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.

Valproate Therapy for Borderline Personality Disorder

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.

Fluoxetine Long-Term Treatment: Obsessive-Compulsive Disorder

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 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.

Olanzapine as First-Line Treatment for First-Episode Schizophrenia

As part of an ongoing study of first-episode patients with schizophrenia, a cohort were studied with 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.

Antidepressant Onset: Fluoxetine, Venlafaxine and Placebo

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.

Mirtazapine Versus Citalopram in Major Depressive Disorder

The antidepressant and anxiolytic effects, tolerability, and effects on quality of life of mirtazapine (Remeron) and citalopram (Celexa) were compared in a randomized, double-blind, multicenter study. The results of the first eight weeks of treatment were presented by the Nordic Antidepressant Study Group. Efficacy was evaluated by the MADRS, HAM-Anxiety Scale, CGI and LESQ. The efficacy of analyses were performed on the Intent-To-Treat Group using the Last Observation Carried Forward method.

Analysis of these data verified that both drugs were well-tolerated, with a low number of patients in either group prematurely terminating the study due to adverse events. Sweating and nausea were statistically significant more frequently in the citalopram group, and increased appetite and weight increase in the mirtazapine group. Mirtazapine and citalopram were equally effective in reducing symptoms of depression and anxiety. However, mirtazapine was significantly more effective than citalopram after two weeks of treatment on MADRS, HAM-A and CGI-Quality of Life Scales. This finding, consistently present at all major efficacy variables, suggests potentially faster onset of action for mirtazapine.

Long-Term (One Year) Risperidone Therapy in Elderly Dementia Patients

A multicenter double-blind study assessed the efficacy and safety of risperidone in 625 institutionalized patients with dementia (73% Alzheimer's disease, 15% vascular, 12% mixed). Patients were randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day or 2 mg/day of risperidone for 12 weeks. According to scores on the Behavior Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory, the severity and frequency of aggressive behaviors were reduced significantly more in patients receiving 1 mg/day or 2 mg/day of risperidone than placebo. A one-year open-label follow-up study consisting of 330 patients was completed. The mean modal risperidone dose was 0.96 mg/day. Efficacy scores (BEHAVE-AD) continued to improve throughout the one-year period.

Only one case of tardive dyskinesia (TD) was clinically observed during the 12-month study (crude rate: 0.3%). Among patients without dyskinesia at baseline (n=255), there were only six cases of persistent emergent TD (2.4%), and the one-year survival rate of patients free of persistent TD was 97.4%. These data from a group of well-known American psychiatrists suggest a much lower incidence of TD with risperidone than that reported in elderly patients treated with conventional neuroleptics for one year. In addition, patients with symptoms of dyskinesia at baseline experienced significant reductions in the severity of dyskinesia as measured by Extrapyramidal Symptom Rating Scale scores (dyskinetic movements, hyperkinesia, buccolingo-masticatory factor, choreoathetoid movements and clinical global impression of dyskinesia).

Risperidone: Follow-Up on Once-Daily Dosage in a Day Treatment Program

The patients (n=27) in this study were on a once-daily (nightly) risperidone dosage over an extended period of time while attending a day treatment program. They were periodically assessed using rating scales such as the Brief Psychiatric Rating Scale, SANS, AIMS and the Simpson-Angus as part of the clinical follow-up. Their medical records were reviewed for information pertaining to medication side effects (akathisia, dystonic reactions and drug-induced parkinsonism).

The diagnostic categories included schizophrenia (14), schizoaffective disorder (4), bipolar disorder (5), major depression with psychosis (3) and posttraumatic stress disorder (1). The risperidone once daily (dose range 1 mg to 16 mg) was well-tolerated by the patients as demonstrated by the low Simpson-Angus scores and the record review. The mean risperidone dosage was 6.1 mg (range 1 mg to 16 mg) and the mean duration of once-daily treatment was 18.5 months (range eight to 36 months). According to the patients' perceptions, the improvement was profound (2), moderate (16), mild (8) and none (2). The patients had been compliant with their treatment. These data demonstrate that 1) risperidone is effective, safe and well-tolerated even at high doses in a once-daily dosing schedule over an extended period of time and 2) once-daily dosing enhances compliance in the community setting.

