ACNP Focuses on Recent Treatment Advances

(This is the third in a series of articles summarizing presentations at the American College of Neuropsychopharmacology-Ed.)

Recent advances in the treatment of mental and addictive disorders, along with research findings in basic neuroscience, molecular genetics and molecular biology that contribute to the understanding of such disorders, were discussed at the American College of Neuropsychopharmacology's 37th annual meeting in Puerto Rico. The following are brief reports from selected presentations.

To assess the efficacy of divalproex (Depakote) in borderline personality disorder (BPD), behavioral responses were examined in 16 outpatients meeting Structured Clinical Interview for Diagnosis (SCID) criteria for BPD. These patients, who were randomized to 10 weeks of double-blind, placebo-controlled treatment, comprised seven healthy males and nine nonpregnant females. Ten were white, three were black and three were Hispanic.

They were randomized to divalproex or placebo starting at 250 mg/day and gradually increased to doses equivalent to 80 mcg/mL. Outcome measures included the Global Assessment Scale (GAS), the CGI Improvement Scale, the Aggression Questionnaire (AQ), the Overt Aggression Scale-Modified and the Beck Depression Inventory (BDI). The endpoint CGI improvement score was two (much improved) on divalproex versus five (minimally worse) on placebo. The GAS change score significantly improved from 49.1 (serious symptomatology of impairment in functioning) to 68 (some mild symptoms, generally functioning well) on divalproex versus 53 to 50 on placebo. Substantial decreases were found on the BDI (baseline=15.5, endpoint 2.6 on divalproex versus 14.6 to 21 on placebo) and on the AQ (baseline=79.6, endpoint=66.4 on divalproex versus 82 to 98 on placebo). These results suggest that divalproex may be an efficacious pharmacological treatment for BPD and indicate the need for larger controlled studies.

Patients (n=130) who met DSM-IV obsessive-compulsive disorder (OCD) criteria and had Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores =19 were treated with single-blind fluoxetine(Drug information on fluoxetine) at 20 mg/day, 40 mg/day or 60 mg/day based on physician assessment of response and tolerability. Seventy-one patients (55%) met acute phase response criteria (60 mg/day, n=52 [73%]; 40 mg/day, n=18 [25%]; 20 mg/day, n=1 [1%]).

For acute responders to 60 mg/day, continued fluoxetine treatment provided greater protection against relapse than placebo. Among acute responders to 20 mg/day to 40 mg/day, relapse rates were low for both fluoxetine- and placebo-randomized patients. Though the acute response rate was consistent with previous reports, the placebo relapse rate was lower than described elsewhere. Perhaps the long acute phase (20 weeks) optimized stability of response, reducing likelihood of symptom deterioration. Fluoxetine treatment was well-tolerated during 52 weeks, a factor that may contribute to successful long-term OCD management. This study was reported by Eli Lilly and Company researchers.

As part of an ongoing study of first-episode patients with schizophrenia, a cohort were studied with olanzapine(Drug information on olanzapine) as their first-line drug of treatment by investigators at Hillside Hospital, Glen Oaks, N.Y. Twelve patients, six who participated in the study and six who were screened as clinically appropriate but chose not to consent to the study, were treated with open-label olanzapine. Olanzapine was started at 2.5 mg/day and titrated weekly based on clinical response. Preliminary clinical data suggest that these patients required olanzapine dosages from 10 mg/day to 25 mg/day. Only one patient responded to a dose of 10 mg/day. This dosage range is similar to or higher than the presently recommended dosage for patients with chronic schizophrenia. This finding is somewhat contrary to previous reports indicating that first-episode patients respond well to lower than average doses of antipsychotic drugs.

A randomized, double-blind, placebocontrolled study was conducted by Wyeth-Ayerst Laboratories researchers to compare the onset of the antidepressant activity of venlafaxine (Effexor) titrated to 300 mg/day during week 1 with that of placebo and fluoxetine (Prozac) titrated to 60 mg/day during week 1 in outpatients with major depressive disorder. Patients (n=460) meeting DSM-IV criteria for major depressive disorder and with a minimum baseline score of 26 on the Montgomery-Asberg Depression Rating Scale (MADRS), began treatment with placebo, venlafaxine 75 mg/day or fluoxetine 20 mg/day.

The primary efficacy evaluations were time to sustained response (Clinical Global Impression [CGI] improvement score of one or two; 50% decrease on the MADRS total or Hamilton Depression Scale [HAM-D] total) and time to sustained improvement (20% decrease on MADRS or HAM-D total). To be classified as sustained, responses and improvements had to persist until the end of the study and be at least two weeks in duration. Cumulative proportions of sustained response or improvement over the course of the trial were compared with the log-rank test.

By the end of week 1, significantly more venlafaxine- than placebo-treated patients had an onset of sustained response and sustained improvement. Based on the CGI improvement scores, the sustained response rates for venlafaxine and placebo groups at day 7 were 17% and 5%, respectively; at day 14 the corresponding rates were 30% for venlafaxine and 16% for placebo. Sustained response and improvement rates were greater with venlafaxine than with fluoxetine during weeks 1 and 2. No significant differences were found between fluoxetine and placebo during week 1, and few were found during week 2. These results indicate that rapid titration of venlafaxine to high doses may offer significant benefits to patients in whom a rapid response to therapy is important.