Acute and maintenance treatment with mood stabilizers

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1 International Journal of Neuropsychopharmacology (2003), 6, Copyright f 2003 CINP DOI: /S Acute and maintenance treatment with mood stabilizers SPECIAL SECTION Charles L. Bowden The University of Texas Health Science Center at San Antonio, Department of Psychiatry, 7703 Floyd Curl Drive, San Antonio, TX , USA Abstract Treatment of bipolar disorder is complicated by the multiple phases of the illness, dimensional symptomatology that varies considerably across individuals, and a limited spectrum of activity for all mood stabilizers. Randomized, blinded, placebo-controlled studies provide clear guidelines to the overall efficacy of treatments for mania. However, for secondary questions, such as the treatment to employ when lithium or valproate is inadequate as monotherapy, evidence is incomplete, and usually derived from both smaller and less well-designed studies. For mania, the spectrum of efficacy of valproate is broader than for other mood stabilizers. However, many patients obtain inadequate benefit from monotherapy regimens of all mood stabilizers. Recent studies indicate that for patients who develop mania while taking a mood stabilizer, combinations of an antipsychotic and a mood stabilizer yield greater improvement than does continuation of the mood stabilizer alone. Maintenance-treatment studies support the efficacy of lithium, valproate and lamotrigine, although with a different spectrum of benefits and limitations for each. Valproate and lithium provide greater benefits for prevention of manic relapses and control of manic symptomatology than for depression. Several studies indicate actual worsening in depressive aspects of bipolar disorder with lithium treatment. Lamotrigine appears effective in delaying relapse into a new episode, with most benefits limited to delaying time to depression. Lamotrigine has not shown anti-manic activity in placebo-controlled studies. In contrast to traditional antidepressant medications, lamotrigine has not been associated with induction of mania, or of rapid-cycling illness symptomatology. Recent studies reported that carbamazepine was inferior to valproate in acute mania, and inferior to lithium in maintenance treatment. Other putative mood stabilizers have to date yielded negative or inconclusive results in studies in mania. Systematic studies are needed to clarify treatment guidelines for youth with bipolar disorder, and for other special populations, e.g. pregnant women and the elderly. Received 28 July 2002; Reviewed 13 November 2002; Revised 24 January 2003; Accepted 9 February 2003 Key words: Bipolar disorder, lamotrigine, lithium, mania, valproate. Introduction Treatment guidelines have assumed prominence in psychiatry and other areas of medicine over the past decade. One general factor in this development is the increased complexity of therapeutics in many areas of medicine. This is certainly the case for bipolar disorder. Psychiatrists have moved from a view of lithium as sufficient for mania, depression and prophylaxis, to an expanded repertoire of medications, often employed in combination, and to a realization that psychosocial interventions are also an essential Address for correspondence: Dr C. L. Bowden, The University of Texas Health Science Center at San Antonio, Department of Psychiatry (mail code 7792), 7703 Floyd Curl Drive, San Antonio, TX , USA. Tel.: Fax: Bowdenc@uthscsa.edu component of treatment. A second factor is that there is more attention to evidence based-practice. Evidence comes in several varieties. The widely and positively received expert consensus guidelines surveyed experts and asked a series of questions about preferred treatments for paradigmatic clinical situations in bipolar disorder (Sachs et al., 2000). This approach yielded clear consensus for a majority of the 1000-plus vignettes, and is particularly useful for situations for which high-quality studies are lacking. However, most authorities recommend that evidence be derived principally from randomized, parallel-group, prospective studies, preferably with a placebo group and an active comparator. This goal is not easy to achieve in all situations. To provide one example about the limitations of such studies, such trials generally exclude the most severely ill patients (those with comorbid substance abuse, other medical problems

