The armamentarium of treatments for bipolar disorder: a review of the literature

International Journal of Neuropsychopharmacology (2007), 10, 411 431. Copyright f 2006 CINP doi:10.1017/s1461145706007413 The armamentarium of treatments for bipolar disorder: a review of the literature REVIEW CINP David A. Cousins 1 and Allan H. Young 2 1 Newcastle Magnetic Resonance Centre, Newcastle General Hospital, Newcastle Upon Tyne, UK 2 University Department of Psychiatry, Leazes Wing, Royal Victoria Infirmary, Newcastle upon Tyne, UK Abstract To assess current pharmacotherapeutic options for bipolar disorder, with particular emphasis on the use of antipsychotic agents, Medline and EMBASE were searched between January 1980 and December 2005 using the keywords schizoaffective disorder and bipolar disorder, combined with various antidepressants, antipsychotics, lithium or other mood stabilizers. English-language articles, review articles and original research articles were reviewed. Most data are available for the mood stabilizers lithium and valproate. However, these agents have important limitations regarding their tolerability and efficacy in certain groups. Newer anticonvulsants, especially lamotrigine, have demonstrated efficacy across mood-symptom domains. Antidepressants are not generally favoured as monotherapy in patients with bipolar depression or schizoaffective disorder, due to their potential to induce switching to manic states. However, data are emerging for the efficacy of selective serotonin reuptake inhibitors for bipolar depression in combination with atypical antipsychotics. Atypical antipsychotics may also be used as monotherapy or in conjunction with mood stabilizers for the treatment of acute mania and for continuing maintenance therapy. The choice of antipsychotic may be influenced by the therapeutic situation; formulations that facilitate administration in the acute scenario can provide rapid tranquillization, whereas those that enhance compliance may have a place in maintenance therapy. Our results suggest a growing role for atypical antipsychotics in the treatment of bipolar disorder and further data are anticipated. Received 14 June 2006; Reviewed 26 July 2006; Revised 19 September 2006; Accepted 25 September 2006; First published online 19 December 2006 Key words: Anticonvulsant, antidepressant, antipsychotic, bipolar disorder, mood stabilizer. Introduction Bipolar disorder is a severe and chronic condition with a broad spectrum of symptomatology, encompassing mild hypomania and depression through to more severe mania and depression accompanied by profound psychosis (Muller-Oerlinghausen et al., 2000; Thomas, 2004). Classically, bipolar disorder is described as a condition characterized by repeated periods of illness (mania, depression or mixed states) interspersed with complete recovery. However, one-third of patients suffer residual chronic symptoms and up to 60% of patients develop rapid cycling disorder, where four or more episodes occur within a year (Muller- Oerlinghausen et al., 2000; Post et al., 2003; Schneck et al., 2004; Young et al., 2000a). Address for correspondence: Dr D. Cousins, Newcastle Magnetic Resonance Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE, UK. Tel.: +44(0)191 2563446 Fax: +44(0)191 2820485 E-mail: D.A.Cousins@newcastle.ac.uk Bipolar disorder places a significant burden on both the individual and society. The lifetime risk of a patient with bipolar disorder attempting to commit suicide may be as high as 50%, and due to the disabling nature and young age of onset of the illness (<25 yr), bipolar disorder imposes a high economic burden (Slama et al., 2004; Thomas, 2004). Compounding this is the not uncommon association with comorbid disorders such as substance abuse (Keck et al., 1997; Maarbjerg et al., 1988). Manic phases of bipolar disorder can be destructive to the patient s ability to work and to form and continue relationships, and may even lead to criminal activity (Belmaker, 2004; Calabrese et al., 2003b). Depressive symptoms may present as full major depressive episodes, or as subthreshold, minor or dysthmic depressions (Mitchell and Malhi, 2004), and all of these presentations can significantly impair social and occupational functioning (Altshuler et al., 2002; Marangell, 2004). Persistent impairment of functioning may increase the risk of relapse. Rapid cycling is associated with poorer global functioning and a greater severity of illness than

412 D. A. Cousins and A. H. Young bipolar disorder where episodes do not occur as frequently (Mackin and Young, 2004; Schneck et al., 2004). Even when in apparent remission, individuals with bipolar disorder may suffer from cognitive and functional impairment (Altshuler et al., 2002; Martinez-Aran et al., 2002; Thompson et al., 2005). Lifelong pharmacotherapy may be required for bipolar disorder. The primary goals of treatment are to manage both the acute manic and depressive episodes and also to prevent the occurrence of further episodes. Within this remit, treatment itself should not precipitate mania or depression or induce rapid cycling (Muller-Oerlinghausen et al., 2000; Young et al., 2000a). Acute mania should be considered as a medical emergency and rapid control of symptoms such as aggression, agitation and impulsivity is necessary. The consequences of not treating these presentations of acute mania can be serious in terms of harm to others and to the patient. In the long term this may also hinder the patient s ability to return to work and to continue or form relationships. Conversely, intervention with antidepressants in the treatment of an acute episode of depression must be performed with the knowledge that such treatment may induce a switch from depression to mania a review of the individual s history and severity of depressive episodes is, therefore, essential (Belmaker, 2004). Although mania is the most dramatic expression of bipolar disorder frequently resulting in hospitalization patients spend approximately three times longer with depressive symptoms, and these present the highest risk for suicide attempts and significant psychosocial impairment (Isometsa et al., 1993; Judd et al., 2002). Maintenance treatment may be indicated in patients who have experienced a single manic