Lights and shadows of schizophrenia therapy research: Lessons from oral risperidone and olanzapine.

BACKGROUND: Recently, patents of several atypical antipsychotics have reached their expiration date. AIMS: The purpose of the study was to highlight whether modifications of economic/scientific factors may be associated with possible changes in ongoing clinical research on antipsychotic drugs. METHODS: A large systematic analysis was used to depict the time-dependent distribution of published research articles addressing the clinical properties of oral risperidone and olanzapine conventional tablets, two largely prescribed atypical antipsychotics for which the patents have already expired in most of the countries. RESULTS: The systematic analysis indicated that the time-dependent distribution of the selected research articles followed a wave-shape pattern. A dramatic decline of primary and secondary analyses investigating the clinical effects of oral risperidone and olanzapine has occurred in the last decade, complemented by an expected strong reduction in the numbers of industrial-supported clinical studies and a smaller, but significant, decline in the amount of independent research articles. CONCLUSIONS: To date, greater involvement of independent research seems to be the only realistic chance to properly continue the investigation on the clinical properties of oral risperidone and olanzapine conventional tablets, as well as those of other off-patent antipsychotic drugs. However, the limits and potentialities of independent research in accomplishing such a demanding and enduring scientific effort should be addressed.

Withania somnifera (L.) Dunal root extract alleviates formalin-induced nociception in mice: involvement of the opioidergic system.

Withania somnifera (L.) Dunal extracts (WSEs) may possess therapeutic perspectives in the treatment of inflammation and pain. We aimed to evaluate the antinociceptive property of a WSE in the formalin test and to investigate the involvement of several neurotransmitter systems in this effect. The time spent licking the formalin-injected paw was recorded in CD1 mice after pretreatment with increasing doses of WSE. Also, c-Fos spinal cord expression and the effects of different compounds were investigated under these experimental conditions. Finally, the efficacy of WSE was analyzed following an injection of glutamate. WSE reduced the antinociceptive response during the tonic but not the acute phase of the formalin test and decreased formalin-induced c-Fos expression in spinal neurons. These effects were antagonized by the opioid antagonist naltrexone, whereas GABA, cannabinoid, δ-opioid, and nitric oxide compounds were ineffective. The administration of WSE also reduced nociception and c-Fos expression induced by glutamate injection. These results showed that WSE is effective in assays of chemical-induced nociception, indicating that this plant has potential valuable properties for the treatment of specific painful conditions. The antinocicetive effects of WSE in the formalin test appeared to be specifically mediated by the opioidergic system, although the involvement of the glutamatergic system cannot be excluded.

On the use of the Positive and Negative Syndrome Scale in randomized clinical trials.

In the last 25 years, the Positive and Negative Syndrome Scale (PANSS) has been largely used to assess schizophrenia symptom intensity, but little information is available on how this scale was generally applied when evaluating the efficacy of schizophrenia therapies in randomized clinical trials. In the attempt to address this topic, a systematic PubMed Search was carried out using the keywords "PANSS" and "Randomized Clinical Trials". The analysis of retrieved articles highlighted that PANSS has constituted a suitable psychometric instrument to investigate the efficacy of pharmacological and non-pharmacological therapies. However, the information potentially provided by this scale was only partially reported in research articles, when characterizing the symptomatic features of patients at baseline. Furthermore, a consensus is needed to identify methodological strategies that may properly adapt PANSS-subscale structure with the symptomatic profiles of individuals enrolled in randomized controlled trials. The possibility that PANSS interview procedures and enrollment eligibility criteria may influence the symptomatic composition of patients involved in these studies is also discussed.

Prediction and prevention of the first psychotic episode: new directions and opportunities.

In the last few decades, substantial research has focused on the possibility of early detection and prevention of the first psychotic episode in young individuals at risk of developing this mental disturbance; however, unresolved clinical and ethical issues still call for further investigations. New perspectives and opportunities may come from the identification of selective psychopathological and instrumental markers linking the appearance of subtle psychotic symptoms with the clinical outcome of specific mental pathologies. Furthermore, empirically derived algorithms and risk staging models should facilitate the identification of targeted prevention therapies, possibly improving the efficacy of well-tolerated therapeutic approaches, such as psychological interventions and natural compound supplementations. To date, the collected evidence on the efficacy and tolerability of pharmacological prevention therapies raises more doubts than hopes. A very early detection of risk and appropriate symptomatic pattern classifications may provide a chance to better match prevention strategies with the development of psychosis.