2 270 C. L. Bowden Percent % improvement in manic syndrome score or active suicidal plans). Therefore, treatment recommendations for persons with these conditions must perforce come from lesser quality studies. Treatment of mania Classic Mixed Rapid cycling Figure 1. Divalproex Acute Mania Study.%, Divalproex; &, lithium. * Only one subject with rapid-cycling randomized to lithium. (From Bowden, 1995.) For bipolar disorder, evidence, and therefore consensus are best for treatment of mania. Several treatment guidelines have developed relatively clean schematics for first- and second-line treatment decisions. However, by the third-line recommendations and later ones, the evidence becomes partial and inconsistent. Even for mania, the most conclusive studies often have layers of information that should not be ignored by the practising psychiatrist. The primary outcome results for the largest study of divalproex in mania, and the only randomized, parallel-group, placebo-controlled study of lithium demonstrated the superiority of both drugs over placebo in alleviating manic symptoms in hospitalized manic patients (Bowden et al., 1994). However, this study had several additional findings, some published in the primary article, others in separate articles, which also have practical implications for treatment of bipolar disorder. One of these is shown in Figure 1. Those patients with mania accompanied by two or more pure depressive symptoms had greater improvement from divalproex than lithium, whereas those with pure mania had response rates that did not differ significantly between divalproex and lithium (Bowden, 1995; Swann et al., 1997). Students of bipolar disorder should read articles carefully, as important details, albeit often less conclusive in nature, are frequently given less prominence * than the primary measure. One often sees this in studies of bipolar disorder, as it is difficult to accumulate very large samples of bipolar disorder in controlled studies, in part as a consequence of the severity of manic states and the impaired insight and judgement of many persons in full bipolar episodes (Altman et al., 1994). As a result, investigators often address secondary issues either in prospectively planned analyses, or in post-hoc analyses that often provide clear, albeit inconclusive results on additional treatment issues. Study of treatments for bipolar disorder, as well as studies on pathophysiology and illness course are very active areas of investigation at present. Recently the first randomized, blinded, parallel-group comparison of valproate and carbamazepine in mania was published. Valproate was superior on nearly every measure reported, and was better tolerated than carbamazepine (Vasudev et al., 2000). This lesser efficacy is similar to the generally reduced efficacy of carbamazepine compared to lithium in both acute and maintenance studies (Greil et al., 1998; Lerer et al., 1987). Serious studies of combination therapies have begun to emerge. Two studies have enrolled patients who were experiencing a manic episode into treatment with lithium or valproate, and randomized half to received risperidone and half placebo. Risperidone+ mood stabilizer was superior to mood stabilizer alone (Sachs et al., 2002; Yatham, 2000). One of the two studies also employed haloperidol as an active comparator, and it was also superior in combination with mood stabilizer to the mood stabilizer alone, although less well tolerated than risperidone (Sachs et al., 2002). The risperidone mood-stabilizer combination was superior to mood stabilizer alone among those patients who had developed a manic episode while taking either lithium or valproate, but not among patients for whom olanzapine was started concurrently with lithium or valproate. Similar positive results were present in an olanzapine+mood stabilizer study (Tohen et al., 2000). A similar design took patients experiencing a manic episode and treated all with haloperidol, or an alternative antipsychotic if the patient was not tolerant of haloperidol, then randomized half to receive valproate, half placebo (Müller-Oerlinghausen et al., 2000). Those who received both haloperidol (or equivalent)+valproate had significantly greater improvement than those who received haloperidol alone. Additionally, patients receiving the combination therapy had their haloperidol doses lowered to levels significantly below those of patients treated with haloperidol alone (Müller-Oerlinghausen et al., 2000).

3 Mood stabilizer use in bipolar disorder Lithium Depakote Placebo Maintenance treatment Wilcoxon Test p Divalproex vs. placebo 0.46 Divalproex vs. lithium Lithium vs. placebo 0.04 Figure 2. Time to any mood episode or early termination for any reason in 1-yr randomized, double-blind trial. Bonferroni adjusted for 4 pairwise comparisons (adjusted p=0.02). (From Bowden et al., 2000.) Building on the studies in mania, two placebocontrolled studies of combination maintenance therapy have been completed. Olanzapine+lithium or valproate, was not superior to lithium or valproate as monotherapy on the primary outcome measure (time to development of a full mood episode, in an 18-month study of patients who were re-randomized following completion of a 6-wk study of olanzapine+mood stabilizer, vs. mood stabilizer alone), in mania. However, among the subset of 68 patients who were recovered at the point of randomization for maintenance treatment, combination treatment was superior to lithium or valproate monotherapy (Tohen M, Chengappa KNR, Suppes T, Baker RW, Zarate CA, Bowden CL, Sachs GS, Kupfer DJ, Ghaemi SN, Feldman PD, Risser RC, Evans AR and Calabrese JR. Prevention of recurrence of bipolar I disorder in patients responsive to treatment with olanzapine combined with lithium or valproate: An 18-month comparison of continued combination treatment versus lithium or valproate monotherapy. American Journal of Psychiatry (submitted for publication), 2003). Olanzapine