episode in order to prevent recurrences, to reduce subthreshold symptoms and to reduce the risk of suicide (APA, 2002; Goodwin, 2003; Muller-Oerlinghausen et al., 2000). In patients experiencing rapid cycling, reduction of cycling frequency is important, as this is associated with increased depressive morbidity and suicide attempts (Coryell et al., 2003). Maintenance treatment should ideally enable patients to regain normal or nearnormal levels of functioning in social, occupational and family settings. Choice of treatment will depend upon symptomatology (history and severity of mania and/or depression), the presence of rapid cycling or comorbidities, and previous drug treatments. Continuation of subthreshold symptoms or breakthrough episodes may necessitate the addition of another medication (APA, 2002). The objective of this review is to critically assess the literature available for all the current pharmacotherapeutic options for bipolar disorder, which have demonstrated efficacy in clinical trials in the various symptom domains. Specifically, the place of antipsychotics in bipolar disorder will be evaluated. In addition, therapies used for schizoaffective disorder will be reviewed, as there are key mood symptoms (depression and/or mania) of this condition that may be considered within the spectrum of bipolar illness (Levinson et al., 1999; Adler and Strakowski, 2003; Thomas, 2004). Methods The search strategy employed was performed in two parts to take into account the extensive information available for older agents such as lithium and sodium valproate (Table 1). Part one consisted of searching Medline and EMBASE for English-language articles of any kind published between January 1980 and December 2005 using the keywords schizoaffective disorder and bipolar disorder in combination with the following terms: benzodiazepine, anticonvulsants (gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide), antipsychotics (amisulpride, aripiprazole, bromperidol, chlorpromazine, clopenthixol, clozapine, flupenthixol, fluphenazine, haloperidol, olanzapine, quetiapine, risperidone, sulpiride, ziprasidone, zotepine) and antidepressants (citalopram, escitalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, reboxetine, sertraline, trazodone, nefazodone, venlafaxine). Part two consisted of searching Medline and EMBASE for English-language review articles only published between December 1994 and December 2005 using the keywords schizoaffective disorder and bipolar disorder in combination with the following terms: lithium, anticonvulsants (carbamazepine, phenytoin, valproate/divalproex), tricyclic antidepressants and monoamine oxidase inhibitors. Articles were included in the review if they contained evidence pertaining to randomized controlled trials (RCTs) in patients with bipolar disorder or schizoaffective disorder (excluding studies also involving patients with a diagnosis of schizophrenia), including systematic reviews and meta-analyses. Controlled trials included those which investigated a medication vs. an active comparator. Where such data were not available for a particular agent, placebocontrolled trials were included. In addition, further data were extracted from the citations listed within any relevant review articles obtained.

Treatment options for bipolar disorder 413 Table 1. Search terms used in the review Benzodiazepines Anticonvulsants: Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Tiagabine Topiramate Vigabatrin Zonisamide Antipsychotics: Amisulpride Aripiprazole Bromperidol Chlorpromazine Clopenthixol Clozapine Flupenthixol Fluphenazine Haloperidol Olanzapine Quetiapine Risperidone Sulpiride Ziprasidone Zotepine Lithium Anticonvulsants: Carbamazepine Phenytoin Valproate/divalproex Results This literature search identified a number of relevant papers. Data from RCTs in patients with bipolar disorder or schizoaffective disorder, and systematic reviews and meta-analyses for each type of agent, including lithium, benzodiazepines, anticonvulsants, antidepressants and antipsychotic agents will be presented. Lithium Antidepressants: Citalopram Escitalopram Fluoxetine Fluvoxamine Mirtazapine Paroxetine Reboxetine Sertraline Trazodone Nefazodone Venlafaxine Tricyclic antidepressants Monoamine oxidase inhibitors Lithium has been the mainstay of bipolar disorder therapy for more than 50 yr, and current treatment recommendations advocate its use as first-line therapy for both acute and maintenance treatment (APA, 2002; British Association for Psychopharmacology, 2005; Calabrese et al., 2004; Goodwin, 2003). However, issues remain regarding its effectiveness in treating depressive symptoms, mixed states, rapid cycling and its narrow therapeutic window (Young et al., 2000a). In acute mania, a meta-analysis of RCTs (treatment periods 3 4 wk) has shown that the response rate for lithium is nearly twice that for placebo, with five being the number needed to treat to achieve a treatment response (Poolsup et al., 2000). In addition, the same analysis demonstrated that lithium treatment was twice as likely to achieve a response as chlorpromazine. However, there were no differences between lithium, carbamazepine and valproate (Poolsup et al., 2000). In some cases, lithium may take up to 8 wk to achieve its full effectiveness in mania (Cookson, 2001) and a history of more than 10 previous episodes has been putatively associated with a decline in response to lithium (Swann et al., 1999). The presence of dysphoria or dysphoric (mixed) mania has also been shown to be predictive of a poor response to lithium (Dilsaver et al., 1993; Swann et al., 1997). There are limited data from RCTs regarding the efficacy of lithium in the treatment of acute bipolar depression. However, literature reviews and guidelines support the use of lithium as initial therapy, with the addition of other agents as necessary to achieve a response (APA, 2002; Calabrese et al., 2004; Goodwin, 2003; Malhi et al., 2003; Nolen and Bloemkolk, 2000; Yatham et al., 2003a; Zornberg and Pope, 1993). One benefit of using lithium in acute bipolar depression is that it has a decreased risk of promoting switching to a manic state compared with some specific antidepressant medications (Nolen and Bloemkolk, 2000). A key advantage of lithium therapy is