Professional Documents
Culture Documents
Poon2012 PDF
Poon2012 PDF
BIPOLAR DISORDERS
Review Article
Bipolar disorder (BD) is a persistent and a year (1, 6). The long-term course of BD includes
potentially disabling and fatal psychiatric illness high proportions of both major and minor morbid
that ranks among the top ten leading causes of states with often chronic symptoms, multiple
disability in young adults (1, 2). Clinical onset relapses, and infrequent euthymic periods as well
typically is during adolescence or early adulthood as marked functional disability despite the use of
(3, 4), and the estimated lifetime prevalence of current treatment options. Such long-term morbidity
various forms of BD is over 2.0% (5). The illness is accounts for 40% of follow-up duration— even from
characterized by diverse and changing clinical illness onset—and three-quarters of this morbidity is
presentations ranging from depression to mania, accounted for by major and minor depressive as well
including mixed manic-depressive states, and as mixed states. Subsyndromal symptoms are more
sometimes rapid recurrences with several episodes common than syndromal states in both type I and
573
Poon et al.
type II BD (7–9). In addition, the disorder is associated adequacy of doses and durations of treatment
with substantial cognitive deficits, frequent anxiety trials, and treatment acceptance and adherence (1,
symptoms and substance abuse, and variable 29, 30). Precise estimates of the prevalence of
functional disability, as well as high rates of suicide treatment resistance in BD are not available, but
in youth and premature death from inter-current clinical experience indicates that the majority of
medical disorders at older ages to yield substantial BD patients show clinically unsatisfactory re-
risks of premature mortality (1, 3, 10–12). sponses at some time. A major limitation to efforts
Contrary to earlier views of BD as having a to define treatment resistance in BD is that the
favorable prognosis and high level of response to disorder is highly recurrent, with tendencies to shift
relatively simple treatment, the emerging picture is and change clinically over time, often leaving
of a complex, often severe and disabling or fatal uncertain the sustained clinical effectiveness of
illness, with high levels of morbidity even with therapeutic interventions even with well-demon-
largely untested, but widely employed, combina- strated short-term efficacy (31).
tions of a broadening array of pharmacological Given the high prevalence of incomplete or
and psychosocial treatments (1). Many clinical unsatisfactory treatment responses in BD, and the
experts and investigators have considered such potentially devastating nature of this very common
unfavorable outcomes as manifestations of treat- disorder, we have undertaken a review of reported
ment resistance, although definitions and concep- clinical trials of innovative therapeutic approaches
tualizations of this term vary considerably (13–16). that might have clinical value in treatment-resistant
Incomplete responses to treatment also vary mark- BD.
edly with different clinical states in BD, and are
especially challenging in the depressive phases of
Methods
both type I and type II BD (17–19). The term
Ôtreatment resistanceÕ may well represent a euphe- We searched the research literature using the
mism that avoids dealing more directly with the database of the U.S. National Center for Biotech-
severity, persistence, and variability that are typical nology Information (NCBI)–MedLine ⁄ PubMed
of BD and the routine failure of available treat- system. We considered published research reports
ments to provide adequate control of its symp- apparently related to treatment-resistant BD
toms, particularly long-term and through appearing through February 2012, based on apply-
depressive phases, or to fully counteract its dis- ing various combinations of the following search
abling or fatal potential. terms: bipolar disorder, treatment ⁄ drug ⁄ medication
Based on previous reports and clinical observa- resistant or resistance, treatment refractory, and
tions, a plausible, proposed working definition of difficult to treat. Abstracts of promising reports
treatment resistance in BD would involve responses were reviewed by three of the authors (SHP, KS
considered clinically unsatisfactory following at and RJB), and copies of the full reports of those
least two, presumably adequate (by dose and that appeared to meet entry criteria were reviewed
duration), trials of dissimilar treatments within a in detail to extract relevant data. We also scanned
specific phase of the illness (mania, depression, or the bibliographies of accepted reports for addi-
subsyndromal breakthrough symptoms during tional information. Minimal entry criteria included
maintenance treatment), excluding patients who patients identified as having some form of BD
have responded, but are intolerant of the treatment based on a credible international diagnostic stan-
regime (20–24). Importantly, however, criteria for dard, such as DSM-III or -IV or International
adequate dosage and duration of particular treat- Classification of Diseases (ICD)-9 or -10. In view
ments for particular states in BD and for long-term of the paucity of such reports, we did not apply
prophylactic treatment are far more difficult to rigorous quality criteria to the experimental
specify. Typically, resistance is considered follow- designs of studies, such as substantial subject
ing treatment trials for least 6 weeks in mania, numbers, random assignment, adequate controls,
12 weeks in bipolar depression, and 12 months or blinding, reliable methods of assessment, and long-
more for long-term maintenance treatment (25, term follow-up.
26). However, such duration criteria are probably
minimal, as some phases of BD require prolonged
Results
treatment exposure to provide maximal treatment
responses (27, 28). Adequate assessment of treat- Salient characteristics of studies identified are
ment-resistant BD also includes consideration of summarized and classified as pertinent to treatment
potential contributions of other forms of psychiat- resistance based on manic, depressive, or mainte-
ric or medical illnesses, as well as the apparent nance phases of BD (Table 1).
