Molecular Psychiatry (2002) 7, S8–S14  2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp ORIGINAL RESEARCH ARTICLE What makes a a primary mood stabilizer? PE Keck Jr1, SL McElroy1, N Richtand2 and M Tohen3,4

1Biological Psychiatry Program, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 2Cincinnati Veteran Affairs Medical Center, Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH, USA; 3Eli Lilly and Company, Indianapolis, IN, USA; 4Consolidated Department of Psychiatry, Harvard Medical School, Boston, MA, USA

The term ‘mood stabilizer’ has been applied to a number of for the treatment of patients with . The operational definition of the properties of a mood-stabiliz- ing has varied according to the properties of specific medications and the clinical characteristics of the illness. Randomized controlled trials of agents accepted or proposed as mood stabilizers are reviewed to marshall the available evidence in support of this claim. In addition, potential pharmacological mechanisms underlying mood-stabilizing effects of established compounds are reviewed. Molecular Psychiatry (2002) 7, S8–S14. DOI: 10.1038/sj/mp/4001013 Keywords: bipolar disorder; ; antiepileptics; atypical ; ; depression

Introduction Clinical treatment targets Bipolar disorder is a common, recurrent, often lifelong, The diagnostic criteria for mania and depression, as major psychiatric disorder and a major public health specified in the Diagnostic and Statistical Manual of problem.1 This illness is characterized by recurrent Mental Disorders, Fourth Edition-Text Revision (DSM- manic, mixed and depressive episodes. These epi- IV-TR),11 consist of symptoms reflecting disturbances sodes, in turn, consist of disturbances in mood, in mood, thought, behavior and perception. Other thought, behavior and perception.2 Without treatment, symptoms of mania not listed in DSM-IV-TR include bipolar disorder is associated with substantial risks of anxiety, hostility, impulsivity, violence, poor insight, morbidity and mortality. Data from a number of long- confusion, memory impairment and sensory hyperacu- term outcome studies indicate that full recovery from ity.12 Collectively, these symptoms are the targets for discrete mood episodes often lags behind symptomatic pharmacological and psychotherapeutic interventions improvement by many months.3–5 Prognosis for full and require more diverse therapeutic actions than recovery from acute episodes also appears to be implied by the term ‘mood stabilization’ alone. affected by the number of prior episodes, and recurrent The stereotypical characterization of mania as a state episodes are associated with a risk of progressive of sustained and grandiosity applies to a min- deterioration in functioning. Response to at least one ority of patients. Data from many phenomenological primary mood stabilizer, lithium, appears to be studies of the manic syndrome indicate that most inversely related to the number of prior mood episodes patients experience irritability (80%), depressed mood a patient has experienced.6 Bipolar disorder was the (72%) and mood lability (69%), as often as euphoria sixth leading cause of disability worldwide in 1990.7 (71%).13 The predominance of specific mood states or This illness can also be lethal. At least 25% of patients their combination is determined in part by the severity attempt suicide, and patients with mixed episodes dis- of illness and comorbid psychiatric illnesses, such as play increased rates of suicidal ideation.8,9 These alcohol- and substance-use disorders and anxiety dis- potentially devastating effects of bipolar disorder make orders.14 early accurate diagnosis and thorough treatment essen- Cognitive dysfunction of varying degrees is common tial. Since the introduction of lithium more than 50 in mania and depression. Grandiosity (78%) and racing years ago, pharmacological treatment has been the cor- thoughts (71%) are common nonpsychotic cognitive nerstone of management of this illness.10 disturbances in mania.13 Impaired insight and lack of recognition of symptoms are also common in mania.14 Inattention, indecisiveness and psychomotor retar- dation are common cognitive symptoms of depression. Studies of the prevalence of behavioral symptoms of Correspondence: Dr P Keck, Department of Psychiatry, University mania found that the most common manifestations of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 559, were pressured speech (98%), logorrhea (89%), psych- Cincinnati, OH 45267–0559, USA. E-mail: keckpeȰemail.uc.edu omotor agitation (87%), decreased