its beneficial effect in preventing suicide. In reviews and metaanalyses of clinical studies involving several thousand patients, the risk of attempted suicide was decreased by 6 15 times, and completed suicide by 3 17 times compared with patients not receiving lithium (Baldessarini et al., 2006; Cipriani et al., 2005; Schou, 1998). The rate of suicide attempts and completions with lithium treatment may even approach that of the general population. In addition, these studies have found that discontinuation of lithium is associated with a 9-fold increase in the rate of completed suicide (Baldessarini et al., 2003; Tondo et al., 1997, 1998b, 2001b). In a recent retrospective study, it was estimated that the risk of death from suicide is 2.7 times lower for patients receiving lithium than for valproate, although the patients studied were permitted other psychotropic medications (Goodwin et al., 2003). In a 15-yr observational study of 402 patients receiving maintenance lithium therapy for 5 yr, 23% had

414 D. A. Cousins and A. H. Young no recurrence of affective episodes during this period (Maj et al., 1998). The Cochrane systematic review of lithium vs. placebo as maintenance therapy in bipolar disorder (nine studies, n=825) estimated a decrease in the risk of relapse of 71% (Burgess et al., 2001). A subsequent analysis has estimated the risk of recurrence with lithium as more than three times less likely than with placebo in patients with bipolar I and II disorders (Deshauer et al., 2005). In a similar recent systematic review performed by Geddes and colleagues, lithium reduced the overall risk of relapses by 35%, manic relapses by 38%, but had a smaller effect on preventing depressive relapses (relative risk reduction of 28%; Geddes et al., 2004). This may be explained by the differential degree of effects of lithium on depressive symptoms between the bipolar I and bipolar II disorder subtypes (Tondo et al., 1998a, 2001a). Adverse effects of lithium are largely related to serum drug concentrations and, therefore, careful monitoring is required (Hopkins and Gelenberg, 2000; Sproule, 2002). With chronic treatment (>10 years), lithium progressively impairs renal tubular function, increasing the risk of developing interstitial nephritis. However, this risk may be minimized by using the lowest possible effective serum concentrations and by monitoring renal function on a yearly basis (Gitlin, 1999). Lithium is also known to induce both subclinical and overt hypothyroidism (Caykoylu et al., 2002; Schiemann and Hengst, 2002). However, it has been proposed that as individuals with acute mania may exhibit hyperthyroxinaemia, this decrease in thyroid function may be linked to the efficacy of lithium in such patients (Lee et al., 2000; Marangell et al., 1997). A meta-analysis of studies in bipolar disorder has also identified potential adverse effects of lithium on cognitive function, in particular on memory and speed of information processing (Honig et al., 1999). This may be a direct effect of lithium independent of diagnosis, as similar cognitive effects have been observed in some studies on normal human volunteers (Pachet and Wisniewski, 2003). Dose reduction or substitution with another agent may be warranted in cases with cognitive dysfunction impacting on function (Honig et al., 1999). Some studies have suggested that lithium exposure during pregnancy may have adverse effects on the fetus (Pinelli et al., 2002). However, a prospective controlled study showed that the incidence of birth defects in children born to women taking lithium was not significantly different to that of matched controls (Jacobson et al., 1992; Kallen and Tandberg, 1983). Caution must always be advised when prescribing in pregnancy, with decisions to treat, or continue treatment being made after due consideration of the risks and benefits in each individual case. Benzodiazepines Benzodiazepines are conventionally used as adjuncts to other mood-stabilizing therapies in the treatment of acute mania and agitation, and to promote sleep in such circumstances due to their sedative action. In addition, benzodiazepines may be used as short-term adjuncts if known stressors are present or early symptoms of relapse such as insomnia occur (APA, 2002; Goodwin, 2003). One study has compared intramuscular injections of lorazepam, olanzapine and placebo, in agitated patients with bipolar mania, over a 24-h period. At 2 h after the first drug administration, lorazepam was significantly less effective in reducing agitation than olanzapine, but this difference was not apparent after 24 h (Meehan et al., 2001). Lorazepam has also been shown to achieve a similar mean decrease in aggression and agitation as haloperidol, and a significantly superior improvement in manic symptoms when compared with chlorpromazine (Foster et al., 1997; Salzman et al., 1991). In patients already receiving maintenance therapy, lorazepam and clonazepam have demonstrated similar efficacy to haloperidol in terms of changes in Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS) and Clinician s Global Impression (CGI) scale. However, clonazepam may exhibit a longer time to onset of action than the other two agents (Chouinard et al., 1993; Lenox et al., 1992). When comparing benzodiazepines, lorazepam has shown greater efficacy than clonazepam in terms of symptomatic response and remission rates in one small study of patients with acute mania (Bradwejn et al., 1990). In general, benzodiazepines are well tolerated. However, respiratory depression may occur, which can be reversed with flumazenil (McAllister-Williams and Ferrier, 2002). Disinhibition, in terms of loss of control over aggressive impulses, is estimated to occur in less than 1% of cases treated (Dietch and Jennings, 1988; Rothschild, 1992; Rothschild et al., 2000). When used in conjunction with lithium in patients of both sexes with bipolar disorder, benzodiazepines have been associated with an increased incidence of sexual dysfunction compared with lithium monotherapy (Ghadirian et al., 1992). In addition, there is an increased incidence of benzodiazepine abuse in patients with severe mental illness, as these agents carry a high risk of dependency (Brunette et al., 2003; McAllister- Williams and Ferrier, 2002).

