Bipolar Disorders 2012: 14: 573–584  2012 John Wiley and Sons A/S

BIPOLAR DISORDERS

Review Article

Evidence-based options for treatment-resistant

adult bipolar disorder patients
Poon SH, Sim K, Sum MY, Kuswanto CN, Baldessarini RJ. Evidence- Shi Hui Poona, Kang Sima,b,
based options for treatment-resistant adult bipolar disorder patients. Min Yi Sumb,
Bipolar Disord 2012: 14: 573–584.  2012 The Authors. Carissa Nadia Kuswantob and
Journal compilation  2012 John Wiley & Sons A ⁄ S. Ross J Baldessarinic,d
a
Department of General Psychiatry, Institute of
Objectives: Many patients diagnosed with bipolar disorder (BD)
Mental Health, bResearch Division, Institute of
respond incompletely or unsatisfactorily to available treatments. Given
Mental Health, Singapore, cDepartment of
the potentially devastating nature of this prevalent disorder, there is a
Psychiatry, Harvard Medical School, dInternational
pressing need to improve clinical care of such patients.
Consortium for Bipolar Disorder Research, McLean
Division of Massachusetts General Hospital,
Methods: We performed a literature review of the research findings
Boston, MA, USA
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-dysthymic-
dysphoric-mixed phases of BD and long-term prophylaxis. Therapeutic
trials for treatment-resistant bipolar depression have assessed
anticonvulsants, modern antipsychotics, glutamate [N-methyl-D-
aspartate (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 doi: 10.1111/j.1399-5618.2012.01042.x
promising but limited in effectiveness. Several innovative Key words: bipolar disorder – depression – mania
pharmacological treatments (an anticholinesterase, a glutamine – polytherapy – treatment resistance
antagonist, a calcium-channel blocker, triiodothyronine, olanzapine and
topiramate), ECT, and cognitive-behavior therapy have some support Received 13 June 2011, revised and accepted for
for long-term treatment of resistant BD patients, but most of trials of publication 18 May 2012
these treatments have been methodologically limited.
Corresponding author:
Conclusions: Most studies identified were small, involved Dr. Kang Sim
supplementation of typically complex ongoing treatments, varied in Department of General Psychiatry
controls, randomization, and blinding, usually involved brief follow-up, Institute of Mental Health
and lacked replication. Clearer criteria for defining and predicting 10 Buangkok View
treatment resistance in BD are needed, as well as improved trial Singapore 539747
design with better controls, assessment of specific clinical subgroups, and Fax: (65) 6385-5900
longer follow-up. E-mail: kang_sim@imh.com.sg

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
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
573
Poon et al.
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, combina-
tions of a broadening array of pharmacological
and psychosocial treatments (1). Many clinical
experts and investigators have considered such
unfavorable outcomes as manifestations of treat-
ment resistance, although definitions and concep-
tualizations of this term vary considerably (13–16).
Incomplete responses to treatment also vary mark-
edly 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 euphe-
mism that avoids dealing more directly with the
severity, persistence, and variability that are typical
of BD and the routine failure of available treat-
ments to provide adequate control of its symp-
toms, particularly long-term and through
depressive phases, or to fully counteract its dis-
abling or fatal potential.
Based on previous reports and clinical observa-
tions, 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 treat-
ments for particular states in BD and for long-term
prophylactic treatment are far more difficult to
specify. Typically, resistance is considered follow-
ing 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 treat-
ment-resistant BD also includes consideration of
potential contributions of other forms of psychiat-
ric or medical illnesses, as well as the apparent
574
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 re-
sponses 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-demon-
strated 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 Biotech-
nology Information (NCBI)–MedLine ⁄ PubMed
system. We considered published research reports
apparently related to treatment-resistant BD
appearing through February 2012, based on apply-
ing 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 addi-
tional information. Minimal entry criteria included
patients identified as having some form of BD
based on a credible international diagnostic stan-
dard, 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 long-
term follow-up.
Results
Salient characteristics of studies identified are
summarized and classified as pertinent to treatment
resistance based on manic, depressive, or mainte-
nance phases of BD (Table 1).
 Table 1. Therapeutic trials for treatment-resistant bipolar disorder

Resistance: Failed Females Age Onset age Treated

Report Design definition trials Treatments Subjects (%) (years) (years) (months) Main findings Remarks

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.