Withania somnifera root extract prolongs analgesia and suppresses hyperalgesia in mice treated with morphine.

Previous studies demonstrated that Withania somnifera Dunal (WS), a safe medicinal plant, prevents the development of tolerance to the analgesic effect of morphine. In the present study, we investigated whether WS extract (WSE) (100 mg/kg, i.p.) may also modulate the analgesic effect induced by acute morphine administration (2.5, 5, 10 mg/kg, s.c.) in the tail-flick and in the hot plate tests, and if it may prevent the development of 2.5 mg/kg morphine-induced rebound hyperalgesia in the low intensity tail-flick test. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for opioid (µ, δ, k), cannabinoid (CB1, CB2), glutamatergic (NMDA), GABAergic (GABAA, GABAB), serotoninergic (5HT2A) and adrenergic (α2) receptors. The results demonstrated that (i) WSE alone failed to alter basal nociceptive threshold in both tests, (ii) WSE pre-treatment significantly protracted the antinociceptive effect induced by 5 and 10 mg/kg of morphine only in tail-flick test, (iii) WSE pre-treatment prevented morphine-induced hyperalgesia in the low intensity tail-flick test, and (iv) WSE exhibited a high affinity for the GABAA and moderate affinity for GABAB, NMDA and δ opioid receptors. WSE prolongs morphine-induced analgesia and suppresses the development of morphine-induced rebound hyperalgesia probably through involvement of GABAA, GABAB, NMDA and δ opioid receptors. This study suggests the therapeutic potential of WSE as a valuable adjuvant agent in opioid-sparing therapies.

Effects of controlled-release formulations of atypical antipsychotics on functioning and quality of life of schizophrenic individuals.

INTRODUCTION: Controlled-release formulations of atypical antipsychotics have recently been introduced into clinical practice. Clinical studies have indicated that these new therapies induce meaningful improvements in the functioning and quality of life of schizophrenic individuals. AREAS COVERED: The present analysis makes an attempt to address the clinical relevance of these studies and their contribution to the understanding of the mechanisms of action of these new drugs. A Medline search was done using the keywords 'antipsychotic', 'plasma level', 'quality of life' and 'functioning'. EXPERT OPINION: After reviewing the literature, it seems that symptom control and side effects may play a role in modulating the functioning and quality of life of schizophrenic individuals treated with controlled-release formulations of atypical antipsychotics. The analysis also highlights that these new drugs may possess peculiarities and similarities in regulating patient functioning. However, the low number of clinical analyses that have focused on these aspects of antipsychotic therapy limits the interpretation of the results. Additional comparative clinical trials are needed to evaluate how the pharmacokinetic/pharmacodynamic properties of antipsychotic drugs may modulate the functioning and quality of life of schizophrenic individuals, as well as to establish whether new clinical benefits may come from the use of these drugs in schizophrenia therapy.

Evaluation of amphetamine-induced hyperlocomotion and catalepsy following long-acting risperidone administration in rats.

It has been proposed that long-acting risperidone could provide a constant antipsychotic efficacy associated with a reduced liability to induce extra-pyramidal symptoms. To ascertain this hypothesis, antagonism of amphetamine-induced hyperlocomotion and catalepsy were analyzed in rats for a period of 1-6 weeks following long-acting risperidone (20-60 mg/kg) injection. Long-acting risperidone reduced amphetamine-induced hyperlocomotion after 2-5 weeks from drug injection, without producing significant extra-pyramidal symptoms. Following the administration of long-acting risperidone a constant ability to antagonize amphetamine-induced hyperlocomotion was observed during the day, but not when the antipsychotic was chronically administered using a short-acting formulation. The pre-clinical results confirmed that long-acting risperidone may represent an advance in antipsychotic therapy.

Delta-9-tetrahydrocannabinol differently affects striatal c-Fos expression following haloperidol or clozapine administration.