Anticonvulsants Older agents Current guidelines recommend the use of valproate or carbamazepine either as monotherapy or in combination with lithium for the treatment of acute mania. In addition, valproate is considered as a first-line therapy for patients experiencing rapid cycling, and as part of maintenance treatment (APA, 2002; Goodwin, 2003). Unlike lithium, valproate may achieve or maintain response in patients with acute mania who have experienced more than 10 previous episodes and in patients with co-existing depressive symptoms or mixed states (Freeman et al., 1992; Swann et al., 1997, 1999). In addition, the efficacy of valproate is apparently independent of prior responsiveness to lithium (Bowden et al., 1994). An early study in acute mania showed that valproate achieved a greater than 50% reduction in YMRS scores vs. 5% for placebo (Pope et al., 1991). A recent Cochrane review of valproate in acute mania has suggested that it is as effective as lithium and carbamazepine, but less effective than olanzapine (Macritchie et al., 2003). However, two studies directly comparing valproate with olanzapine have shown no significant differences in efficacy between treatments (Revicki et al., 2003; Zajecka et al., 2002). A third study showed a significantly shorter time to achievement of symptomatic remission for olanzapine, and a greater improvement in YMRS scores (Tohen et al., 2003b). Carbamazepine has separately been demonstrated to be as effective as lithium in patients with bipolar mania (Small et al., 1991), although a comprehensive review is warranted. In a subgroup analysis of a randomized, placebocontrolled study, valproate was equally effective in manic patients both with and without rapid cycling (Bowden et al., 1994). In a similar study, only 19% of patients with rapid cycling disorder responded to treatment with carbamazepine, compared with 28% of patients receiving lithium (Denicoff et al., 1997). A year-long study comparing valproate, lithium and placebo in the prevention of recurrence of any mood episodes failed to show any differences between the three treatment groups (Bowden et al., 2000). However, when compared with olanzapine, valproate achieved similar rates of mania episode recurrence over a 47-wk study period (Tohen et al., 2003b). In a study specifically investigating recurrence of depressive symptoms, valproate prolonged the relapse-free period compared with lithium (Gyulai et al., 2003). Over a 20-month treatment period in patients with bipolar I or II disorder and rapid cycling, the rate of relapse into a mood episode was 56% on lithium vs. 51% on valproate (p=non significant), and 22% for manic/mixed episodes with both treatments (Calabrese et al., 2005). Data for comparisons between carbamazepine and lithium maintenance treatment vary in outcomes, between greater efficacy of lithium and no significant differences between treatments in terms of recurrence of mood episodes. However, in the study by Denicoff and colleagues, around one-third of participants discontinued treatment due to lack of efficacy within the first year in both groups (Denicoff et al., 1997; Greil et al., 1997a,b). When patients receiving maintenance treatment were divided into classical bipolar disorder (bipolar I) and other disorders within the spectrum (including mixed states), publications from the same study have also shown varying results. Three have demonstrated greater efficacy for lithium (bipolar I) and carbamazepine (other disorders), respectively, whereas another has demonstrated no significant differences between these treatments (Greil et al., 1998; Greil and Kleindienst, 1999a,b; Kleindienst and Greil, 2000). A preliminary, small study has demonstrated that phenytoin, added in to existing therapy, is significantly superior to placebo in preventing relapses in patients with bipolar disorder (Mishory et al., 2003). Valproate and carbamazepine have been compared in a small study (n=30) of patients with bipolar mania. Although both agents demonstrated efficacy, valproate achieved a significantly greater reduction in YMRS score and response in more patients, in a shorter time than carbamazepine (Vasudev et al., 2000). Valproate and carbamazepine are both associated with thrombocytopenia and significant weight gain. Valproate may also cause tremor and alopecia, and it is known to be teratogenic. Carbamazepine may cause the potentially severe Stevens Johnson syndrome, and reduces the therapeutic efficacy of other agents such as oral contraceptives and the atypical antipsychotic risperidone, due to its enzyme-inducing action (de Berarids et al., 2003; Macritchie et al., 2001; Nemeroff, 2000; Risperdal 1, 2005). An extended-release formulation of carbamazepine has recently been developed and demonstrates a significantly greater efficacy compared with placebo in the treatment of acute mania (Weisler et al., 2004, 2005). Newer agents Treatment options for bipolar disorder 415 Lamotrigine is the most widely studied of the newer anticonvulsants in the treatment of bipolar disorder.

416 D. A. Cousins and A. H. Young Treatment guidelines recommend its use in the management of depressive episodes, for patients experiencing rapid cycling, and as maintenance therapy. Conversely, on the basis of no published studies, oxcarbazepine is recommended as adjunctive treatment for acute manic episodes, as well as maintenance treatment (APA, 2002; Calabrese et al., 2004; Goodwin, 2003). Data from RCTs for oxcarbazepine, levetiracetam, zonisamide, vigabatrin and tiagabine were not obtained from the search strategy employed here. In a small 4-wk pilot comparative study in 30 patients with acute bipolar mania, lamotrigine was as effective as lithium in terms of improvements in BPRS, Global Assessment of Functioning (GAF), YMRS and CGI severity (Ichim et al., 2000). Gabapentin has been studied as an adjunct to existing maintenance therapy with lithium and/or valproate in patients experiencing manic or mixed episodes. No significant differences from placebo were observed (Pande et al., 2000). Topiramate has shown some efficacy in patients with mania when compared with placebo in a single controlled study (Chengappa et al., 2001), although the negative results of a number of trials are in press. In bipolar I patients experiencing an acute depressive episode, lamotrigine has demonstrated significant improvements in Hamilton Depression (HAMD), Montgomery Asberg Depression Rating Scale (MADRS) and CGI scores, compared with placebo, when measured after 7 wk of treatment (Calabrese et al., 1999). In a study of patients with recent manic or hypomanic episodes, lamotrigine was significantly more effective than placebo in prolonging the time to requirement for additional drug treatment for depressive episodes; however, it was not different from placebo in prolonging time to requirement for additional drug treatment for manic episodes, unlike lithium (Bowden et al., 2003). In