Belgian Schizophrenia Outcome Survey – Results of a 2-year naturalistic study in patients stabilised on monotherapy with olanzapine,risperidone or haloperidol

ObjectivesThis Schizophrenia Outcome Survey compared medical costs, psychopathology and adverse events in outpatients for 2 years following hospitalisation for an acute schizophrenic episode.MethodsAdults stabilised with haloperidol, olanzapine or risperidone entered this observational study ≤1 month after discharge and were assessed at baseline, 3, 6, 12, 18 and 24 months using Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI), Global Assessment of Functioning and adverse events reporting.ResultsAmong 323 patients (haloperidol 32, olanzapine 149, risperidone 142), baseline characteristics were similar in the olanzapine and risperidone groups, except for more first episodes in the risperidone group (p = 0.01). Haloperidol patients were more often single and institutionalised, less educated, had more residual schizophrenia, were longer hospitalised in the previous year, took more corrective and psychotropic drugs and had more extrapyramidal symptoms (EPS) and gynaecomastia (all significantly). Sixty-eight percent of patients completed a 2-year follow-up. In all groups, CGI and GAF improved during the first 3 months (both p < 0.0001) while BPRS deteriorated in the first year (all within group changes p < 0.05, between group changes NS) before it stabilised. There were no significant differences in hospitalisations and no change in social profile. At the last visit, 66% of haloperidol (p < 0.01), 35% of olanzapine (NS) and 39% (NS) of risperidone patients had ≥1 EPS; 69% (p < 0.013), 40 and 44%, respectively, had ≥1 sexual problem (NS). Mean weight gain was 0.4 (NS), 2.6 (p < 0.05) and 2.6 kg (p < 0.05), respectively.ConclusionsIn this naturalistic study, treatment allocation might have introduced a bias in the interpretation of efficiency results, but olanzapine and risperidone caused less EPS than haloperidol during 2 years of outpatient follow-up.     

The antidepressant sertraline prevents the behavioral and EEG changes induced in two animal models of seizures

In order to investigate a potential anticonvulsive action of sertraline (i.p.), its effects on seizures, EEG epileptiform activity and EEG amplitude increases induced by two convulsive agents were evaluated and compared with the effects of carbamazepine. Around 20 min following 4-aminopyridine (4-AP, 2.5 mg/kg, i.p.), tonic-clonic seizures and epileptiform activity were observed in control animals. A single sertraline pre-injection of 2.5 mg/kg, but not of 0.75 mg/kg, prevented these changes to 4-AP. Repeated daily administration of 0.75 mg/kg for one week, however, effectively inhibited the changes induced by 4-AP. The first generalized tonic-clonic seizure and EEG changes in response to pentylenetetrazole (PTZ, 50 mg/kg, i.p.) were observed near the first minute in control animals. Single sertraline doses above 5 mg/kg prevented the PTZ-induced changes. Moreover, a single carbamazepine dose of 25 mg/kg (i.p.), but not of 15 mg/kg, prevented the changes induced by the above convulsive agents. An anti-seizure action of the antidepressant sertraline is strongly suggested by these findings.     

Effects of d-penicillamine on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide/NMDA pathways

Besides the clinical applications of penicillamine, some reports show that use of d-penicillamine (d-pen) has been associated with adverse effects such as seizures. So, the purpose of this study was to evaluate the effects of d-pen on pentylenetetrazole (PTZ)-induced seizures in male NMRI mice. It also examined whether N-methyl-d-aspartate (NMDA) receptor/nitrergic system blockage was able to alter the probable effects of d-pen.Different doses of d-pen (0.1, 0.5, 1, 10, 100, 150, and 250 mg/kg) were administered intraperitoneally (i.p.) 90 min prior to induction of seizures. d-Penicillamine at a low dose (0.5 mg/kg, i.p.) had anticonvulsant effects, whereas at a high dose (250 mg/kg, i.p.), it was proconvulsant. Both anti- and proconvulsant effects of d-pen were blocked by a single dose of a nonspecific inhibitor of nitric oxide synthase (NOS), l-NAME (10 mg/kg, i.p.), and a single dose of a specific inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitroindazole (30 mg/kg, i.p.). A selective inhibitor of iNOS, aminoguanidine (100 mg/kg, i.p.), had no effect on these activities. An NMDA receptor antagonist, MK-801 (0.05 mg/kg, i.p.), alters the anti- and proconvulsant effects of d-pen.The results of the present study showed that the nitric oxide system and NMDA receptors may contribute to the biphasic effects of d-pen, which remain to be clarified further.     

