New Compounds, Novel Applications Described

Several new substances and new uses for available products were evaluated in research projects reported at the 47th annual NIMH-sponsored New Clinical Drug Evaluation Unit, held this past June in Boca Raton, Fla. The agonists included a melatonergic compound for depression, 2 new agents for schizophrenia, some g-aminobutyric acid (GABA)-ergic antipsychotics, and several drugs being evaluated for non-approved indications.

Agomelatine for depression

Novartis' melatonergic compound agomelatine (Valdoxan) was evaluated for antidepressant effect in comparison to the selective serotonin norepinephrine reuptake inhibitor antide- pressant venlafaxine (Effexor) in 2 multicenter studies described by Sidney Kennedy, MD, of the University of Toronto. The investigational agent is an agonist at both the melatonin MT1 and MT2 receptors as well as a serotonin 5-HT2c receptor antagonist.

In a 12-week trial, patients were randomized to a fixed 50-mg daily dose of agomelatine or 150 mg of venlafaxine; and in a separate 6-week trial, to flexible dosing of 25 to 50 mg of agomelatine or 75 to 150 mg of venlafaxine. The primary outcome in the longer study was a reduction of 50% or more on the Montgomery-Asberg Depression Rating Scale (MADRS) by week 10 and score of 12 or lower by week 12. The Hamilton Depression Rating Scale (HAM-D) was used to measure symptom improvement over the 6-week trial.

Kennedy reported that patients who received either the investigational agent or venlafaxine had similar reductions in mean MADRS scores, and a similar percentage in each group reduced their baseline score by at least half (57% of 165 patients who received agomelatine and 60% of 167 who received venlafaxine). There were also comparable reductions in mean HAM-D total scores of 16 points for patients who received agomelatine and 15 points for patients who received venlafaxine in the 6-week trial.

It was not unexpected for a melatonergic agent to improve disrupted sleep patterns in depression, and Kennedy noted that patients who received agomelatine had statistically significantly greater improvement on the Leeds Sleep Evaluation Questionnaire items of "ease of getting to sleep" and "quality of sleep," beginning at week 1 and continuing throughout the 12-week study. In visual analog scale assessments of "daytime sleepiness" and "feeling good," however, the agents were comparable at study end.

Bufeprunox and arsenapine for schizophrenia

Two investigational agents demonstrated promise for schizophrenia in reported studies. Bifeprunox, from H Lundbeck A/S, Solvay Pharmaceuticals, and Wyeth Pharmaceuticals, is a partial dopamine agonist; and asenapine, from Organon International, is a serotonin and dopamine receptor antagonist in common with second-generation antipsychotics.

Michael Bourin, MD, PharmD, of the University of Nantes, France, reported on the efficacy of bifeprunox relative to placebo in prolonging time to deterioration in a 6-month study of 497 patients with stable schizophrenia. The 20- and 30-mg doses of bifeprunox were associated with significantly longer periods of stability than was placebo; 41% of those who received 20 mg and 38% of those who received 30 mg deteriorated within the 6-month period, compared with 59% of those who took placebo.

The study also assessed the safety of the investigational agent in daily doses ranging from 0.25 to 30 mg. Although metabolic adverse effects have been associated with this drug category, John Newcomer, MD, of the Washington University School of Medicine, St Louis, reported that both in the 6-month study and in pooled data from several 6-week trials, there was a decrease in body weight and improvement in lipid profiles associated with bifeprunox.

"These findings suggest that bifeprunox may have cardiometabolic advantages in the long-term treatment of patients with schizophrenia," Newcomer said.

Asenapine has evidenced antipsychotic efficacy in phase 3 trials, and it is now being evaluated for particular use in improving negative symptoms and cognitive functioning in those with schizophrenia. John Panagides, PhD, of Organon International, described 2 ongoing studies--the Aphrodite trials--that compare asenapine with olanzapine (Zyprexa) in patients who have predominant and persistent negative symptoms.

Dosing in each 26-week trial is flexible, with 5 to 10 mg of asenapine given twice daily, and 5 to 20 mg of olanzapine given once daily. The primary outcome is a reduced total score on the 16-item Negative Symptom Assessment scale; key secondary measures of patient functioning and quality of life are assessed with a battery of measures.

