2012 John Wiley and Sons A/S

Bipolar Disorders 2012: 14: 573–584

BIPOLAR DISORDERS

Review Article

Evidence-based options for treatment-resistant adult bipolar disorder patients Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ. Evidencebased options for treatment-resistant adult bipolar disorder patients. Bipolar Disord 2012: 14: 573–584.  2012 The Authors. Journal compilation  2012 John Wiley & Sons A ⁄ S.

Shi Hui Poona, Kang Sima,b, Min Yi Sumb, Carissa Nadia Kuswantob and Ross J Baldessarinic,d a

Objectives: Many patients diagnosed with bipolar disorder (BD) respond incompletely or unsatisfactorily to available treatments. Given the potentially devastating nature of this prevalent disorder, there is a pressing need to improve clinical care of such patients. Methods: We performed a literature review of the research findings related to treatment-resistant BD reported through February 2012. Results: Therapeutic trials for treatment-resistant bipolar mania are uncommon, and provide few promising leads other than the use of clozapine. Far more pressing challenges are the depressive-dysthymicdysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic trials for treatment-resistant bipolar depression have assessed anticonvulsants, modern antipsychotics, glutamate [N-methyl-Daspartate (NMDA)] antagonists, dopamine agonists, calcium-channel blockers, and thyroid hormones, as well as behavioral therapy, sleep deprivation, light therapy, electroconvulsive therapy (ECT), transcranial magnetic stimulation, and deep brain stimulation—all of which are promising but limited in effectiveness. Several innovative pharmacological treatments (an anticholinesterase, a glutamine antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and topiramate), ECT, and cognitive-behavior therapy have some support for long-term treatment of resistant BD patients, but most of trials of these treatments have been methodologically limited. Conclusions: Most studies identified were small, involved supplementation of typically complex ongoing treatments, varied in controls, randomization, and blinding, usually involved brief follow-up, and lacked replication. Clearer criteria for defining and predicting treatment resistance in BD are needed, as well as improved trial design with better controls, assessment of specific clinical subgroups, and longer follow-up.

Bipolar disorder (BD) is a persistent and potentially disabling and fatal psychiatric illness that ranks among the top ten leading causes of disability in young adults (1, 2). Clinical onset typically is during adolescence or early adulthood (3, 4), and the estimated lifetime prevalence of various forms of BD is over 2.0% (5). The illness is characterized by diverse and changing clinical presentations ranging from depression to mania, including mixed manic-depressive states, and sometimes rapid recurrences with several episodes

Department of General Psychiatry, Institute of Mental Health, bResearch Division, Institute of Mental Health, Singapore, cDepartment of Psychiatry, Harvard Medical School, dInternational Consortium for Bipolar Disorder Research, McLean Division of Massachusetts General Hospital, Boston, MA, USA

doi: 10.1111/j.1399-5618.2012.01042.x Key words: bipolar disorder – depression – mania – polytherapy – treatment resistance Received 13 June 2011, revised and accepted for publication 18 May 2012 Corresponding author: Dr. Kang Sim Department of General Psychiatry Institute of Mental Health 10 Buangkok View Singapore 539747 Fax: (65) 6385-5900 E-mail: [email protected]

a year (1, 6). The long-term course of BD includes high proportions of both major and minor morbid states with often chronic symptoms, multiple relapses, and infrequent euthymic periods as well as marked functional disability despite the use of current treatment options. Such long-term morbidity accounts for 40% of follow-up duration— even from illness onset—and three-quarters of this morbidity is accounted for by major and minor depressive as well as mixed states. Subsyndromal symptoms are more common than syndromal states in both type I and