Evidence for the involvement of 5-HT1A receptor in the acute antidepressant-like effect of creatine in mice

Creatine was previously shown to produce an antidepressant-like effect in the tail suspension test through a modulation of the dopaminergic system. In this study, the mechanisms underlying its antidepressant-like effect were further evaluated by investigating the involvement of the serotonergic system in its effect. The anti-immobility effect of creatine (1 mg/kg) was prevented by the pretreatment of mice with p-chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., for 4 consecutive days, an inhibitor of serotonin (5-HT) synthesis). Creatine (0.01 mg/kg, sub-effective dose) in combination with sub-effective doses of WAY100635 (0.1 mg/kg, s.c., a 5-HT_1A receptor antagonist), 8-OH-DPAT (0.1 mg/kg, i.p., a 5-HT_1A receptor agonist) or selective serotonin reuptake inhibitors fluoxetine (5 mg/kg, p.o.), paroxetine (0.1 mg/kg, p.o.), citalopram (0.1 mg/kg, p.o.) and sertraline (3 mg/kg, p.o.) reduced the immobility time in the tail suspension test as compared with either drug alone. These results indicate that the antidepressant-like effect of creatine is likely mediated by an interaction with 5-HT_1A receptors. Of note, the present results also indicate that creatine improves the effectiveness of the selective serotonin reuptake inhibitors, a finding that may have therapeutic implications for the treatment of depressive disorders.     

The effects of coenzyme Q10 on seizures in mice: The involvement of nitric oxide

Coenzyme Q10 is a potent antioxidant in both mitochondria and lipid membranes. It has also been recognized to have an effect on gene expression. This study was designed to investigate whether acute or subchronic treatment with coenzyme Q10 altered the seizures induced by pentylenetetrazole or electroshock in mice. We also evaluated the involvement of nitric oxide in the effects of coenzyme Q10 in pentylenetetrazole-induced seizure models. Acute oral treatment with different doses of coenzyme Q10 did not affect the seizure in intraperitoneal pentylenetetrazole, intravenous pentylenetetrazole, and electroshock models in mice. Subchronic oral administration of coenzyme Q10 (100 mg/kg or more) increased time latencies to the onset of myoclonic jerks and clonic seizures induced by intraperitoneal pentylenetetrazole and at the doses of 25 mg/kg or more increased the seizure threshold induced by intravenous infusion of pentylenetetrazole. Subchronic doses of coenzyme Q10 (50 mg/kg or more) also decreased the incidence of tonic seizures in the electroshock-induced seizure model. Moreover, acute treatment with the precursor of nitric oxide synthesis, l-arginine (60 mg/kg), led to a significant potentiation of the antiseizure effects of subchronic administration of coenzyme Q10 (400 mg/kg in intraperitoneal and 6.25 mg/kg in intravenous pentylenetetrazole tests). Acute treatment with l-NAME (5 mg/kg), a nonspecific nitric oxide synthase inhibitor, significantly attenuated the antiseizure effects of subchronic doses of coenzyme Q10 in both seizure models induced by pentylenetetrazole. On the other hand, acute administration of aminoguanidine (100 mg/kg), a specific inducible nitric oxide synthase inhibitor, did not affect the seizures in mice treated with subchronic doses of coenzyme Q10 in both intraperitoneal and intravenous pentylenetetrazole tests. In conclusion, only subchronic and not acute administration of coenzyme Q10 attenuated seizures induced by pentylenetetrazole or electroshock. We also demonstrated, for the first time, the interaction between nitric oxide and coenzyme Q10 in antiseizure activity probably through the induction of constitutive nitric oxide synthase.     

Orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets

We compared the changes in weight (kg) and body mass index (BMI) (kg/m²) in 52 hospitalized adolescents between baseline and after 12 weeks of monotherapy with either (i) olanzapine (OLZ) orally disintegrating tablets (ODT) (N = 16; 16.6 mg/day ± 4.4 [SD]), or (ii) OLZ standard oral tablets (SOT) (N = 10; 18.0 mg/day ± 4.2), or (iii) risperidone (N = 26; 2.8 mg/day ± 1.2). Significantly greater increases in mean weight and BMI were observed in the patients treated with OLZ SOT (8.9 ± 5.1 [SD] kg; 1.9 ± 0.6 kg/m², respectively) than in those with ODT (3.0 ± 2.1 kg; 1.1 ± 0.8 kg/m²). Similarly, OLZ ODT treatment was associated with significantly greater increases in weight and BMI than risperidone (1.0 ± 1.8 kg; 0.4 ± 0.7 kg/m²). These findings suggest that adolescents gain less weight with OLZ ODT than OLZ SOT, possibly because the former formulation shortens the time of interaction with digestive serotonin receptors mediating satiety.     

A possible participation of gonadotropin-releasing hormone in the neuroleptic and cataleptic effect of haloperidol

Haloperidol, an antipsychotic agent, stimulates the release of gonadotropin-releasing hormone (GnRH), and this hormone is known to mimic some of the behavioral effects of haloperidol. Hence, the present study was carried out to find out the contribution of GnRH in the behavioral effects of haloperidol. The studies revealed that haloperidol (0.15, 0.25 and 0.5 mg/kg, i.p.) and leuprolide (GnRH agonist; 50, 100, 200 and 400 μg/kg, s.c.) dose-dependently inhibited conditioned avoidance response (CAR) in male Sprague–Dawley rats. In higher doses, haloperidol (0.5, 1 mg/kg, i.p.) and leuprolide (200, 400 μg/kg, s.c.) produced catalepsy in rats. Co-administration of sub-effective dose of leuprolide (50 or 100 μg/kg, s.c.) and haloperidol (0.15 or 0.5 mg/kg, i.p.) similarly inhibited CAR and induced catalepsy. Pre-treatment of rats with antide (GnRH antagonist; 10 μg/rat, s.c.), attenuated the inhibitory effect of both the agents on CAR; blocked leuprolide-induced catalepsy; and attenuated the intensity and reduced the duration of haloperidol-induced catalepsy. In conclusion, the studies suggest a possible role of GnRH in the neuroleptic and cataleptic effect of haloperidol.     

Anticonvulsant activity of the cyclooxygenase-2 (COX-2) inhibitor etoricoxib in pentylenetetrazole-kindled rats is associated with memory impairment

PurposeVarious selective and nonselective cyclooxygenase (COX) inhibitors are known to have effects on development and progression of seizures. In the present study, the effect of the selective COX-2 inhibitor etoricoxib on seizures, oxidative stress, and learning and memory was studied.MethodMale Wistar rats were kindled using subconvulsant dose of pentylenetetrazole (PTZ) (30 mg/kg, i.p.), on alternating days until animals were fully kindled. After a one-week PTZ-free period, kindled rats were challenged with PTZ 30 mg/kg, and the latency, duration, and severity of seizures were recorded. Etoricoxib was then administered intraperitoneally at 1 mg/kg and 10 mg/kg in kindled rats for nine days (days 6–14). On the ninth day of etoricoxib treatment, PTZ challenge (30 mg/kg) was given, and seizure parameters were noted. On day 15, behavioral assessment was carried out. The Morris water maze (MWM) apparatus and the passive avoidance (PA) apparatus were used for studying cognitive impairment. The rats were then sacrificed, and malondialdehyde (MDA) and glutathione (GSH), markers of oxidative stress, were estimated in the brain samples.ResultsEtoricoxib at lower dose (1 mg/kg) had an anticonvulsant effect which was reduced or reversed at higher dose (10 mg/kg). Etoricoxib also impaired the learning and memory in rats as tested by passive avoidance and Morris water maze tests.ConclusionThe results of the present study suggest that use of etoricoxib, especially at low dose, in patients with epilepsy may not be detrimental with regard to seizure control. However, attention should be paid to cognitive parameters.     

