for the treatment of bipolar depression, one might expect the evidence for lithium’s efficacy as a single treatment or when combined with another agent to be overwhelming. In fact, quite simply, it is not.
3. Lithium as monotherapy There are few trials comparing lithium with placebo for the treatment of patients with bipolar depression and all but
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one of them were conducted more than 20 years ago. Only controlled trials with a minimum of ten patients with bipolar depression are discussed here. These numbers may not be the total number of patients in the trial. Seven controlled trials were published in the 10 year period between 1968 and 1978. All employed a crossover design rather than a parallel group comparison, which would now be preferred, and most of these trials were no more than 4 weeks in duration and some were as short as a week. Fieve et al. [9] studied 29 acutely depressed inpatients with bipolar disorder (retrospectively reported as Bipolar I), all of whom had a history of one or more affective episodes in each of the previous 2 years or two episodes in the last year. All patients were treated with placebo for a varying period of 2–4 weeks (exact duration and reason for variability was unspecified) and were subsequently randomly assigned to imipramine or lithium for 3 weeks. No details were provided on lithium dose or serum levels. Compared with the placebo run-in period, patients treated with lithium experienced a 32% reduction in depressive symptoms after 4 weeks of treatment: imipramine-treated patients in fact did slightly better. The trial was viewed as convincing because a flat placebo run-in was followed by apparent acute response. The response to lithium may have been less than that to imipramine, but the study was of course underpowered and the interval over which responses occurred was not placebo-controlled. Goodwin et al. [10] studied 12 inpatients with bipolar depression, six with previous manic episodes, the others with previous hypomanic episodes. Some form of response was seen in ten patients started on lithium after a placebo run-in but only five had a complete response and the others had a partial response. The dose of lithium carbonate used was 900–1800 mg per day with serum levels of 0.8–1.3 mEq/l. Goodwin et al. [11] reported a further cohort of 40 acutely depressed bipolar patients (it is unclear if the sample included the 12 patients reported previously). The design again involved an initial placebo period of at least 6 days followed by lithium for at least 2 weeks. An unequivocal response was seen in 12 patients, an equivocal response in 20, while eight did not respond or worsened. No details were provided regarding dosage, plasma lithium levels or numbers of bipolar I or II patients. Stokes et al. [12] reported a study of 18 patients with bipolar I disorder treated with lithium for 7–10 days following placebo. No advantage of lithium over placebo over this short period could be detected. Mendels reported a placebo-controlled study in a group of 13 moderately to severely depressed bipolar patients [13]. All patients had a 1–2 week period on placebo followed by 3 weeks on lithium and finally a 1–3 week period on placebo. He reported an improvement in nine patients on lithium followed by a relapse in six on placebo substitution. Remarkably, this trial may be the best evidence we have for lithium’s efficacy since we have data on the postresponse interval.
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Given the relative weakness of the efficacy data, it would be surprising if we had any subsidiary information on who responds best to lithium. Donnelly et al. attempted to evaluate possible associations between pre-treatment measures on the Minnesota Multiphasic Personality Inventory (MMPI) and behaviourally rated responses to lithium in bipolar depression [14]. The group included 17 patients with bipolar disorder I and 16 with bipolar II (14 men, 19 women). A total of 11/17 bipolar I patients and 10/17 bipolar patients responded to a 4 week trial of lithium (median 1500 mg/day; 0.9–1.3 mEq/l) after a 5 day placebo washout period. Lithium response was tentatively associated with some items on the MMPI. The only recent acute study that employed lithium compared it as monotherapy with the combination of lithium plus paroxetine or imipramine in bipolar depression [15]. This trial recruited 117 patients who were randomly allocated treatments across 19 participating centres. The main finding was negative: no difference between the different treatment arms. However, in an attempt to make sense of the findings a post-hoc secondary analysis of the data suggested that a positive treatment response was associated with serum lithium levels greater than 0.08 mEq/l. This supports a lithium treatment effect. However, the result is open to other interpretation: for example, high lithium levels may only be achieved by healthy compliers, who tend to do well in all trials. The evidence barely supports the basic claim that lithium is superior to placebo in the treatment of bipolar depression. Patients were on varying durations of placebo treatment prior to crossing over to lithium with consequences that are at best unclear and may make interpretation difficult. Crossover methodology is susceptible to carry-over effects of lithium and the rate of relapse in placebo withdrawal phases might be inflated because of abrupt discontinuation of lithium [16]. Furthermore, no distinction is possible between bipolar I and II nor is there an adequate comparison with a unipolar group treated with lithium monotherapy. Thus, there is almost no reliable basis other than clinical experience and habit for the usual advice to treat acute bipolar depression preferentially with lithium.
