Anxiety symptoms are very common in people with bipolar disorder (BD) and are considered an independent marker of the severity of the illness.
At least 50% of people with BD are likely to meet diagnostic criteria for an anxiety disorder during their lifetime. The prevalence of these disorders does not differ significantly between TB subtypes, being three times higher than that of the general population.
For individuals with BD, the presence of clinically significant anxiety disorders or symptoms is associated with more frequent and severe mood disturbances, longer duration of illness, greater prevalence of substance use, and increased rates of suicidal behavior. Even sub-syndromal levels of anxiety affect treatment response in BD.
Since comorbid anxiety is associated with a more severe and complicated course of the disease, its identification and treatment are of critical importance.
Treatment of anxiety symptoms in patients with TB presents a significant challenge. While anxiety disorders alone can be effectively treated with serotonergic antidepressants, this option is problematic in BD given the associated risk of mood destabilization.
Benzodiazepines, another commonly used pharmacotherapy for anxiety, carry a potential risk for abuse and dependence, which is problematic in these patients.
Current treatment guidelines lack information on the management of these comorbid conditions and the Canadian Network for Mood and Anxiety Treatments (CANMAT) working group has called for more research in this area.
The present study develops a systematic review and meta-analysis of the available evidence on pharmacotherapy for anxiety symptoms in BD.
| Results |
Of 4031 articles identified, 167 full text articles were reviewed. A total of 37 randomized controlled studies (RCTs) met the eligibility criteria; 36 included a placebo comparator, and one RCT used another pharmacological comparison.
Twenty-six RCTs focused on the treatment of a depressive episode; three in the treatment of hypomanic or manic symptoms; one in the treatment of a mixed sample of manic, hypomanic and depressed patients; two in treatment during euthymia; and five did not specify the presence or absence of a mood episode.
All participants had a formal diagnosis of TB; only four RCTs were conducted in a sample with a formal comorbid diagnosis of generalized anxiety disorder (GAD) or panic disorder (PD).
> Narrative review of RCTs not included in the meta-analysis
Twenty of the 37 articles did not provide sufficient information to be included in the meta-analysis. Of these, 7 examined the effect of quetiapine: 5 reported a significant improvement in anxiety and depression symptoms in participants with a depressive episode; one reported significant improvement in comorbid PD; and one reported no effect. Single RCTs of lurasidone and asenapine reported significant improvement in symptoms of anxiety and depression compared with placebo, while an RCT of ziprasidone found no difference between groups.
Other RCTs provided some evidence for the anxiolytic effects of paroxetine, or escitalopram plus celecoxib, while the effect of amitriptyline on anxiety did not differ significantly from the effect of L-sulpiride.
Two RCTs of ketamine and one of methylene blue reported a significant improvement in symptoms of anxiety and depression compared to placebo. Single RCTs of minocycline plus aspirin or levothyroxine reported no differences in outcomes compared with placebo.
Finally, two RCTs of modafinil reported no improvement in anxiety or mania compared with placebo.
> Meta-analysis
Seventeen articles (4695 participants) provided sufficient data to calculate comparative effect sizes for medication vs. placebo, including 13 RCTs for anxiety symptoms, 16 for depression symptoms and 10 for mania/hypomania symptoms.
No treatment as usual (HT) RCTs had data available for inclusion in the meta-analysis, therefore all included RCTs were placebo-controlled.
> Efficacy of pharmacotherapy for anxiety symptoms
The 13 RCTs included in the meta-analysis involved 2175 patients. The drugs were found to have significantly greater efficacy than placebo with a small effect size.
There was little evidence of heterogeneity at the study level. Follow-up analyzes did not indicate that heterogeneity was due to study quality or treatment duration. However, meta-regression analyzes of baseline severity of anxiety symptoms in the 6 RCTs using the Hamilton Anxiety Rating Scale (HAM-A) indicated that higher baseline severity was associated with greater efficacy of medications vs. placebo.
The meta-regression also indicated that the efficacy of pharmacotherapy for anxiety symptoms was associated with efficacy for depression.
> Efficacy of pharmacotherapy for symptoms of depression or mania/hypomania
The random effects meta-analysis on depression symptoms from the 16 included RCTs involved 2511 participants and indicated that the medications had significantly greater efficacy than placebo for depression with a small effect size.