was also studied as a combination maintenance regimen with lithium, compared to lithium alone, in bipolar I patients. Combination treatment was superior to lithium on time to a new mood episode. The combination regimen was also superior on time to development of a manic episode, but the combination regimen and lithium as monotherapy did not differ on time to development of depression (Tohen et al., unpublished observations). Increased attention has been devoted towards the maintenance phase of treatment in recent years. This stems from evidence that a large percentage of patients retain subthreshold symptoms following cessation of full episodes. Furthermore, such subthreshold Table 1. Number of days to relapse in 1-yr randomized maintenance study of bipolar disorder Time to 50% relapse to any episode Time to 25% relapse to mania Time to 25% relapse to depression From Bowden et al. (2000). Divalproex (n=187) Placebo (n=94) > Lithium (n=91) symptoms are significantly associated with functional and social impairment (Gitlin et al., 1995). Increased appreciation of the difficulties posed by non-adherence to treatment regimens has also fuelled interest in treatments that yield better tolerability and thus adherence, and psychosocial treatment strategies that may enhance adherence (Miklowitz and Goldstein, 1990). The study by Johnson and McFarland (1996) found that bipolar I patients who started on lithium treatment while hospitalized for manic episodes continued to take lithium following discharge for a mean of only 65 d. One consequence of early discontinuation of a mood stabilizer is increased treatment costs, principally as a function of higher rates of relapse requiring hospitalization (Hirschfeld et al., 1999). These findings have altered the views of investigators regarding the most important outcome measures in maintenance studies. The 1-yr randomized, double-blind, study of divalproex, lithium and placebo by Bowden et al. (2000) did not find a significant difference in time to any mood episode, although a trend favoured divalproex over lithium (p=0.06). However, such survival analyses require that all events other than the outcome measure be randomly distributed across the treatment groups. This requirement is not generally met in bipolar disorder if only full episode recurrence is considered a failure event, since non-adherence to the treatment medication and protocol is in part a function of uncontrolled bipolar symptomatology. Similarly, non-adherence due to side-effects, or early discontinuation due to sideeffects is essentially an unsatisfactory outcome, and in this study they occurred more frequently among lithium-treated than divalproex- or placebo-treated patients (Bowden et al., 2000). A post-hoc survival analysis which counted both time to any mood episode and time to early discontinuation for any reason as failure events indicated significantly longer time in study for divalproex- than lithium-treated patients

4 272 C. L. Bowden Table 2. Outcomes in randomized, open yr study of lithium vs. carbamazepine in bipolar disorder in completers Lithium (n=38 48) Carbamazepine (n=53 56) Hospitalized 37% 55% 0.09 Recurrence 40% 59% 0.09 Recurrence/concom 44% 67% 0.04 med Recur/concom/adverse 46% 71% 0.01 effects Recur/subclinical symptoms 48% 71% 0.04 From Greil and Kleindienst (1999a,b). (p=0.004) (Figure 2; Bowden et al., 2003). The study also found much more robust benefit for divalproex, as well as lithium, on prolongation of time to mania than time to depression. As shown in Table 1 the time to mania was doubled for divalproex compared to placebo, and 55% greater for lithium than placebo. By contrast, time to depression was 26% greater for divalproex than placebo, and actually shorter with lithium treatment than placebo. A second large randomized maintenance study with a different design had complementary findings. The study compared lithium to carbamazepine in an open, yr trial (see Table 2). No placebo was utilized, thereby making it easier to enrol patients with more severe forms of bipolar disorder. The planned primary comparison, time to re-hospitalization for a new episode, did not differentiate between lithium and carbamazepine. However, broader measures that included time to relapse, time to receiving additional medications, or intolerance did yield significant superiority for lithium over carbamazepine (Greil et al., 1998). In addition to the Bowden et al. (2000) study suggestive of lesser benefits of divalproex and lithium on depressive symptoms in the maintenance treatment of bipolar disorder, two other maintenance studies of lithium also support lithium having weak or no prophylactic antidepressant effects. The early randomized, blinded, placebo-controlled study by Dunner et al. (1976) of rapid-cycling bipolar patients, compared with non-rapid-cycling patients, found lithium to be more effective than placebo regarding number of new manic episodes over the follow-up period, but reported that the number of depressive episodes was greater for lithium-treated than placebo patients among both rapid-cycling and non-rapid-cycling patients. Analogous results were reported by Denicoff et al. (1997). Taken