Open clinical trial on the sigma ligand panamesine in patients with schizophrenia

Abstract

The sigma (sigma) receptor has been proposed as a target of neuroleptic drugs. Preclinical data suggest that panamesine (EMD 57445), a novel sigma ligand, has antipsychotic effects and is free of side effects related to the extrapyramidal motoric system (EPMS). Here we report the results of an exploratory study aimed at determining the appropriate dose range and the safety of panamesine in patients with an acute episode of schizophrenia. The first trial with four patients revealed insufficient clinical efficacy of a protocol where the daily dosage was increased stepwise from 7.5 mg during week 1, up to 30 mg during weeks 3 and 4. In a second set of trials, 12 patients received 15 mg at the beginning, this being increased up to 60 mg/day within 3 days and then maintained at this level for 4 weeks. As assessed by a decrease in the Brief Psychiatric Rating Scale score by at least 50%, five patients were judged as responders, whereas six patients showed only a slight improvement, and one deteriorated. Moreover, intent-to-treat analysis showed significant improvement in psychometric variables. In all patients prolactin levels increased during treatment, probably due to an active metabolite with weak dopamine-2-receptor antagonistic effects. No major side effects occurred, and in particular, no EPMS symptoms were seen.

Characterization of the sigma ligand panamesine, a potential antipsychotic, by immune response in patients with schizophrenia and by sleep-EEG changes in normal controls

“…Interestingly, in young controls PAN exerted sedative e¤ects, as evidenced by an increase in TST and sleep e¦ciency, and a decrease in time awake. These sleep-consolidating e¤ects seem to be in contrast to our observation that patients under PAN treatment do not su¤er from daytime sedation compared with inßuences of other neuroleptics (Frieboes et al 1997).…”

“…In an open clinical trial on the e¤ects of PAN in patients with acute schizophrenia, the intent-to-treat analysis showed a signiÞcant improvement in the psychometric variables in 16 patients during a 4-week protocol. Neither extrapyramidal motoric system (EPMS)-related side e¤ects, nor any other adverse e¤ects such as daytime sedation were observed (Frieboes et al 1997). The mean prolactin concentration increased signiÞcantly after the administration of PAN, as has been reported for other r ligands (Gudelsky and Nash 1992).…”

“…These patients are a subgroup (nos. 7, 910, 1214, 16, 1920, 22) of a sample of 22 inpatients with schizophrenia (described in detail in an earlier paper in this journal : Frieboes et al 1997), who completed the 4-week treatment with PAN (EMD 57445; Merck KGaA, Darmstadt, Germany) of up to 90 mg of the substance per day, and in whom blood plasma sampling was possible at every time point. At least Þve patients were drug-naive, in the other patients the protocol required the patients not to have received depot neuroleptics for 2 months and oral antipsychotics for more than 3 days.…”

“…Classical neuroleptics, on the other hand, lead to improved sleep continuity (decreased sleep latency, increased TST, improved sleep e¦ciency), but not to changes in the amount of time spent in the di¤erent sleep stages, and they do not induce alterations in REM density (Wetter et al 1996). Here, we report on a randomized placebocontrolled sleep-EEG investigation after the administration of PAN, which is the Þrst human study of sleep under a r ligand, with the exception of a preliminary descriptive analysis in patients with schizophrenia (Frieboes et al 1997). In rats, the behavioral arousal increased and the electrocortical power spectrum desynchronized after the administration of a r receptor agonist through a chronically implanted cannula into the locus coeruleus (LC) (Bagetta et al 1990).…”

Inhibition by sigma receptor ligand, MS-377, of N -methyl- D -aspartate-induced currents in dopamine neurons of the rat ventral tegmental area

“…In addition, regardless of the lack of binding with dopamine D 2 and 5-HT 2 receptors, MS-377 antagonized apomorphine-induced climbing behavior and 5-HTPinduced head twitching behavior (Takahashi et al 1999). Furthermore, several clinical trials of sigma receptor ligands have been conducted; these agents were found to be effective against negative symptoms and to have no extrapyramidal side effects (Modell et al 1996;Frieboes et al 1997). Therefore, it appears to be important to elucidate the mechanism underlying modulating effects of MS-377 on neuronal activities.…”