4. Continuation and maintenance treatment with lithium Given the inadequacy of the acute treatment data, the evidence from patients randomized to receive long-term lithium is of considerable interest. This is probably appropriate because episodes of depression in bipolar patients tend to be shorter than for unipolars and spontaneous recovery may be more likely. Maintenance of effect is anyway more important in a highly recurrent condition. A systematic review of the placebo-controlled maintenance data suggests that lithium is effective in preventing recurrence to both mania and depression in bipolar and unipolar patients [17]. While it cannot prove acute efficacy one
way or the other, it has undoubtedly influenced practice because of the strength of the evidence. It also justifies the assumption that patients with bipolar depression will be at a reduced risk of switching to mania when treated with lithium. The original maintenance studies used hard outcomes such as hospital admission or new episodes. More recent relapse prevention studies with lamotrigine, lithium and placebo arms in patients with an index episode of depression or mania have used a lower threshold (time to intervene for a mood episode) for ethical and practical reasons. Two large new landmark studies have been completed and suggest that lithium has a greater potential to prevent manic relapse than depressive relapse [18,19]. Some action against depression in these studies compared to placebo appears likely but power to detect the size of effect present was limited. However, these studies may have important negative implications for how lithium is viewed in the future.
5. Lithium and active comparators or in combination treatment While the evidence reviewed above suggests that lithium is only possibly superior to placebo in the treatment of bipolar depression, evidence of superiority to an active comparator or in the presence of another agent would be equally convincing and clinically reassuring. In fact, there appears to be little to suggest the superiority of one treatment over another alone or in combination for bipolar depression. In the study already mentioned above [9], after 3 weeks of active treatment with imipramine or lithium, the patients on lithium were regarded as improved with a 32% decrease in depressive symptom score while the imipramine group had a 58% reduction in depressive symptom scores. Watanabe et al. [20] similarly compared lithium with imipramine. In 64 patients with depression (of whom only five had a bipolar disorder; depressed state, circular type) no significant differences were found between the two treatments in the rate of response, depression scale scores or clinical effects. The results for the five bipolar patients are not given separately. However, the average lithium levels reported were low: 0.41–0.45 mEq/l. Trials describing responses to antidepressants co-administered with lithium or other mood stabilizers have been inconsistent. Cohn et al. [21] conducted a 6 week, doubleblind comparison of fluoxetine, imipramine, and placebo in 89 patients with bipolar depression. Importantly there was a response to fluoxetine (and imipramine compared with placebo). Of the patients who completed the trial, a number were also on lithium [21]: 4/17 fluoxetine subjects, 1/14 imipramine subjects and 2/10 subjects treated with placebo. The numbers were insufficient to allow any comment about the value of combination treatment. There are two studies which have examined the efficacy
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of paroxetine in combination with lithium. Despite some initial concern that it might produce a serotonin syndrome, the combination has been reported to be safe [22,23]. Bauer et al. [24] reported a trial of lithium-maintained patients suffering from a breakthrough episode of major depression who were randomly assigned under double-blind conditions to receive paroxetine 20 mg/day (n ¼ 19) or amitriptyline 75 mg/day (n ¼ 23). After 4 weeks, a significantly greater proportion of patients in the paroxetine group had achieved a 50% reduction in baseline Hamilton Rating Scale for Depression scores, and the mean improvement in Clinical Global Impression severity of illness was significantly greater in the paroxetine group at weeks 3 and 5. Serum lithium levels were not affected by either antidepressant. The authors proposed that the more rapid improvement demonstrated by the group receiving the combination of lithium and paroxetine may be due to the synergistic serotonergic effects of these two medications. This finding contrasts with that of the largest study to compare the combination of lithium and paroxetine or imipramine which showed no difference from lithium plus placebo in the treatment of patients with bipolar depression [15]. As already noticed this may be a failed rather than a negative trial. In a randomized, double-blind, parallel group, multicentre study of moclobemide (450–750 mg daily) and imipramine (150–250 mg daily) in 156 patients with bipolar disorder there were no statistically significant differences between the two groups on any efficacy measures [25]. Though this trial was not designed to study the efficacy of combined treatment with lithium, the proportion of patients on lithium was broadly similar in the moclobemide (n ¼ 37; 46%) and imipramine (n ¼ 37; 49%) groups. The similar efficacy of the two antidepressants may also translate to similar efficacy of the combination of lithium plus imipramine and lithium plus moclobemide. A recent underpowered study compared the efficacy of combined mood stabilizer treatment against mood stabilizer with an antidepressant in 27 patients with bipolar disorder [26]. There were no differences in the efficacy of the two treatments. Nineteen of the 27 patients in the trial were on lithium.
