Novel Agents and Investigations Abroad

In addition to reports on psychotherapeutic agents now available and anticipated in the United States, the presentations at the 22nd annual Collegium Internationale Neuropsychopharmacologicum (CINP) Congress, held from July 8 to 13, in Brussels, provided a unique view of varied investigational compounds and approaches outside our country.

SAM-e (s-adenosyl-methionine), a naturally occurring methyl donor in transmethylation reactions within the central nervous system, is an increasingly popular health food supplement/"nutraceutical" in the United States and Europe because of purported antidepressant effects. Although some of the earliest investigations of its possible antidepressant mechanisms were conducted by researchers at McLean Hospital in Belmont, Mass. (Cohen et al., 1989), their results and most others have been published in European journals. At the CINP, Delle Chiaie et al. from University La Sapienza in Rome reported on two large multicenter trials comparing the efficacy and safety of SAM-e with that of imipramine (Tofranil) in patients with depression.

According to their meta-analysis of trials carried out between 1973 and 1995, the antidepressant activity of SAM-e appeared "superior to that of placebo and comparable to that of standard tricyclic antidepressants." To contribute data from double-blind studies, the investigators had conducted two small trials with 800 mg/day intravenous (IV) SAM-e: one in comparison to placebo and the other in comparison to IV clomipramine (Anafranil) 100 mg/day. In these studies, SAM-e appeared more effective than placebo, but slightly less effective than IV clomipramine.

In their third trial, reported at CINP, 281 outpatients with major depression in 33 centers were randomized to receive six weeks of either 1600 mg/day SAM-e orally or 150 mg/day imipramine. At the end of the treatment period, there were no significant differences between patients treated with SAM-e or imipramine either on the primary efficacy measure of change in Hamilton Rating Scale for Depression (HAM-D) or in secondary measures of the rate of response of at least 50% reduced HAM-D score, or final Montgomery-Asberg Depression Rating Scale (MADRS) scores. While there were no apparent efficacy differences between the agents, SAM-e was significantly better tolerated, with fewer adverse events than imipramine.

In the fourth trial, 400 mg/day SAM-e was administered intramuscularly (IM) with oral placebo and compared to placebo injections and imipramine 150 mg/day orally. Patients with major depression (n=295) at 31 centers were randomized to receive either treatment for four weeks and were assessed with the same efficacy measures employed in the third trial. Here, again, there appeared comparable antidepressant efficacy, with SAM-e being better tolerated. In this study, however, the investigators noted a "trend towards greater antidepressant efficacy of SAM-e at endpoint with respect to MC3 [the six-week study]." They suggested this might reflect a faster onset of the effects of SAM-e.

In other CINP reports, novel agents were assessed as adjuncts to antidepressant medication in the treatment of major depression. A group at the University of Pisa (Dell'Osso et al.) evaluated the dopamine D2, D3 receptor agonists ropinirole (Requip) and pramipexole (Mirapex) in separate studies. In the group's investigation with pramipexole, 0.375 mg/day was added to the antidepressant regimen of 20 patients who had not previously improved, and was increased by 0.375 mg weekly to a maximum of 0.84 mg/day (mean dose of 0.66 mg).

Sixteen patients completed four weeks of follow-up and 10 completed eight weeks. Response criteria were a 50% reduction of MADRS score from baseline and an "improved" or "very improved" Clinical Global Impression (CGI) assessment. At week 4, 10 of 16 patients appeared to have responded to adjunctive pramipexole; and eight of 10 by week 8. The investigators reported that two patients discontinued the pramipexole because of dysphoria and hypotension, respectively.

Researchers from the University of Cagliari and the University of Florence, Italy (Carta et al.), reported combining amisulpride (Solian), an atypical antipsychotic with high affinity for dopamine D3 and D2 receptors, with the selective serotonin reuptake inhibitor fluvoxamine (Luvox) in an effort to hasten antidepressant response. They related a previous serendipitous observation that this combination appeared to result in "increased tolerability, a rapid response to therapy, and an early onset of antidepressant activity."

The combination of amilsulpride 50 mg/day and fluvoxamine 100 mg/day was administered open-label for six weeks to an unspecified number of outpatients with major depression. Utilizing the HAM-D at baseline and weekly, the researchers measured a statistically significant improvement of depressive symptoms in each patient after the course of therapy, with disappearance of sleep difficulty at end of the first week. While this report did not yield sufficient evidence to corroborate their earlier impression of antidepressant synergy, there have been recent published investigations into the possible antidepressant effect of amisulpride from Italy (Ravizza, 2000) and Poland (Papp and Wieronska, 2000).