Mechanisms operated by endothelin ETA and ETB receptors in the trigeminal ganglion contribute to orofacial thermal hyperalgesia induced by infraorbital nerve constriction in rats

Endothelins, acting through specific endothelin ET_A and/or ET_B receptors, participate in nociceptive processing in models of cancer, inflammatory and neuropathic pain. The present study investigated which cell types express endothelin receptors in the trigeminal ganglion, and the contribution of mechanisms mediated by endothelin ET_A and ET_B receptors to orofacial heat hyperalgesia induced by unilateral constriction of the infraorbital nerve (CION). Both receptor types were identified by immunohistochemistry in the trigeminal ganglion, ET_A receptors on small-sized non-myelinated and myelinated A-fibers and ET_B receptors on both satellite glial cells and small-sized non-myelinated neuronal cells. CION promoted ipsilateral orofacial heat hyperalgesia which lasted from Day 2 until Day 10 after surgery. Ongoing CION-induced heat hyperalgesia (on Day 4) was reduced transiently, but significantly, by systemic or local treatment with antagonists of endothelin ET_A receptors (atrasentan, 10 mg/kg, i.v.; or BQ-123, 10 nmol/lip), endothelin ET_B receptors (A-192621, 20 mg/kg, i.v.; or BQ-788, 10 nmol/ lip), or of both ET_A/ET_B receptors (bosentan, 10 mg/kg, i.v.; or BQ-123 plus BQ-788, each at 10 nmol/lip). On the other hand, CION-induced heat hyperalgesia was transiently abolished over the first 90 min following i.p. injection of morphine hydrochloride (2.5 mg/kg), but fully resistant to reversal by indomethacin (4 mg/kg, i.p.) or celecoxib (10 mg/kg, i.p.). Thus, heat hyperalgesia induced by CION is maintained, in part, by peripheral signaling mechanisms operated by ET_A and ET_B receptors. Endothelin receptors might represent promising therapeutic targets for the control of trigeminal neuropathic pain.     

Effects of agomelatine on pentylenetetrazole-induced kindling,kindling-associated oxidative stress,and behavioral despair in mice and modulation of its actions by luzindole and 1-(m-chlorophenyl) piperazine

In view of well-evidenced antiepileptic effects of melatonin and few reports of anticonvulsant action of agomelatine, the present study investigated whether agomelatine protects against pentylenetetrazole (PTZ)-induced kindling in mice and kindling-associated oxidative stress, depression, and impairment of spatial memory. In order to explore whether effects are mediated by melatonergic or serotonergic mechanisms, 1-(m-chlorophenyl) piperazine (mCPP), selective 5HT2c receptor agonist and luzindole, melatonergic receptor antagonist, were taken as pharmacological tools. In view of few hepatotoxic reports on agomelatine, the study evaluated effects on hepatic enzyme levels. Swiss strain albino mice were injected with PTZ (25 mg/kg, i.p.) once every two days for 5 weeks to induce kindling. The effects of agomelatine (10 mg/kg, p.o.) alone and in combination with luzindole (2.5 mg/kg, i.p.) or mCPP (7 mg/kg, i.p.) on seizure severity during induction and % incidence of animals kindled at the end of 5 weeks were recorded. Modified forced swim test was used for studying depression-like behavior while spontaneous alternation behavior was used for studying effects on spatial memory. Serum AST and ALT concentrations, cortical and hippocampal malondialdehyde, and reduced glutathione were measured. Agomelatine 10 mg/kg, p.o. effectively delayed development of kindling, reduced seizure severity, and decreased % incidence. Luzindole reversed the protective effects of agomelatine while mCPP failed to show such a reversal, indicating melatonergic (and not serotonergic) mechanisms in the observed effects. Agomelatine also showed antioxidant effects that can partially contribute to its anticonvulsant action. In addition, it alleviated PTZ-kindling-associated behavioral despair and favorably modulated liver enzymes. Its effects on improvement of kindling-associated spatial memory could possibly be related to its effects on locomotor activity. Agomelatine, thus, could be explored as an adjunct to antiepileptic drugs for seizure control and for alleviating epilepsy-associated depression.     