a similar study by the same group investigating prophylactic therapy in recently depressed patients, lamotrigine and lithium were again significantly more effective than placebo for preventing depressive and manic episodes, respectively (Calabrese et al., 2003a). However, when the data for these studies were pooled, lamotrigine was shown to be superior to placebo for prolonging time to additional drug therapy for mania as well as depression (Goodwin et al., 2004). In a further analysis of this dataset with patients aged o55 yr, lamotrigine, but not lithium, significantly delayed time to intervention for any mood episode vs. placebo, although there were no significant differences between the active treatment groups (Sajatovic et al., 2005). Lamotrigine and gabapentin have been directly compared in a small study of patients with refractory bipolar disorder. The response rate for lamotrigine, as measured by CGI improvement, was higher than that for gabapentin or placebo (52% vs. 23%). However, gabapentin was not significantly different from placebo for this measure (Frye et al., 2000). In patients experiencing rapid cycling, lamotrigine has shown modest efficacy in preventing relapses when compared with placebo (Calabrese et al., 2000). An estimated one in 500 1000 patients may develop exfoliative dermatitis following treatment with lamotrigine. In addition, it may be associated with headache, nausea, infection and insomnia (Bowden et al., 2004; Goldsmith et al., 2003; Hurley, 2002). Topiramate has been associated with attention, concentration and memory problems, fatigue, nausea and anorexia. It may also cause weight loss (Chengappa et al., 2001). Antidepressants Although a systematic review of 12 RCTs (n=1088) demonstrated that antidepressants are effective in the short-term treatment of bipolar depression (Gijsman et al., 2004), antidepressant monotherapy is currently not recommended as first-line treatment of acute bipolar depression, due to the risk of switching to manic states and induction of rapid cycling. Instead, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and venlafaxine, may be used in conjunction with antimanic mood stabilizers in order to reduce this risk. During maintenance therapy, the addition of an antidepressant for a short period only may be considered if breakthrough depressive symptoms occur (APA, 2002; Goodwin, 2003). Data from RCTs in bipolar disorder for sertraline, citalopram, escitalopram, fluvoxamine, reboxetine, mirtazapine, trazodone or nefazodone were not obtained using the search criteria outlined above. Tricyclic antidepressants In a study of patients with bipolar depression, after 6 wk of treatment, significantly more patients had >50% improvement in HAMD scores with fluoxetine compared with imipramine (Cohn et al., 1989). However, when compared with the MAOI moclobemide, imipramine demonstrated similar efficacy in improving depressive symptom scores (Silverstone, 2001). In patients with schizoaffective disorder and depression, addition of desipramine or amitriptyline

Treatment options for bipolar disorder 417 to haloperidol and benztropine had no significant beneficial effects on depressive symptoms (Kramer et al., 1989). In a review of clinical data from patients with bipolar depression, tricyclic antidepressants (TCAs) were shown to be associated with switching to a manic state in 11% of cases, compared with 3.7% for SSRIs (Peet, 1994). In a systematic review of six RCTs in patients with bipolar depression, TCAs were associated with switching to a manic state in 10% of cases, compared with 3.2% for all other antidepressants (Gijsman et al., 2004). Another study confirmed the trend for switching with imipramine rather than moclobemide (Silverstone, 2001). In studies investigating the addition of imipramine to lithium for maintenance therapy, there were no significant benefits associated with the TCA in either bipolar I or bipolar II disorder (Kane et al., 1982; Nemeroff et al., 2001; Prien et al., 1984; Quitkin et al., 1981). In addition, imipramine treatment may be associated with anticholinergic effects such as dry mouth and tremor, and weight gain (Nemeroff et al., 2001; Silverstone, 2001). MAOIs Tranylcypromine has been shown to be effective in the treatment of depressive symptoms in patients with bipolar disorder after 6 wk of treatment (Himmelhoch et al., 1982). In addition, a small study demonstrated response to tranylcypromine in patients who had previously not responded to imipramine (Thase et al., 1992). The tendency for switching to manic states may be less for MAOIs than for TCAs (Silverstone, 2001). MAOIs may cause daytime sedation, orthostatic hypotension, weight gain and sexual dysfunction. Irreversible inhibitors of MAOA can also cause hypertensive crises by preventing the breakdown of the vasoactive amine tyramine from the diet within the gut (Thase and Sachs, 2000). SSRIs In a study comparing the addition of paroxetine, imipramine or placebo to lithium in patients with bipolar disorder, there were no significant differences between treatment groups in terms of antidepressant response (Nemeroff et al., 2001). When compared with the addition of a second mood stabilizer, adjunctive paroxetine therapy has been shown to be of similar efficacy, but significantly more patients receiving paroxetine completed the 6-wk study (Young et al., 2000b). Adverse effects of SSRIs include tremor, insomnia, somnolence, weight gain and sexual dysfunction (Kennedy et al., 2000; Nemeroff et al., 2001; Thase and Sachs, 2000). However, they are generally considered to be safer than TCAs in overdose (Thase and Sachs, 2000). Other antidepressants In patients with bipolar depression receiving mood stabilizers, venlafaxine has demonstrated comparable efficacy to that of paroxetine in a single study, according to changes in depressive symptom scale scores. However, there may be an increased tendency for switching to manic states with venlafaxine (Vieta et al., 2002). Venlafaxine may be associated with increased blood pressure, somnolence, insomnia and dizziness (Thase and Sachs, 1998). Antipsychotics Antipsychotics may be used either as monotherapy or in combination with a mood stabilizer for the treatment of acute manic episodes, including breakthrough episodes, depending on the severity of symptoms. Conventional agents have been shown to be effective in up to 70% of patients with acute mania, particularly those with psychomotor agitation and psychosis (Vestergaard, 1992). Furthermore, a number of retrospective surveys have reported that depot conventional agents are effective in the maintenance treatment of bipolar disorder (Ahlfors et al, 1981; Littlejohn et al., 1994; Mannion et al., 1999; White et al., 1993). Although more recent research has shown that the newer atypical agents may be more effective than older drugs in the management of acute mania (Galvin et al., 1999; Rosenheck et al., 1997), it is important to note that many randomized, controlled trials exclude severe, violent or suicidal patients. Whether conventional antipsychotics have an advantage in severely ill patients has not been empirically demonstrated. Today, the atypical agents are generally preferred due to their reduced incidence of extrapyramidal side-effects (APA, 2002; Goodwin, 2003) compared with conventional antipsychotic agents. Recent guidelines recommend that depressive episodes with psychotic features or breakthrough mania may also be treated with antipsychotics (Calabrese et al., 2004). Similarly, schizoaffective disorder may be treated with a combination of an antipsychotic and an antidepressant. Treatment with these agents may also be continued into the maintenance phase of bipolar disorder management, according to

