Antipsychotics in the Treatment of Comorbid Anxiety in Bipolar Disorder

The comorbidity of anxiety disorders with bipolar disorder is a rule, not an exception, with a negative impact on both course and treatment outcome. So far, there are no guidelines or consensus for the treatment of this comorbidity. There are also no efficacy data that support the use of antidepressants or benzodiazepines in the treatment of anxiety disorder in this population. Benzodiazepines, the second-line agents for some primary anxiety disorders, may be riskier for patients with bipolar disorder because they are associated with a high rate of comorbid substance use disorder. Some preliminary data have shown that antipsychotics, especially atypical anti- psychotics, may be a viable alternative for patients with comorbid bipolar and anxiety disorders with or without substance use disorder.

COMORBIDITY Incidence

Data from the National Comorbidity Survey have shown that patients with bipolar I disorder (BPI) had high rates of lifetime Axis I comorbidity and that anxiety disorder and substance use disorder were the 2 most common comorbid conditions with BPI.¹ Of the 59 patients with BPI, 93% had at least one anxiety disorder and 61% had at least one substance use disorder.

More recently, the findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have shown that patients with BPI (n = 1411) had high rates of comorbid anxiety disorders with specific phobia (30%), panic disorder with/ without agoraphobia (26%), generalized anxiety disorder (GAD) (25%), and social phobia (24%).² Bauer and colleagues³ have reported that in clinical outpatient samples, the lifetime rates of anxiety disorder ranged from 24% to 53% with BPI and 16% to 46% with bipolar II disorder (BPII).³ Data from a cohort of patients with rapid cycling BPI or BPII (n = 566) have shown that 35% of patients had lifetime GAD, 27% had panic disorder, and 7% had obsessive-compulsive disorder (OCD).⁴

Comorbid substance use disorder with bipolar disorder is also a rule, not an exception. In the Epidemiologic Catchment Area study, patients with BPI or BPII had the highest rates of substance use disorder among all patients with mental illness, with a lifetime incidence of alcohol use disorder of 44% and a lifetime incidence of drug use disorder of 34%.⁵ In the NESARC, more than half of the patients with BPI (58%) had a lifetime history of alcohol use disorder, and more than one third (37.5%) had a lifetime history of drug use disorder.² In clinical outpatient studies, the rates of lifetime comorbid substance use disorder with bipolar disorder were 42% to 61% with BPI and 31% to 48% with BPII.^6-8

Although the exact rates of double or multiple comorbidities of anxiety disorders and substance use disorders in bipolar disorder are unknown, high rates of these comorbidities in bipolar disorder have been observed in various study populations. These include national surveys,^1,2 a bipolar research network or program,^7,9 a Veterans Affairs cooperative study,³ and our research center.⁴ In our sample, at least 31% of patients with rapid cycling bipolar disorder had both comorbid anxiety disorder and substance use disorder.

Impact

Comorbid anxiety disorder has a significantly negative impact on the quality of life of patients who have bipolar disorder, as manifested by earlier onset of illness,^10-12 more rapid cycling, suicidal behavior, substance use disorder,^9,11-14 poorer response to lithium or anticonvulsants,^14-16 and worse prognosis.^14,15,17,18 The data from a study of patients with rapid cycling bipolar disorder have shown that comorbid anxiety disorder and/or substance use disorder was associated with an increased risk of hospitalization or suicide attempt(s).¹⁹

Treatment issues

Findings from the Systematic Treatment Enhancement Program-Bipolar Disorder (STEP-BP) have shown that comorbid anxiety and bipolar disorders were usually undertreated, although antidepressants were more commonly prescribed for patients with the comorbidity.²⁰ More recently, data from the STEP-BP have shown that a current anxiety diagnosis at study entry was associated with the increased risk of depression recurrence; the proportion of days with anxiety in the previous year was an independent predictor for depression recurrence.²¹ However, it is still unclear whether adequate treatment of anxiety disorders will change the course and treatment outcome in patients with bipolar disorder.

Although newer antidepressants, especially SSRIs, have proved efficacious in the treatment of primary anxiety disorders and have commonly been prescribed for patients with bipolar disorder,²⁰ there are no data to support their use in treating anxiety in bipolar disorder. The issue of antidepressant-induced mania remains controversial²² although there is evidence that antidepressants may trigger mania or destabilize the course of the bipolar disorder, especially without the concomitant use of a mood stabilizer.^17,23-25

In a 6-year follow-up study of patients with schizophrenia or bipolar and substance use disorders, treatment with a benzodiazepine was not associated with any of the measured outcomes other than increasing the likelihood of benzodiazepine abuse-15% in the treatment group versus 6% in the nontreatment group.²⁶ Clearly, benzodiazepines for anxiety disorder should be used with caution in patients who have bipolar disorder and a substance use disorder.