6. Lithium and suicide Suicide is a tragic consequence of the depressive pole of bipolar disorder [27]. In a meta-analysis of suicide risk among patients with a mental illness, Harris and Barraclough [28] demonstrated that patients with bipolar disorder had a risk of suicide 15 times greater than the expected value though there was considerable variability between studies. Given that depression is usually the final common pathway to suicide, it follows that better treatment of and protection against bipolar depression might be the key to a reduction in the suicide rates in bipolar disorder.
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There is good evidence for an association between lithium treatment and lowered suicide rates. It is based on a number of careful naturalistic studies [29–34]. In a recent meta-analysis of the effect of long-term lithium treatment on suicide rates in 5647 patients with a major affective illness, the number of suicides by patients on lithium was 0.159 per 100 patient years compared with 0.875 per 100 patient years in patients off lithium [35]. In a sub-analysis of 12 studies reporting observations with and without lithium and also rates of suicide greater than 0 in the untreated condition, the overall risk ratio of 8.85 (95% confidence intervals 4.14–19.1) favoured lithium and was highly statistically significant (P ¼ 0:0001). This reduction of suicide rates by lithium of slightly more than 82% was seen in a population where the main diagnosis was bipolar disorder, although patients with schizoaffective disorder were also included in the study. The beneficial effect of lithium also seems to extend to attempted suicide with good evidence for a reduction in suicidal behaviour while on lithium [36]. Interpretation of these studies is constrained by a number of factors that may bias the results. None are randomized studies, so all rely on naturalistic comparisons. The most convincing are studies where the same patient populations contribute estimates of rates on and off lithium. The least convincing are those where a clinic population treated with lithium can sometimes be shown to have a mortality rate from suicide lower than the general population. In the latter studies, the most important confound is the healthy compliance factor of good clinic attenders.
7. Conclusion Lithium is a widely used treatment for patients with bipolar depression. Its use is strongly promoted by guidelines dominated by North American opinion. It is the weight of opinion and not evidence that shapes practice at present. Indeed, it would be difficult, actually impossible, to imagine a drug with lithium’s portfolio surviving contemporary regulatory scrutiny for acute treatment of depressive episodes in bipolar disorder. There is almost no evidence that lithium has been shown to be superior to placebo or any active comparator in randomized controlled trials. Randomized trials are not the only kind of evidence, however: clinical experience counts and if guidelines were followed they should show low rates of antidepressant use in North America. In fact, even pragmatic surveys suggest that the recourse to antidepressants by clinicians is common and probably necessary. Audit suggests that antidepressants are compatible with satisfactory outcomes [37]. Thus, lithium’s promotion as an acute antidepressant agent is not entirely at one either with the evidence base or clinical practice. It is unclear whether lithium in combination with an antidepressant offers particular advantages for the treatment of bipolar depression. It has long been thought to augment the actions of antidepressants in the treatment of unipolar states [38].
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The evidence for lithium as an effective maintenance treatment in bipolar disorder is good, if not overwhelming, given the extent of its use. There is a reasonable basis for saying that lithium prevents both manic and depressive relapse when these are severe, but recent trials suggest that it may be more effective in preventing the return of manic than depressive symptoms. It is also widely accepted that lithium seems to have a beneficial effect on the rate of suicide and deliberate self-harm in patients with affective disorders. This may be via its effects upon bipolar depression, or conceivably by an independent anti-suicidal action. Lithium remains of central importance for maintenance treatment. That its use is often neglected in North America in favour of other compounds of less certain efficacy is a matter of regret. However, its position as an acute treatment for bipolar depression merits greater scepticism and may currently be overstated. It is, however, a key reference compound for comparator studies in all phases of bipolar illness. With the rising interest in treating bipolar depression, it will be essential for lithium to be included as an active comparator. Only then, and very belatedly, are we likely to discover how efficacious it really is, and whether we should promote its use in acute bipolar depression.
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