The way to treat anxiety in bipolar disorder is to treat bipolar disorder. Anxiety is synonymous with distress, and almost all mental disorders cause distress, except perhaps the classic euphoric manias that put the patient in a carefree state of bliss.
Some moods are more terrifying than others, and mixed states are at the top of the list. While anxiety does not appear in the mixed-state criteria, it is often created when depression and mania go together.1 The International Society for Bipolar Disorders has even calculated the exact ratios for this troubling recipe. It only takes 1 manic symptom during depression, or 2 depressive symptoms during mania, to induce anxiety.1
Mixed states tend to be more responsive to anticonvulsants and atypical antipsychotics than to lithium, which may be why anxiety predicts resistance to lithium in bipolar disorder.2 However, there are 2 exceptions to this rule: suicide and panic disorder. Both mixed states and anxiety increase the risk of suicide in bipolar disorder, and lithium lowers that risk six-fold.3 This preventive effect is independent of the mood of lithium, so it is worth considering lithium in patients who are suicidal, even if it has a lower chance of reducing core symptoms.
Although the classic lithium-responsive patient tends to have pure manias and hypomanias and no co-morbidity with 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 very alert to threat, which is the essence of panic disorder. One study found that they had more panic-sensation phobias 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 (eg, drug 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 determine whether the drug is worsening the mixed presentation. Given these uncertainties, it is best to taper off slowly, over weeks or months.6 Rapid discontinuation can cause mania and other mood symptoms. The work is very similar to tapering off a benzodiazepine. If symptoms get worse, increase the dose and slow down.
Anxiolytic mood stabilizers
In bipolar disorder, anxiety is a nonspecific symptom with multiple causes, including mood periods, stress, and comorbid anxiety disorders. With so many different causes, can any mood stabilizer really be said to be anxiolytic? Probably not, but we have a few studies that can lead the way in selecting a mood stabilizer for a patient with significant anxiety.
Of the anticonvulsants, valproate and lamotrigine improved anxiety in small controlled studies in anxiety bipolar disorder.7-9 The evidence of valproate is more robust here, and this drug also improved anxiety in patients who do not have bipolar disorder, perhaps because of its 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 reduce 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 be noticeable to the casual observer (0.35 for olanzapine and 0.56 for quetiapine).13.14 Quetiapine had similar anxiolytic effects at the 300 mg and 600 mg doses, and olanzapine had similar anxiolytic effects as monotherapy or in combination with fluoxetine.
These anxiolytic properties do not appear to extend to other atypical antipsychotics. Ziprasidone and risperidone both failed in placebo-controlled studies of bipolar disorder with anxiety, and risperidone actually exacerbated anxiety in a study of bipolar disorder with comorbid panic disorder.7
The unanswered question here is whether these drugs targeted anxiety directly or treated mild mixed states. Most patients had 1 to 2 manic symptoms in addition to their depression, judging by their average Young Mania Rating Scale of 5, and anxiety was higher with increasing manic symptoms.13.14 Quetiapine, on the other hand, 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 held back because the FDA didn’t think this condition was serious enough to justify all the risks of an antipsychotic. That lesson also applies to bipolar disorder. Quetiapine can be very effective for anxiety, but it should not be used in mild cases.
Anxious sorrow
Anxiety may not provide a direct path to pharmacotherapy for bipolar disorder, but it does tell us something about patient care. These patients are at greater risk of treatment failure, drug side effects, substance abuse and suicide. Supportive psychotherapy, fast-acting treatment, and an extra phone call to make sure they tolerate new medications go a long way in these cases.
Dr. Aiken is the section editor for mood disorders Psychiatric timesTM, the editor-in-chief of The Carlat Psychiatry Report, and the director of the Mood Treatment Center. Most recently, he has 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 it The Depression and Bipolar Workbook and from WW Norton & Co. fobipolar, not so much.
References
1. Swann AC, Lafer B, Perugi G, et al .; Bipolar Mixed States: An International Association for Bipolar Disorders, reports symptom structure, disease course, and diagnosis. Am J Psychiatry. 2013; 170 (1): 31-42.
2. Swann AC, Secunda SK, Katz MM, et al .; Lithium treatment of mania: clinical features, 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. Current 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: Susceptibility to anxiety as a possible mediator of panic during manic states. J affect disorder. 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. Treatment of nonspecific anxiety and anxiety disorders in patients with bipolar disorder: an overview. 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 disorder. 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 disorder. 2013; 145 (1): 83-94.
10. Bach DR, Korn CW, Vunder J, Bantel A. Effect of valproate and pregabalin on human anxiety-like behavior in a randomized 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.
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, Schioler H, et al .; Quetiapine monotherapy for the treatment of anxiety symptoms in patients with bipolar depression: a pooled analysis of the results of 2 double-blind, randomized, placebo-controlled studies. First-line 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 disorder. 2007; 104 (1-3): 137-146.
15. Slee A, Nazareth I, Bondaronek P, Liu Y, Cheng Z, Freemantle N. Pharmacological treatments for generalized anxiety disorder: a systematic review and network meta-analysis. Lancet2019; 393 (10173): 768-777.