EXPERIENCE WITH ANTIPSYCHOTICS Primary GAD

There is a long history of interest in antipsychotics for the treatment of anxiety disorders, but the data for the treatment of GADs are limited to the typical agents. In a large randomized, double-blind, placebo-controlled study, Mendels and colleagues²⁷ found that trifluoperazine was superior to placebo in the acute treatment of DSM-III-diagnosed GAD.²⁷ In this multicenter study, 415 patients with moderate to severe anxiety symptoms on the Hamilton Anxiety Rating Scale (HAM-A) equal to a score of 20 were randomly assigned to receive either 2 to 6 mg of trifluoperazine (n = 207) or placebo (n = 208) for 4 weeks. Efficacy was assessed using the HAM-A and other scales. Trifluoperazine showed superiority to placebo in all outcome measures including HAM-A total scores and subscores (Figure 1).

In less well-designed studies, other typical antipsychotics appeared to be superior to placebo or as effective as benzodiazepines in the treatment of GAD or other anxiety disorders.²⁸ In terms of atypical antipsychotics, there is only one small randomized, placebo-controlled study (N = 20) of olanzapine in the treatment of refractory primary GAD.²⁹

OCD or chronic posttraumatic stress disorder

Before the introduction of newer atypical antipsychotics, the efficacy of haloperidol in the treatment of refractory OCD was explored with mixed results. One study found there were no differences among 3 groups: those receiving chlorimipramine, those receiving chlorimipramine-haloperidol, and those taking chlorimipramine-diazepam for the treatment of phobic-obsessive psychoneurosis as measured with the Brief Psychiatric Rating Scale and Inpatient Multidimensional Psychiatric Scale.³⁰ Another study found that haloperidol adjunctive to fluvoxamine (n = 17) was superior to placebo (n = 17) in the treatment of refractory OCD.³¹

With the introduction of newer atypical antipsychotics and the realization of the incomplete effect of SSRIs on the treatment of OCD, investigators have explored atypical antipsychotic augmentation to SSRI treatment in refractory OCD. After a small open-label study of risperidone augmentation for the treatment of refractory OCD with positive results,³² the efficacy of risperidone, olanzapine, and quetiapine was assessed in open-label or double-blind, placebo-controlled studies.

In addition, these 3 agents were explored for the treatment of chronic posttraumatic stress disorder (PTSD). Most of the studies showed that adding risperidone, olanzapine, or quetiapine to an SSRI produced results superior to those achieved with placebo in the treatment of refractory OCD or chronic PTSD. However, the sample sizes of these studies were relatively small, ranging from 15 to 66 patients.²⁸

Comorbid anxiety symptoms in bipolar disorder

There are 2 large randomized, double-blind, placebo-controlled studies, one with olanzapine and the other with quetiapine, for the acute treatment of bipolar depression.^33,34 In both studies, changes in HAM-A scores were used as secondary outcome measures. Tohen and colleagues³³ analyzed HAM-A scores of 695 patients (placebo, n = 315; olanzapine, n = 309; olanzapine-fluoxetine combination [OFC], n = 71). At baseline, HAM-A scores were comparable among the 3 groups with a mean range of 15.8 to 17.1 points. After the 8-week treatment, both olanzapine and OFC were significantly superior to placebo in reducing HAM-A total scores. However, there was no difference between olanzapine monotherapy and OFC (Figure 2).

In the quetiapine study, patients were randomized to treatment with 600 mg/d of quetiapine (n = 180), 300 mg/d of quetiapine (n = 181), or placebo (n = 181).³⁴ The changes in HAM-A scores of 511 patients (342, BPI; 169, BPII) were analyzed. Similar to the olanzapine study, the baseline HAM-A mean scores were comparable among the 3 groups, ranging from 18.6 to 18.9 points. At the end of week 8, both dosages of quetiapine significantly reduced HAM-A total scores compared with placebo (Figure 2). In a post hoc analysis, quetiapine significantly decreased HAM-A items of anxious mood, tension, fear, insomnia, and depressed mood and intellectual, somatic (muscular), and genitourinary symptoms compared with placebo.³⁵ However, only the patients with BPI showed a significant and robust reduction in HAM-A total scores compared with placebo (Figure 3).

