A Review of Psychotherapeutic Approaches
The concept of treatment resistance in bipolar disorder is clinically familiar but lacks a standard definition.1
Whether the term refers to nonresponse to 1 or more standard
treatments, at what dosages, and for what phases of bipolar disorder is
unclear. Treatment resistance in bipolar disorder should always be based
on a specific phase of treatment: mania or depression and acute or
is extremely common. Even under optimal maintenance conditions, almost
half of bipolar patients with symptom remission will have a recurrence
in 2 years under standard care (including medication combinations).2
phase-specific evidence-based treatments is crucial. This may include
raising the dosage of an initial treatment according to response unless
limited by adverse effects. Acute treatments are often continued into
maintenance. Combinations are commonplace, and the number of potential
combinations is large. Decisions about which medications to use first or
in what combinations, as well as dosing issues, require good clinical
judgment on the part of each clinician because there is little evidence
to drive such decisions.
Traditionally, lithium(Drug information on lithium)
and anticonvulsants have been used as first-line treatments for acute
mania; antipsychotics were reserved for resistant, severely ill, or
psychotic patients. This practice is based on the long history of
lithium and divalproex use rather than on comparative efficacy trials.
The range of FDA-approved uses for atypical antipsychotics in bipolar
disorder is growing; these agents can now be considered first-line
treatments even for moderately ill manic patients.
To dramatically reduce treatment resistance and enhance stability, comorbid conditions, such as substance abuse,
need to be addressed. And, destabilizing medications, such as
antidepressants, need to be discontinued. Evidence-based intensive
psychotherapies are clearly useful in maintenance. For truly resistant
conditions, clozapine(Drug information on clozapine)
and electroconvulsive therapy (ECT) are also recommended for depression
and mania in both acute and maintenance treatment. If these fail, a
number of novel treatments have been suggested, and some have been
studied in placebo-controlled trials.
Treatment-resistant bipolar disorder
suggested that the term “treatment-resistant bipolar disorder” should
be reserved for patients who do not respond to a combination of 2
standard medications in a specific period, such as 6 weeks for mania,
and 6 months or 3 cycle-lengths for maintenance. Others have required
multiple trials of combinations or that patients fail to respond to
nonstandard treatments, such as antidepressants.4,5
resistance in unipolar depression and schizophrenia is usually defined
as failure to respond during an acute episode to 2 adequate monotherapy
trials of agents with established efficacy and implies that a novel
treatment should be considered. In schizophrenic patients, this makes
sense because clozapine has shown efficacy for treatment-resistant
schizophrenia. In unipolar depression, this conceptualization of
treatment resistance may be less useful because failure to respond to
one SSRI is not associated with an increased risk of not responding to
Treatment resistance in bipolar disorder is
even harder to define. Standard care in any phase often includes more
than 1 medication, which implies some degree of resistance in most
patients.7 Furthermore, treatments lack any unifying
mechanism of action, an evidence-based rationale for combining is
lacking, and dosing of combinations has not been standardized.
process of selecting medication combinations is often simplified by
grouping treatments into classes, such as anticonvulsants and atypical
antipsychotics—distinctions based on their uses in epilepsy and
schizophrenia. Unfortunately, specific medications within these classes
have considerably different efficacy.
Phase of illness
basic approach to managing treatment-resistant bipolar disorder should
be to first clarify the phase of treatment and then to optimize
evidence-based treatments for that phase.8 This includes
titrating the dosage of a standard medication as tolerated and,
possibly, considering combinations. For acute depression and
maintenance, psychotherapy should also always be part of the treatment
Standard treatments for bipolar disorder are listed in the Table. Some are more effective for treating or preventing mania (eg, lithium, divalproex, carbamazepine(Drug information on carbamazepine), aripiprazole(Drug information on aripiprazole), olanzapine(Drug information on olanzapine)). Others are more effective for treating or preventing depression (eg, lamotrigine(Drug information on lamotrigine), quetiapine(Drug information on quetiapine)).
Treatment-resistant mania/mixed episode
acute mania, antidepressants should be discontinued immediately. The
focus should be on using evidence-based treatments for mania. Although
lithium is not recommended for mixed episodes or for patients with many
previous episodes, lithium and divalproex are often used before an
atypical antipsychotic because they are thought to be safer with
An atypical antipsychotic may have greater efficacy
in severe mania and can be added as needed. In most studies of mania,
antipsychotic dosing has approximated commonly used dosages for
schizophrenia. Monotherapy with each of the atypical antipsychotics has
been shown to have evidence-based efficacy in acute mania studies that
included participants with psychosis (about 40%).9,10
therapy fail, there are many reasonable and creative possibilities for
combining standard treatments, although they have not been supported by
controlled studies. These include higher doses of an atypical
antipsychotic, lithium with divalproex, 2 anticonvulsants, and other
The most commonly recommended nonstandard treatments
for treatment-resistant mania are clozapine and ECT, which have been
shown to have efficacy.8,11,12 A combination of clozapine and ECT has also been suggested.13
novel treatments have been studied using an augmentation approach in
combination with standard treatments for treatment-resistant mania.
