The way to treat anxiety in bipolar disorder is to treat the bipolar disorder. Anxiety is a synonym for distress, and almost all mental disorders cause distress, except perhaps the classic, euphoric mania that elevates the patient into a carefree state of happiness.
Some moods are more anxious than others, and mixed moods are at the top of the list. Although anxiety does not appear in the criteria for mixed conditions, it is often created when depression and mania merge.1 The International Society for Bipolar Disorders has even calculated the exact ratios for this worrying recipe. To induce anxiety, only 1 manic symptom during depression or 2 depressive symptoms during mania are needed.1
Mixed conditions usually respond better to anticonvulsants and atypical antipsychotics than to lithium, which is why anxiety predicts resistance to lithium in bipolar disorder.2 However, there are two exceptions to this rule: suicide and panic disorder. Both mixed conditions and anxiety increase the risk of suicide in bipolar disorder, and lithium reduces the risk 6 times.3 This preventive effect is independent of the benefits of lithium, and therefore it is worth considering lithium in patients who have suicide, even if it has a lower chance of reducing the core symptoms.
Although the classical lithium-responsive patient has pure mania and hypomania and has no anxiety disorder comorbidities, a recent study has been identified as a predictor of lithium response.4 Although anxiety is low in pure mania and hypomania, these patients are on their guard for threat, which is the core of panic disorder. One study found that they had more phobias of panic sensations than patients in 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 (e.g., drugs, steroids, and irregular circadian rhythms). Most patients who are in a mixed condition have had an antidepressant for a long time, and it can be difficult to know if the drug aggravates the mixed presentation. Given these uncertainties, it is best to take them slowly, over weeks or months.6 Rapid cessation can cause mania and other mood symptoms. The job is a lot like reducing a benzodiazepine. If the symptoms worsen, increase the dose and slow down the taper.
Anxiety stabilizers
In bipolar disorder, anxiety is a non-specific symptom with multiple causes, including mood swings, stress, and anxiety disorders that occur with it. Can it be said with so many different causes that any mood stabilizer is anxious? Probably not, but we do have some trials that may show the way when choosing a mood stabilizer for a patient with significant anxiety.
Among the anticonvulsants, valproate and lamotrigine improved anxiety in small controlled trials of anxious bipolar disorder.7-9 The evidence of Valproate here is more robust, and this medication has also improved anxiety in patients who do not have a bipolar disorder, perhaps because of the benzodiazepine – like gabaergic properties.10.11 Lamotrigine can also treat obsessive compulsive disorder through glutamatergic effects, based on a small placebo-controlled and several uncontrolled studies.12
The atypical antipsychotics can also improve anxiety. Quetiapine and olanzapine reduced anxiety in large, randomized, placebo-controlled trials in patients with bipolar depression and nonspecific anxiety (both were secondary analyzes). The effect sizes were large enough to make it noticeable to the casual 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 similar anxiolytic effects as monotherapy or when linked to fluoxetine.
These anti-anxiety properties do not appear to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled trials of bipolar disorder with anxiety, and risperidone actually exacerbated the anxiety in a study of bipolar with comorbid panic disorder.7
The unanswered question here is whether this drug is aimed directly at anxiety or treats the mild mixed conditions. Most of the patients had 1 to 2 manic symptoms and their depression, judging by their average Young Mania scale of 5, and 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), indicating a more direct effect.15 Quetiapine came close to FDA approval in GAD but was withheld because the FDA did not think this disorder was serious enough to justify all the risks of an antipsychotic. The lesson also applies to bipolar disorder. Quetiapine can be very effective for anxiety, but it should not be used in mild cases.
Anxious need
Anxiety may not provide a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about the patient’s care. These patients are at greater risk of treatment failure, adverse drug reactions, drug abuse, and suicide. Supportive psychotherapy, prompt treatment and an extra call to make sure they tolerate any new medication come in handy in these cases.
Dr Aiken is the Division Editor for Mood Disorders for Psychiatric timesTM, the editor-in-chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. He has recently written several books on mood disorders The depression and bipolar workbook. The author does not accept fees from pharmaceutical companies, but receives royalties from PESI for The Depression and Bipolar Workbook and from WW Norton & Co. for Bipolar, not so much.
References
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