Resistance: Failed Females Age Onset age Treated

Report Design definition trials Treatments Subjects (%) (years) (years) (months) Main findings Remarks

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)

Resistance: Failed Females Age Onset age Treated

Report Design definition trials Treatments Subjects (%) (years) (years) (months) Main findings Remarks

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.

Treatment-resistant mania appreciable increase in short-term adverse effects.

However, this study was uncontrolled (e.g., for
Treatments of proven efficacy for manic or hypo-
crucial effects of time), and the long-term benefits
manic phases of BD, which often include mixed or
and risks of this approach are not known (22).
psychotic features, include anticonvulsants and
Based on early evidence that centrally active
virtually all antipsychotic drugs, as well as high
cholinergic agents may produce apparent anti-
doses of potent benzodiazepine sedatives (25). The
manic effects (45), there has been an interest in
most notable, and widely internationally
exploring the potential of such drugs to improve
employed, agent with long-term mood-stabilizing
outcomes of acute mania not responding to stan-
effects as well as short-term antimanic efficacy is
dard treatments. This approach includes a favor-
lithium. In addition, several drugs developed as
able, but uncontrolled, assessment of donepezil
anticonvulsants also have antimanic effects, nota-
(a reversible central cholinesterase inhibitor and
bly carbamazepine and sodium valproate, although
anti-dementia agent) in patients in various BD
neither has regulatory approval for long-term
states (46). However, these initial findings were not
prophylaxis (31). At present, many, if not most,
supported in a later placebo-controlled trial, at
BD patients are exposed to two or more mood-
least in treatment-resistant mania, when donepezil
altering drugs (ÔpolytherapyÕ), mostly as plausible,
was added to standard antimanic agents (47).
but largely untested combinations of uncertain
Moreover, donepezil may even worsen or induce
additional efficacy and safety (32–34). Such com-
mania in some patients (48, 49).
plex regimens greatly complicate testing of added
experimental treatments in acute BD episodes
which typically require many weeks to reach Treatment-resistant bipolar depression
remission and recovery, even though most con-
Given that depression has been identified as the
trolled efficacy trials in mania are carried out for
most burdensome phase of BD, it follows that we
only a few weeks (27, 28).
identified more studies of treatment resistance in
We identified only a few trials of innovative
depressive phases of BD. The anticonvulsant
treatments for treatment-resistant mania. These
lamotrigine has been used to augment ongoing
include studies of clozapine with evidence of
combinations of standard mood stabilizers and
efficacy in treatment-resistant mania (with or
antidepressants. In one study, 66 depressed type I
without psychotic features), either as a monother-
or II BD patients were randomized to adjunctive
apy or as an add-on to existing pharmacotherapy
treatment with lamotrigine or to inositol or
(35–37). Clozapine add-on use in BD also has been
risperidone, without a placebo control. The anti-
associated with reductions in the number and
convulsant yielded slightly more instances of clin-
duration of hospitalizations over time (38). Com-
ical recovery, with lower ratings of depression and
pared with other psychotic spectrum conditions,
higher ratings of functioning, than either inositol
clozapine administration in treatment resistant BD
or risperidone (50). These findings support an
is associated with greater response rates and
earlier favorable report of lamotrigine treatment in
improvements in psychosocial functioning (37).
refractory BD compared with gabapentin or pla-
Manic polarity, in turn, may predict better clinical
cebo (51), although the earlier study was con-
response to clozapine (39).
founded by patients with unipolar depression.
The efficacy of other second-generation antipsy-
A retrospective chart review also considered effects
chotics (SGAs) has also been investigated. Chen
of adding lamotrigine to other treatments of 31
and colleagues (40) found that 88.5% of the patients
depressed bipolar II disorder (BD-II) patients, of
with treatment-resistant mania achieved a response
whom 84% showed some clinical-symptomatic
[defined by a ‡ 50% reduction in Young Mania
improvement but without a control group for
Rating Scale (YMRS) total scores] and 77.8%
comparison (24). Nearly half of the initial respond-
achieved remission (defined by a YMRS total score
ers later relapsed during 19 months of follow-up
£ 9 at endpoint) with olanzapine monotherapy.
(24). A recent study examined the effectiveness of
Adjunctive use of aripiprazole has been effective in
combining lamotrigine with quetiapine in BD
acute mania (41, 42), but with equivocal evidence of
patients who had been resistant to either lamotri-
long-term benefits (43, 44). One study involving
gine or quetiapine, alone or combined with a range
patients with psychotic mania or a schizoaffective
of other standard treatments. In that trial, lamo-
disorder who had failed at least two trials of mood
trigine and quetiapine improved rates of achieving
stabilizers or antipsychotics including clozapine
euthymia, and decreased syndromal and subsyn-
found that adding aripiprazole to clozapine was
dromal depression rates over 3 months (52).
effective in reducing symptom severity with no