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type II BD (7–9). In addition, the disorder is associated with substantial cognitive deficits, frequent anxiety symptoms and substance abuse, and variable functional disability, as well as high rates of suicide in youth and premature death from inter-current medical disorders at older ages to yield substantial risks of premature mortality (1, 3, 10–12). Contrary to earlier views of BD as having a favorable prognosis and high level of response to relatively simple treatment, the emerging picture is of a complex, often severe and disabling or fatal illness, with high levels of morbidity even with largely untested, but widely employed, combinations of a broadening array of pharmacological and psychosocial treatments (1). Many clinical experts and investigators have considered such unfavorable outcomes as manifestations of treatment resistance, although definitions and conceptualizations of this term vary considerably (13–16). Incomplete responses to treatment also vary markedly with different clinical states in BD, and are especially challenging in the depressive phases of both type I and type II BD (17–19). The term Ôtreatment resistanceÕ may well represent a euphemism that avoids dealing more directly with the severity, persistence, and variability that are typical of BD and the routine failure of available treatments to provide adequate control of its symptoms, particularly long-term and through depressive phases, or to fully counteract its disabling or fatal potential. Based on previous reports and clinical observations, a plausible, proposed working definition of treatment resistance in BD would involve responses considered clinically unsatisfactory following at least two, presumably adequate (by dose and duration), trials of dissimilar treatments within a specific phase of the illness (mania, depression, or subsyndromal breakthrough symptoms during maintenance treatment), excluding patients who have responded, but are intolerant of the treatment regime (20–24). Importantly, however, criteria for adequate dosage and duration of particular treatments for particular states in BD and for long-term prophylactic treatment are far more difficult to specify. Typically, resistance is considered following treatment trials for least 6 weeks in mania, 12 weeks in bipolar depression, and 12 months or more for long-term maintenance treatment (25, 26). However, such duration criteria are probably minimal, as some phases of BD require prolonged treatment exposure to provide maximal treatment responses (27, 28). Adequate assessment of treatment-resistant BD also includes consideration of potential contributions of other forms of psychiatric or medical illnesses, as well as the apparent

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adequacy of doses and durations of treatment trials, and treatment acceptance and adherence (1, 29, 30). Precise estimates of the prevalence of treatment resistance in BD are not available, but clinical experience indicates that the majority of BD patients show clinically unsatisfactory responses at some time. A major limitation to efforts to define treatment resistance in BD is that the disorder is highly recurrent, with tendencies to shift and change clinically over time, often leaving uncertain the sustained clinical effectiveness of therapeutic interventions even with well-demonstrated short-term efficacy (31). Given the high prevalence of incomplete or unsatisfactory treatment responses in BD, and the potentially devastating nature of this very common disorder, we have undertaken a review of reported clinical trials of innovative therapeutic approaches that might have clinical value in treatment-resistant BD. Methods

We searched the research literature using the database of the U.S. National Center for Biotechnology Information (NCBI)–MedLine ⁄ PubMed system. We considered published research reports apparently related to treatment-resistant BD appearing through February 2012, based on applying various combinations of the following search terms: bipolar disorder, treatment ⁄ drug ⁄ medication resistant or resistance, treatment refractory, and difficult to treat. Abstracts of promising reports were reviewed by three of the authors (SHP, KS and RJB), and copies of the full reports of those that appeared to meet entry criteria were reviewed in detail to extract relevant data. We also scanned the bibliographies of accepted reports for additional information. Minimal entry criteria included patients identified as having some form of BD based on a credible international diagnostic standard, such as DSM-III or -IV or International Classification of Diseases (ICD)-9 or -10. In view of the paucity of such reports, we did not apply rigorous quality criteria to the experimental designs of studies, such as substantial subject numbers, random assignment, adequate controls, blinding, reliable methods of assessment, and longterm follow-up. Results

Salient characteristics of studies identified are summarized and classified as pertinent to treatment resistance based on manic, depressive, or maintenance phases of BD (Table 1).

Open, prospective

Random add-on Failed ‡ 1 trial versus PBO, (AD + MS) blinded, crossover

Diazgranados et al. 2010 (23)

Failed 1–3 trials (ADs ‡ 6 weeks)

Open, prospective

Dell’Osso et al. 2009 (13) ‡1

‡1

‡1

Failed ‡ 1 ADs

Open, prospective

Benedetti et al. 2005 (17)

Treatment-resistant depression Ahn Open, et al. 2011 (52) prospective

Suppes et al. 1999 (36)

‡2

Add KTM or PBO

Add QTP (188 mg ⁄ d) to:LTG (228 mg ⁄ d) or LTG (204 mg ⁄ d) to QTP (208 mg ⁄ d) ± other Rxs Add sleep deprivation ± light to ADs or Li Add rTMS

