The way to treat anxiety in bipolar disorder is to treat bipolar disorder. Anxiety is synonymous with anxiety and almost all mental disorders cause anxiety, except perhaps the classic euphoric mania that elevates the patient to a carefree state of happiness.
Some episodes of humor cause more anxiety than others and at the top of the list are mixed states. Although anxiety does not appear in the mixed-state criteria, it is often created when depression and mania combine.1 The International Society for Bipolar Disorders has even calculated the exact proportions of this troubling recipe. It only takes 1 manic symptom during a depression or 2 depressive symptoms during a mania to cause anxiety.1
Mixed states tend to respond better to anticonvulsants and atypical antipsychotics than to lithium, which is why anxiety predicts lithium resistance in bipolar disorder.2 There are, however, two exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety increase the risk of suicide in bipolar disorder and lithium reduces this risk by 6 times.3 This preventative effect is independent of the mood benefits of lithium, so it is worth considering lithium in suicidal patients, even when it is less likely to reduce the underlying symptoms.
Although the classic lithium-sensitive patient usually has pure mania and hypomania and no comorbidities in anxiety disorders, a recent study identified panic disorder as a predictor of the lithium response.4 Although anxiety is low in pure mania and hypomania, these patients are on high alert for threat, which is the essence of panic disorder. One study found that they had more phobias in panic sensations than patients with bipolar depression or mixed states.5
The next step in treating mixed states is to reduce antidepressants and anything else that contributes to manic symptoms (e.g., drug abuse, steroids, and irregular circadian rhythms). Most patients in a mixed state have been taking an antidepressant for a long time and it can be difficult to know if the drug exacerbates the mixed presentation. Given these uncertainties, it’s best to slowly slow down for weeks or months.6 Rapid interruption can cause mania and other mood symptoms. The work is very similar to reducing the intensity of a benzodiazepine. If symptoms worsen, increase the dose and slow down the volume.
Anxiolytic mood stabilizers
In bipolar disorder, anxiety is a nonspecific symptom with multiple causes, including mood episodes, stress, and comorbid anxiety disorders. With so many different causes, can it really be said that any mood stabilizer is anxiolytic? Probably not, but we have some trials that may point the way when it comes to selecting a mood stabilizer for a patient with significant anxiety.
Among anticonvulsants, valproate and lamotrigine improved anxiety in small controlled trials of anxiety bipolar disorder.7-9 Valproate tests here are more robust and this drug also improved anxiety in patients who do not have bipolar disorder, perhaps because of its benzodiazepine-like gaba-ergotic properties.10.11 Lamotrigine can also treat obsessive-compulsive disorder through glutamatergic effects, based on a small placebo-controlled trial and several uncontrolled studies.12
Atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large randomized, placebo-controlled trials of patients with bipolar depression and nonspecific anxiety (both were secondary analyzes). The effect sizes were large enough to be noticed by the occasional observer (0.35 for olanzapine and 0.56 for quetiapine).13.14 Quetiapine had similar anxiolytic effects at doses of 300 mg and 600 mg, and olanzapine had anxiolytic effects similar to 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 trials of bipolar disorder with anxiety, and risperidone worsened anxiety in a bipolar study with comorbid panic disorder.7
The unanswered question here is whether these medications directly targeted anxiety or treated mild mixed states. Most patients had 1 to 2 manic symptoms along with their depression, judging by their average Young Mania rating scale of 5, and anxiety was greater as manic symptoms increased.13.14 On the other hand, quetiapine has a large effect size on generalized anxiety disorder (GAD), suggesting a more direct effect.15 Quetiapine approached FDA approval for 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.
Distressing anguish
Anxiety may not offer a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about patient care. These patients have an increased risk of treatment abandonment, adverse drug effects, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment, and an additional phone call to make sure they tolerate any new medication will go a long way in these cases.
Dr. Aiken is the editor of the Mood Disorders section Psychiatric timesTM, the editor in chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. The author does not accept fees from pharmaceutical companies, but receives PESI rights for The Depression and Bipolar Workbook and from WW Norton & Co. for Bipolar, not so much.
References
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