Effect of atypical antipsychotics on phencyclidine-induced expression of arc in rat brain

The effect of atypical antipsychotics on the immediate-early gene, arc (activity-regulated cytoskeleton-associated gene), expression was investigated in phencyclidine (PCP)-treated rats using RT-PCR. Administration of PCP (10 mg/kg) increased arc mRNA levels in the prefrontal cortex, nucleus accumbens and posterior cingulate cortex. Pretreatment with clozapine (20 mg/kg), olanzapine (10 mg/kg) and risperidone (2 mg/kg), but not haloperidol (2 mg/kg), prevented PCP-induced arc expression in the prefrontal cortex and nucleus accumbens. Pretreatment of haloperidol increased the striatal arc mRNA levels. Clozapine, olanzapine and haloperidol inhibited the PCP-induced arc expression in the posterior cingulate cortex. These results suggest that the effects of antipsychotic drugs on PCP-induced arc expression in the prefrontal cortex and nucleus accumbens are useful for distinguishing atypical antipsychotic properties of the drugs.     

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

The Na⁺/Ca²⁺ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic–clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, and 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic–clonic components in 12–62% and 25–62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, and 30 mg/kg; p.o.), clonic and tonic–clonic PTZ-induced generalized seizures were reduced in 25–50% and 38–63% of treated animals, respectively. SN-6 (0.3, 1, and 3 mg/kg; p.o.) also significantly reduced PTZ-induced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3 and 30 mg/kg; p.o.) or SN-6 (3 and 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic–clonic PTZ-induced seizures. These findings suggested that Ca²⁺ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic–clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.     

Anticonvulsant effect of dextrometrophan on pentylenetetrazole-induced seizures in mice: Involvement of nitric oxide and N-methyl-d-aspartate receptors

Dextrometrophan (DM), widely used as an antitussive, has recently generated interest as an anticonvulsant drug. Some effects of dextrometrophan are associated with alterations in several pathways, such as inhibition of nitric oxide synthase (NOS) enzyme and N-methyl d-aspartate (NMDA) receptors. In this study, we aimed to investigate the anticonvulsant effect of acute administration of dextrometrophan on pentylenetetrazole (PTZ)-induced seizures and the probable involvement of the nitric oxide (NO) pathway and NMDA receptors in this effect. For this purpose, seizures were induced by intravenous PTZ infusion. All drugs were administrated by intraperitoneal (i.p.) route before PTZ injection. Our results demonstrate that acute DM treatment (10–100 mg/kg) increased the seizure threshold. In addition, the nonselective NOS inhibitor L-NAME (10 mg/kg) and the neural NOS inhibitor, 7-nitroindazole (40 mg/kg), at doses that had no effect on seizure threshold, augmented the anticonvulsant effect of DM (3 mg/kg), while the inducible NOS inhibitor, aminoguanidine (100 mg/kg), did not affect the anticonvulsant effect of DM. Moreover, the NOS substrate l-arginine (60 mg/kg) blunted the anticonvulsant effect of DM (100 mg/kg). Also, NMDA antagonists, ketamine (0.5 mg/kg) and MK-801 (0.05 mg/kg), augmented the anticonvulsant effect of DM (3 mg/kg). In conclusion, we demonstrated that the anticonvulsant effect of DM is mediated by a decline in neural nitric oxide activity and inhibition of NMDA receptors.     

The evaluation of antimuscarinic-induced convulsions in fasted rats after food intake

The present study was performed to evaluate convulsions after food intake in fasted rats pretreated with scopolamine or atropine and to determine whether these convulsions respond to drugs found effective in fasted mice. Scopolamine (2.4 mg/kg) and atropine (2.4 mg/kg) were given intraperitoneally (i.p.) to rats fasted for 52 h. Both drugs induced convulsions after animals were allowed to eat ad lib. Another group of fasted rats pretreated with saline, MK-801 (0.1 mg/kg), clonidine (0.1 mg/kg), chlorpromazine (2 and 4 mg/kg), valproate (200 mg/kg), diazepam (1.5 and 2 mg/kg) or gabapentin (50 mg/kg) were treated i.p. with saline or scopolamine (2.4 mg/kg) and were allowed to eat ad lib. Clonidine, MK-801, chlorpromazine (4 mg/kg) and diazepam (2 mg/kg) reduced the incidence of scopolamine-induced convulsions in fasted rats. Gabapentin could only prolong the onset of convulsions. Neither treatment was effective against myoclonus of hindlimbs. Present results showed that fasted rats also develop antimuscarinic-induced convulsions which do not completely respond to treatments found effective in convulsions of fasted mice.     

