The way to treat anxiety in bipolar disorder is to treat the bipolar disorder. Anxiety is a synonym for distress, and nearly all mental disorders cause distress, except perhaps the classic, euphoric manias that lift the patient into a carefree state of bliss.
Some mood episodes are more anxiety-provoking 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 together.1 The International Society for Bipolar Disorders has even calculated the exact proportions for this troubling recipe. It takes only 1 manic symptom during a depression, or 2 depressive symptoms during a mania, to spark anxiety.1
Mixed states tend to respond better to anticonvulsants and atypical antipsychotics than to lithium, which may be why anxiety predicts resistance to lithium in bipolar disorder.2 There are, however, 2 exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety raise the risk of suicide in bipolar disorder, and lithium lowers that risk 6-fold.3 This preventative effect is independent of lithium’s mood benefits, so it is worth considering lithium in patients who are suicidal, even when it has a lower chance of reducing the core symptoms.
Although the classic lithium-responsive patient tends to have pure manias and hypomanias and no anxiety disorder comorbidities, 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 high alert for threat, which is the essence of panic disorder. One study found that they had more phobias of panic sensations than patients in 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 (eg, drugs of abuse, steroids, and irregular circadian rhythms). Most patients who are in a mixed state have been on an antidepressant for a long time, and it can be difficult to tell if the drug is exacerbating the mixed presentation. Given these uncertainties, it is best to taper slowly, over weeks or months.6 Rapid discontinuation can trigger mania and other mood symptoms. The work is much like tapering a benzodiazepine. If the symptoms worsen, raise back the dose and slow down the taper.
Anxiolytic Mood Stabilizers
In bipolar disorder, anxiety is a non-specific symptom with multiple causes, including mood episodes, stress, and comorbid anxiety disorders. With so many different causes, can any mood stabilizer truly be said to be anxiolytic? Probably not, but we do have a few trials that may point the way when selecting 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 Valproate’s evidence here is more robust, and this medication also improved anxiety in patients who do not have bipolar disorder, perhaps because of its benzodiazepine-like gaba-ergic properties.10,11 Lamotrigine may 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 of patients with bipolar depression and non-specific anxiety (both were secondary analyses). The effect sizes were large enough to make them noticeable to the casual observer (0.35 for olanzapine and 0.56 for quetiapine).13,14 Quetiapine had similar anxiolytic effects in the 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects as monotherapy or when paired with fluoxetine.
These anxiolytic properties do not seem to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled trials of bipolar disorder with anxiety, and risperidone actually worsened anxiety in a study of bipolar with comorbid panic disorder.7
The unanswered question here is whether these medications were targeting anxiety directly or treating mild mixed states. Most of the patients had 1 to 2 manic symptoms along with their depression, judging from their average Young Mania Rating Scale of 5, and anxiety was higher as the manic symptoms went up.13,14 On the other hand, quetiapine has a large effect size in generalized anxiety disorder (GAD), suggesting a more direct effect.15 Quetiapine came close to FDA approval in GAD, but was held back because the FDA did not think this disorder was severe enough to warrant all the risks of an antipsychotic. That lesson applies to bipolar disorder as well. Quetiapine may be very effective for anxiety, but it should not be used in mild cases.
Anxiety may not offer a direct path to pharmacotherapy in bipolar disorder, but it does tell us something about the care of the patient. These patients are at greater risk for treatment dropout, adverse effects of medications, substance abuse, and suicide. Supportive psychotherapy, fast-acting treatment, and an extra phone call to make sure they are tolerating any new medication go a long way in these cases.
Dr Aiken is the Mood Disorders Section Editor for 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 honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much.
1. Swann AC, Lafer B, Perugi G, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170(1):31-42.
2. Swann AC, Secunda SK, Katz MM, et al. Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome. Psychiatry Res. 1986;18(2):127-141.
3. Tondo L, Baldessarini RJ. Suicidal Behavior in Mood Disorders: Response to Pharmacological Treatment. Curr Psychiatry Rep. 2016;18(9):88.
4. Nunes A, Ardau R, Berghöfer A, et al. Prediction of lithium response using clinical data. Acta Psychiatr Scand. 2020;141(2):131-141.
5. Simon NM, Otto MW, Fischmann D, et al. Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states. J Affect Disord. 2005;87(1):101-105.
6. Phelps J, Manipod V. Treating anxiety by discontinuing antidepressants: a case series. Med Hypotheses. 2012;79(3):338-341.
7. Rakofsky JJ, Dunlop BW. Treating nonspecific anxiety and anxiety disorders in patients with bipolar disorder: A review. J Clin Psychiatry. 2011;72(1):81-90.
8. Davis LL, Bartolucci A, Petty F. Divalproex in the treatment of bipolar depression: a placebo-controlled study. J Affect Disord. 2005;85(3):259-266.
9. Sheehan DV, Harnett-Sheehan K, Hidalgo RB, et al. Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. J Affect Disord. 2013;145(1):83-94.
10. Bach DR, Korn CW, Vunder J, Bantel A. Effect of valproate and pregabalin on human anxiety-like behaviour in a randomised controlled trial. Transl Psychiatry. 2018;8(1):157.
11. Aliyev NA, Aliyev ZN. Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study. Eur Psychiatry. 2008;23(2):109-114.
12. Bruno A, Micò U, Pandolfo G, et al. Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder: a double-blind, placebo-controlled study. J Psychopharmacol. 2012;26(11):1456-1462.
13. Lydiard RB, Culpepper L, Schiöler H, et al. Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies. Prim Care Companion J Clin Psychiatry. 2009;11(5):215-225.
14. Tohen M, Calabrese J, Vieta E, et al. Effect of comorbid anxiety on treatment response in bipolar depression. J Affect Disord. 2007;104(1-3):137-146.
15. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for generalised anxiety disorder: a systematic review and network meta-analysis. Lancet. 2019;393(10173):768-777.