Add DPZ (5–10 mg ⁄ d) or PBO Add CLZ

YMRS ‡ 15 after ‡1 Li, VPA, or CBZ ‡ 2 weeks Failed 2 MSs ‡2

Evins et al. 2006 (47) Blinded versus PBO

Failed QTP or LTG + other Rxs

OLZ only (5–40 mg ⁄ d)

‡2

Failed ‡ 2 MSs or APs (no OLZ)

Open, prospective

Chen et al. 2011 (40)

CLZ only

Failed trials Treatments

‡3

Resistance: definition

Failed Li, ACs + ‡ 2 APs

Design

Treatment-resistant mania Calabrese Open, et al. 1996 (35) prospective

Report

Table 1. Therapeutic trials for treatment-resistant bipolar disorder

73.7

58.0

81.8

38.9

–

N = 18

BD-I or BD-II (N = 11)

66.7

72.7

47.9

54.4

49.8

40.1

38.0

39.0

44.4

–

20.3

39.6

34.6

18.4

17

–

–

–

0.5

0.8

9.0

3.0

12.0

3.5

3.0

3.3

Remarks

55% improved ‡ 50% (HDRS), no switches KTN: 71% improved ‡ 50% (MADRS) PBO: 6% responded

70% improved 50% (HDRS): 17% stable 9 months

100% improved (CGI, GAF) 20% dropped out (side effects) 20% required other Rxs

Significant improvement (BPRS, CGI, BRMS)

KTM effective and safe acutely

No controls

Both useful short-term

–

CLZ effective

Marked improvements: CLZ effective 72% (YMRS), 32% (BPRS) Less with SzAff 88%: ‡ 50% reduction OLZ effective (YMRS) 78%: remission No improvement DPZ ineffective

Females Age Onset age Treated (%) (years) (years) (months) Main findings

(N = 60; – 55% resistant)

15 BD-I 22 BD-II 1 BD-NOS

26 BD-I 12 SzAff

N = 11

N = 18

10 BD 15 SzAff

Subjects

Treatment-resistant bipolar disorder

575

576

Retrospective, Failed 2 trials MSs ± naturalistic ADs

Sharma et al. 2008 (24)

>2

>2

Long-term maintenance treatment Burt et al. 1999 (46) Retrospective, Failed ‡ 2 MS ⁄ AD ‡2 chart study Gonza´lez-Isasi Randomized, ‡ 2 episodes ⁄ ‡2 et al. 2010 (15) placebo12 months on Combos controlled trial or ECT

Failed 1–2 MSs + ADs to 12 weeks

Open, prospective

‡2

Failed ‡ 2 MSs + ADs (MD or Mx)

Nierenberg et al. 2006 (50)

>2

Failed ‡ 12 weeks (MSs + ADs)

Open, prospective

Kemp et al. 2007 (54)

Medda et al. 2010 (69)

‡4

Failed ‡ 4 trials (ADs)

Open, prospective (sham lead-in) Open, prospective

Holtzheimer et al. 2012 (73)

>2

Failed ‡ 2 trials (ADs + MS)

Randomized, versus PBO

Goldberg et al. 2004 (18)

56.3

58.3

59.0

50.0

61.5

N = 11 N = 20

Add CBT versus continue Rx

BD-II (N = 31)

–

63.6

–

40.0

39.2

43.6

–

51.0 39.3

48.3

42.0

42.1

48.4

–

–

26.7

–

28.5 23.5

–

19.9

–

–

12.0

–

19.4

4.0

–

2.0

24.0

1.5

1.0

Remarks

54% responded (CGI) 27% slightly improved CBT: 45% improved Controls: 20% improved Better by 12 months

66% and 70% improved ‡ 50% (HDRS); 26% remission Recovered: LTG (24%), INS (17%), RSP (5%) 84% ‡ much improved (CGI) 45% remission 8 weeks 39% recurrences

33% improved ‡ 50% (MADRS)

Improved ‡ 50% (HDRS):67% PPX, 20% PBO Remissions rare, 1 switch HDRS improved by 70%; 92% remitted

–

No controls;

LTG somewhat superior No controls

ECT useful

–

–

Short trial

62% improved ‡ 50% No controls; (MADRS); no switches switches rare

Females Age Onset age Treated (%) (years) (years) (months) Main findings

BD-I or – BD-II (N = 66)