574
Table 1. Therapeutic trials for treatment-resistant bipolar disorder
Treatment-resistant mania
Calabrese Open, Failed Li, ACs ‡3 CLZ only 10 BD – – – 3.3 Marked improvements: CLZ effective
et al. 1996 (35) prospective + ‡ 2 APs 15 SzAff 72% (YMRS),
32% (BPRS)
Less with SzAff
Chen Open, Failed ‡ 2 MSs or ‡2 OLZ only N = 18 38.9 44.4 – 3.0 88%: ‡ 50% reduction OLZ effective
et al. 2011 (40) prospective APs (no OLZ) (5–40 mg ⁄ d) (YMRS)
78%: remission
Evins et al. 2006 (47) Blinded YMRS ‡ 15 after ‡1 Add DPZ N = 11 81.8 39.0 – 3.5 No improvement DPZ ineffective
versus PBO Li, VPA, or CBZ ‡ (5–10 mg ⁄ d)
2 weeks or PBO
Suppes Open, Failed 2 MSs ‡2 Add CLZ 26 BD-I 58.0 38.0 17 12.0 Significant CLZ effective
et al. 1999 (36) prospective 12 SzAff improvement
(BPRS, CGI,
BRMS)
Treatment-resistant depression
Ahn Open, Failed QTP or ‡2 Add QTP 15 BD-I 73.7 40.1 18.4 3.0 100% improved –
et al. 2011 (52) prospective LTG + other Rxs (188 mg ⁄ d) 22 BD-II (CGI, GAF)
to:LTG 1 BD-NOS 20% dropped out
(228 mg ⁄ d) (side effects)
or LTG (204 mg ⁄ d) 20% required other
to QTP (208 mg ⁄ d) Rxs
± other Rxs
Benedetti Open, Failed ‡ 1 ADs ‡1 Add sleep (N = 60; – 49.8 34.6 9.0 70% improved 50% Both useful
et al. 2005 (17) prospective deprivation 55% resistant) (HDRS): short-term
± light to ADs 17% stable 9 months
or Li
Dell’Osso Open, Failed 1–3 trials ‡1 Add rTMS BD-I or BD-II 72.7 54.4 39.6 0.8 55% improved ‡ 50% No controls
et al. 2009 (13) prospective (ADs ‡ 6 weeks) (N = 11) (HDRS),
no switches
Diazgranados Random add-on Failed ‡ 1 trial ‡1 Add KTM or PBO N = 18 66.7 47.9 20.3 0.5 KTN: 71% improved KTM effective
et al. 2010 (23) versus PBO, (AD + MS) ‡ 50% (MADRS) and safe
blinded, PBO: 6% responded acutely
crossover
Treatment-resistant bipolar disorder
575
576
Table 1.(Continued)
Poon et al.
Erfurth Open, Failed ‡ 2 trials ‡2 Add BUP to: 4 UP 61.5 48.4 – 1.0 62% improved ‡ 50% No controls;
et al. 2002 (14) prospective (MS + AD) ADs (92%), 7 BD (MADRS); no switches switches
APs (15%), Li (8%), rare
AEDs (31%)
(1.5 Rxs ⁄ case)
Goldberg Randomized, Failed ‡ 2 trials >2 Add PPX (1.7 mg ⁄ d) N = 22 50.0 42.1 – 1.5 Improved ‡ 50% Short trial
et al. 2004 (18) versus PBO (ADs + MS) or PBO to: AEDs (HDRS):67%
(91%), Li (27%) PPX, 20% PBO
(1.2 Rxs ⁄ case) Remissions rare,
1 switch
Holtzheimer Open, Failed ‡ 4 trials ‡4 DBS · 6 months 10 UP 59.0 42.0 19.9 24.0 HDRS improved by –
et al. 2012 (73) prospective (ADs) 7 BD 70%; 92% remitted
(sham lead-in)
Kemp Open, Failed ‡ 12 weeks >2 Add APZ 4 BD-I 58.3 48.3 – 2.0 33% improved ‡ 50% –
et al. 2007 (54) prospective (MSs + ADs) (15 mg ⁄ d) to 7 BD-II (MADRS)
APs (75%), 1 BD-NOS
ADs (67%),
AEDs (50%),
(3.7 Rxs ⁄ case)
Medda Open, Failed ‡ 2 MSs + ‡2 Add ECT 46 MD 56.3 51.0 28.5 – 66% and 70% ECT useful
et al. 2010 (69) prospective ADs (MD or Mx) 50 Mx 39.3 23.5 improved ‡ 50%
(HDRS); 26%
remission
Nierenberg Open, Failed 1–2 MSs + >2 Add INS, LTG, or BD-I or – – – 4.0 Recovered: LTG LTG
et al. 2006 (50) prospective ADs to 12 weeks RSP BD-II (N = 66) (24%), INS (17%), somewhat
to MS + ADs RSP (5%) superior
Sharma Retrospective, Failed 2 trials MSs ± >2 Add LTG BD-II – 43.6 26.7 19.4 84% ‡ much No controls
et al. 2008 (24) naturalistic ADs 199 mg ⁄ d) to: (N = 31) improved (CGI)
APs (64%), MSs (45%) 45% remission
alone or combined, 8 weeks 39%
other or no Rxs recurrences
(19%)
Long-term maintenance treatment
Burt et al. 1999 (46) Retrospective, Failed ‡ 2 MS ⁄ AD ‡2 Add DPZ N = 11 63.6 39.2 – – 54% responded (CGI) No controls;
chart study 27% slightly improved
González-Isasi Randomized, ‡ 2 episodes ⁄ ‡2 Add CBT versus N = 20 – 40.0 – 12.0 CBT: 45% –
et al. 2010 (15) placebo- 12 months on Combos continue Rx improved Controls:
controlled trial or ECT 20% improved
Better by 12 months
Table 1.(Continued)
Kelly and Lieberman Retrospective Failed 14 trials ‡2 Add T3 125 BD-II 37.7 45.5 – – 85% improved (CGI) T3 effective
2009 (59) chart review (90.4 lg ⁄ d) 34 BD-NOS 33% remitted (GAF)
(N = 159) 2% more depression;
no switch
Koulopoulos Open, Failed ‡ 2 trials ‡2 Add memantine N = 18 77.8 42.0 – 6.0 72% ‡ much improved –
et al. 2010 (84) prospective (MSs or APs) (10–30 (CGI)
