Attendees Consider New Therapies At Annual American College of Neuropsychopharmacology Meeting

Possible Role for Olanzapine in Posttraumatic Stress Disorder

Noting the frequent unresponsiveness of posttraumatic stress disorder (PTSD) to standard drug treatments, Stein and colleagues reported results of the first double-blind, placebo-controlled trial of an adjunct to selective serotonin reuptake inhibitors for the treatment of this disorder.

Study participants were 19 combat veterans whose PTSD was deemed minimally responsive to at least 12 weeks of treatment with SSRIs. For eight weeks, olanzapine (Zyprexa) 10 mg to 20 mg qhs or placebo was added to the steady SSRI dosage. To assess efficacy, changes on the following rating instruments were compared between the two groups: Clinician-Administered PTSD Scale for DSM-IV (CAPS), Center for Epidemiologic Studies-Depression Scale (CES-D), Pittsburgh Sleep Quality Inventory (PSQI) and Clinical Global Impression-Improvement Scale (CGI-I). On all scales but the CGI, patients in the olanzapine group had significantly reduced scores compared to those in the placebo group.

The authors concluded that, despite their small sample size, the results suggested that augmentation with olanzapine or other atypical antipsychotics may be useful in treating refractory PTSD.

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Sertraline in Patients With Heart Disease

Major depression occurs in up to 20% of patients with ischemic cardiovascular disease and also puts patients at risk for myocardial infarction (MI). To evaluate the safety and efficacy of sertraline (Zoloft) in depressed patients hospitalized for acute MI or unstable angina, Glassman and colleagues conducted a 24-week, double-blind, placebo-controlled study involving 369 patients at 40 outpatient cardiology centers and psychiatry clinics in seven countries. Sixty-four percent of patients were males having a mean age of 57.1 years, and whose mean score on the 17-item Hamilton Rating Scale for Depression (HAM-D) was 19.6. Seventy-four percent of patients were diagnosed with MI.

After receiving placebo single-blind for two weeks, patients were randomized to sertraline in flexible doses ranging from 50 mg to 200 mg. Cardiovascular outcome measures were left ventricular ejection fraction (LVEF), Holter monitoring, electrocardiogram intervals and serious adverse events. Depression efficacy was measured using the HAM-D (defined as HAM-D>18), CGI-I and previous history of major depression.

At the end of the study, there were no significant differences between sertraline and placebo on cardiovascular measures, including LVEF changes, ventricular arrhythmias and severe side effects. Furthermore, CGI-I response rates were 82% for sertraline and 46% for placebo. The authors concluded that sertraline is both safe and effective for depressed patients with recent MI or unstable angina.

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Switching to Once-Weekly Fluoxetine

Can patients whose depression has responded well to daily doses of an SSRI be switched successfully to the recently introduced, enteric-coated weekly formulation of fluoxetine (Prozac Weekly)? Results of a study by Miner and colleagues at Eli Lilly and Company indicate the answer is yes.

Study participants were 246 patients who met DSM-IV criteria for major depressive disorder. After six to 52 weeks of treatment with citalopram (Celexa) 20 mg/day to 40 mg/day, paroxetine (Paxil) 20 mg/day or sertraline 50 to 100 mg/day, all patients achieved low rating scale scores (CGI-Severity [CGI-S]

2; modified 17-item HAM-D

10). Patients were maintained on their current antidepressant for one week, then switched to the once-weekly dosage of fluoxetine (90 mg) for 12 weeks. To assess safety and efficacy, investigators compared spontaneous and solicited side effects, and they compared change from baseline to endpoint using the CGI-S and HAM-D-17 scales. The Short-Form Health Survey was used to gauge quality-of-life measures.

In 79% of patients, the switch to weekly fluoxetine was well-tolerated and produced no significant increases in depression rating scores. In 9.3% of patients, fluoxetine 90 mg was discontinued because of relapse or lack of efficacy. The authors concluded that in patients who have responded to SSRIs, enteric-coated, once-weekly fluoxetine may be effective and well-tolerated for continuation and maintenance therapy.

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Predicting SSRI-Response in Women

Major depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, Young and colleagues have found that adrenocorticotropic hormone (ACTH) response to evening administration of metyrapone (Metopirone) indicates HPA axis hyperactivity. To determine if ACTH response to a metyrapone challenge is associated with response to standard treatment with an SSRI, they recruited depressed women who scored 17 or higher on the 23-item HAM-D. At baseline, women with major depression showed a significantly greater ACTH response to evening metryrapone than age- and sex-matched control subjects. The women were treated with fluoxetine for six weeks. Approximately half the subjects did not achieve a 60% or greater decrease in their HAM-D scores at the end of six weeks. Compared to fluoxetine responders and normal control subjects, those who failed to respond to fluoxetine treatment had a significantly greater pre-treatment ACTH response to metyrapone.

Noting that animal data suggest that fluoxetine is not capable of normalizing HPA axis dysregulation, the researchers concluded that there may be an association between failure to normalize HPA axis hyperactivity and poor treatment response.

