In 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 long-term use.
The most commonly recommended nonstandard treatments for treatment-resistant mania are clozapine and ECT, which have been shown to have efficacy.A combination of clozapine and ECT has also been suggested.
Several novel treatments have been studied using an augmentation approach in combination with standard treatments for treatment-resistant mania. These include donepezil, gabapentin, topiramate, mexiletine, and intravenous magnesium sulphate. The reported efficacy in these uncontrolled reports is confounded by the continuation of the previous treatments. One exception is tamoxifen, which, like lithium and valproate, inhibits protein kinase C and was found to have antimanic efficacy superior to placebo.
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. In particular, antidepressants with norepinephrine activity including tricyclics and serotonin-norepinephrine reuptake inhibitors may have a greater risk of inducing switching than SSRIs.
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.
Other approaches include augmentation with hypermetabolic thyroid supplementation, diltiazem, aripiprazole, topiramate, gabapentin, mexiletine, levetiracetam, and chromium, as well as vagus nerve stimulation. Efficacy has also been reported for levetiracetam monotherapy and a combination of topiramate and clozapine.
Treatment-Resistant Bipolar Disorder
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