need for sleep What makes a drug a primary mood stabilizer? PE Keck Jr et al S9 (81%), hypersexuality (57%) and extravagant behavior Thus, pharmacological treatment of bipolar disorder (55%).13 Other, less frequent, symptoms included viol- has been empirically based on the results of ran- ence (49%), religiosity (39%), regression (28%) and domized controlled trials of agents observed by clin- catatonia (22%), which is more common in mood dis- ician-scientists to be therapeutic for various symptoms orders than schizophrenia.13 Although patients with of the illness. Mood-stabilizing medications are bipolar depression often display symptoms indis- effective in ameliorating symptoms of the illness, but tinguishable from (unipolar) major depressive disorder, cannot be said to restore normal homeostasis to the some studies suggest that atypical features of hyper- underlying biological mechanisms of the illness based somnia, hyperphagia and leaden paralysis may be more on current understanding. Emerging data from neuro- common in bipolar patients.15 imaging and preclinical studies suggest that bipolar Psychotic or perceptual symptoms are a common disorder may be associated with impairments of struc- complication of mania. In studies reviewed by Good- tural plasticity and cellular resilience.21,22 win and Jamison,13 at least two thirds of patients with Over the years, the term ‘mood stabilizer’ has bipolar disorder experienced during a mood become synonymous with lithium’s therapeutic effects: episode, and in recent data from the Stanley Foun- the amelioration of mood and psychotic symptoms dation Bipolar Network, more than 90% of patients during manic episodes and the prevention of sub- reported experiencing psychotic symptoms during at sequent mood episodes with maintenance treatment at least one mood episode (Keck PE et al, unpublished therapeutic levels.20 Substantial research efforts have data). All forms of psychosis, including hallucinations, been devoted to unraveling the mechanism(s) by which (mood-congruent and mood-incongruent; lithium exerts its mood-stabilizing actions.21,22 In first-rank Schneiderian symptoms) and formal thought parallel with basic research in lithium neuropharma- disorder, can occur during manic or mixed episodes.16 cology, data from clinical studies revealed gaps in lith- The prevalence of psychosis in bipolar depression has ium’s therapeutic effects. Patients with severe mania,13 been less extensively investigated, but may occur in up rapid cycling23 and mixed episodes24 have been to one third of patients.17 Because the acute affective reported to have lower response rates to lithium than episodes of bipolar disorder are characterized by this patients without these clinical features. In addition to broad range of symptoms, primary mood-stabilizing these limitations in lithium’sefficacy, lithium is asso- agents would ideally have efficacy in treating multiple ciated with a number of bothersome day-to-day side symptom domains. effects that limit its tolerability in a substantial min- ority of patients.25 These limitations have spurred the development of pharmacological alternatives for Course of illness and relapse prevention patients intolerant or poorly responsive to lithium. However, for several decades following lithium’s intro- Bipolar disorder is a recurrent illness in more than duction, there was little progress in the development 90% of patients who experience an index manic epi- of other medications with mood-stabilizing properties. sode.18 The prevention of mood episodes, eradication In recent years, a proliferation of new agents have been of interepisode subsyndromal symptoms and inhi- actively studies for their potential mood-stabilizing bition of the inherent cyclicity and mood lability that properties.26 characterize the illness are the most important goals Divalproex was approved by the US Food and Drug of long-term pharmacological management of bipolar Administration (FDA) in 1994 for the treatment of disorder. Unfortunately, because of many methodolog- manic episodes associated with bipolar disorder. Olan- ical obstacles, randomized controlled trials of mainte- zapine received similar approval in 2000. Divalproex nance treatment in bipolar disorder have been difficult and expanded the therapeutic range of to execute.19 Traditionally, mood-stabilizing medi- mood-stabilizing agents in having equal efficacy in cations, eg, lithium, divalproex and , manic and mixed episodes24,27 and acute efficacy in have been antimanic agents.20 However, efficacy in the patients