It was previously shown that haloperidol, but not clozapine, induced intense rat catalepsy when co-administered with delta-9-tetrahydrocannabinol. The present study investigated whether similar alterations could be observed on striatal c-Fos immunoreactivity after administration of the same drug combinations. Western Blot and immunocytochemistry stereological analyses indicated that delta-9-tetrahydrocannabinol (0.5 mg/kg) increased striatal c-Fos immunoreactivity induced by haloperidol (0.1 mg/kg). Conversely, no significant alterations of striatal c-Fos immunoreactivity were observed after injections of clozapine (10 mg/kg)+vehicle, clozapine+delta-9-tetrahydrocannabinol or vehicle+delta-9-tetrahydrocannabinol. The present results indicate that the behavioral effects induced by delta-9-tetrahydrocannabinol in haloperidol- and clozapine-treated rats are associated with different striatal c-Fos expressions.

Blockade of neurotensin receptors affects differently hypo-locomotion and catalepsy induced by haloperidol in mice.

Antipsychotic drug treatment increases neurotensin (NT) neurotransmission, and the exogenous administration of NT produces antipsychotic-like effects in rodents. In order to investigate whether "endogenous" NT may act as a natural occurring antipsychotic or may mediate antipsychotic drug activity, the effects of the selective NT receptor antagonists SR 48692 and SR 142948A were analyzed in different behavioural tests of locomotor activity using vehicle, amphetamine, or haloperidol in mice. SR 48692 (0.1-1 mg/kg, i.p.) and SR 142948A (0.03-0.1 mg/kg, i.p.) failed to affect mouse spontaneous locomotor activity and amphetamine-induced (2.5 mg/kg, i.p.) hyper-locomotion. However, SR 48692 (0.1 and 0.3 mg/kg, i.p.) and SR 142948A (0.03 and 0.05 mg/kg, i.p.) significantly alleviated the reduction of locomotor activity elicited by haloperidol (0.01 and 0.04 mg/kg, s.c.) in vehicle- or amphetamine-treated mice. Finally, SR 48692 (0.3 mg/kg, i.p.) and SR 142948A (0.05 and 0.1 mg/kg, i.p.) increased mouse catalepsy produced by haloperidol (0.3 mg/kg, s.c.). The present results indicate that while endogenous NT is not involved in the modulation of either mouse spontaneous locomotor activity or amphetamine-induced hyper-locomotion, it might act by enhancing the therapeutic effects of haloperidol and by attenuating the extrapyramidal side effects elicited by this antipsychotic.

Haloperidol, but not clozapine, produces dramatic catalepsy in delta9-THC-treated rats: possible clinical implications.

The effect on rat catalepsy induced by Delta9-tetrahydrocannabinol (Delta9-THC) in association with haloperidol (HP) or clozapine (CLOZ) administration was investigated. Delta9-THC dose-dependently increased HP (0.05-1 mg kg-1, s.c.)-induced rat catalepsy, while no catalepsy was observed after CLOZ (1-20 mg kg-1, s.c.) or Delta9-THC+CLOZ administration. The CB1 antagonist SR141716A (0.5-5 mg kg-1, i.p.) reversed the increase mediated by Delta9-THC on HP-induced catalepsy. The D2 agonist quinpirole completely reversed the catalepsy induced by both HP and HP+Delta9-THC; however, higher doses of quinpirole were needed in the presence of Delta9-THC. The M1 antagonist scopolamine and alpha2 antagonist yohimbine were able to reduce the catalepsy induced by HP and HP+Delta9-THC in a similar manner. CLOZ and the 5-HT2A/2C antagonists ritanserin, RS102221 and SB242084 were more effective in antagonizing HP than HP+Delta9-THC-induced catalepsy.7 HP and CLOZ failed to inhibit in vitro [3H]CP-55,940 binding, while Delta9-THC and SR141716A did not show an appreciable affinity for the D2 receptor. It was suggested that the different effects on rat catalepsy induced by Delta9-THC following HP or CLOZ administration may depend on the receptor-binding profiles of the two antipsychotics. The preferential use of CLOZ rather than HP in the treatment of psychotic symptoms in cannabis abusers was discussed.