Antipsychotics for patients without psychosis?
What clinical trials support
Response rates were 58% with quetiapine and 36% with placebo; remission rates were 53% with quetiapine and 28% with placebo. Most symptoms, including core depression items, improved significantly with quetiapine, compared with placebo.18 Results of a second double-blind study (BOLDER II) have been presented at conferences but have not been fully published.
Risperidone. A smaller double-blind study compared risperidone plus placebo, paroxetine plus placebo, and risperidone plus paroxetine in 30 patients in the depressed phase of bipolar I or II disorder. Patients continued taking mood stabilizers during the study. After 12 weeks, depressive symptoms improved significantly in all three groups, with no significant differences.19
Maintenance therapy. Olanzapine and aripiprazole are FDA-approved for maintenance therapy in bipolar disorder (Table 1).
Unipolar depression
FGAs have shown efficacy in depression in multiple controlled studies.20 SGAs have been evaluated mostly as add-on therapies in antidepressant-resistant depression.
Olanzapine. Shelton et al21 compared olanzapine monotherapy, fluoxetine monotherapy, and combined treatment in 34 nonpsychotic, treatment-resistant depressed subjects. Olanzapine plus fluoxetine was more effective than either agent alone. A subsequent double-blind study, however, showed similar efficacy after 8 weeks among the three treatments and nortriptyline monotherapy. Patients in the double-blind trial appeared to respond more rapidly to combined treatment than to the monotherapies.22
Risperidone. A multiphase study of the efficacy of risperidone augmentation in treatment-resistant major depression began when 489 outpatients (2% with psychotic symptoms) received open-label citalopram, 20 to 60 mg/d. After 4 to 6 weeks, 386 nonresponders entered the augmentation phase with open-label risperidone, 0.25 to 2 mg/d. After 4 to 6 weeks of combination therapy, 241 (63%) patients whose symptoms resolved entered a double-blind discontinuation phase, in which they were randomly assigned to augmentation with risperidone or placebo, while on citalopram.
Median time to relapse during the double-blind phase was 102 days with risperidone augmentation and 85 days with placebo—not a statistically significant difference. Relapse rates after 24 weeks were 53.3% and 54.6%, respectively.23 This study showed that the improvement observed after adding risperidone was not sustained over time.
Quetiapine. In a prospective single-blind study, paroxetine augmented with quetiapine, 200 mg/d, was compared to paroxetine alone in major depression with anxiety.24 Combination therapy was more effective in improving anxiety and depression symptoms.
Others. Open-label, add-on studies indicate that aripiprazole and ziprasidone can improve treatment-resistant depression.25-27
Anxiety disorders
OCD. SGAs also have been investigated as augmentation therapy for patients with OCD resistant to SRIs. A single-blind study of 27 patients found adjunctive quetiapine more effective than placebo in improving OCD symptoms.28 SGAs were more effective than placebo as augmentation therapy to SRIs for treatment-refractory OCD in double-blind, placebo-controlled studies using mean dosages of:
In other trials:
- A small double-blind study of patients with social anxiety disorder found olanzapine monotherapy more effective than placebo.34
- Low-dose risperidone (mean dosage 1.1 mg/d) improved core symptoms of generalized anxiety disorder in a 5-week, double-blind, placebo-controlled trial.35
- Some authors have reported clinical improvement of panic disorder with olanzapine augmentation.36
Developmental disorders
Antipsychotics represent one-third of all filled psychotropic prescriptions for individuals with pervasive developmental disorders (PDD).37 Haloperidol and thioridazine are the only two FDA-approved FGAs for severe behavioral problems in PDD (and for hyperactivity with conduct disorders). Recently, risperidone received FDA approval for the treatment of irritability associated with autistic disorder in children.
Risperidone—the most-studied SGA in the PDD population—has shown efficacy in autism and in PDD not otherwise specified. Risperidone at dosages >3 mg/d improved repetitive behavior and aggression in adult patients.38
In children with autism, risperidone can improve tantrums, aggression, and self-injury. In a study of risperidone’s effect on autism’s core symptoms, the authors reported improvements in repetitive and stereotyped behavior but not in social relatedness or verbal communication.39
Double-blind studies have shown positive effects on aggression and behavioral disturbances in children with conduct disorder, oppositional defiant disorder, and other disruptive disorders, developmentally delayed adolescents, and mentally retarded subjects of various ages.40-42 Children and adolescents appear to be more sensitive than adults to risperidone’s side effects such as weight gain, EPS, and pancreatitis.
Personality disorders
Antipsychotics have been recommended for paranoid ideas and psychotic-like symptoms in borderline personality disorder and in paranoid personality disorder.43
Olanzapine. A 24-week, double-blind study found low-dose olanzapine (mean dosage 5.3 mg/d) more effective than placebo for anxiety, interpersonal sensitivity, paranoia, and anger/hostility in women with borderline personality disorder.44
In another double-blind study, 12 weeks of olanzapine therapy (mean 6.9 mg/d) was more effective than placebo for inappropriate anger in borderline personality disorder, as measured by a modified Clinical Global Impression scale.45