46 MD 50 Mx

4 BD-I 7 BD-II 1 BD-NOS

10 UP 7 BD

N = 22

4 UP 7 BD

Subjects

Add DPZ

Add INS, LTG, or RSP to MS + ADs Add LTG 199 mg ⁄ d) to: APs (64%), MSs (45%) alone or combined, other or no Rxs (19%)

Add APZ (15 mg ⁄ d) to APs (75%), ADs (67%), AEDs (50%), (3.7 Rxs ⁄ case) Add ECT

DBS · 6 months

Add BUP to: ADs (92%), APs (15%), Li (8%), AEDs (31%) (1.5 Rxs ⁄ case) Add PPX (1.7 mg ⁄ d) or PBO to: AEDs (91%), Li (27%) (1.2 Rxs ⁄ case)

‡2

Failed ‡ 2 trials (MS + AD)

Open, prospective

Erfurth et al. 2002 (14)

Failed trials Treatments

Resistance: definition

Design

Report

Table 1.(Continued)

Poon et al.

Open, prospective

Vieta et al. 2002 (81)

‡2

‡2

Failed Li and ‡ 1 MS (CBZ ± VPA, 6 months)

Failed ‡ 2 trials (MS ± other Rxs)

N=6

N = 40

N = 18

33.0

–

77.8

Add DLT to: BD-I or BD-II 100 Li (25%),AEDs (88%), (N = 8) ADs (1.7 ⁄ case), APs (12%) N = 23 43.5 Add OLZ (12 mg ⁄ d) to: Li (70%), AEDs (56%), ADs (48%), APs (31%), ± others (82%) Add TOP 28 BD-I 67.6 (202 mg ⁄ d) 3 BD-II 2 BD-NOS 1 SzAff

Add memantine (10–30 mg ⁄ day) Add memantine (10–30 mg ⁄ day) ECT (3 ⁄ week · 12 weeks)

42.0

39.9

–

29–61

49.0

42.0

45.5

–

24.2

–

–

–

–

–

6.0

10.8

12.0

1.0

12.0

6.0

–

Remarks

58% improved ‡ 50% (YMRS, HDRS, or CGI) Recurrences: 44%

100% improved (CGI)

100% improved ‡ 50% (YMRS or HDRS 100% improved

72.5% ‡ much improved CGIº

No controls

–

No controls

–

–

85% improved (CGI) T3 effective 33% remitted (GAF) 2% more depression; no switch 72% ‡ much improved – (CGI)

Females Age Onset age Treated (%) (years) (years) (months) Main findings

125 BD-II 37.7 34 BD-NOS (N = 159)

Subjects

Clinical: BD = bipolar disorder; BD-I = bipolar I disorder; BD-II = bipolar II disorder; BD-NOS = bipolar disorder not otherwise specified; MD = major depression; Mx = mixed-state; Rx = treatment; SzAff = schizoaffective; UP = unipolar major depressive disorder. Ratings: BPRS = Brief Psychiatric Rating Scale; BRMS = Bech-Rafaelsen Mania Scale; CGI = Clinical Global Impression; GAF = Global Assessment of Functioning; HDRS = Hamilton ˚ sberg Depression Rating Scale; YMRS = Young Mania Rating Scale. Depression Rating Scale; MADRS = Montgomery-A Treatments: AD = antidepressant; AC = anticonvulsant; AP = antipsychotic drug; APZ = aripiprazole; BUP = bupropion; BZD = benzodiazepine; CBT = cognitive behavioral therapy; CBZ = carbamazepine; CLZ = clozapine; Combo = combination of psychotropics; DLT = diltiazem; DPZ = donepezil; ECT = electroconvulsive therapy; INS = inositol; KTM = ketamine; Li = lithium carbonate; LTG = lamotrigine; MS = mood stabilizer; OLZ = olanzapine; PBO = placebo; PPX = pramipexole; QTP = quetiapine; RSP = risperidone; rTMS = repetitive transcranial magnetic stimulation; T3 = triiodothyronine; TOP = topiramate; VPA = valproate.