Naringin ameliorates pentylenetetrazol-induced seizures and associated oxidative stress,inflammation, and cognitive impairment in rats: Possible mechanisms of neuroprotection

Oxidative stress and cognitive impairment are associated with PTZ-induced convulsions. Naringin is a bioflavonoid present in the grapefruit. It is a potent antioxidant, and we evaluated its effect on PTZ-induced convulsions. Rats were pretreated with normal saline, naringin (20, 40, and 80 mg/kg, i.p.), or diazepam (5 mg/kg, i.p.) 30 min prior to the administration of PTZ. The administration of PTZ induced myoclonic jerks and generalized tonic–clonic seizures (GTSs). We observed that naringin significantly prolonged the induction of myoclonic jerks dose-dependently. Naringin (80 mg/kg, i.p.) pretreatment protected all rats, and this protective effect was annulled by the GABA_A receptor antagonist, flumazenil. In addition, naringin reduced brain MDA and TNF-α levels and conserved GSH. The pretreatment also enhanced the performance of rats in the passive avoidance task. Our observations highlight the antioxidant, antiinflammatory, and anticonvulsant potential of naringin. Also, naringin modulates the GABA_A receptor to produce anticonvulsant effects and to ameliorate cognitive impairment.     

Étude coût-efficacité du pamoate d’olanzapine : analyse en miroir sur un an

IntroductionOlanzapine pamoate has a higher cost of treatment than the oral form and requires administration in a hospital setting (unlike other long-acting antipsychotics), and the cost-effectiveness of this treatment may be questioned. Many scientific societies and national health systems are increasingly interested in the pharmacoeconomic impact of health products. The search for efficacy of a treatment can be done in two ways: medico-economic modeling studies or observational studies i.e. randomized controlled trials or mirror studies. The models are based on theoretical models from published clinical data simulating the course and evolution of patient health conditions, which benefit from a particular therapeutic strategy. Even if the design of observational mirror studies makes it possible to get closer to the clinical reality by observing the patient before and after the initiation of the treatment, the majority of the pharmacoeconomic studies published on olanzapine pamoate are modeling works that do not reflect actual conditions of care. The Guillaume Régnier Hospital Center in Rennes has a large cohort of patients treated with olanzapine pamoate: 121 instauration treatments are recorded from April 1, 2010 to Mars 1, 2015. The objective of this study is to evaluate the cost-effectiveness of olanzapine pamoate in actual clinical practice.MethodsThis is a one-year cost-effectiveness retrospective observational mirror-image study of a cohort of 52 patients with schizophrenia who were treated for at least three months with olanzapine pamoate. The primary efficacy endpoint is the differential in the number of full-time hospitalizations before and after the introduction of olanzapine pamoate versus the hospital cost differential. The secondary criteria are the difference of the number of the days spent in hospital and the number of outpatient consultations between the year preceding the injection and the year following it. The results were calculated on the general cohort and within 2 subgroups: patients treated for more than one year and those receiving less than one year of treatment with olanzapine pamoate.ResultsFifty-two patients were included (median age = 35 years, sex ratio H/F = 2.7) and only 38.5% discontinued treatment. For patients who maintained long-acting treatment, they received a dosage of 25 mg oral olanzapine (min = 7.5 mg, max = 60 mg), 5 mg more medially than the group having stopped the olanzapine pamoate (20 mg; min = 10 mg, max = 40 mg). The majority of these patients were receiving off-label authorized marketing doses of oral olanzapine, whereas 22% of them had off-label dosages of olanzapine pamoate. The main causes of discontinuation were symptom persistence, loss of vision and the occurrence of adverse effects (including weight gain and sedation). Olanzapine pamoate significantly reduced the number of hospitalizations compared to the previous management strategy (1 less hospitalization, P < 0.001 in patients treated more than one year and in the general cohort). As a logical consequence the number of hospitalization days in day care increased after the establishment of this long-acting antipsychotic with hospital reserve status (18 in median; min = 0, max = 159). We observed a non-statistically significant tendency of decrease in the number of days of full-time hospitalization and an increase in the number of ambulatory procedures, particularly in patients who have maintained the treatment for one year. This efficiency had a non-significant additional cost of €3361 per year. There was an average multiplication by 8,5 of the drug cost a year later in the general cohort (5.5 in the group of patients treated less than one year and 10.4 in the group of patients who maintained it a year). There was a 23,2% average increase in the cost of hospitalization in the general cohort (3.75 % in patients who maintained treatment compared to 48.9% in patients who discontinued treatment).ConclusionBy its mirror design, the study was placed in real conditions of care of the patient with schizophrenia. A total of 61.5% of patients maintained treatment with olanzapine pamoate for a minimum of one year. This APAP is more effective without significantly increasing the cost compared to the previous therapeutic strategy (including oral olanzapine). The additional cost is partly due to the administration restriction in a hospital setting in relation to risk of Post-Injection Delirium/Sedation Syndrom (PDSS). There is currently no acceptable efficiency limit. The results of this cost-effectiveness analysis cannot be extrapolated to the other long-acting antipsychotics since it is the only one with hospital reserve status. The current limitations of medico-economics in psychiatry derive from the heterogeneity of clinical forms and the management of mental pathologies.     