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Quetiapine, Cognition and Adaptive Functioning

Velligan and colleagues at University of Texas, San Antonio, recruited 40 outpatients with a DSM-IV diagnosis of schizophrenia who were clinically stable on standard antipsychotics to determine if a six-month trial of quetiapine (Seroquel) would improve their cognitive and functional outcomes. The patients, ages 18 to 55 years old (mean=43.15), had not been hospitalized during the year before the study. All had at least one of the following inclusion criteria: (a) moderate positive symptoms, defined as a Brief Psychiatric Rating Scale (BPRS) score of 4 or higher on one of the four items that measure psychosis, and a total BPRS score of at least 40; (b) moderate negative symptoms, defined as a Global Negative Symptom Assessment rating of 4 or higher; and (c) moderate side effects, defined as a Simpson-Angus Scale (SAS) score of 3 or higher or an Abnormal Involuntary Movement Scale (AIMS) score of 4 or higher.

Half the patients were randomly switched to quetiapine; the other 20 continued their conventional neuroleptic. Dosages were given according to patients' clinical requirements and, in both treatment groups, there was no significant change in dosage over the course of the study.

In addition to using the assessment scales above, blinded raters scored patients at baseline, three months and six months on the Multnomah Community Ability Scale (measuring social functioning, independent living skills, behavior problems and the extent to which schizophrenia symptoms interfere with functioning) and the Heinrich-Carpenter Quality of Life Scale (assessing interpersonal relationships, occupational roles, sense of purpose and the possession of common necessary objects). Data were analyzed by blinded statisticians using repeated-measures analyses of covariance for mixed models.

Three patients in each treatment group withdrew before the three-month assessment, and four patients in the conventional neuroleptic and two in the quetiapine group withdrew before the six-month assessment. One additional quetiapine patient was excluded because they could not perform cognitive testing.

Data analysis showed no significant differences between treatments in extrapyramidal symptoms and effects on positive and negative psychosis symptoms. At the end of the study, none of the quetiapine patients, but 60% of the conventional-treatment patients, remained on benztropine (Cogentin).

In the quetiapine group, global neurocognitive function improved over the six-month study and remained unchanged in patients on standard neuroleptics. When baseline functioning was taken into account, the difference between groups at endpoint was more than one standard deviation. Furthermore, when changes in positive and negative symptoms, changes in side effects, and the presence or absence of benztropine use were used as covariates, these results remained unchanged. On two cognitive items in particular--verbal fluency (initiation) and verbal memory--there was significant improvement in quetiapine patients. On quality of life measures, there were also significant differences favoring quetiapine, but no differences in social functioning were found between the two treatment groups.

Noting that their finding of neurocognitive improvement with quetiapine corresponds with results from efficacy trials, the investigators concluded that patients whose symptoms are well-controlled with conventional antipsychotics may receive significant neurocognitive benefit if switched to quetiapine. The authors suggested, however, that psychosocial programming may be needed to improve patients' social functioning.

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Depression Associated With Risperidone in Patients With Tourette's Syndrome

Tourette's syndrome (TS) and depression often go together. In most psychiatric patients, risperidone (Risperdal) usually does not induce depression. In patients with TS, however, risperidone trials of four to 12 weeks have been associated with a depression incidence of 2.6% to 30.8%. To further study this phenomenon, Margolese and colleagues retrospectively examined the charts of 58 adult and adolescent patients with TS treated with risperidone between January 1993 and December 2000.

Their study showed that 17 patients (29.3%) developed a major depressive disorder. Of these, nine cases were relapses in patients with a previous history of depression, which was the only significant predictor of depression onset during risperidone therapy. In the 13 patients (22.4%) who became dysphoric while taking risperidone, use of anticholinergics was a risk factor for dysphoria. Of the 30 patients who became depressed or dysphoric, 71.4% stopped risperidone because of that side effect, including one patient who committed suicide.

The authors concluded that depression and dysphoria may be common among patients with TS who are given risperidone and that the risk may be heightened in those with a previous history of depression.

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Low-Dose Risperidone Combination Treatment of Irritable
Aggression in PTSD

Psychiatrists associated with Boston University School of Medicine, the National Center for PTSD and the Veterans Affairs Boston Health Care System in Boston reported the results of a double-blind, placebo-controlled study examining low-dose adjunctive risperidone and its potential to reduce aggression and posttraumatic stress disorder (PTSD)-related symptoms in combat veterans.

The subjects were male combat veterans who met DSM-IV criteria for PTSD and scored 20 or more on Cluster D (hyperarousal) of the PTSD Checklist, Military Version (PCL-M). Subjects were randomly assigned to either risperidone or placebo treatment groups. Drugs were administered over a six-week treatment period following a double-blind design. Subjects received either risperidone 0.5 mg/day (n=7) or matched placebo tablets (n=8) during the first two weeks of the treatment period. Thereafter, the dose of risperidone could be increased up to 2.0 mg/day, based on the patients' clinical response. Subjects were continued on their pre-randomization psychotropic regimen. They were evaluated using the PCL-M and the Overt Aggression Scale, Modified for Outpatients (OAS-M).

Data at the end of the trial indicated, "Administration of low-dose risperidone may reduce symptoms of irritability and intrusive thoughts in PTSD patients who exhibit high levels of irritable aggression. The possibility remains that this treatment regimen also may reduce aggression in these patients."