with rapid cycling.27,28 Data from randomized treatment of acute mania does not necessarily imply controlled trials indicate that divalproex and olanzap- that an agent will also have or prophy- ine effectively ameliorate behavioral, perceptual and lactic efficacy. It is possible that an agent effective in cognitive symptoms in patients with acute manic or preventing mood episodes could have limited to no mixed episodes.27,29–32 Recent data also indicate that, efficacy in treating acute episodes. Such a medication unlike typical agents, which exert anti- with selective prophylactic benefit would address the manic effects but may also be depressogenic, olanza- core traits of bipolar disorder, its cyclicity and propen- pine improved both manic and depressive symptoms sity for recurrence. To date, such an agent has yet to compared with haloperidol.32 be identified. There are currently no published data from ran- domized controlled trials regarding the efficacy of divalproex or olanzapine in the treatment of acute Primary mood stabilizers bipolar depression. Only indirect evidence is available to suggest that these agents may also have antidepress- Although bipolar disorder is a heritable biological ill- ant effects in bipolar depression.24,27,32–34 In one pla- ness, its etiology and pathophysiology remain obscure. cebo-controlled randomized comparison of the efficacy

Molecular Psychiatry What makes a drug a primary mood stabilizer? PE Keck Jr et al S10 of divalproex and lithium in the prevention of relapse From these initial impressions of ’s appar- into manic or depressive episodes, there was no sig- ent mood-stabilizing activity, as well as the evidence nificant difference in time to relapse among the three of olanzapine’sefficacy in the treatment of manic and treatment groups.35 In a secondary analysis, however, mixed episodes in patients with bipolar disorder, con- patients who began the trial on divalproex and were siderable interest has grown regarding the potential of randomized to continue divalproex were significantly other atypical antipsychotics as mood-stabilizing less likely to relapse than patients randomized to pla- agents. To date, there are no controlled trials of any cebo. There are no published randomized controlled in the acute treatment of bipolar trials of olanzapine in the maintenance treatment of depression, only preliminary observations from case bipolar disorder. Data from open trials suggest that it series.36,37,57–59 Similarly, there are no blinded con- may have efficacy in the long-term management of trolled trials of these agents in the maintenance treat- patients with bipolar disorder,36,37 but these obser- ment of bipolar disorder. was comparable vations require confirmation in controlled studies. in efficacy to haloperidol and lithium in a small 4-week Although data sufficient for an approved US FDA comparison trial in hospitalized patients with acute indication for treating any phase of bipolar disorder are bipolar mania.60 This study had insufficient power to lacking for carbamazepine, studies in acute mania, detect possible differences in efficacy among these depression and prophylaxis suggest that this agent also agents. A second controlled trial of risperidone com- has mood-stabilizing properties.38 The efficacy of car- pared its efficacy with haloperidol and placebo as bamazepine in the treatment of acute mania was adjunctive treatment to lithium or divalproex.61 Both superior to placebo in one crossover trial,39 and compa- antipsychotics produced significantly greater reductions rable to lithium40,41 and chlorpromazine42,43 in com- in manic symptoms than placebo during the first 2 parison studies. Three small placebo-controlled studies weeks of the trial. has been studied in one found carbamazepine to have efficacy as monotherapy large, multicenter, placebo-controlled trial in patients or in conjunction with lithium in patients with bipolar with acute bipolar mania.62 In this study, ziprasidone depression.44–46 The efficacy of carbamazepine as a was superior to placebo in reducing manic, psychotic, maintenance treatment has been less clearly substan- cognitive and behavioral symptoms. These findings tiated.47 Interpretation of the results of the only pla- confirmed earlier impressions of ziprasidone’s thymo- cebo-controlled trial is limited by the use of adjunctive leptic effects from controlled trials in patients with antimanic and antidepressant medications for break- .63 Data from controlled trials through symptoms during the trial.48 Two comparison of in bipolar