mg ⁄ day)
Koulopoulos Open, Failed ‡ 2 trials ‡2 Add memantine N = 40 – 49.0 – 12.0 72.5% ‡ much –
et al. 2012 (85) prospective (MSs or APs) (10–30 improved CGIº
mg ⁄ day)
Macedo-Soares Open, Failed ‡ 2 adequate ‡2 ECT (3 ⁄ week · N=6 33.0 29–61 – 1.0 100% improved –
et al. 2005 (70) prospective (6 week) antimanic or 12 weeks) ‡ 50% (YMRS or
AD trials HDRS
Silverstone and Retrospective Failed ‡ 2 trials ‡2 Add DLT to: BD-I or BD-II 100 – – 12.0 100% improved No controls
Birkett 2000 (83) chart review (MS ± other Rxs) Li (25%),AEDs (88%), (N = 8)
ADs (1.7 ⁄ case),
APs (12%)
Vieta Open, Failed Li and ‡ ‡2 Add OLZ N = 23 43.5 39.9 24.2 10.8 100% improved (CGI) –
et al. 2001 (77) prospective 1 MS (CBZ ± VPA, (12 mg ⁄ d) to:
6 months) Li (70%),
AEDs (56%),
ADs (48%),
APs (31%),
± others (82%)
Vieta Open, Failed ‡ 2 trials ‡2 Add TOP 28 BD-I 67.6 42.0 – 6.0 58% improved No controls
et al. 2002 (81) prospective (MS ± other Rxs) (202 mg ⁄ d) 3 BD-II ‡ 50% (YMRS,
2 BD-NOS HDRS, or CGI)
1 SzAff Recurrences: 44%
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
Depression Rating Scale; MADRS = Montgomery-Åsberg Depression Rating Scale; YMRS = Young Mania Rating Scale.
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 trans-
cranial magnetic stimulation; T3 = triiodothyronine; TOP = topiramate; VPA = valproate.
Treatment-resistant bipolar disorder
577
Poon et al.
578
Treatment-resistant bipolar disorder
579
Poon et al.
24 months, highlighting the need for larger studies added to insufficiently effective standard treatments
to replicate these findings (73). for 6 months (81). Calcium-channel blockers also
lack convincing evidence of efficacy in BD (82), but
an uncontrolled trial of treatment with adjunctive
Long-term maintenance treatment
diltiazem for 12 months was associated with some
Most of the preceding treatment trials are limited long-term stabilization in eight BD patients who
by moderate numbers of subjects, complex treat- had failed a series of complex standard treatments
ment regimens, lack of controls, and relatively brief (83). More recent open prospective studies have
observation. In assessing treatment responses in investigated the role of augmentation with meman-
BD, it is essential to observe effects of treatment tine, a selective uncompetitive NMDA receptor
over sufficiently prolonged periods, and with ade- antagonist, in treatment-refractory BD and found
quate controls, so as to evaluate gains in sustained improvements in CGI scores in patients treated and
mood stabilization and not merely effects of followed up for at least a year (84, 85).
spontaneous shifts in mood and behavior over Very few studies have considered the potential
time, as are characteristic of BD (1, 32). However, benefits of psychosocial interventions, long-term,
very few well-designed studies have considered among BD patients considered to be otherwise
long-term, prophylactic, mood-stabilizing effects of treatment-resistant, although such interventions
innovative treatments among initially treatment- appear to be beneficial among BD patients gener-
resistant cases of BD. ally (86, 87). In a recent trial, 20 treatment-resistant
A chart review (without randomization or con- BD patients were randomized to receive adjunctive
trols) considered effects of adding sodium valproate psychoeducational and cognitive-behavioral inter-
to lithium, carbamazepine, or both lithum and ventions or to continue ongoing treatment (15).
carbamazepine, which had proved to be unsatis- There was little difference in clinical status or
factory in 63 BD or schizoaffective disorder patients psychosocial functioning [Global Assessment of
(74). Beneficial responses were observed in 75% of Functioning (GAF) scores] with the active psycho-
subjects, at somewhat higher rates among those social intervention versus treatment-as-usual at
previously treated with lithium (84%) than with 6 months of follow-up, but there was a suggestive,
carbamazepine (69%); the dropout rate was 14% though statistically non-significant, difference by
(74). More broadly, the possible effectiveness of 12 months (5 ⁄ 10 versus 2 ⁄ 10; Fisher p = 0.17).
