The way to treat anxiety in bipolar disorder is to treat bipolar disorder. Anxiety is synonymous with stress and almost all mental disorders cause stress, except perhaps the classic, euphoric mania, which lifts the patient into a state of worry-free happiness.
Some mood swings cause more anxiety than others, and at the top of the list are mixed states. Although anxiety does not appear in the criteria for mixed states, it is often created when depression and mania mix.1 The International Society for Bipolar Disorder has even calculated the exact proportions for this worrying recipe. It takes only 1 manic symptom during a depression or 2 depressive symptoms during a mania to trigger anxiety.1
Mixed conditions tend to respond better to atypical anticonvulsants and antipsychotics than to lithium, which is why anxiety predicts lithium resistance in bipolar disorder.2 There are, however, 2 exceptions to this rule: suicide and panic disorder. Both mixed conditions and anxiety increase the risk of suicide in bipolar disorder, and lithium decreases this risk 6 times.3 This preventative effect is independent of the mood benefits of lithium, so it is worth considering lithium in patients who are suicidal, even when it is less likely to reduce the underlying symptoms.
Although the classic lithium-responsive patient tends to have pure mania and hypomania and no comorbidities of anxiety disorders, a recent study identified panic disorder as a predictor of lithium response.4 Although anxiety is low in pure mania and hypomania, these patients are on alert for the threat, which is the essence of panic disorder. One study found that they had more phobias of panic than patients with bipolar depression or mixed conditions.5
The next step in treating mixed conditions is to reduce antidepressants and anything else that contributes to manic symptoms (eg, drug abuse, steroids, and irregular circadian rhythms). Most patients who are in a mixed condition have been taking an antidepressant for a long time and it can be difficult to tell if the medicine is exacerbating the mixed presentation. Given these uncertainties, it is best to slow down in weeks or months.6 Rapid discontinuation can trigger mania and other mood symptoms. The work is very similar to the reduction of benzodiazepine. If symptoms worsen, increase the dose and slow down the taper.
Anxiolytic mood stabilizers
In bipolar disorder, anxiety is a nonspecific symptom with multiple causes, including mood swings, stress, and comorbid anxiety disorders. With so many different causes, can it be said that any mood stabilizer is anxiolytic? Probably not, but we have some studies that could point the way when selecting a mood stabilizer for a patient with significant anxiety.
Among the anticonvulsants, valproate and lamotrigine have improved anxiety in small controlled studies of bipolar anxiety disorder.7-9 The evidence for Valproate here is more robust and this drug has also improved anxiety in patients without bipolar disorder, probably due to its benzodiazepine-like gaba-ergic properties.10.11 Lamotrigine can also treat obsessive-compulsive disorder with glutamatergic effects, based on a small placebo-controlled study and several uncontrolled studies.12
Atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large, randomized, placebo-controlled studies in patients with bipolar depression and nonspecific anxiety (both were secondary analyzes). The effect sizes were large enough to make them visible to the occasional observer (0.35 for olanzapine and 0.56 for quetiapine).13.14 Quetiapine had similar anxiolytic effects at 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects with monotherapy or in combination with fluoxetine.
These anxiolytic properties do not appear to extend to other atypical antipsychotics. Ziprasidone and risperidone failed in placebo-controlled studies of anxiety bipolar disorder, and risperidone actually worsened anxiety in a study of bipolar comorbid panic disorder.7
The unanswered question here is whether these drugs targeted anxiety directly or treated mild mixed conditions. Most of the patients presented with 1-2 manic symptoms along with depression, judging by the average Young Mania evaluation scale of 5, and the anxiety was higher as the manic symptoms increased.13.14 On the other hand, quetiapine has a large effect size in generalized anxiety disorder (GAD), suggesting a more direct effect.15 Quetiapine was close to FDA approval in GAD, but was withheld because the FDA did not believe the disorder was severe enough to justify all the risks of an antipsychotic. This lesson also applies to bipolar disorder. Quetiapine can be very effective for anxiety, but should not be used in mild cases.
Anxious Distress
Anxiety may not provide a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about patient care. These patients are at higher risk for treatment discontinuation, adverse drug effects, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment and an extra phone call to make sure you tolerate any new medication go a long way in these cases.
Dr. Aiken is the editor of the mood disorders section for Psychiatric TimesTM, editor in chief of Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently Workbook for depression and bipolar. The author does not accept fees from pharmaceutical companies, but receives royalties from PESI for Workbook for depression and bipolar and from WW Norton & Co. for Bipolar, not so much.
reference
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