POSSIBLE MECHANISMS OF ACTION

The neuronal basis for anxiety is complex and unclear, although the serotonergic system may play a role. Recently, the involvement of the dopamine system in anxiogenesis has been speculated. The amygdala and the mesolimbic dopaminergic systems are believed to play an important role in conditioned fear and anxiety in animals and anxiety disorder in humans.^36-38

Anxiety-provoking environments increased dopamine release in the amygdala,³⁷ the prefrontal cortex,^39,40 and other brain areas of rats.⁴¹ The increase in dopamine in the prefrontal cortex during stress or anxiogenic administration could be totally blocked by anxiolytics, such as diazepam⁴² or antidepressants.^43,44 The anxiogenic-like response induced by chronic amphetamine treatment in rats could be totally blocked by haloperidol injection.⁴⁵ Similarly, other antipsychotics could also block the acquisition of conditioned fear.^46-48

Neuroimaging studies in humans have demonstrated that an increased release of dopamine caused by stimulants was positively correlated with an increase in anxiety symptoms in healthy persons.^49-52 These data from animal and human studies suggest that direct blockade of dopamine action with antipsychotic drugs may be an alternative way to reduce anxiety symptoms.

IS USE OF ANTIPSYCHOTICS FOR ANXIETY JUSTIFIED?

Good quality data for antipsychotics in the treatment of anxiety disorder are limited to trifluoperazine. It is the only antipsychotic that has been approved by the FDA for the short-term treatment of primary GAD. At present, the use of other antipsychotics in primary or comorbid anxiety disorder should be considered off-label.

Although adjunctive atypical antipsychotics appeared to be useful in refractory OCD or chronic PTSD, and monotherapy appeared useful in bipolar depression with anxiety symptoms, the results were confounded by small sample sizes or lack of systematic assessment of the nature of anxiety. Therefore, caution should be followed in the use of these agents for primary or comorbid anxiety symptoms/disorders.

Anxiety is a very complicated phenomenon. So far, there is no single agent that can be used effectively and safely by all patients. A systemic consideration of the risks and benefits of antidepressants, antipsychotics, benzodiazepines, and other agents should be carried out before the initiation of treatment.

SPECIAL CONSIDERATIONS

Since there are no efficacy data supporting the use of any agent in the treatment of comorbid anxiety disorder in patients with bipolar disorder, attention should be paid to the potential adverse effects. For antidepressants, in addition to the common adverse effects experienced by patients who are not bipolar, patients with bipolar disorder may experience treatment-related mania/hypomania. To minimize this risk, adequate treatment with a mood stabilizer is essential when an antidepressant is indicated. Benzodiazepine use in patients with bipolar disorder and a history of substance use disorder, especially current substance use disorder, should be carefully documented and monitored because of the abuse/dependence potential of benzodiazepines. Using an agent with a long half-life may minimize the risk of abuse or withdrawal.

Although antipsychotics do not pose a risk for mania/hypomania or abuse/ dependence with bipolar disorder, the burden of potential adverse effects cannot be ignored. The lower prevalence of atypical antipsychotic-induced extrapyramidal symptoms (EPS) compared with typical agents has led clinicians to prioritize their use, but atypical antipsychotic-induced EPS do occur in the treatment of schizophrenia or acute mania. More important, there is evidence, although inconsistent, that bipolar disorder is a risk factor for EPS. Similarly, metabolic abnormalities have been reported in patients with schizophrenia who are treated with typical or atypical antipsychotics. Therefore, patients treated with antipsychotics should be closely monitored for metabolic syndrome and movement disorders regardless of the drug classes.

CONCLUSION

There is no pharmacological study designed for a cohort of patients with bipolar disorder and a specific comorbid anxiety disorder. Low-dose trifluoperazine was well tolerated and superior to placebo in the short-term treatment of primary GAD.²⁷ Adjunctive therapy with an atypical antipsychotic (risperidone, olanzapine, or quetiapine) was superior to placebo in the treatment of refractory OCD or chronic PTSD, but these studies were confounded by small sample sizes.

The preliminary data on olanzapine and quetiapine in reducing anxiety symptoms in patients with bipolar depression suggest that this class of agents may have promise for the treatment of comorbid anxiety disorders with bipolar disorder. There exists an urgent need for large randomized controlled trials of the various atypical antipsychotic agents in patients who have bipolar disorder and comorbid specific anxiety disorders, especially in those with substance use disorder.

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