Mirtazapine: Premenstrual Dysphoric Disorder

In an open two-phase trial, 95 women (ages 21 to 45 years) in good physical and mental health who met DSM-IV criteria for premenstrual dysphoric disorder (PMDD) were enrolled in mirtazapine treatment. Of the 95 patients assessed, 32 met criteria for the study and were included. Phase I was a two-cycle screening and Phase II was a three-cycle treatment. In Phase II, women were treated with mirtazapine 7.5 mg daily for the first cycle. A flexible dose of 7.5 mg daily or 15 mg daily was utilized for the last two cycles. Of the 32 patients included in Phase II, 27 patients completed the three-cycle treatment. Each patient scored her symptoms on a visual analogue scale.

Analysis of this open trial reveals that the symptoms in the luteal phase were significantly lower on mirtazapine treatment. Moreover, mirtazapine seems to be well-tolerated by this patient population: only three patients stopped their treatment because of side effects. This study demonstrates that mirtazapine is an effective and well-tolerated treatment for PMDD patients. Double-blind, placebo-controlled studies should be initiated to verify the results of this open trial.

Citalopram: Effects on Body Weight

Results from clinical studies of acute trials of citalopram indicate that it does not produce significant weight gain or loss. In a parallel placebo-controlled trial of up to eight weeks' duration that included more than 1,000 citalopram-treated patients, citalopram patients lost an average of 0.5 kg (1.1 lb) as compared to a gain of 0.2 kg (0.4 lb) in the placebo group. Anorexia was reported by 4% and weight decrease was reported by less than 2% of citalopram-treated patients. Long-term weight change associated with citalopram treatment was evaluated in clinical trials of six and 12 months' duration.

In one study, a slight weight gain was associated with a decrease in the reduced appetite item of the MADRS from 3.2 at baseline to 0.2 after 12 months, suggesting that it reflects an improvement in depressive symptomatology rather than appetite enhancement. These results suggest that citalopram has minimal effects on body weight during either acute or long-term therapy.

Cytochrome P450 Inhibition: A Comparison of Newer Antidepressants

The selective serotonin reuptake inhibitors (SSRIs) and other new antidepressants are all metabolized by CYP450. Each of these antidepressants also has an individual profile of inhibitory effects upon the CYP isozymes. This inhibitory profile is important in the selection of the optimal antidepressant to use in patients who are taking multiple medications, since the clearance of such medications can be substantially reduced by an inhibitor of their metabolic pathway. Pharmacologists from Tufts University compiled data based on clinical pharmacokinetic studies and in vitro studies using human liver microsomes. These data suggest that fluvoxamine (Luvox), fluoxetine, nefazodone (Serzone) and paroxetine (Paxil) have a relatively high risk of interaction with one or more enzymes of the CYP450 system; whereas citalopram, mirtazapine, sertraline (Zoloft) and venlafaxine have lower risks of such interactions.

Switching From Conventional Neuroleptics or Risperidone to Olanzapine

Eli Lilly researchers reported the results of a multisite study involving 209 outpatients with a diagnosis of schizophrenia or schizoaffective disorder and with documented clinical stability while treated with a conventional antipsychotic drug (APD) (n=139) or with risperidone (n=70) who were openly randomized to either abrupt discontinuation or graduated withdrawal of their prior APD. Patients were further randomized in a double-blind fashion to receive either: a) olanzapine 10 mg QD for three weeks or b) a sequence of one week each on placebo, olanzapine at 5 mg QD and olanzapine at 10 mg QD.

The efficacy of these four medication-switching paradigms was assessed using the CGI Scale, Patient Global Impression Scale and Positive and Negative Syndrome Scale (PANSS). Safety assessments included ratings for extrapyramidal side effects and treatment emergent adverse events.

Gradual APD discontinuation combined with an initial full dose of olanzapine at 10 mg showed the greatest efficacy and tolerability, evident as early as week 1. None of the four switching paradigms was associated with overall clinical worsening. These data suggest that stable outpatients can be switched to olanzapine treatment, if indicated, possibly without experiencing an increased vulnerability to relapse or to occurrence of clinically burdensome APD withdrawal symptoms.

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