Rosmarinic acid is anticonvulsant against seizures induced by pentylenetetrazol and pilocarpine in mice

Epilepsy is a chronic neurological disease characterized by spontaneous recurrent seizures (SRS). Current anticonvulsant drugs are ineffective in nearly one-third of patients and may cause significant adverse effects. Rosmarinic acid is a naturally occurring substance which displays several biological effects including antioxidant and neuroprotective activity. Since oxidative stress and excitotoxicity play a role in the pathophysiology of seizures, we aimed the present study to test the hypothesis that rosmarinic acid displays anticonvulsant and disease-modifying effects. Female C57BL/6 mice received rosmarinic acid (0, 3, 10, or 30 mg/kg; p.o.) 60 min before the injection of pentylenetetrazol (PTZ, 60 mg/kg; i.p.) or pilocarpine (300 mg/kg, i.p.). Myoclonic and generalized tonic–clonic seizure latencies and generalized seizure duration were analyzed by behavioral and electroencephalographic (EEG) methods. The effect of acute administration of rosmarinic acid on mice behavior in the open-field, object recognition, rotarod, and forced swim tests was also evaluated. In an independent set of experiments, we evaluated the effect of rosmarinic acid (3 or 30 mg/kg, p.o. for 14 days) on the development of SRS and behavioral comorbidities in the pilocarpine post-status epilepticus (SE) model of epilepsy. Rosmarinic acid dose-dependently (peak effect at 30 mg/kg) increased the latency to myoclonic jerks and generalized seizures in the PTZ model and increased the latency to myoclonic jerks induced by pilocarpine. Rosmarinic acid (30 mg/kg) increased the number of crossings, the time at the center of the open field, and the immobility time in the forced swim test. In the chronic epilepsy model, treatment with rosmarinic acid did not prevent the appearance of SRS or behavioral comorbidities. In summary, rosmarinic acid displayed acute anticonvulsant-like activity against seizures induced by PTZ or pilocarpine in mice, but further studies are needed to determine its epilepsy-modifying potential.     