These include donepezil(Drug information on donepezil), gabapentin(Drug information on gabapentin), topiramate(Drug information on topiramate), mexiletine(Drug information on mexiletine), and intravenous magnesium sulphate.14-20
The reported efficacy in these uncontrolled reports is confounded by
the continuation of the previous treatments. One exception is tamoxifen(Drug information on tamoxifen), which, like lithium and valproate(Drug information on valproate), inhibits protein kinase C and was found to have antimanic efficacy superior to placebo.21
Treatment-resistant bipolar depression
treatments have been shown to have efficacy in acute bipolar
depression. Only 2 have been FDA-approved: quetiapine and a combination
of olanzapine and fluoxetine(Drug information on fluoxetine).
Other treatments that have been recommended include lithium and
lamotrigine. If any of these standard treatments is partially effective,
an increase in dose may be considered. Vagus nerve stimulation has also
been shown to have efficacy.22
Regardless of the
approach selected, bipolar depression should be treated until there are
no residual symptoms, which are associated with recurrence.2
Evidence-based intensive psychotherapies may further enhance positive
outcomes in acute and maintenance treatment of bipolar depression.23
standard antidepressants are used for treatment-resistant bipolar
depression, typically in combination with antimanic treatments. However,
antidepressants (other than fluoxetine in combination with olanzapine)
have not been shown to be efficacious in acute bipolar depression and
may be associated with switching.24 In particular, antidepressants with norepinephrine(Drug information on norepinephrine)
activity including tricyclics and serotonin-norepinephrine reuptake
inhibitors may have a greater risk of inducing switching than SSRIs.25
patients who do not respond to standard treatment for acute bipolar
depression, the clinician must be creative in finding a combination that
can help. Lithium, lamotrigine, and quetiapine can be used in
combination with one another; all are FDA-approved for maintenance
Given the relatively small number of evidence-based
treatments available for acute bipolar depression, many clinicians have
borrowed from the unipolar depression literature and have tried
antidepressants, antidepressant-lithium combinations,
antidepressant-anticonvulsant combinations, antidepressant–atypical
antipsychotic combinations, hypermetabolic thyroid augmentation, and
For treatment-resistant acute bipolar depression, the dopaminergic agonist pramipexole and the wakefulness-promoting agent modafinil(Drug information on modafinil) have been shown to have efficacy greater than placebo as augmentation to standard treatments.4,26 Other pharmacotherapies have been studied in uncontrolled augmentation, including donepezil, bupropion, riluzole(Drug information on riluzole), gabapentin, levetiracetam(Drug information on levetiracetam),
and aripiprazole. Two brain-stimulating therapies—magnetic seizure
therapy and repetitive transcranial magnetic stimulation (TMS)—have been
studied as well.27-29
Treatment-resistant bipolar maintenance
most common approach to maintenance is to simply continue the
treatments that were used to manage the acute episode. Once the patient
is stabilized, the focus is on maximizing effectiveness and minimizing
adverse effects. This is an ideal opportunity to simplify complex
treatment regimens. Medications should always be combined with intensive
long-term psychotherapies such as cognitive-behavioral therapy,
interpersonal social rhythm therapy, and family-focused therapy, which
clearly enhance maintenance outcomes for bipolar depression.23
treatment should be conceptualized in terms of desired direction of
efficacy, and treatments selected based on anticipated direction of
relapse. This should include consideration of both number and duration
of previous episodes, in particular, the most recent episode. Some
treatments do not have equal directional maintenance effectiveness. For
example, lithium is more effective as prophylaxis against mania, while
lamotrigine is more effective as prophylaxis against depression. Lithium
is the only treatment for bipolar disorder shown to possibly have
Many patients require a
combination of treatments with complementary directional effectiveness.
Others may need more than 1 medication for unidirectional effectiveness.
Perhaps even more commonly, patients are cycling in both manic and
despressive directions despite 1 or more standard treatments. There is
some evidence that combination treatment may be effective in patients
who failed monotherapy on each separate component of the combination.31
of antidepressants is generally not recommended in bipolar maintenance
because of concerns about switching, although early discontinuation of
antidepressants in responsive bipolar depressed patients has also been
associated with depression relapse. It may be even more important to
reduce other comorbidities such as substance dependence during
Several novel approaches have been suggested for treatment-resistant bipolar maintenance
(either depression or cycling) including clozapine, at either low or standard doses, and maintenance ECT.35-38 Other
approaches include augmentation with hypermetabolic thyroid
supplementation, diltiazem, aripiprazole, topiramate, gabapentin,
mexiletine, levetiracetam, and chromium, as well as vagus nerve
stimulation.19,39-46 Efficacy has also been reported for levetiracetam monotherapy and a combination of topiramate and clozapine.47,48
disorder is associated with significant morbidity. Numerous
evidence-based treatments exist for all phases of bipolar disorder, and
these should be optimized and fully explored before resorting to
treatments with limited evidence of efficacy. Medication dosage should
be titrated to response and emergence of adverse effects.
of evidence-based treatments are often used. When a treatment has
failed, careful consideration should be made about whether it should be
discontinued before adding another. Comorbidities such as substance
abuse that complicate treatment must be minimized. Often, lithium or an
anticonvulsant is used initially and an antipsychotic is added if
response is not adequate. However, antipsychotics have been shown to be
efficacious in nonpsychotic moderately ill bipolar manic and depressed
patients. If evidence-based treatments are truly unsuccessful, clozapine
and ECT have some evidence of efficacy as an augmentation to standard
treatments. If these too fail, then novel treatments may be considered.
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