"Management of negative symptoms remains an unmet need in clinical practice," Panagides observed. "Novel . . . agents that can effectively alleviate these symptoms and robust clinical trial designs that can assess their effectiveness are needed."

A placebo-controlled study of asenapine effects on cognitive functioning was reported by Kirsten Fleming, PhD, in private practice in Newport Beach, Calif. Asenapine 5 mg twice daily, risperidone (Risperdal) 3 mg twice daily, or placebo was administered for 6 weeks to 180 patients with acute schizophrenia. Fleming indicated that patients who received asenapine improved on tests of verbal learning and memory and on most tests for speed of processing. Risperidone was associated with improved speed of processing but lower performance on tests of reasoning and problem solving, she reported.

GABAergic agents

A "first in class" GABA-enhancing antipsychotic was described by Michael Davidson, MD, of Sheba Medical Center, Tel-Hashomer, Israel. The compound, BL-1020, from BioLineRx, Jerusalem, is a conjugate of the dopamine D₂ antagonist neuroleptic perphenazine (Trilafon) and GABA. Pharmacokinetic studies demonstrated that the conjugate compound effectively transports GABA into the brain, and catalepsy animal models indicated less propensity than perphenazine to produce extrapyramidal symptoms. In a placebo-controlled safety study with 48 subjects, BL-1020 appeared to be generally well tolerated. However, one subject did experience facial twitching with a 40-mg dose, equimolar to 20 mg of perphenazine, and there was also a dose-dependent elevation in serum prolactin.

Another GABAergic compound, the GABA_A partial agonist pagoclone, from Indevus Pharmaceuticals Inc, is being studied as a treatment for stuttering. Timothey Denko, MD, of the University of Pittsburgh, noted that this speech disorder is a DSM-IV Axis I illness for which there have been few pharmacotherapeutic investigations. Denko characterized the 8-week multicenter, placebo-controlled trial of pagoclone in 132 adults with severe persistent developmental stuttering as the most comprehensive pharmacological study for the condition to date.

The study employed rater and patient self-assessment measures of stuttering frequency and duration, in addition to the Clinical Global Impres- sion of Improvement scale (CGI-I). Denko reported significantly greater improvement with pagoclone than with placebo on the CGI-I on percentage of syllables stuttered, patient self-assessment of severity of stuttering, and stuttering-related social anxiety measures.

"In light of its favorable safety and tolerability profile and the internal consistency of efficacy effects, pagoclone shows considerable promise as a pharmacological treatment for stuttering," Denko concluded.

New applications of drugs affecting NMDA glutamate activity

Medications were evaluated for non-approved indications based on known drug actions and posited neurobiological mechanisms of illnesses. Three different medications affecting N-methyl d-aspartate (NMDA) glutamate receptor activity were assessed for behavioral disorders in which there may be abnormal functioning of this neurotransmitter system.

Bernard Fischer, MD, and colleagues at the Maryland Psychiatric Research Center, Catonsville, are planning an investigation of acamprosate (Campral) for schizophrenia to determine whether it can remediate a hypothesized NMDA glutamate receptor hypofunctioning. One observation that suggested this possibility to Fischer is that dissociative anesthetics, which block NMDA glutamate receptor activity, produce symptoms not unlike those of schizophrenia.

Fischer explained that acamprosate appears to "dampen" NMDA glutamate receptor overactivity during alcohol detoxification but acts as a receptor agonist in conditions in which there is lowered activity. "This 'smart' drug action makes acamprosate appealing for use in schizophrenia," Fischer said. He acknowledged, however, that if the drug's dampening effect predominates in patients with schizophrenia, it could possibly exacerbate psychotic symptoms.

Fischer has received funding for an exploratory safety and biomarker study with 10 patients with schizophrenia and has plans to expand that number to 30 in a placebo-controlled design. The initial 4-week study will seek to ascertain the effect of acamprosate on brain glutamate/glutamine levels, with the enlarged study to determine whether acamprosate will increase concentrations and reduce symptoms.