GABAB receptor activation exacerbates spontaneous spike-and-wave discharges in DBA/2J mice

Rich evidence has highlighted that stimulation of γ-amino-butyric acid (GABA)_B receptors increases the occurrence of spike-and-wave discharges (SWDs), the electroencephalographic (EEG) landmark of absence epilepsy (AE). Recent findings suggest that the outcomes of GABA_B activation in vivo are contingent on the chemical characteristics of the agonist. In particular, the endogenous ligand γ-hydroxybutyrate (GHB) and its precursor γ-butyro-lactone (GBL) have been shown to elicit different effects than the prototypical GABA_B agonist baclofen. In view of these premises, the present study was aimed at the characterization of the effects of baclofen (0.5–10 mg/kg, i.p.) and GBL (5–100 mg/kg, i.p.) on the spontaneous SWDs and locomotor activity of DBA/2J mice.While both baclofen and GBL dose-dependently increased SWDs episodes, high doses of the latter (100 mg/kg, i.p.) reduced the occurrence of these phenomena and increased the number of isolated spikes. Interestingly, both compounds elicited a dose-dependent reduction of locomotor activity, in comparison with their vehicle-treated controls. The GABA_B selective antagonist, SCH50911 (50 mg/kg, i.p.), reversed the changes in SWD occurrence and locomotion induced by baclofen and GBL, but failed to elicit intrinsic effects on either paradigm. These results indicate that GABA_B receptor signaling might exert differential effects on SWDs in DBA/2J mice.     

In search of optimal lithium levels and olanzapine doses in the long-term treatment of bipolar I disorder. A post-hoc analysis of the maintenance study by Tohen et al. 2005

PurposeThe aim of this study was to investigate whether lower lithium levels (LoLi) or olanzapine doses (LoOL) are risk factors for future mood episodes in patients with bipolar I disorder.MethodsA post-hoc analysis of the olanzapine-lithium-maintenance study [31] was performed using proportional hazards Cox regression models and marginal structural models (MSMs), adjusting for non-random assignments of dose during treatment.ResultsThe LoLi group (< 0.6 mmol/L) had a significantly increased risk of manic/mixed (hazard ratio [HR] = 1.96, p = 0.042), but not depressive (HR = 2.11, p = 0.272) episodes, compared to the combined medium (0.6–0.79 mmol/L) and high lithium level (≥ 0.8 mmol/L) groups. There was no significant difference in risk between the two higher lithium level groups (0.6-0.79 mmol/L; ≥ 0.8 mmol/L) for new manic/mixed (HR = 0.96, p = 0.893) or depressive (HR = 0.95, p = 0.922) episodes. The LoOL group (< 10 mg/day) showed a significantly increased risk of depressive (HR = 2.24, p = 0.025) episodes compared to the higher olanzapine (HiOL) dose group (HiOL: 10–20 mg/day), while there was no statistically significant difference in risk for manic/mixed episodes between the two groups (HR = 0.94, p = 0.895).ConclusionLithium levels ≥ 0.6 mmol/L and olanzapine doses ≥ 10 mg/day may be necessary for optimal protection against manic/mixed or depressive episodes, respectively in patients with bipolar I disorder.     

Neuroprotective effects of edaravone,a free radical scavenger,on the rat hippocampus after pilocarpine-induced status epilepticus

PurposeEdaravone (MCI-186) is a newly developed antioxidative radical scavenger for the treatment of acute cerebral infarction, exerting neuroprotective effects against ischemic insult. The neuroprotective effects of edaravone on pilocarpine-induced seizures in rats were investigated.MethodsRats were treated intraperitoneally with saline or edaravone (1–30 mg/kg), applied 30 min before pilocarpine hydrochloride (330 mg/kg). The onset of status epilepticus (SE) and mortality were recorded for a period of at least 3 days. The cell loss and immunoreactivities of nitric oxide synthase (NOS) in the hippocampus from control and the day 3 rats after SE, treated with saline or edaravone, were evaluated.ResultsEdaravone (1 mg/kg) significantly prevented cell loss in the hippocampus after SE while easier inducing SE. The higher dose of drug could not induce SE significantly but tended to increase the rate of mortality. Inducible NOS (iNOS) expression was significantly decreased in the hippocampus from day 3 rats treated with 1 mg/kg edaravone, compared with saline group, while neuronal NOS (nNOS) and iNOS significantly increased in the hippocampus treated with saline, compared with control group. Significant alteration of endothelial NOS (eNOS) expression in the hippocampus among control group, saline group, and edaravone group was not shown.ConclusionsEdaravone may act as a neuroprotector for the hippocampus after SE by reducing at least iNOS although the low dose of drug easier induces SE because of preventing an endogenous antiepileptic effect of NO.