valproate, long-term, in BD remains incompletely
resolved, and such use, though prevalent, continues
Discussion
to lack formal regulatory approval. Retrospective
reviews or naturalistic studies of clozapine use in Overall, studies testing the effectiveness of treatment
refractory BD over moderately prolonged times options among BD patients who have not responded
indicate that clozapine may be effective in reducing adequately to standard treatments remain in
symptoms of BD and in improving functioning (37, remarkable disproportion to the apparent preva-
38); however, required dosing and possible benefits lence of the problem. Very few have involved large
and risks of longer-term maintenance treatment, numbers of patient-subjects, adequate controls, or
including potential effects on suicidal risk (75, 76), long-term observations to evaluate sustained bene-
all remain to be studied. fits and safety, and most trials are complicated by
The mood-stabilizing properties of olanzapine in adding novel treatments to already typically com-
treatment-resistant BD have also been studied in a plex regimens. Improved therapeutic options are
small, open-label trial involving 23 treatment-resis- especially urgently required for depressive and
tant subjects who had responded unsatisfactorily to mixed phases of BD, which carry high risks of
lithium and other mood stabilizers, including car- comorbidity, disability, and mortality (88–92).
bamazepine and valproate, for at least 6 months Another potentially valuable approach to anticipat-
(77). Augmentation of treatment with olanzapine ing treatment resistance is to ascertain characteris-
was associated with significant reductions in Clin- tics of BD that are associated with inferior treatment
ical Global Impression (CGI) scores, with good responses. Previous suggestions include: very early
tolerability of the treatment. The weight-reducing onset age, rapid cycling, prominent psychotic fea-
anticonvulsant topiramate has not shown evidence tures, comorbidities, and others, but the topic
of efficacy in BD patients, short-term (78, 79), or requires further study (1). Moreover, it does not
when used to supplement standard mood-stabiliz- necessarily follow that optimal treatments for type I
ing treatments in a long-term, placebo-controlled and II BD, or among juvenile, adult, and elderly BD
trial (80). Nevertheless, one uncontrolled trial patients are necessarily the same, so that consider-
found that topiramate may be beneficial when ation of defined subgroups is recommended.
580
Treatment-resistant bipolar disorder
Another basic issue raised by this review is that resistance is a trait or condition worthy of further
definitions of treatment resistance, if it is a valid clinical or biological exploration, or simply a char-
concept, vary among investigators, making com- acteristic of BD and of available treatments. Nev-
parisons of innovative interventions difficult. ertheless, there may be value in attempting to clarify
In general, we found very few studies of options characteristics of BD patients who are most versus
for treating otherwise resistant mania, although least likely to benefit from, or to tolerate specific
this phase of the disorder is far more responsive treatments. The high prevalence of incomplete
than the depressive-dysphoric-mixed phases (7). control of morbidity by currently standard treat-
This rarity suggests that clinicians and patients are ments for BD encourages routine, empirical use of
less concerned about selecting among the many combinations of both pharmacological and psycho-
options among treatments for mania of proven social treatments, most of which remain largely
efficacy (31). One of the few options to emerge untested for effectiveness, safety, and costs (7, 32).
from the present review was some indication that This is an additional challenge to be addressed, even
the highly effective, but potentially toxic, antipsy- though it is unlikely to gain industrial support.
chotic drug clozapine may have utility in treat- In conclusion, we can offer several general
ment-resistant mania or to gain better mood recommendations. It would be helpful to develop
stabilization in BD patients (35, 36, 39, 93, 94). standardized definitions of treatment resistance,
Concerning treatment-resistant BD depression, especially for particular types and phases of BD, if
we identified several reports with at least suggestive only to permit better comparisons among thera-
and preliminary support for such adjunctive treat- peutic trials, and to further clarify distinctions that
ment options as lamotrigine, second-generation can be made between such resistance and the
antipsychotics, ketamine, dopamine agonists, natural history of BD, at least in its current clinical
mementine, or triiodothyronine, as well as for manifestations with available treatments. Future
sleep deprivation, ECT, deep brain stimulation, or studies should further investigate psychosocial
rTMS. However, most trials for all of these approaches and their combination with pharma-
interventions have involved varied and complex cotherapy in patients with apparently treatment-
ongoing treatments, small numbers of patients, and resistant BD. Finally, a particularly important
inadequate controls or randomization, as well as recommendation concerning the profoundly
relatively brief follow-up times (Table 1). important clinical challenge of improving both
A clinically most important aspect of treating short- and long-term treatment for BD patients is
BD patients is to secure long-term mood-stabiliz- to employ designs of therapeutic trials that are
ing effects. Among the few trials identified, it was scientifically credible and clinically interpretable.
not clear that any of the innovative treatments
considered has secure evidence of long-term effec-
Acknowledgements
tiveness. Nevertheless, suggestive findings of long-
term benefits were reported for clozapine, deep This study was supported, in part, by a grant from the Bruce J.
brain stimulation and psychosocial interventions Anderson Foundation and by the McLean Private Donors
Bipolar Disorder Research Fund (RJB).
combined with standard mood-stabilizing treat-
ments. In general, the value of psychosocial and
rehabilitative efforts in the overall treatment of Disclosures
patients with BD remains inadequately studied, No authors of this paper or any close family members have any
particularly with respect to efficacy in conditions of current financial relationships with the pharmaceutical or
treatment resistance (95, 96). biotechnology industries.
