ACNP Focuses on Recent Treatment Advances

The antidepressant and anxiolytic effects, tolerability, and effects on quality of life of mirtazapine(Drug information on 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.

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).

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.

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.

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.

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(Drug information on fluvoxamine) (Luvox), fluoxetine(Drug information on fluoxetine), nefazodone(Drug information on nefazodone) (Serzone) and paroxetine(Drug information on 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.

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.

In a four-month, multicenter, open-label trial, the tolerability and efficacy of quetiapine(Drug information on quetiapine) (Seroquel) and risperidone were compared in 751 adult outpatients with psychotic disorders. Patients were randomized in a 3:1 ratio (quetiapine:risperidone) and were flexibly dosed. Assessments included the extrapyramidal symptoms (EPS) checklist, the HAM-D, the CGI, the PANSS and the Drug Attitude Inventory (DAI-10), in addition to adverse event monitoring and recording of concomitant medications. At the completion of the trial, the mean quetiapine dose was 253.9 mg and the mean risperidone dose was 4.4 mg. EPS events in both treatment groups delineate substantially over the four-month treatment period, with no differences between groups in the rate of decline in EPS symptoms.

However, the quetiapine group required less adjustment of antipsychotic medication and less adjunctive medication to control EPS than did the risperidone group. The quetiapine and risperidone groups had improvements in all efficacy measures. The quetiapine group had significantly (p=0.0280) greater improvement in HAM-D than the risperidone group. A higher percentage of patients in the quetiapine group relative to the risperidone group had improvement in the CGI at each visit. No statistically significant differences between groups were evident in the PANSS positive scale, negative scale, general psychopathology score or total score, although greater improvement tended to occur with quetiapine. Quetiapine was more effective than risperidone in treating depressive symptoms, and was as effective as risperidone in treating the positive and negative symptoms of outpatients with psychosis. This report was compiled by employees of Zeneca Pharmaceuticals Group.