578

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 akathisia-
like restlessness and abnormal mood elevation or
confusion in as many as half of the patients so
treated (53, 54).
Thyroid hormones may facilitate central synap-
tic transmission mediated by serotonin and
catecholamines, and plasma levels of serotonin
may co-vary with triiodothyronine (T3) concentra-
tions (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 dose-
dependent 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-methyl-
D-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 randomi-
zation to ketamine or placebo (23). Following
single doses, 71% of ketamine-treated patients
were rated as showing improvement of depressive
symptoms based on Montgomery-Åsberg Depres-
sion 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-
Treatment-resistant bipolar disorder
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 treatment-
resistant 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). Sub-
sequent 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-pharmaco-
logical interventions in treatment-resistant bipolar
depression. Electroconvulsive therapy (ECT) was
found to be a favorable option in treatment-
resistant bipolar depression in a study by Medda
and colleagues (69), with response of depressive
symptoms [defined by Hamilton Depression Rat-
ing 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 interven-
tions, 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 improve-
ment (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-resis-
tant unipolar or bipolar depression reported
considerable improvements in depression rating
scores (70.1%) and remission rates of 58% at
579
Poon et al.
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 treat-
ment 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 ade-
quate 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 treatment-
resistant cases of BD.
A chart review (without randomization or con-
trols) considered effects of adding sodium valproate
to lithium, carbamazepine, or both lithum and
carbamazepine, which had proved to be unsatis-
factory 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-resis-
tant subjects who had responded unsatisfactorily to
lithium and other mood stabilizers, including car-
bamazepine and valproate, for at least 6 months
(77). Augmentation of treatment with olanzapine
was associated with significant reductions in Clin-
ical 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-stabiliz-
ing 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 meman-
tine, 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 gener-
ally (86, 87). In a recent trial, 20 treatment-resistant
BD patients were randomized to receive adjunctive
psychoeducational and cognitive-behavioral inter-
ventions 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 psycho-
social 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 preva-
lence of the problem. Very few have involved large
numbers of patient-subjects, adequate controls, or
long-term observations to evaluate sustained bene-
fits and safety, and most trials are complicated by
adding novel treatments to already typically com-
plex 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 anticipat-
ing treatment resistance is to ascertain characteris-
tics of BD that are associated with inferior treatment
responses. Previous suggestions include: very early
onset age, rapid cycling, prominent psychotic fea-
tures, 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 consider-
ation of defined subgroups is recommended.

Another basic issue raised by this review is that
definitions of treatment resistance, if it is a valid
concept, vary among investigators, making com-
parisons 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, antipsy-
chotic drug clozapine may have utility in treat-
ment-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 treat-
ment 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-stabiliz-
ing effects. Among the few trials identified, it was
not clear that any of the innovative treatments
considered has secure evidence of long-term effec-
tiveness. Nevertheless, suggestive findings of long-
term benefits were reported for clozapine, deep
brain stimulation and psychosocial interventions
combined with standard mood-stabilizing treat-
ments. 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, inconsis-
tent definitions of treatment resistance, addition of a
new treatment to already complex and varied
treatments, lack of adequate controls and random-
ization, relatively brief observations, and heavy
reliance on symptom rating scales rather than on
assessment of clinically meaningful or functional
improvements, especially those sustained for pro-
longed periods. As a general matter, treatment
responses among BD patients often are unsatisfac-
tory, raising the question of whether treatment
Treatment-resistant bipolar disorder
resistance is a trait or condition worthy of further
clinical or biological exploration, or simply a char-
acteristic of BD and of available treatments. Nev-
ertheless, 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 treat-
ments for BD encourages routine, empirical use of
combinations of both pharmacological and psycho-
social 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 thera-
peutic 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 pharma-
cotherapy in patients with apparently treatment-
resistant 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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