To recapitulate, most of the trials identified for
this review involved relatively small numbers of
References
almost certainly heterogeneous patients, inconsis-
tent definitions of treatment resistance, addition of a 1. Goodwin RK, Jamison KR. Manic-Depressive Illness, 2nd
new treatment to already complex and varied edn. New York: Oxford University Press, 2007.
2. World Health Organization. The Global Burden of
treatments, lack of adequate controls and random- Disease: 2004 Update. Geneva, Switzerland: WHO
ization, relatively brief observations, and heavy Press, 2008. Available from: http: ⁄ ⁄ www.who.int ⁄ health
reliance on symptom rating scales rather than on info ⁄ global_burden_disease ⁄ GBD_report_
assessment of clinically meaningful or functional 2004update_full.pdf. [accessed May 19, 2010].
improvements, especially those sustained for pro- 3. Baldessarini RJ, Tondo L, Vázquez GH et al. Interna-
tional study of functional and symptomatic outcome
longed periods. As a general matter, treatment versus onset-age in 1437 bipolar-I disorder patients. World
responses among BD patients often are unsatisfac- Psychiatry 2012; 11: 40–46.
tory, raising the question of whether treatment
581
Poon et al.
4. Tondo L, Lepri B, Cruz N, Baldessarini RJ. Age at onset in 24. Sharma V, Khan M, Corpse C. Role of lamotrigine in the
3014 Sardinian bipolar and major depressive disorder management of treatment-resistant bipolar II depression:
patients. Acta Psychiatr Scand 2010; 121: 446–452. chart review. J Affect Disord 2008; 111: 100–105.
5. Merikangas KR, Akiskal HS, Angst J et al. Lifetime and 25. Baldessarini RJ, Tarazi FI. Drugs for psychosis and mania.
12-month prevalence of bipolar spectrum disorder in the In: Brunton LL, Lazo JS, Parker KL eds. Goodman and
National Co-morbidity Survey replication. Arch Gen GilmanÕs The Pharmacological Basis of Therapeutics, 11th
Psychiatry 2007; 64: 543–552. edn. New York: McGraw-Hill Press, 2005: 461–500.
6. Müller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar 26. Tohen M, Frank E, Bowden CL et al. The International
disorder. Lancet 2002; 359: 241–247. Society for Bipolar Disorders (ISBD) task force report on
7. Baldessarini RJ, Salvatore P, Khalsa HM et al. Morbidity the nomenclature of course and outcome in bipolar
in 303 first-episode bipolar I disorder patients. Bipolar disorders. Bipolar Disord 2009; 11: 453–473.
Disord 2010; 12: 264–270. 27. Tohen M, Zarate CA Jr, Hennen J et al. The McLean-
8. Judd LL, Akiskal HS, Schettler PJ et al. Long-term Harvard First-Episode Mania Study: prediction of recovery
natural history of the weekly symptomatic status of bipolar and first recurrence. Am J Psychiatry 2003; 160: 2099–2107.
I disorder. Arch Gen Psychiatry 2002; 59: 530–537. 28. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of
9. Perlis RH, Ostacher MJ, Patel JK et al. Predictors of antimanic treatments: meta-analysis of randomized, con-
recurrence in bipolar disorder: primary outcomes from the trolled trials. Neuropsychopharmacology 2011; 36: 375–389.
STEP-BP program. Am J Psychiatry 2006; 163: 217–224. 29. Keck PE Jr, McElroy SL. Definition, evaluation, and
10. Harvey PD, Wingo AP, Burdick KE, Baldessarini RJ. management of treatment refractory mania. Psychophar-
Cognition and disability in bipolar disorder: lessons from macol Bull 2001; 35: 130–148.
schizophrenia research. Bipolar Disord 2010; 12: 364–375. 30. Sackeim HA. Definition and meaning of treatment-resistant
11. Osby U, Brandt L, Correia N, Ekbom A, Sparén P. Excess depression. J Clin Psychiatry 2001; 62 (Suppl. 16): 10–17.
mortality in bipolar and unipolar disorder in Sweden. Arch 31. Baldessarini RJ. Chemotherapy in Psychiatry, 3rd edn.
Gen Psychiatry 2001; 58: 844–850. New York: Springer-Verlag, 2012.
12. Tondo L, Lepri B, Baldessarini RJ. Risks of suicidal 32. Baldessarini RJ, Henk HJ, Sklar AR, Chang J, Leahy LF.
ideation, attempts and suicides among 2826 men and women Psychotropic medications for bipolar disorder patients in
with types I and II bipolar, and recurrent major depressive the United States: polytherapy and adherence. Psychiatr
disorders. Acta Psychiatr Scand 2007; 116: 419–428. Serv 2008; 59: 1175–1183.