Open, prospective

Vieta et al. 2001 (77)

Silverstone and Birkett 2000 (83)

Failed ‡ 2 adequate ‡2 (6 week) antimanic or AD trials Retrospective Failed ‡ 2 trials ‡2 chart review (MS ± other Rxs)

Open, prospective

Macedo-Soares et al. 2005 (70)

‡2

Failed ‡ 2 trials (MSs or APs)

Open, prospective

Koulopoulos et al. 2012 (85)

‡2

Open, prospective

Koulopoulos et al. 2010 (84)

Add T3 (90.4 lg ⁄ d)

Failed trials Treatments

Failed ‡ 2 trials (MSs or APs)

Resistance: definition ‡2

Design

Kelly and Lieberman Retrospective Failed 14 trials 2009 (59) chart review

Report

Table 1.(Continued)

Treatment-resistant bipolar disorder

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Poon et al. Treatment-resistant mania

Treatments of proven efficacy for manic or hypomanic phases of BD, which often include mixed or psychotic features, include anticonvulsants and virtually all antipsychotic drugs, as well as high doses of potent benzodiazepine sedatives (25). The most notable, and widely internationally employed, agent with long-term mood-stabilizing effects as well as short-term antimanic efficacy is lithium. In addition, several drugs developed as anticonvulsants also have antimanic effects, notably carbamazepine and sodium valproate, although neither has regulatory approval for long-term prophylaxis (31). At present, many, if not most, BD patients are exposed to two or more moodaltering drugs (ÔpolytherapyÕ), mostly as plausible, but largely untested combinations of uncertain additional efficacy and safety (32–34). Such complex regimens greatly complicate testing of added experimental treatments in acute BD episodes which typically require many weeks to reach remission and recovery, even though most controlled efficacy trials in mania are carried out for only a few weeks (27, 28). We identified only a few trials of innovative treatments for treatment-resistant mania. These include studies of clozapine with evidence of efficacy in treatment-resistant mania (with or without psychotic features), either as a monotherapy or as an add-on to existing pharmacotherapy (35–37). Clozapine add-on use in BD also has been associated with reductions in the number and duration of hospitalizations over time (38). Compared with other psychotic spectrum conditions, clozapine administration in treatment resistant BD is associated with greater response rates and improvements in psychosocial functioning (37). Manic polarity, in turn, may predict better clinical response to clozapine (39). The efficacy of other second-generation antipsychotics (SGAs) has also been investigated. Chen and colleagues (40) found that 88.5% of the patients with treatment-resistant mania achieved a response [defined by a ‡ 50% reduction in Young Mania Rating Scale (YMRS) total scores] and 77.8% achieved remission (defined by a YMRS total score £ 9 at endpoint) with olanzapine monotherapy. Adjunctive use of aripiprazole has been effective in acute mania (41, 42), but with equivocal evidence of long-term benefits (43, 44). One study involving patients with psychotic mania or a schizoaffective disorder who had failed at least two trials of mood stabilizers or antipsychotics including clozapine found that adding aripiprazole to clozapine was effective in reducing symptom severity with no

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appreciable increase in short-term adverse effects. However, this study was uncontrolled (e.g., for crucial effects of time), and the long-term benefits and risks of this approach are not known (22). Based on early evidence that centrally active cholinergic agents may produce apparent antimanic effects (45), there has been an interest in exploring the potential of such drugs to improve outcomes of acute mania not responding to standard treatments. This approach includes a favorable, but uncontrolled, assessment of donepezil (a reversible central cholinesterase inhibitor and anti-dementia agent) in patients in various BD states (46). However, these initial findings were not supported in a later placebo-controlled trial, at least in treatment-resistant mania, when donepezil was added to standard antimanic agents (47). Moreover, donepezil may even worsen or induce mania in some patients (48, 49). Treatment-resistant bipolar depression

Given that depression has been identified as the most burdensome phase of BD, it follows that we identified more studies of treatment resistance in depressive phases of BD. The anticonvulsant lamotrigine has been used to augment ongoing combinations of standard mood stabilizers and antidepressants. In one study, 66 depressed type I or II BD patients were randomized to adjunctive treatment with lamotrigine or to inositol or risperidone, without a placebo control. The anticonvulsant yielded slightly more instances of clinical recovery, with lower ratings of depression and higher ratings of functioning, than either inositol or risperidone (50). These findings support an earlier favorable report of lamotrigine treatment in refractory BD compared with gabapentin or placebo (51), although the earlier study was confounded by patients with unipolar depression. A retrospective chart review also considered effects of adding lamotrigine to other treatments of 31 depressed bipolar II disorder (BD-II) patients, of whom 84% showed some clinical-symptomatic improvement but without a control group for comparison (24). Nearly half of the initial responders later relapsed during 19 months of follow-up (24). A recent study examined the effectiveness of combining lamotrigine with quetiapine in BD patients who had been resistant to either lamotrigine or quetiapine, alone or combined with a range of other standard treatments. In that trial, lamotrigine and quetiapine improved rates of achieving euthymia, and decreased syndromal and subsyndromal depression rates over 3 months (52).