disorder are not available. trials with lithium were recently completed.49,50 In the However, preliminary observations from case series first study, patients receiving carbamazepine required suggest that this agent may also have antimanic63,64 and significantly more adjunctive medications for break- antidepressant effects in bipolar disorder.65 through symptoms and experienced significantly more New antiepileptic agents are also being actively stud- side effects leading to treatment discontinuation.49 In ied as potential mood-stabilizing agents. , the second trial, relapse rates were not significantly dif- , and have been ferent between lithium- and carbamazepine-treated studied in randomized controlled trials in patients patients.50 with bipolar disorder. Two studies assessed the effi- cacy of gabapentin in the treatment of affective symp- toms.66,67 In both studies, the efficacy of gabapentin Candidate agents was not significantly different than placebo. Lamotrigine has been studied in randomized con- In the late 1980s and early 1990s, the thymoleptic trolled trials in all phases of bipolar disorder. Three properties of the prototypical atypical antipsychotic, studies assessed the efficacy of lamotrigine in the treat- clozapine, were first suggested to be mood stabilizing, ment of acute bipolar mania or .67–69 The and thus distinct from the specific antimanic activity first study randomized patients with bipolar I and II of typical agents.51 These observations have been based disorders to lamotrigine, gabapentin or placebo in a primarily on case reports and case series in highly crossover series of 6-week monotherapy trials.67 There treatment-refractory patients with bipolar disorder and were no significant differences among the three treat- the bipolar subtype of schizoaffective disorder.51–54 ment groups in reduction of manic symptoms. In the Two randomized controlled trials of clozapine treat- second trial, outpatients with manic, mixed or hypo- ment of patients with bipolar disorder have been pub- manic symptoms who were inadequately responsive or lished to date.55,56 One randomized controlled trial intolerant to lithium at therapeutic dosages were found comparable efficacy for clozapine and chlorpro- randomized to receive lamotrigine or placebo for 8 mazine in the treatment of hospitalized patients with weeks.68 Lamotrigine or placebo were either added to acute bipolar mania.55 The second randomized con- ongoing lithium treatment or administered as mono- trolled trial compared the addition of clozapine vs therapy to patients unable to tolerate lithium side treatment as usual in patients displaying manic symp- effects. There were no significant differences between toms with treatment-refractory bipolar or schizoaffec- lamotrigine and placebo in reduction of manic symp- tive disorder.56 In this long-term maintenance study, toms or response rate. In one other small inpatient trial, clozapine was superior to treatment as usual. lamotrigine was comparable to lithium in reduction of

Molecular Psychiatry What makes a drug a primary mood stabilizer? PE Keck Jr et al S11 acute manic symptoms.69 However, these latter two pelling data for efficacy in bipolar depression are only trials had insufficient sample sizes to detect significant available for lithium and lamotrigine. Similarly, main- difference between treatment groups, and the lithium- tenance efficacy data from randomized controlled trials comparator study lacked a placebo group and used a are only available for lithium, with more limited data low therapeutic lithium dosage of 800 mg day−1.In for divalproex, carbamazepine and lamotrigine. These contrast to these equivocal results in bipolar mania medications represent a diverse array of molecules trials, lamotrigine was superior to placebo in a large, with an even greater diversity of pharmacological multicenter, placebo-controlled, parallel-group study mechanisms. Some common mechanisms may be as monotherapy in patients with acute bipolar shared among certain agents. For example, the atypical depression.70 In addition, there were no significant dif- antipsychotics may exert antimanic effects via dopam- ferences in the proportion of patients switching into ine D2 receptor antagonism and antidepressant activity 77–79 manic or mixed episodes between the lamotrigine and by serotonin 5HT2 receptor antagonism. Although placebo treatment groups. Finally, lamotrigine was these proposed mechanisms may be overly simplistic, compared with placebo in a maintenance relapse pre- they represent real pharmacological