The random effects meta-analysis on mania/hypomania symptoms of the 10 included RCTs involved 1309 participants and indicated a very small and non-significant difference in the efficacy of medications and placebo. There was evidence of study-level heterogeneity for depression symptoms but was low for mania/hypomania symptoms.
> Acceptability of pharmacotherapy
Medications and placebo were associated with comparable rates of all-cause discontinuation based on meta-analysis of 28 RCTs with 7424 participants. There was no evidence of study-level heterogeneity for all causes of discontinuation. A separate analysis of data from three RCTs in 350 participants with comorbid anxiety disorder led to similar results.
| Discussion |
The results of this systematic review and meta-analysis suggest that pharmacotherapy improves anxiety symptoms in BD more than placebo. The effect size was small and comparable to the antidepressant effect of the medications.
Despite the high prevalence rates and symptom burden associated with comorbid anxiety in BD, depressive symptoms were the primary outcome in the majority of RCTs identified in this review.
Only five of the 37 RCTs focused on anxiety as a primary outcome and investigated the effects of atypical antipsychotics. This highlights the paucity of research on pharmacotherapy options for this group of patients.
Looking at the analysis at the individual study level for anxiety symptoms, cariprazine, olanzapine monotherapy, olanzapine and fluoxetine combined, and quetiapine were associated with a greater reduction in anxiety symptoms than placebo. However, there are no comparisons of these medications. These findings align with the most recent guidelines from CANMAT and the International Society of Bipolar Disorders, which recommend quetiapine as a first-line treatment for the management of individuals with BD and comorbid anxiety, while other atypical antipsychotics such as olanzapine or the combination Olanzapine-fluoxetine are considered second- and third-line approaches.
The modest size of the anxiolytic effect of the pharmacotherapies included in this meta-analysis may be explained in part by an inadequate duration of treatment. Most of the included RCTs lasted only 6–12 weeks, with a mean of 8.9 weeks.
In several RCTs of anxiolytics, response did not occur until 12 weeks after the start of treatment and even improved in up to 6 months. Additionally, effective treatment of anxiety symptoms often requires higher doses of medication.
We attempted to minimize dose effects by considering only RCTs that included anxiety symptoms as an a priori clinical outcome. However, in the current review, it was not possible to account for the influence of medication dose, which varied between drugs and RCTs and may have contributed to heterogeneity.
Clinicians treating patients with TB and comorbid anxiety, and those developing treatment guidelines, are interested not only in the efficacy of medications but also in their tolerability. No difference was found in all-cause discontinuation between medications and placebo.
While discontinuation rates provide some information about drug tolerability, the eligibility criteria of most RCTs exclude participants prone to adverse effects, poor adherence, and study withdrawal. Although discontinuation rates did not differ in this analysis, antipsychotics
They are often associated with problematic adverse effects. New studies are needed to examine the use of atypical antipsychotics in the treatment of comorbid anxiety symptoms of BD and to better assess their risk (tolerability) vs. benefit (efficacy).
Several limitations prevent drawing conclusions from these results. First, research on the treatment of anxiety symptoms in BD is scarce. Only four RCTs included participants with a comorbid anxiety disorder and did not provide sufficient data to allow a sensitivity analysis of drug efficacy in patients with BD and a comorbid diagnosis of GAD or PD.
The majority of identified studies evaluated patients during a depressive episode. It is possible that the anxiety symptoms experienced during these episodes were associated with depression rather than representing comorbid anxiety. This would suggest that the medications’ benefits on anxiety symptoms could be the result of improvements in depression symptoms. However, although some evidence of an association was found between improvement in depression and anxiety symptoms, an independent effect of medications on anxiety symptoms remained.
Although there is a significant burden of comorbid anxiety in euthymic patients with BD, only two RCTs focused on these patients. The heterogeneity of anxiety disorders and their clinical phenotypes, compounded by the heterogeneity of measures used to assess anxiety, make it difficult to draw clinical inferences from the overall effect shown in the current review.
| Conclusion |
Comorbid anxiety symptoms are highly prevalent in BD and are associated with worse clinical outcomes. This review highlights the paucity of research relevant to this comorbidity.
While certain benefits were observed with some atypical antipsychotics, these results are not sufficient to conclude that atypical antipsychotics are the preferred treatment for comorbid anxiety in BD or to provide specific guidance for clinicians.
New RCTs of these and other medications are needed to evaluate short- and long-term outcomes on anxiety in all phases of TB.