Treatment-resistant bipolar disorder Although aripiprazole is clinically useful in mania, its adjunctive use in bipolar depression has shown limited evidence of beneficial effects in treatment-resistant cases. In fact, it was found to be associated with substantial risks of akathisialike restlessness and abnormal mood elevation or confusion in as many as half of the patients so treated (53, 54). Thyroid hormones may facilitate central synaptic transmission mediated by serotonin and catecholamines, and plasma levels of serotonin may co-vary with triiodothyronine (T3) concentrations (55). There is some evidence that T3 may improve treatment responses in treatment-resistant unipolar major depression (56, 57), and anecdotal support for use of L-thyroxine (T4) to limit rapid cycling in BD patients (58). Adjunctive use of T3 was studied in 159 cases of treatment-resistant depression in BD-II or BD not otherwise specified (NOS) patients, with symptomatic improvement in 84% and full clinical remission in 33%, with no evidence of pathological mood elevation (59). Although this informal finding seems encouraging, the effectiveness, practicality, and safety of using supplemental thyroid hormones in apparently euthyroid patients long-term are uncertain (60, 61). Bupropion, a stimulant-like agent with a dosedependent risk of inducing epileptic seizures, has been used as an antidepressant in BD depression and has a reputation for having a relatively low risk of inducing manic ⁄ hypomanic switches (62). However, this apparent safety may reflect its relatively low recommended dosing range to limit risk of seizures (29). An uncontrolled pilot study evaluating the efficacy of adjunctive bupropion added to other standard treatments for BD found that 62% of 13 treatment-resistant depressed type I or II BD patients receiving a complex array of other treatments experienced improvement in symptoms within 4 weeks of treatment, with no pathological mood elevation (14). Ketamine is a mood-altering, and potentially psychotomimetic, antagonist of central N-methylD-aspartate (NMDA) glutamate receptors with reported beneficial effects in depressed patients (63). It was tested recently in 18 patients with treatment-resistant BD depression, with randomization to ketamine or placebo (23). Following single doses, 71% of ketamine-treated patients were rated as showing improvement of depressive symptoms based on Montgomery-A˚sberg Depression Rating Scale (MADRS) scores, compared to only 6% of placebo-treated patients. Although small and preliminary, this trial strongly suggests that ketamine may be beneficial in treatment-

resistant BD depression and encourages further study, especially with long-term follow-up. Pramipexole is a non-ergoline, benzthiazole, dopamine D2 receptor partial agonist used mainly to treat ParkinsonÕs disease and EkbomÕs restless legs syndrome (64). It has some evidence of yielding antidepressant effects in both treatmentresistant unipolar and BD depressed patients, especially those with type II BD (65–68). Among a total of 22 treatment-resistant BD depressed patients, pramipexole was compared to placebo added to various standard treatments (18). Subsequent short-term (6-week) response rates of 67% versus 20% were observed, suggesting a beneficial effect of this dopaminergic agent (18). There have been few studies of non-pharmacological interventions in treatment-resistant bipolar depression. Electroconvulsive therapy (ECT) was found to be a favorable option in treatmentresistant bipolar depression in a study by Medda and colleagues (69), with response of depressive symptoms [defined by Hamilton Depression Rating Scale (HDRS) depression scores reduced by ‡ 50%] in 66–70% and remission (HDRS £ 8) in 26%. Also, Macedo-Soares and colleagues (70) studied six BD patients with either refractory mania or depression and found that all the patients had more than 50% improvement in YMRS or HDRS scores after 12 sessions of ECT. More studies with larger samples are needed to extend findings, with longer treatment and follow-up. Among other non-pharmacological interventions, a study of 60 treatment-resistant BD patients combined sleep deprivation with intensive light therapy as an adjunct to standard treatments (17). A minority of patients (44%) appeared to improve clinically within a week, but no controls were included, and few showed sustained improvement (17% at 9 months of follow-up). In addition, repetitive transcranial magnetic stimulation (rTMS) has also been found helpful in other forms of depression (71, 72), and was evaluated without controls in 11 type I or II BD patients diagnosed with treatment-resistant depression (13). Of those treated, 55% showed more than 50% improvement in depression ratings within 3 weeks (responders); several were considered to have attained clinical remission as defined by very low depression ratings, and none underwent a switch of mood (13). A recent study of deep brain stimulation of the subcallosal cingulate brain white matter in 17 patients with treatment-resistant unipolar or bipolar depression reported considerable improvements in depression rating scores (70.1%) and remission rates of 58% at