differences vention study in outpatients with rapid cycling bipolar between atypical and typical antipsychotics which, in I and II disorders.71 Lamotrigine was superior to pla- turn, may reflect the unidirectional (antimanic) effects cebo in time to need for supplemental medications and of typical agents compared with bidirectional duration of time in the trial for bipolar II patients, but (antimanic and antidepressant) effects of atypicals. The not bipolar I patients. These findings are consistent effects of proven and putative mood stabilizers on with the hypothesis that lamotrigine may have antide- other neurotransmitter systems and receptors may also pressant, but no significant antimanic, effects in be relevant to their thymoleptic effects. Dysregulation bipolar disorder. This profile has been used to propose of neurotransmission involving catecholamines,80 ace- an alternative definition of a mood stabilizer, a medi- tylcholine,81 serotonin,82 GABA83 and glutamate84 have cation that effectively treats at least one aspect of been implicated in the pathophysiology of bipolar dis- bipolar disorder without exacerbating other phases of order. Neuronal sensitization and kindling have also the illness.20 been proposed as possible pathophysiological mech- Oxcarbazepine, an antiepileptic drug related to car- anisms.85 Recently, brain-derived neurotrophic factor bamazepine, has been studied in two active comparator has been shown to control dopamine D3 receptor trials in acute bipolar mania: one vs haloperidol72 and expression and to trigger behavioral sensitization by one vs lithium.73 There were no significant differences inducing overexpression of this receptor.86 The effects in efficacy among the treatment groups in these two of atypical antipsychotics on D3 receptors could rep- trials. However, the studies lacked sufficient power to resent an unexplored mechanism contributing to their detect potential therapeutic difference, and neither mood-stabilizing properties.87 contained a placebo control group. No studies, to our These or other receptor interactions may also simply knowledge, have assessed the efficacy of oxcarbazepine represent the most overt and readily measurable phar- in the treatment of bipolar depression. Two studies of macological properties of atypical agents. The effects oxcarbazepine maintenance treatment were too small of the atypical antipsychotics and new antiepileptics to interpret.74,75 on second messenger systems and cell survival path- Topiramate has been studied in one randomized pla- ways, including cAMP response element binding pro- cebo-controlled trial in inpatients with acute bipolar tein, brain-derived neurotrophic factor, Bcl-2 and mania.76 An interim analysis of this study revealed mitogen activated protein kinases, have yet to be exten- efficacy trends for topiramate (at approximately 250 mg sively studied. Some of these agents could exert mood- day−1 and 500 mg day−1) over placebo in reduction of stabilizing effects via these mechanisms.21,22,88 manic symptoms. However, at the conclusion of the Mood-stabilizing agents may also exert therapeutic trial, there were no significant differences in efficacy effects via mechanisms that are only indirectly or per- in reduction of manic symptoms among the topiramate ipherally related to the pathophysiology of bipolar dis- dosage groups and placebo. order. Such effects could be additive or synergistic and raise the possibility that treatment with more than one agent, each exerting effects at different points along a Primary mood stabilizers and mechanisms of pathophysiological process, might be more beneficial action in acute and long-term treatment than treatment with one agent alone. This possibility has only recently been A number of pharmacological agents have been or are supported by preliminary acute treatment61,89 and being studied as potential mood stabilizers. Data sup- maintenance studies.50,90 porting efficacy in the treatment of different symptom domains of mania are greatest for lithium, divalproex, Conclusions olanzapine, typical antipsychotics and ziprasidone. More modest evidence exists for carbamazepine, oxcar- In recent years, rapid advances in basic and clinical bazepine, risperidone and lamotrigine as antimanic neuroscience have yielded a number of potential pri- agents. Mood stabilizers as in acute mary mood-stabilizing medications and a promising bipolar depression have been much less studied. Com- means of exploring and understanding the mechanisms

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