Treatment-Resistant Bipolar Disorder: Page 2 of 3

Treatment-Resistant Bipolar Disorder: Page 2 of 3

Treatment-resistant bipolar depression

Fewer 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. 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

Often, 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 activity including tricyclics and serotonin-norepinephrine reuptake inhibitors may have a greater risk of inducing switching than SSRIs.25

For 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 treatment.

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 other approaches.

For treatment-resistant acute bipolar depression, the dopaminergic agonist pramipexole and the wakefulness-promoting agent 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, gabapentin, 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

The 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

Maintenance 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 antisuicidal effects.30

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

Use 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 maintenance treatment.32-34


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