Another NMDA-glutamate modulating agent, N-acetylcysteine (NAC, Mucomyst), was investigated in the treatment of pathological gambling. It was hypothesized that increased extracellular glutamate concentration in the nucleus accumbens from administering NAC could moderate addictive behavior. Jon Grant, MD, of the University of Minnesota, Minneapolis, described the study of 27 subjects who received 8 weeks of open-label NAC, with an additional 6 weeks of double-blind, placebo-controlled NAC administration for 13 of the 16 responders.

Grant reported that 83% of those who received NAC continued to meet response criteria at study end, compared with 30% of those who received placebo. Response was defined as a reduction of at least 30% on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Modified for Pathological Gambling. The mean effective daily dose of NAC was about 1477 mg.

"The efficacy of NAC lends support to the hypothesis that pharmacological manipulation of the glutamate system may target core symptoms of reward-seeking addictive behaviors such as gambling," Grant said.

An additional manipulation of NMDA-glutamate receptor activity was accomplished with glycine, in an investigation of its effect on obsessive-compulsive disorder (OCD). William Greenberg, MD, of the Nathan Kline Institute, Orangeburg, NY, reported on a placebo-controlled study with gly-cine titrated up to 60 g/d, as an adjunct to an ongoing OCD medication regimen. Of 24 initial participants, 14 remained to receive at least 30 g/d through the second visit. The high dropout rate was attributed principally to complaints of nausea or dislike of the taste in addition to the desire to change medication and non-adherence to study protocol.

In the remaining cohort, those receiving glycine had a mean 0.82 greater reduction in the Y-BOCS score for each week of the study than did those who received placebo. Complaints among some subjects who withdrew from the study notwithstanding, Greenberg noted that those who completed the study on the glycine adjunct continued taking it from their regular treating psychiatrist because of the significant perceived benefit.

"The NMDA-glutamate receptor agonist, glycine, was efficacious for OCD in this study," Greenberg reported. "More palatable formulations should be sought, and larger controlled studies are needed to replicate this finding."

Galantamine for post-ECT memory impairment

The possibility that an agent that supports memory functioning in Alzheimer disease by acting on nicotinic acetylcholine receptors might reduce the memory impairment that is associated with electroconvulsive therapy (ECT) was explored in a placebo-controlled study with the cholinesterase inhibitor galantamine (Razadyne). John Matthews, MD, of Massachusetts General Hospital, Boston, described the progress of a study in which 18 patients who were receiving ECT were randomized to receive either galantamine 4 mg twice daily titrated to 8 mg twice daily, or placebo.

At the time of his report, the galantamine group demonstrated significantly better scores on the delayed list recognition task and was trending better for figure recall and short memory tasks. Matthews was hopeful that final results from the study will evidence efficacy of galantamine in reducing or preventing cognitive impairment from ECT.

Two studies were reported on the use of doxepin (Sinequan) for primary and transient insomnia, respectively. Although it is not uncommon for this tricyclic antidepressant to be used for its sedative side effect, there has been little data to support its use as a sedative-hypnotic. These studies, sponsored by Somaxon Pharmaceuticals, provide initial evidence of its efficacy for insomnia in low doses of 3 and 6 mg. The investigators indicated that the low-dose formulations were superior to placebo in hastening sleep onset and in aiding sleep maintenance and sleep quality, with no reports of anticholinergic adverse effects and no significant next-day "hangover" residual effects.

Not all trials of drugs for novel applications yielded promising results, however. Levetiracetam (Keppra), an antiepileptic drug for complex partial seizures, was not found useful in a preliminary study for impulsive aggression. Jeffrey Mattes, MD, of Psychopharmacology Research Associates, Princeton, NJ, noted that his study of levetiracetam in 40 patients showed no improvement in total aggression score on the Overt Aggression Scale-Modified (OAS-M).

Mattes lamented the lack of treatment studies for impulsive aggression, despite its common occurrence. He expressed hope, however, that his methodology using research criteria for intermittent explosive disorder and the OAS-M will make additional treatment studies feasible. **