13. DellÕOsso B, Mundo E, DÕUrso N et al. Augmentative 33. Yatham LN, Kennedy SH, Schaffer A et al. Canadian
repetitive navigated transcranial magnetic stimulation Network for Mood and Anxiety Treatments (CANMAT)
(rTMS) in drug-resistant bipolar depression. Bipolar Dis- and International Society for Bipolar Disorders (ISBD)
ord 2009; 11: 76–81. collaborative update of CANMAT guidelines for the
14. Erfurth A, Michael N, Stadtland C, Arolt V. Bupropion as management of patients with bipolar disorder. Bipolar
Add-on strategy in difficult-to-treat bipolar depressive Disord 2009; 11: 225–255.
patients. Neuropsychobiology 2002; 45 (Suppl. 1): 33–36. 34. Centorrino F, Ventriglio A, Vincenti A, Talamo A,
15. González-Isasi A, Echeburúa E, Mosquera F, Ibáñez B, Baldessarini RJ. Changes in medication practices for
Aizpuru F, González-Pinto A. Long-term efficacy of hospitalized psychiatric patients: 2009 versus 2004. Hum
psychological intervention program for patients with Psychopharmacol 2010; 25: 179–186.
refractory bipolar disorder: pilot study. Psychiatry Res 35. Calabrese JR, Kimmel SE, Woyshville MJ et al. Clozapine
2010; 176: 161–165. for treatment-refractory mania. Am J Psychiatry 1996; 153:
16. Pacchiarotti I, Mazzarini L, Colom F et al. Treatment- 759–764.
resistant bipolar depression: towards a new definition. 36. Suppes T, Webb A, Paul B, Carmody T, Kraemer H, Rush
Acta Psychiatr Scand 2009; 120: 429–440. AJ. Clinical outcome in a randomized 1-year trial of
17. Benedetti F, Barbini B, Fulgosi MC et al. Combined total clozapine versus treatment as usual for patients with
sleep-deprivation and light therapy in the treatment of treatment-resistant illness and a history of mania. Am J
drug-resistant bipolar depression: acute response and long- Psychiatry 1999; 156: 1164–1169.
term remission rates. J Clin Psychiatry 2005; 66: 1535– 37. Ciapparelli A, DellÕOsso L, Bandettini di Poggio A et al.
1540. Clozapine in treatment-resistant patients with schizophre-
18. Goldberg JF, Burdick KE, Endick CJ. Preliminary ran- nia, schizoaffective disorder, or psychotic bipolar disorder:
domized, double-blind, placebo-controlled trial of pram- a naturalistic 48-month follow-up study. J Clin Psychiatry
ipexole added to mood-stabilizers for treatment-resistant 2003; 64: 451–458.
bipolar depression. Am J Psychiatry 2004; 161: 564–566. 38. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y.
19. Baldassano CF, Hosey A, Coello J. Bipolar depression: an The effects of long-term clozapine add-on therapy on the
evidence-based approach. Curr Psychiatry Rep 2011; 13: rehospitalization rate and the mood polarity patterns in
483–487. bipolar disorders. J Clin Psychiatry 2006; 67: 461–467.
20. Sachs GS. Treatment-resistant bipolar depression. Psychi- 39. Banov MD, Zarate CA Jr, Tohen M et al. Clozapine
atr Clin North Am 1996; 19: 215–236. therapy in refractory affective disorders: polarity predicts
21. Gitlin M. Treatment-resistant bipolar disorder. Mol Psy- response in long-term follow-up. J Clin Psychiatry 1994;
chiatry 2006; 11: 227–240. 55: 295–300.
22. Benedetti A, Di Paolo A, Lastella M et al. Augmentation 40. Chen J, Muzina DJ, Kemp DE et al. Safety and efficacy of
of clozapine with aripiprazole in severe psychotic and olanzapine monotherapy in treatment-resistant bipolar
schizoaffective disorders: pilot study. Clin Pract Epidemiol mania: a 12-week open-label study. Hum Psychopharma-
Ment Health 2010; 6: 30–35. col 2011; 26: 588–595.
23. Diazgranados N, Ibrahim L, Brutsche NE et al. Random- 41. Keck PE Jr, Marcus R, Tourkodimitris S et al. Placebo-
ized add-on trial of an N-methy-D-aspartate antagonist in controlled, double-blind study of efficacy and safety of
treatment-resistant bipolar depression. Arch Gen Psychi- aripiprazole in patients with acute bipolar mania. Am J
atry 2010; 67: 793–802. Psychiatry 2003; 160: 1651–1658.
582
Treatment-resistant bipolar disorder
42. Sachs GS, Sanchez R, Marcus R et al. Aripiprazole in the logical doses of levothyroxine in affective disorders: a
treatment of acute manic or mixed episodes in patients longitudinal study. J Affect Disord 2004; 83: 183–190.
with bipolar I disorder: a 3-week placebo-controlled study. 61. Gyulai L, Bauer M, Garcia-Espana F et al. Bone mineral
J Psychopharmacol 2006; 20: 536–546. density in pre- and post-menopausal women with affective
43. Keck PE Jr, Calabrese JR, McQuade RD et al. Random- disorder treated with long-term L-thyroxine augmentation.
ized, double-blind, placebo-controlled 26-week trial of J Affect Disord 2001; 66: 185–191.
aripiprazole in recently manic patients with bipolar I 62. Tondo L, Vázquez G, Baldessarini RJ. Mania associated
disorder. J Clin Psychiatry 2006; 67: 626–637. with antidepressant treatment: comprehensive meta-ana-
44. Tsai AC, Rosenlicht NZ, Jureidini JN, Parry PI, Spielmans lytic review. Acta Psychiatr Scand 2010; 121: 404–414.
GI, Healy D. Aripiprazole in the maintenance treatment of 63. Zarate C Jr, Machado-Vieira R, Henter I, Ibrahim L,
bipolar disorder: a critical review of the evidence and its Diazgranados N, Salvadore G. Glutamatergic modulators:
dissemination into the scientific literature. PLoS Med 2011; the future of treating mood disorders? Harv Rev Psychi-
8: e1000434. atry 2010; 18: 293–303.