in the aggregate, these findings p indicate that current mood-stabilizing drugs have greater effectiveness on the manic aspects of bipolar disorder than the depressive aspects, with the difference being qualitatively different for lithium. Recent studies of lamotrigine indicate that its profile may be complementary, in benefiting principally depressive aspects of bipolar disorder, compared to low or possibly no direct benefits on manic symptomatology. The strongest evidence for acute antidepressant effects in bipolar depression comes from a 7-wk randomized, blinded study in bipolar I patients (Calabrese et al., 1999). Although the planned primary analysis did not indicate a significant difference, two more sensitive secondary measures, especially the Montgomery Asberg Depression Rating Scale (MADRS), indicated superiority of lamotrigine, with more robust advantage for the 200 mg/d dose than the 50 mg/d dose (Calabrese et al., 1999). The weaker results with the HAMD stem largely from the heavy weighting given somatic symptoms in the HAMD, compared with more emphasis on pure depressive mood and cognitive symptoms with the MADRS. All of the large, generally well-designed clinical trials of bipolar disorder of this decade have had at least one methodological weakness such as this. A principal reason for this is that the near absence of systematic studies treatments for bipolar disorder for 25 yr left little basis to select the most powerful dependent variables. Each study in a way serves as a pioneering experiment, with any methodological points learned then combined into the design of the next study of that particular aspect of bipolar disorder. The results of the acute depression study were consistent with an earlier systematic open trial, which also included an analysis of the comparative response of rapid-cycling vs. non-rapid-cycling patients enrolled in the 1-wk trial. Rapid-cycling patients had significant improvements in both mean depressive and manic symptomatology, with no difference in magnitude of benefit on depressive symptoms, but a somewhat lower rate of improvement of manic symptoms among rapid-cycling patients (Bowden et al., 1999). The study had suggestive evidence that only the subset of rapid-cycling patients with high manic symptomatology scores on entry did not improve with lamotrigine treatment. These studies led to the design of a study on the maintenance efficacy of lamotrigine in rapid-cycling patients. Patients could be enrolled in any mood state, but had to be stably responsive to qualify for randomization to lamotrigine or placebo. Any treatment needed could be employed during the open pre-randomization phase, but the patient could only be taking lamotrigine at the time of

5 Mood stabilizer use in bipolar disorder 273 randomization. The study therefore had components of an enriched design, in which the tolerability of lamotrigine, and the improvement while taking lamotrigine during the open phase would be expected to provide a group of patients who would be likely to improve further if randomized to lamotrigine. The prior primary efficacy measure was time to need for additional medication for depressive or manic symptoms. Lamotrigine and placebo did not differ significantly on this measure, in part a function of the lower than expected number of patients requiring intervention. However, two secondary measures indicated significant advantage for lamotrigine compared to placebo. Time to intervention for a new episode, or early discontinuation for any reason favoured lamotrigine significantly. Also, rates of study completion without intervention were superior for lamotrigine compared to placebo. Separate analysis of bipolar I and II patients indicated that lamotrigine was superior to placebo for bipolar II patients, but not for bipolar I patients (Bowden CL, Calabrese JR, Sachs G, Yatham LN, Asghar SA, Hompland M, Montgomery P, Earl N, Smoot TM, DeVeaugh-Geiss J, unpublished observations). A recent study of lamotrigine as maintenance therapy for bipolar I patients who were in, or had recently experienced a manic episode has been completed. Patients were treated with any medication as required for stabilization, but the only medication that patients could be taking at the point of randomization was lamotrigine, with any other medications taken having been tapered off prior to randomization. Patients were then randomized to treatment with lamotrigine, lithium or placebo for 18 months. The primary efficacy measure was again time to additional treatment for a mood episode, but with the longer study duration, which increased power, both lamotrigine and lithium yielded significantly longer time to event than placebo (Bowden et al., 2003). The other primary analysis, time to a mood episode, additional treatment, or early discontinuation for any reason, addressed the fact that early discontinuation was not randomly distributed across the three treatment groups, but rather was greater among placebo and lithium-treated groups. The main reason for differences in early drop out was adverse effects, which accounted for 5% of lamotrigine, 4% of placebo, but 24% of lithium-treated early dropouts. On this measure