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24 months, highlighting the need for larger studies to replicate these findings (73). Long-term maintenance treatment

Most of the preceding treatment trials are limited by moderate numbers of subjects, complex treatment regimens, lack of controls, and relatively brief observation. In assessing treatment responses in BD, it is essential to observe effects of treatment over sufficiently prolonged periods, and with adequate controls, so as to evaluate gains in sustained mood stabilization and not merely effects of spontaneous shifts in mood and behavior over time, as are characteristic of BD (1, 32). However, very few well-designed studies have considered long-term, prophylactic, mood-stabilizing effects of innovative treatments among initially treatmentresistant cases of BD. A chart review (without randomization or controls) considered effects of adding sodium valproate to lithium, carbamazepine, or both lithum and carbamazepine, which had proved to be unsatisfactory in 63 BD or schizoaffective disorder patients (74). Beneficial responses were observed in 75% of subjects, at somewhat higher rates among those previously treated with lithium (84%) than with carbamazepine (69%); the dropout rate was 14% (74). More broadly, the possible effectiveness of valproate, long-term, in BD remains incompletely resolved, and such use, though prevalent, continues to lack formal regulatory approval. Retrospective reviews or naturalistic studies of clozapine use in refractory BD over moderately prolonged times indicate that clozapine may be effective in reducing symptoms of BD and in improving functioning (37, 38); however, required dosing and possible benefits and risks of longer-term maintenance treatment, including potential effects on suicidal risk (75, 76), all remain to be studied. The mood-stabilizing properties of olanzapine in treatment-resistant BD have also been studied in a small, open-label trial involving 23 treatment-resistant subjects who had responded unsatisfactorily to lithium and other mood stabilizers, including carbamazepine and valproate, for at least 6 months (77). Augmentation of treatment with olanzapine was associated with significant reductions in Clinical Global Impression (CGI) scores, with good tolerability of the treatment. The weight-reducing anticonvulsant topiramate has not shown evidence of efficacy in BD patients, short-term (78, 79), or when used to supplement standard mood-stabilizing treatments in a long-term, placebo-controlled trial (80). Nevertheless, one uncontrolled trial found that topiramate may be beneficial when

580

added to insufficiently effective standard treatments for 6 months (81). Calcium-channel blockers also lack convincing evidence of efficacy in BD (82), but an uncontrolled trial of treatment with adjunctive diltiazem for 12 months was associated with some long-term stabilization in eight BD patients who had failed a series of complex standard treatments (83). More recent open prospective studies have investigated the role of augmentation with memantine, a selective uncompetitive NMDA receptor antagonist, in treatment-refractory BD and found improvements in CGI scores in patients treated and followed up for at least a year (84, 85). Very few studies have considered the potential benefits of psychosocial interventions, long-term, among BD patients considered to be otherwise treatment-resistant, although such interventions appear to be beneficial among BD patients generally (86, 87). In a recent trial, 20 treatment-resistant BD patients were randomized to receive adjunctive psychoeducational and cognitive-behavioral interventions or to continue ongoing treatment (15). There was little difference in clinical status or psychosocial functioning [Global Assessment of Functioning (GAF) scores] with the active psychosocial intervention versus treatment-as-usual at 6 months of follow-up, but there was a suggestive, though statistically non-significant, difference by 12 months (5 ⁄ 10 versus 2 ⁄ 10; Fisher p = 0.17). Discussion