45. Janowsky DS, el-Yousef MK, Davis JM, Hubbard B, 64. Antonini A, Barone P, Ceravolo R, Fabbrini G, Tinazzi
Sekerke HJ. Cholinergic reversal of manic symptoms. M, Abbruzzese G. Role of pramipexole in the manage-
Lancet 1972; 1: 1236–1237. ment of ParkinsonÕs disease. CNS Drugs 2010; 24: 829–
46. Burt T, Sachs GS, Demopulos C. Donepezil in treatment- 841.
resistant bipolar disorder. Biol Psychiatry 1999; 45: 959–964. 65. Inoue T, Kitaichi Y, Masui T et al. Pramipexole for stage 2
47. Evins AE, Demopulos C, Nierenberg A, Culhane MA, treatment-resistant major depression: an open study. Prog
Eisner L, Sachs G. A double-blind, placebo-controlled trial Neuropsychopharmacol Biol Psychiatry 2010; 34: 1446–
of adjunctive donepezil in treatment-resistant mania. 1449.
Bipolar Disord 2006; 8: 75–80. 66. Mah L, Zarate CA Jr, Nugent AC, Singh JB, Manji HK,
48. Benazzi F. Mania associated with donepezil. Int J Geriatr Drevets WC. Neural mechanisms of antidepressant efficacy
Psychiatry 1998; 13: 814–815. of the dopamine receptor agonist pramipexole in treatment
49. Benazzi F, Rossi E. Mania and donepezil. Can J Psychiatry of bipolar depression. Int J Neuropsychopharmacol 2011;
1999; 44: 506–507. 14: 545–551.
50. Nierenberg AA, Ostacher MJ, Calabrese JR et al. Treat- 67. Swartz HA, Thase ME. Pharmacotherapy for the treat-
ment-resistant bipolar depression: STEP-BD equipoise ment of acute bipolar II depression: current evidence.
randomized effectiveness trial of antidepressant augmen- J Clin Psychiatry 2011; 72: 356–366.
tation with lamotrigine, inositol, or risperidone. Am J 68. Zarate CA, Payne JL, Singh J et al. Pramipexole for
Psychiatry 2006; 163: 210–216. bipolar II depression: a placebo-controlled proof of
51. Frye MA, Ketter TA, Kimbrell TA et al. A placebo- concept study. Biol Psychiatry 2004; 56: 54–60.
controlled study of lamotrigine and gabapentin monother- 69. Medda P, Perugi G, Zanello S, Ciuffa M, Rizzato S,
apy in refractory mood disorders. J Clin Psychopharmacol Cassano GB. Comparative response to electroconvulsive
2000; 20: 607–614. therapy in medication-resistant bipolar I patients with
52. Ahn YM, Nam JY, Culver JL, Marsh WK, Bonner JC, depression and mixed state. J ECT 2010; 26: 82–86.
Ketter TA. Lamotrigine plus quetiapine combination 70. Macedo-Soares MB, Morena RA, Rigonatti SP, Lafer B.
therapy in treatment-resistant bipolar depression. Ann Efficacy of electroconvulsive therapy in treatment-resis-
Clin Psychiatry 2011; 23: 17–24. tant bipolar disorder: a case series. J ECT 2005; 21: 31–
53. Ketter TA, Wang PW, Chandler RA, Culver JL, Alarcon 34.
AM. Adjunctive aripiprazole in treatment-resistant bipolar 71. Höppner J, Schulz M, Irmisch G, Mau R, Schläfke D,
depression. Ann Clin Psychiatry 2006; 18: 169–172. Richter J. Antidepressant efficacy of two different rTMS
54. Kemp DE, Gilmer WS, Fleck J, Straus JL, Dago PL, procedures. High frequency over left versus low frequency
Karaffa M. Aripiprazole augmentation in treatment-resis- over right prefrontal cortex compared with sham stimula-
tant bipolar depression: early response and development of tion. Eur Arch Psychiatry Clin Neurosci 2003; 253: 103–
akathisia. Progr Neuropsychopharmacol Biol Psychiatry 109.
2007; 31: 574–577. 72. Kauffmann CD, Cheema MA, Miller BE. Slow right
55. Cleare AJ, McGregor A, OÕKeane V. Neuroendocrine prefrontal transcranial magnetic stimulation as a treatment
evidence for an association between hypothyroidism, for medication-resistant depression: double-blind, placebo-
reduced central 5-HT activity and depression. Clin Endo- controlled study. Depress Anxiety 2004; 19: 59–62.
crinol 1995; 43: 713–719. 73. Holtzheimer PE, Kelley ME, Gross RE et al. Subcallosal
56. Lasser RA, Baldessarini RJ. Thyroid hormones in depres- cingulate deep brain stimulation for treatment-resistant
sive disorders: reappraisal of clinical utility. Harv Rev unipolar and bipolar depression. Arch Gen Psychiatry
Psychiatry 1997; 4: 291–305. 2012; 69: 150–158.
57. Papakostas GI. Managing partial response or nonre- 74. Schaff MR, Fawcett J, Zajecka JM. Divalproex sodium in
sponse: switching, augmentation, and combination strate- the treatment of refractory affective disorders. J Clin
gies for major depressive disorder. J Clin Psychiatry 2009; Psychiatry 1993; 54: 380–384.
