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Psychlopedia/Treatment Strategies for Bipolar Depression

Bipolar Depression
This activity is part of the Bipolar Disorder Unit, which is supported by an educational grant from Bristol-Myers Squibb
Company and Otsuka America Pharmaceutical, Inc.

Treatment Strategies for Bipolar Depression

Charles L. Bowden, MD
De partm e nt of Psychiatry, Unive rsity of Te x as He alth Scie nce C e nte r, and the C e nte r for Bipolar Illne ss
Inte rve ntions in Hispanic C om m unitie s, San Antonio

Phases of Bipolar Treatment

The basic strategy and time course for treating bipolar
disorder has shifted in recent years. Successful treatment of
bipolar disorder can generally be divided into 3 phases: acute
assessment and stabilization, continuation therapy, and
maintenance therapy (AV 1).1
To provide syndromal recovery in the acute phase, clinicians
should maximize mood stabilizer treatment and add adjunctive
treatments as needed. Clinicians should provide support, a

A V 1 . P has es of Bipolar D is order

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structured treatment plan, and education about lifestyle

changes, habits, and avoidance of certain destabilizing factors. Clinicians should also involve the
family in the treatment process.
Continuation therapy for bipolar disorder begins after syndromal recovery and is meant to achieve
and sustain functional recovery. Clinicians' general goals during this treatment phase include
optimizing medications for tolerability, tapering adjunctive medications whenever possible to simplify
the regimen, and introducing psychosocial or psychoeducational therapy. A goal of nonpharmacologic
therapy should be to teach patients how to monitor their illness so that they can avoid relapse by
recognizing and managing fluctuations in symptomatology that might impair functionality.
Maintenance therapy should maximize long-term stability and function in patients with bipolar
depression. Patients should learn to anticipate and recognize bipolar prodromes so that the illness
can be managed with longer intervals between clinical checkups. Additionally, clinicians should focus
on optimizing adaptation to the disorder so that patients can function as much as possible like
people without bipolar disorder.
Continuing Acute Pharmacotherapy in the Maintenance Phase
One strategy for maintenance treatment of bipolar disorder is to continue the same treatment
that stabilized the patient during the acute phase. Unfortunately, a dearth of information exists
regarding the specifics involved in moving from acute therapy into the continuation and maintenance
phases of bipolar treatment. The question of whether the drug regimen that resolved the acute
episode remains effective in maintenance treatment has not been extensively studied.

Less
Maintenance Therapy After Depressive Episodes
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In a study2 of recently depressed patients with bipolar I disorder who were stabilized with
lamotrigine monotherapy or lamotrigine in combination with any other psychotropic agent,
maintenance treatment with lamotrigine or lithium was observed for 18 months. Before the doubleblind maintenance treatment began, all agents except lamotrigine (including lithium) were
discontinued. Compared with placebo, lamotrigine was significantly superior at delaying depressive
relapse (P=.047), and lithium was significantly superior at delaying manic relapse (P=.026).
Several atypical antipsychotics are approved for the treatment of acute manic or mixed bipolar
episodes, but only quetiapine and the olanzapine-fluoxetine combination are indicated for bipolar
depression. The BipOLar DEpRession (BOLDER)3,4 studies found quetiapine to be effective for bipolar
depression at doses of 300 mg/d and 600 mg/d. Olanzapine-fluoxetine was found to have superior
depressive symptom improvement compared with lamotrigine in bipolar I disorder, but the
combination treatment was associated with more treatment-emergent side effects than lamotrigine.5
Olanzapine and aripiprazole are approved for bipolar maintenance treatment, but, given the
limited amount of available evidence, the current best strategy for the use of atypical antipsychotics
in the maintenance phase might be to continue using the therapy that was effective for acute
treatment.
Antidepressant monotherapy is not recommended for
bipolar maintenance in patients who were recently
depressed 6 (for more information, see
"Role of Antidepressants in Bipolar Depression").
Unfortunately, psychiatrists and general practitioners alike
are still prescribing antidepressant monotherapy to many
patients with bipolar depression, so these patients fail to
receive mood stabilizers, which are a fundamental part of
A V 2 . E ffic ac y of A djunc tive A ntidepres s ant
With M ood Stabilizer in Bipolar D epres s ion
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treatment. Even when antidepressants are combined with

mood stabilizers, no additional benefit is apparent
compared with mood stabilizer monotherapy (AV 2).7