418 D. A. Cousins and A. H. Young the individual s symptoms and history (APA, 2002; Calabrese et al., 2004; Goodwin, 2003). Conventional agents In an early small study, haloperidol achieved significantly greater improvements compared with lithium (Garfinkel et al., 1980). Subsequently, haloperidol has also demonstrated comparable efficacy to olanzapine and risperidone in large studies of patients with acute mania (Sachs et al., 2002; Tohen et al., 2003a). In addition, in patients with schizoaffective disorder, haloperidol was as effective as risperidone in improving both manic and depressive symptom scores (Janicak et al., 2001). Similar efficacy in comparison to carbamazepine has also been observed with haloperidol (Small et al., 1995). Haloperidol may achieve a rapid (f3 d) and significant response in acute mania when given as oral loading doses, comparable to that observed with valproate (McElroy et al., 1996). In addition, intramuscular haloperidol may be used for rapid tranquillization in agitated patients, as it can achieve a significant reduction in symptoms within 2 h of initial administration (Chouinard et al., 1993). The addition of valproate to haloperidol in patients with acute mania has been demonstrated as more effective than haloperidol monotherapy, and also allows a reduction in haloperidol dose, thus minimizing the potential side-effects of the latter (Muller- Oerlinghausen et al., 2000). A single, small study investigating the effects of adding phenytoin to haloperidol has shown significant improvements in symptom scores in patients with bipolar mania compared with haloperidol alone, but no difference between treatments was observed in patients with schizoaffective mania (Mishory et al., 2000). Sulpiride has been compared with amitriptyline in patients with bipolar depression. Both treatments showed significant improvements in depressive symptom scores, but sulpiride achieved a treatment response more quickly (1 wk) (Bocchetta et al., 1993). There are few data from controlled studies with depot conventional antipsychotics. In patients with bipolar disorder experiencing recurrent mood episodes who had previously suboptimal responses to lithium therapy, switching to flupenthixol decanoate depot was associated with significant reductions in the frequency and duration of manic episodes. However, the switch was also associated with significant increases in the frequency and duration of depressive episodes (Ahlfors et al., 1981). In another small study, flupenthixol decanoate demonstrated no significant prophylactic efficacy against recurrent mood episodes when compared with placebo as adjunctive therapy in lithium-treated patients (Esparon et al., 1986). However, switching to depot haloperidol decanoate from oral antipsychotic therapy has been shown to reduce the incidence of manic relapse (Lowe and Batchelor, 1986). The side-effects of conventional antipsychotics are well documented and include extrapyramidal symptoms, sedation, weight gain and sexual dysfunction (Allison et al., 1999; Small et al., 1995; Zarate, 2000; Tohen et al., 2003a). Atypical agents Clozapine Clozapine has been shown to significantly improve symptom scores in patients with bipolar mania in comparison with placebo, when added to either lithium or valproate therapy. In this year-long study, there were no differences between treatment groups in depressive symptom scores (Suppes et al., 1999). Olanzapine Olanzapine has demonstrated significant improvements in mania symptoms vs. placebo and similar efficacy to lithium in patients with acute mania (Berk et al., 1999; Tohen et al., 1999, 2000). Studies comparing olanzapine with valproate have produced variable results, with one study demonstrating no significant differences between treatments, and two showing a significantly shorter time to symptomatic remission and greater improvements in YMRS scores with olanzapine (Tohen et al., 2002a, 2003b; Zajecka et al., 2002). In the 47-wk study, olanzapine was significantly superior to valproate in terms of improvements in YMRS scores in patients without rapid cycling ( p<0.001), but there were no differences between treatments in patients with rapid cycling (Suppes et al., 2005). Reviews of pooled data have shown no differences between olanzapine and valproate (Hirschfeld et al., 2003). In a study of more than 400 patients with acute bipolar mania, olanzapine and haloperidol were comparable in terms of remission of symptoms (Tohen et al., 2003a). A Cochrane review of olanzapine in acute mania has suggested that olanzapine may be more efficacious than valproate for the treatment of mania (Rendell et al., 2003). However, results of a recent systematic review of the literature have shown that quetiapine and olanzapine are superior to placebo and comparable to lithium

Treatment options for bipolar disorder 419 and valproate in improving manic symptoms (Bridle et al., 2004). A 1-yr study in more than 400 patients with a history of manic or mixed episodes has shown that olanzapine and lithium monotherapy are comparable in terms of rates of recurrence (depressive or manic episodes; 30.0% vs. 38.8%). However, the risk of recurrent manic or mixed episodes was significantly reduced with olanzapine vs. lithium (Tohen et al., 2005). Olanzapine has also been shown to significantly improve symptom scores in patients with bipolar mania in comparison to placebo, when added to either lithium or valproate therapy (Bridle et al., 2004; Tohen et al., 2002b). An analysis of pooled data from two studies has shown that patients with rapid cycling disorder respond early to olanzapine, but then tend to experience relapses, especially of depressive illness, compared with patients without rapid cycling disorder (Vieta et al., 2004). In a 49-wk extension of a double-blind study in patients with bipolar disorder, adjunctive olanzapine significantly improved HAMD scores from baseline to end-point (Sanger et al., 2001). The addition of fluoxetine to olanzapine in patients with bipolar I depression has also recently been investigated. Results showed that the combination was significantly superior to olanzapine monotherapy