Pharmacologic Treatment of Psychotic Depression

Clinical Question

What is the best treatment for depression with psychotic features?

Evidence-Based Answer

An antidepressant such as imipramine (Tofranil) or sertraline (Zoloft), possibly with the addition of an antipsychotic, is the preferred initial pharmacologic treatment for psychotic depression.

Practice Pointers

About 15 percent of patients with major depression exhibit psychotic features such as hallucinations or delusions. Electroconvulsive therapy often is used to treat psychotic depression and has been shown to be effective in comparisons with sham electroconvulsive therapy. Typically, however, it is not considered first-line therapy, and it has not been compared with pharmacologic treatment in a randomized controlled trial (RCT). Most patients initially are treated pharmacologically, and this review by Wijkstra and colleagues compared an antidepressant alone, an antipsychotic alone, and the combination of both.

Only 10 RCTs with a total of 548 patients were identified after a thorough search of the literature. Although only double-blinded studies with appropriate randomization and intention-to-treat analysis were included, most studies were small (mean of 55 patients), and differing dosages and treatment protocols made it inappropriate to combine results from different studies. The conclusions that could be drawn from this literature, therefore, are limited.

The authors found that an antidepressant alone was effective (four RCTs; relative risk [RR] 2.06; 95% confidence interval [CI], 1.41 to 3.00), but an antipsychotic alone was not. Four studies compared different anti-depressants and found that imipramine was more effective than mirtazapine (Remeron) and fluvoxamine (Luvox), that sertraline was more effective than paroxetine (Paxil), and that there was no difference between fluvoxamine and venlafaxine (Effexor). Based on these limited data, the preferred initial agents are imipramine and sertraline. There was a nonsignificant trend toward greater effectiveness of the combination of antidepressant and antipsychotic over an antidepressant alone (two studies, RR 1.44; 95% CI, 0.86 to 2.41). An important practice point for these patients that was not addressed by this meta-analysis is that they should be strongly considered for hospitalization.1

Long-Acting Beta2 Agonists as Steroid-Sparing Agents

Clinical Question

For patients with asthma, does the addition of a long-acting beta2 agonist allow the dosage of maintenance inhaled corticosteroids to be reduced while maintaining asthma control?

Evidence-Based Answer

For adult patients who are taking a minimum maintenance dosage of inhaled corticosteroid for asthma, adding a long-acting beta2 agonist permits reduction of the dosage of inhaled corticosteroid by 253 mcg beclomethasone equivalent per day without worsening the patient's symptoms. In patients taking higher dosages of corticosteroids, the effect of adding a long-acting beta2 agonist was even more pronounced, with a mean reduction in their maintenance inhaled corticosteroid of 600 mcg beclomethasone equivalent per day. There is no evidence of improved symptoms with combination treatment, and it is not recommended as initial treatment for asthma.

Practice Pointers

In adults and children whose asthma is not adequately controlled with inhaled corticosteroids, adding a long-acting beta2 agonist improves lung function and reduces the risk of exacerbation. Adding a long-acting beta2 agonist does not increase serious side effects or withdrawal rates when compared with inhaled steroids alone.1 Long-acting beta2 agonists alone have proven effective compared with placebo, but there are serious concerns about safety. A large study comparing salmeterol (Serevent) with placebo was stopped prematurely because of an increase in the risk of death in the active treatment group.2–4

Gibson and colleagues studied long-acting beta2 agonists as corticosteroid-sparing agents to further refine their role in the treatment of asthma. They found 10 parallel randomized controlled trials involving adult patients who required daily inhaled corticosteroids. Trial quality was good, and the power of the studies was adequate. The trials compared inhaled corticosteroids with combination treatment with reduced-dosage inhaled corticosteroids and a long-acting beta2 agonist. Patients were followed for three to 12 months. The mean reduction in the dosage of inhaled corticosteroid was 60 percent.

The researchers found no significant differences between the groups in exacerbations requiring oral steroids or in withdrawal from the study because of worsening airway inflammation. In the group that used combined treatment, forced expiratory volume in one second improved compared with baseline (weighted mean difference 0.10; 95% confidence interval, 0.07 to 0.12), there was a small but significant improvement in morning peak expiratory flow, and there were fewer days when short-acting beta2 agonists were needed. These results suggest that the beta2 agonists were not masking worsening airway inflammation.

Because adding a long-acting beta2 agonist is effective in reducing the steroid dosage in patients maintaining disease control with long-term inhaled steroids, it is reasonable to question whether combined treatment should be the initial treatment in patients with mild to moderate airway obstruction. This question was addressed by Ni Chroinin and colleagues,5 who found that in a steroid-naive population with asthma, combined therapy does not significantly reduce the rate of exacerbations over inhaled corticosteroids alone. Combined thereapy may improve lung function and symptom-free days, but it does not reduce the use of short-acting beta2 agonists. Overall, there is not sufficient evidence to recommend initiating combined therapy for patients who have never had a trial of inhaled corticosteroids, particularly given the cost of two drugs compared with one.5