Researchers from the Medical University of Lodz, Poland (Sobow et al.), compared the effect of tianeptine (Stablon), an antidepressant that enhances rather than inhibits serotonin reuptake, to the SSRI fluoxetine (Prozac) in 35 patients with depression complicating Alzheimer's disease. Although changes in HAM-D scores were similar in both groups after six weeks of treatment, the researchers reported a faster response to tianeptine.

"This effect can probably be attributed to anxiolytic properties of tianeptine," they indicated, "since the difference both comes from anxiety related items of HAM-D and is lost at week 6."

Claiming a possible "breakthrough to the drastic pharmacotherapy of posttraumatic stress disorder [PTSD]," a researcher at Jichi Medical School in Tochigi, Japan (Kamada), reported using talipexole, a dopamine D2 and a-2 adrenergic agonist used for Parkinson's disease, for symptoms of dissociation and hyperarousal. In the open study of 71 outpatients characterized as survivors of child abuse with PTSD (50 patients having dissociative symptoms), patients were treated for eight weeks with a mean dose of 0.471 mg/day, noted to be lower than the dosage used in Parkinson's.

The severity of dissociative symptoms were judged to be decreased in 33 patients (66%), while remaining at the same level in 15 patients (30%) and worsening in two (4%) patients. Hyperarousal symptoms were reported ameliorated in 39 (78%) of 50 patients with sleep disturbance, 25 (53.2%) of 47 patients with nightmares, and 27 (58.7%) of 46 patients with autonomic sensitization. The report indicated that pharmacological responses appeared within one day of initiating treatment and that no serious side effects were encountered.

U.S. researchers from Parke-Davis Pharmaceutical Research (now part of Pfizer Inc.) (Pande et al.) described their progress with the novel anxiolytic pregabalin in Phase III clinical trials for generalized anxiety disorder (GAD). Pregabalin, like gabapentin (Neurontin), is a 3-substituted analog of g-amino butyric acid (GABA). Three multicenter, controlled trials of similar design have now compared pregabalin 50 mg tid and 200 mg tid to lorazepam (Ativan) 2 mg tid over four weeks.

The Parke-Davis researchers stated that on weekly assessments with the Hamilton Rating Scale for Anxiety (HAM-A), two of the studies evidenced pregabalin 200 mg tid and lorazepam 2 mg tid to be superior to placebo, with one study also showing significant treatment effect of pregabalin 50 mg tid. One of the three studies, however, did not differentiate between treatment groups. The most frequently occurring adverse effects associated with pregabalin were dose-dependent somnolence and dizziness.

Valproate 240 mg bid for eight weeks was compared to placebo in treating aggressive behavior in 42 elderly patients with dementia at Parnassia Psycho-Medical Centre in The Hague, Netherlands (Sival et al.). The primary outcome measures in this double-blind, crossover study were the Social Dysfunction and Aggression Scale-9 (SDAS-9) and the CGI scale. The researchers reported finding no significant differences between valproate and placebo on these measures.

With the wealth of investigators and investigative sites abroad, representatives of Quintiles, the clinical trials coordinating company, expressed regret that research data from these sites cannot be assimilated into reports that hasten the drug approval process in the United States and other countries. Several research coordinators from Quintiles CNS Therapeutics in San Diego, advocated that progress be made toward global clinical trials conducted simultaneously in many countries.

"Global trials offer a very large pool of patients, many of whom have had little access to new medications and may have never been treated for their disorder," they indicated.

They also noted that with many of the investigational medications likely to be marketed globally, it would be advantageous to include more representative populations in the clinical development program so that differences in pharmacokinetics or response could be determined.

While acknowledging a number of challenges to conducting global clinical trials were apparent in their recent survey of selected trials, so were the means to meet those challenges, they indicated. "It is possible to successfully implement international clinical trials in psychiatry with adequate global resources and planning. Sponsors may have confidence in the quality of the data produced to satisfy regulatory authorities."

References:

References

1.

Cohen BM, Stramentinoli G, Sosa AL et al. (1989), Effects of the novel antidepressant S-adenosylmethionine on alpha-1 and beta-adrenoreceptors in rat brain. Eur J Pharmacol 170(3):201-207.

2.

Papp M, Wieronska J (2000), Antidepressant-like activity of amisulpride in two animal models of depression. J Psychopharmacol 14(1):46-52.

3.

Ravizza L (1999), Amisulpride in medium-term treatment of dysthymia: a six-month, double-blind safety study versus amitriptyline. J Psychopharmacol 13(3):248-254.