for the improvement of depressive symptoms and the proportion of patients achieving remission (Tohen et al., 2003c). A subsequent further analysis of the dataset has shown that the risk of mania induction did not differ significantly between treatment groups (<7% for all groups) (Keck et al., 2005). Risperidone In a placebo-controlled study in patients with acute bipolar mania, risperidone monotherapy has demonstrated significant improvements in YMRS, MADRS and Positive and Negative Syndrome Scale (PANSS) scores. The significant between-group differences became apparent as early as day 3 of treatment (Hirschfeld et al., 2004). In a direct comparison, risperidone has been shown to be as effective in the treatment of acute bipolar mania as lithium and haloperidol (Segal et al., 1998). In studies assessing the addition of risperidone to mood stabilizers in patients with acute bipolar mania, risperidone demonstrated superior efficacy to placebo and comparable efficacy to haloperidol (Sachs et al., 2002; Yatham et al., 2003b). In patients with schizoaffective disorder, risperidone and haloperidol were equally effective in reducing mania symptoms and depressive symptoms. However, in a subset of patients with severe depression (HAMD >20), risperidone produced an improvement of >50% in HAMD score in a significantly greater proportion of patients than haloperidol (Janicak et al., 2001). A small study has investigated the effects of risperidone, paroxetine and the two combined for the treatment of bipolar depression. All three groups demonstrated significant improvements in depressive symptoms from baseline to end-point, with no differences between treatments (Shelton and Stahl, 2004). Quetiapine Results from an 8-wk study involving bipolar disorder patients experiencing a major depressive episode have shown that quetiapine (300 or 600 mg/d) achieved significant improvements in MADRS total scores compared with placebo from week 1 onwards. Moreover, the proportions of patients meeting response criteria (o50% MADRS score improvement) at final assessment in the groups taking 600 and 300 mg/d of quetiapine were 58.2% and 57.6% respectively, vs. 36.1% for placebo (Calabrese et al., 2005). Two separate 12-wk studies have investigated the effects of quetiapine in 403 patients with bipolar I mania. Pooled data from these demonstrate a significant improvement in YMRS score for quetiapine vs. placebo from day 4 onwards, maintained throughout the remainder of the study period. In addition, significantly more patients receiving quetiapine achieved a response than those receiving placebo ( p<0.001) (Vieta et al., 2005b). Another 12-wk study has shown that both quetiapine and lithium significantly improve YMRS scores compared with placebo ( p<0.001 for both comparisons), and that the proportion of responders (improvement in YMRS score of o50%) with both active treatments was significantly greater than that observed with placebo (72.0% and 75.5% vs. 41.1%, p<0.001). Similarly, remission rates (defined as YMRS score f12) at day 84 were significantly higher for both active treatments than for placebo (69.2% and 72.4% vs. 33.7%, p<0.001). There were no differences between the quetiapine and lithium groups (Bowden et al., 2005). The addition of quetiapine to either lithium or valproate in patients with bipolar mania has been shown to significantly improve symptom scores in comparison to placebo, or either active comparator treatment alone (Bridle et al., 2004; Delbello et al., 2002; Sachs et al., 2004; Yatham et al., 2004).

420 D. A. Cousins and A. H. Young Ziprasidone In a single 3-wk study, ziprasidone monotherapy achieved rapid and sustained improvements from baseline in YMRS and CGI severity scores, which were significantly superior to placebo (Keck et al., 2003b). Aripiprazole In patients with acute bipolar mania, aripiprazole has been shown to significantly improve YMRS scores and achieve response in a greater proportion of patients compared with placebo, over a 3-wk treatment period (Keck et al., 2003a). Comparative studies In a year-long study in patients with schizoaffective disorder, maintenance therapy with olanzapine was significantly superior to haloperidol in terms of symptom scores and numbers of patients completing the study (Tran et al., 1999). A short-term study (6 wk) comparing these agents in schizoaffective disorder has shown a significantly greater improvement in depressive symptoms and cognitive function with olanzapine compared with haloperidol, but no significant difference in the reduction of manic symptoms (Tohen et al., 2001). In a 4-month open-label study, quetiapine was compared with risperidone in patients with diagnoses including bipolar disorder and schizoaffective disorder. Both treatments achieved significant improvements in HAMD scores. In addition, quetiapine was significantly superior to risperidone (Sajatovic et al., 2002). Aripiprazole has been compared with haloperidol in a 12-wk study in patients with acute manic or mixed episodes. At the end of the treatment period, response rates (defined as improvement in YMRS from baseline of o50%) were 49.7% and 28.4% for aripiprazole and haloperidol, respectively (p<0.001). Notably, a greater proportion of patients remained on study medication at week 12 in the aripiprazole group (50.9%) vs. the haloperidol group (29.1%) (Vieta et al., 2005a). The atypical antipsychotics have a reduced propensity to cause extrapyramidal side-effects at therapeutic doses, compared with conventional agents (Tandon and Jibson, 2002). However, it is important to note that they have a number of side-effects which may influence their tolerability for patients with bipolar disorder. Clozapine and olanzapine are more likely to cause weight gain than quetiapine, risperidone, ziprasidone and aripiprazole (Allison et al., 1999; American Diabetes Association (ADA), 2004; Conley and Mahmoud, 2001). Notably, in one study, weight gain with olanzapine and clozapine was demonstrated to be predictive of treatment response; no such relationship has been determined for haloperidol or risperidone (Czobor et al., 2002). A recent consensus statement from the ADA has proposed that clozapine and olanzapine may also be linked to elevations in blood glucose and cholesterol (ADA, 2004; Lindenmayer et al., 2003). Olanzapine has also been associated with somnolence, oedema, rhinitis, and slurred speech (Rendell et al., 2003; Tohen et al., 2003a,b; Zajecka et al., 2002). Patients receiving clozapine require frequent blood monitoring to manage the risk of developing agranulocytosis associated with this drug. Risperidone produces a dose-related increase in serum prolactin levels, but this phenomenon is not apparently linked to its therapeutic or adverse effects (Potkin et al., 2003; Volavka et al., 2004). As such, the selection of an atypical antipsychotic must take into account both the side-effect profile of the agent, as well as the patient s