Antipsychotics in the Treatment of Comorbid Anxiety in Bipolar Disorder

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(Drug information on 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(Drug information on olanzapine) in the treatment of refractory primary GAD.²⁹

Before the introduction of newer atypical antipsychotics, the efficacy of haloperidol(Drug information on 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(Drug information on 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(Drug information on risperidone) augmentation for the treatment of refractory OCD with positive results,³² the efficacy of risperidone, olanzapine, and quetiapine(Drug information on 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

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).

The neuronal basis for anxiety is complex and unclear, although the serotonergic system may play a role. Recently, the involvement of the dopamine(Drug information on 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 diazepam(Drug information on diazepam)⁴² 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.