However, should an acute bipolar depressive episode be treatment-refractory with mood stabilizer
monotherapy or should a breakthrough depressive episode occur during maintenance therapy, an
antidepressant can be tried. Evidence from a small study8 suggests that, if the patient responds, the
combination treatment can be continued with positive results.
Considering Tolerability
When considering an overall treatment strategy and choosing among drugs that might not have
clear differences in efficacy, tolerability may be a deciding factor. For instance, both lamotrigine and
divalproex are associated with significantly fewer study dropouts due to adverse events compared
with lithium.9
A large maintenance study10 that compared subjects initially in a mixed manic state to those
initially in a nonmixed or euphoric manic state found that subjects in mixed manic states discontinued
treatment because of adverse events at twice the rate of subjects with euphoric mania regardless of
which medication was being used. Thus, for mixed mania, or possibly bipolar depression, the
fundamental psychopathology of the mood episode may predispose patients to increased
intolerability regardless of the medication.
For Clinical Use
After stabilizing an acute episode, institute adjunctive psychoeducation to help prevent relapse
Consider alternatives to lithium monotherapy as it appears to have a weak relationship between
acute and maintenance efficacy
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Do not prescribe antidepressants without mood stabilizers to patients with bipolar disorder
Drug Names
aripiprazole (Abilify), divalproex (Depakote), lamotrigine (Lamictal and others), lithium (Lithobid,
Eskalith, and others), olanzapine (Zyprexa), olanzapine-fluoxetine (Symbyax), quetiapine (Seroquel)
Take the online posttest.
References
1 . Sac hs G S. Bipolar mood dis order: prac tic al s trategies for ac ute and maintenanc e phas e treatment. J Clin Ps ychopharmacol.
1 9 9 6 ;1 6 (2 s uppl 1 ):3 2 S 4 7 S.
2 . C alabres e J R, Bowden C L , Sac hs G , et al, for the L amic tal 6 0 5 Study G roup. A plac ebo- c ontrolled 1 8 - month trial of
lamotrigine and lithium maintenanc e treatment in rec ently depres s ed patients with bipolar I dis order. J Clin Ps ychiatry.
2 0 0 3 ;6 4 (9 ):1 0 1 3 1 0 2 4 .
3 . C alabres e J R, Kec k P E J r, M ac fadden W, et al, for the BO L D E R Study G roup. A randomized, double- blind, plac eboc ontrolled trial of quetiapine in the treatment of bipolar I or I I depres s ion. Am J Ps ychiatry. 2 0 0 5 ;1 6 2 (7 ):1 3 5 1 1 3 6 0 .
4 . T has e M E , M ac fadden W, Weis ler RH , et al. E ffic ac y of quetiapine monotherapy in bipolar I and I I depres s ion: a doubleblind, plac ebo- c ontrolled s tudy (the BO L D E R I I s tudy). J Clin Ps ychopharmacol. 2 0 0 6 ;2 6 (6 ):6 0 0 6 0 9 . C orrec tion in
2 0 0 7 ;2 7 (1 ):5 1 .
5 . Brown E , D unner D L , M c E lroy SL , et al. O lanzapine/fluoxetine c ombination vs . lamotrigine in the 6 - month treatment of
bipolar I depres s ion [publis hed online ahead of print D ec ember 1 1 , 2 0 0 8 ]. I nt J Neurops ychopharmacol. doi:
1 0 .1 0 1 7 /S1 4 6 1 1 4 5 7 0 8 0 0 9 7 3 5 .
6 . Suppes T , D ennehy E B, H irs c hfeld RM A , et al. T he T exas I mplementation of M edic ation A lgorithms : update to the
algorithms for treatment of bipolar I dis order. J Clin Ps ychiatry. 2 0 0 5 ;6 6 (7 ):8 7 0 8 8 6 .
7 . Sac hs G S, N ierenberg A A , C alabres e J R, et al. E ffec tivenes s of adjunc tive antidepres s ant treatment for bipolar depres s ion.
N Engl J Med. 2 0 0 7 ;3 5 6 (1 7 ):1 7 1 1 1 7 2 2 .
8 . A lts huler L L , P os t RM , H ellemann G , et al. I mpac t of antidepres s ant c ontinuation after ac ute pos itive or partial treatment
res pons e for bipolar depres s ion: a blinded, randomized s tudy. J Clin Ps ychiatry. 2 0 0 9 ;7 0 (4 ):4 5 0 4 5 7 .
9 . Smith L A , C ornelius V , Warnoc k A , et al. E ffec tivenes s of mood s tabilizers and antips yc hotic s in the maintenanc e phas e of
bipolar dis order: a s ys tematic review of randomized c ontrolled trials . Bipolar Dis ord. 2 0 0 7 ;9 (4 ):3 9 4 4 1 2 .
1 0 . Bowden C L , C ollins M A , M c E lroy SL , et al. Relations hip of mania s ymptomatology to maintenanc e treatment res pons e with
divalproex, lithium, or plac ebo. Neurops ychopharmacology. 2 0 0 5 ;3 0 (1 0 ):1 9 3 2 1 9 3 9 .

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