the lithium rate was significantly higher than either the placebo or lamotrigine rate of drop out. Analyses of time to a manic episode showed lithium, but not lamotrigine, superior to lithium. On time to a depressive episode, lamotrigine, but not lithium was superior Table 3. Treatment-emergent mood events: all controlled studies to date Placebo a (n=314) Hypomania 1.9% 2.1% Mania 0.3% 1.3% Mixed episode 0.3% 0.3% All events 2.5% 3.7% to placebo. Taken together with other studies of lamotrigine s effectiveness in bipolar depression (Calabrese et al., 1999; Frye et al., 2000) and lack of efficacy of lamotrigine compared to placebo in the treatment of acute mania, these studies form strong evidence that lamotrigine has moderate to marked efficacy in the alleviation of bipolar depression, and maintenance efficacy against new depressive episodes, with limited or no efficacy against mania. In randomized, blinded studies of over 1000 bipolar patients treated with either lamotrigine or placebo, the rates of observed mania or hypomania have not differed between lamotrigine and placebo (Table 3). Therefore, lamotrigine appears to offer a mood-stabilizing agent with benefits on depression, which are complementary to the principal acute and prophylactic benefits on mania that are established for valproate and lithium. Combination drug regimens Lamotrigine b (n=379) a Bipolar disorder (n=166); unipolar disorder (n=148). b Bipolar disorder (n=232); unipolar disorder (n=147). From Suppes et al. (1999). Most recent randomized, placebo-controlled studies address monotherapy regimens. Substantial proportions of patients with bipolar disorders are treated with combination regimens, sometimes for brief periods, but sometimes as maintenance regimens. The studies reviewed which combined mood stabilizers (lithium or valproate) with an antipsychotic establish the proof of principle that a second agent may provide additional benefit to a known efficacious treatment for bipolar disorder, as does the study of valproate added to an antipsychotic (Muller-Oerlinghausen et al., 2000; Sachs et al., 2002; Tohen et al., 2002). The placebocontrolled studies with olanzapine+mood stabilizer suggest some, albeit limited benefits of combination regimens in maintenance therapy (Tohen et al., unpublished observations). Most of the uncontrolled and limited controlled studies of combination therapy also indicate somewhat higher rates of side-effects with

6 274 C. L. Bowden combination regimens. However, combination regimens can often be safely implemented, albeit with initially gradual addition of the second medication. For example, lamotrigine combined with valproate results in higher serum levels of lamotrigine than for lamotrigine alone. However, slow titration of the two drugs, coupled with reducing the early dosage of lamotrigine can result in good tolerability of both drugs, which are the two most commonly combined drugs in the treatment of epilepsy (Tohen et al., unpublished observations). Discussion Recent well-designed studies provide excellent bases to utilize lithium, valproate, lamotrigine, and, somewhat less clearly at present, carbamazepine and antipsychotics. Several other anti-epileptic drugs, e.g. gabapentin, topiramate have been ineffective in controlled trials. Others, e.g. tiagabine, levetiracetam, zonisamide, have not as yet been satisfactorily tested in adequate trials, and/or have generally negative published open results (Grunze et al., 1999). The revised American Psychiatric Association (APA) practice guidelines for the treatment of bipolar disorder recommends that lithium or valproate be employed as the initial treatment for less severe mania states, and that either drug plus an antipsychotic be employed for more severe manic episodes. Atypical antipsychotic drugs are recommended as preferable to standard antipsychotic drugs, based on somewhat superior tolerability, and greater number of drugs with evidence of superiority to placebo in randomized, blinded studies (Hirschfeld et al., 2002). Additionally, the guidelines recommend that all patients with bipolar disorder should be treated with a mood stabilizer for maintenance treatment. Recommendations for combination treatment are less well supported by evidence, but at least some use of combinations of drugs with differing pharmacodynamic properties is supported by positive studies in both acute mania and maintenance therapy. The APA guidelines recommend that bipolar depressed patients be treated with either lithium or lamotrigine, and that antidepressants not be used without concurrent mood stabilization treatment. Recommendations for treatment of the depressed phase of bipolar disorder are less secure, consequent to the small number of adequate studies. A small number of studies also support the use of psychotherapeutic interventions for acute treatment, as well as maintenance treatment (Miklowitz et al., 2000). There are as yet limited bases to select treatments for youth with bipolar disorder or patients with concurrent substance abuse, despite these representing large and seriously ill groups within the spectrum of bipolar disorders. 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