70 (Suppl. 6): 16–25. 75. Meltzer HY, Alphs L, Green AI et al. Clozapine treatment
58. Baumgartner A. Thyroxine and the treatment of affective for suicidality in schizophrenia: International Suicide
disorders: overview of results of basic and clinical research. Prevention Trial (InterSePT). Arch Gen Psychiatry 2003;
Int J Neuropsychopharmacol 2000; 3: 149–165. 60: 82–91.
59. Kelly T, Lieberman DZ. Use of triiodothyronine as an 76. Hennen J, Baldessarini RJ. Reduced suicidal risk during
augmentation agent in treatment-resistant bipolar II and treatment with clozapine: a meta-analysis. Schizophrenia
bipolar disorder-NOS. J Affect Disord 2009; 116: 222– Res 2005; 73: 139–145.
226. 77. Vieta E, Reinares M, Corbella B et al. Olanzapine a long-
60. Bauer M, Fairbanks L, Berghöfer A et al. Bone mineral term adjunctive therapy in treatment-resistant bipolar
density during maintenance treatment with supraphysio- disorder. J Clin Psychopharmacol 2001; 21: 469–473.
583
Poon et al.
78. Levy NA, Janicak PG. Calcium channel antagonists for 87. Lauder SD, Berk M, Castle DJ, Dodd S, Berk L. The role
the treatment of bipolar disorder. Bipolar Disord 2000; 2: of psychotherapy in bipolar disorder. Med J Austral 2010;
108–119. 193 (Suppl. 4): S31–S35.
79. Vasudev K, Macritchie K, Geddes J, Watson S, Young A. 88. Baldessarini RJ, Vieta E, Calabrese JR, Tohen M, Bowden
Topiramate for acute affective episodes in bipolar disorder. C. Bipolar depression: overview and commentary. Harv
Cochrane Database Syst Rev 2006; 25: CD003384. Rev Psychiatry 2010; 18: 143–157.
80. Chengappa RKN, Schwarzman LK, Hulihan JF, Xiang J, 89. Colom F, Vieta E, Daban C, Pacchiarotti I, Sánchez-
Rosenthal NR. Adjunctive topiramate therapy in patients Moreno J. Clinical and therapeutic implications of pre-
receiving a mood stabilizer for bipolar I disorder: a dominant polarity in bipolar disorder. J Affect Disord
randomized, placebo-controlled trial. J Clin Psychiatry 2006; 93: 13–17.
2006; 67: 1698–1706. 90. Gutiérrez-Rojas L, Gurpegui M, Ayuso-Mateos JL, Gut-
81. Vieta E, Torrent C, Garcia-Ribas G et al. Use of topira- iérrez-Ariza JA, Ruiz-Veguilla M, Jurado D. Quality of life
mate in treatment-resistant bipolar spectrum disorders. J in bipolar disorder patients: a comparison with a general
Clin Psychopharmacol 2002; 22: 431–435. population sample. Bipolar Disord 2008; 10: 625–634.
82. Casamassima F, Hay AC, Benedetti A, Lattanzi L, 91. Martinez-Aran A, Vieta E, Torrent C et al. Functional
Cassano GB, Perlis RH. L-type calcium channels and outcome in bipolar disorder: the role of clinical and
psychiatric disorders: brief review. Am J Med Genet B cognitive factors. Bipolar Disord 2007; 9: 103–113.
Neuropsychiatr Genet 2010; 153B: 1373–1390. 92. Malhi GS, Ivanovski B, Hadzi-Pavlovic D, Mitchell PB,
83. Silverstone PH, Birkett L. Diltiazem as augmentation Vieta E, Sachdev P. Neuropsychological deficits and
therapy in patients with treatment-resistant bipolar disor- functional impairment in bipolar depression, hypomania
der: retrospective study. J Psychiatry Neurosci 2000; 25: and euthymia. Bipolar Disord 2007; 9: 114–125.
276–280. 93. Kimmel SE, Calabrese JR, Woyshville MJ, Meltzer HY.
84. Koukopoulos A, Reginaldi D, Serra G, Koukopoulos A, Clozapine in treatment-refractory mood disorders. J Clin
Sani G, Serra G. Antimanic and mood-stabilizing effect of Psychiatry 1994; 55 (Suppl. B): 91–93.
memantine as an augmenting agent in treatment-resistant 94. Scherk H, Pajonk FG, Leucht S. Second-generation
bipolar disorder. Bipolar Disord 2010; 12: 348–349. antipsychotic agents in the treatment of acute mania: a
85. Koukopoulos A, Serra G, Koukopoulos AE, Reginaldi D, systematic review and meta-analysis of randomized con-
Serra G. The sustained mood-stabilizing effect of meman- trolled trials. Arch Gen Psychiatry 2007; 64: 442–455.
tine in the management of treatment resistant bipolar 95. Miklowitz DJ. Functional impairment, stress, and psycho-
disorders: findings from a 12-month naturalistic trial. social intervention in bipolar disorder. Curr Psychiatry
J Affect Disord 2012; 136: 163–166. Rep 2011; 13: 504–512.
86. Huxley NA, Parikh SV, Baldessarini RJ. Effectiveness of 96. Schöttle D, Huber CG, Bock T, Meyer TD. Psychotherapy
psychosocial treatments in bipolar disorder: state of the for bipolar disorder: review of the most recent studies.
evidence. Harv Rev Psychiatry 2000; 8: 126–140. Curr Opin Psychiatry 2011; 24: 549–555.
584