Overall, studies testing the effectiveness of treatment options among BD patients who have not responded adequately to standard treatments remain in remarkable disproportion to the apparent prevalence of the problem. Very few have involved large numbers of patient-subjects, adequate controls, or long-term observations to evaluate sustained benefits and safety, and most trials are complicated by adding novel treatments to already typically complex regimens. Improved therapeutic options are especially urgently required for depressive and mixed phases of BD, which carry high risks of comorbidity, disability, and mortality (88–92). Another potentially valuable approach to anticipating treatment resistance is to ascertain characteristics of BD that are associated with inferior treatment responses. Previous suggestions include: very early onset age, rapid cycling, prominent psychotic features, comorbidities, and others, but the topic requires further study (1). Moreover, it does not necessarily follow that optimal treatments for type I and II BD, or among juvenile, adult, and elderly BD patients are necessarily the same, so that consideration of defined subgroups is recommended.

Treatment-resistant bipolar disorder Another basic issue raised by this review is that definitions of treatment resistance, if it is a valid concept, vary among investigators, making comparisons of innovative interventions difficult. In general, we found very few studies of options for treating otherwise resistant mania, although this phase of the disorder is far more responsive than the depressive-dysphoric-mixed phases (7). This rarity suggests that clinicians and patients are less concerned about selecting among the many options among treatments for mania of proven efficacy (31). One of the few options to emerge from the present review was some indication that the highly effective, but potentially toxic, antipsychotic drug clozapine may have utility in treatment-resistant mania or to gain better mood stabilization in BD patients (35, 36, 39, 93, 94). Concerning treatment-resistant BD depression, we identified several reports with at least suggestive and preliminary support for such adjunctive treatment options as lamotrigine, second-generation antipsychotics, ketamine, dopamine agonists, mementine, or triiodothyronine, as well as for sleep deprivation, ECT, deep brain stimulation, or rTMS. However, most trials for all of these interventions have involved varied and complex ongoing treatments, small numbers of patients, and inadequate controls or randomization, as well as relatively brief follow-up times (Table 1). A clinically most important aspect of treating BD patients is to secure long-term mood-stabilizing effects. Among the few trials identified, it was not clear that any of the innovative treatments considered has secure evidence of long-term effectiveness. Nevertheless, suggestive findings of longterm benefits were reported for clozapine, deep brain stimulation and psychosocial interventions combined with standard mood-stabilizing treatments. In general, the value of psychosocial and rehabilitative efforts in the overall treatment of patients with BD remains inadequately studied, particularly with respect to efficacy in conditions of treatment resistance (95, 96). To recapitulate, most of the trials identified for this review involved relatively small numbers of almost certainly heterogeneous patients, inconsistent definitions of treatment resistance, addition of a new treatment to already complex and varied treatments, lack of adequate controls and randomization, relatively brief observations, and heavy reliance on symptom rating scales rather than on assessment of clinically meaningful or functional improvements, especially those sustained for prolonged periods. As a general matter, treatment responses among BD patients often are unsatisfactory, raising the question of whether treatment

resistance is a trait or condition worthy of further clinical or biological exploration, or simply a characteristic of BD and of available treatments. Nevertheless, there may be value in attempting to clarify characteristics of BD patients who are most versus least likely to benefit from, or to tolerate specific treatments. The high prevalence of incomplete control of morbidity by currently standard treatments for BD encourages routine, empirical use of combinations of both pharmacological and psychosocial treatments, most of which remain largely untested for effectiveness, safety, and costs (7, 32). This is an additional challenge to be addressed, even though it is unlikely to gain industrial support. In conclusion, we can offer several general recommendations. It would be helpful to develop standardized definitions of treatment resistance, especially for particular types and phases of BD, if only to permit better comparisons among therapeutic trials, and to further clarify distinctions that can be made between such resistance and the natural history of BD, at least in its current clinical manifestations with available treatments. Future studies should further investigate psychosocial approaches and their combination with pharmacotherapy in patients with apparently treatmentresistant BD. Finally, a particularly important recommendation concerning the profoundly important clinical challenge of improving both short- and long-term treatment for BD patients is to employ designs of therapeutic trials that are scientifically credible and clinically interpretable. Acknowledgements This study was supported, in part, by a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Bipolar Disorder Research Fund (RJB).

Disclosures No authors of this paper or any close family members have any current financial relationships with the pharmaceutical or biotechnology industries.

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