past experience of sideeffects and their individual preferences. Discussion There is an ever-expanding variety of treatment options available for the acute and maintenance treatment of bipolar disorder. Lithium is effective for classical manic-depressive illness, but may be less so for other types of bipolar disorder within the spectrum, including those with psychotic features. In addition, prospective naturalistic studies in clinical practice have shown that the prophylactic efficacy of lithium may not be as great as that observed in clinical trials, due to poor compliance, social support and stressful life events (Kulhara et al., 1999; Schou, 1997; Schumann et al., 1999; Silverstone et al., 1998). The narrow therapeutic window and the potential for development of serious adverse events with chronic use may progressively limit the utility of lithium, now that better tolerated therapies are becoming available. Similarly, the efficacy of valproate in acute and possibly maintenance treatment, even with its advantages over lithium in patients with mixed states and rapid cycling, may be compromised by its adverse event profile, especially in women of childbearing potential, and by non-compliance (Keck et al., 1997). Of the newer anticonvulsants, lamotrigine has been most widely studied, and has demonstrated efficacy in acute treatment. In addition, an open-label extension of a study with lamotrigine has shown a significant and sustained improvement in depressive symptoms

Treatment options for bipolar disorder 421 as measured by MADRS and episodes of mania or hypomania occurred less frequently than in the year preceding enrolment into the study (McElroy et al., 2004). The data available also indicate that the risk of switching to mania may be lower with SSRIs compared with older antidepressants in patients with bipolar depression. In addition, atypical antipsychotics such as olanzapine and quetiapine are emerging as effective and well-tolerated treatments for manic and depressive symptoms in both acute and maintenance phases of bipolar disorder therapy, and this is reflected in the current management guidelines and the data presented in this review. However, it is important to note that the apparent benefits of the atypical agents over the conventional agents may in part be explained by the much higher degree of sophistication in clinical trials in the past 15 yr, and the fact that well designed, commercial studies often report a clinical advantage for the newest agents. It is of particular interest that a number of pharmacotherapies, diverse in molecular structure, ranging from single ions to more complex molecules, have been shown to be effective in the management of bipolar disorder. As such, it is unlikely that they share a common mechanism of action. However, there is evidence that each may have an effect of key neurostransmitter systems known to be of importance in the development of the symptoms of mania and depression. The dopaminergic system is one such example, and modulation of this system could account for a number of treatment effects. Several possible explanations have been proposed for the effect of lithium on the dopaminergic system. Microdialysis studies in rats have suggested that the mood-stabilizing action of lithium may be in part due to decreased dopamine release (Ferrie et al., 2005a,b). In experimental animals lithium appears capable of reducing the denervationtype supersensitivity of striatial dopaminergic receptors which follows long-term administration of conventional antipsychotic agents (Pert et al., 1978). In addition, lithium inhibits the activity of inositol monophosphatase, resulting in inositol depletion, an effect that could down-regulate second-messenger systems that are linked to the phosphatidylinositol cycle (Bell et al., 2005). The conventional antipsychotic agents are dopamine antagonists with high affinity for both D 1 type and D 2 type dopamine receptors, and it is the antagonism of the latter that is thought to decrease the symptoms of psychosis and aspects of mania (Farde et al., 1988). Atypical antipsychotic agents block both D 2 and serotonin-2 (5-HT 2 ) receptors, which could contribute to antimanic and antidepressive effects, respectively. Atypical antipsychotics also increase prefrontal dopamine activity, thereby providing both antidepressive and cognitive-enhancing effects (Schatzberg, 2004). Inhibition of dopamine reuptake has been postulated as a target of antidepressant action. Some of the SSRIs, such as sertraline, have been shown to inhibit dopamine reuptake (Tatsumi et al., 1997), while other SSRIs, such as fluoxetine, have been shown to increase extracellular dopamine in the rat prefrontal cortex (Bymaster et al., 2002). Furthermore, results from a recent study reported that several types of antidepressants (amitriptyline, desipramine, imipramine and tranylcypromine) significantly increased D 3 receptor messenger ribonucleic acid (mrna) expression in the shell of the nucleus accumbens after 21 d of treatment, while fluoxetine significantly increased D 3 receptor mrna after a 42-d treatment. This has led to the suggestion that the up-regulation of the D 3 pathway, involved in reward and motivation, may represent a common neurobiological mechanism of antidepressant action (Lammers et al., 2000). Finally, the anticonvulsant, valproate has also been shown to possess antidopaminergic properties, thereby reducing dopaminergic transmission. Although it is unlikely that this arises from direct receptor antagonism (Anand et al., 2000), it has been shown to reduce the rate constant for fluorodopa uptake in the striatum of first-onset manic patients, suggesting that it may work by either dampening second-messenger signalling pathways or decreasing dopamine synthesis (Yatham et al., 2002). Optimization of short- and long-term treatment for bipolar disorder can be problematic due to various factors. Short-term treatment for acute episodes of mania requires rapid intervention to take control of symptoms such as aggression, agitation and impulsivity before the individual becomes harmful to themselves or others (APA, 2002). Traditionally, therapies for short-term treatment have been oral tablet formulations requiring daily dosing, often in combination with other therapies. However, agitated patients in particular may be unable to take standard oral preparations of agents for rapid tranquillization. Risperidone and aripiprazole solutions, or oral dispersible risperidone and olanzapine, and short-acting intramuscular olanzapine and ziprasidone are preparations that can be used in acutely agitated patients in order to achieve rapid tranquillization. While an intramuscular injection is available for lorazepam, control of acute symptoms is not as rapid as that seen with atypical antipsychotics (Meehan et al., 2001). Valproate is available as an intravenous, oral nonsustained or sustained release loading therapy for the