Comparative effectiveness and safety of antipsychotic drugs in schizophrenia treatment: a real-world observational study.

OBJECTIVE: The objective was to compare, in a real-world setting, the risk of mental and physical health events associated with different antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine and first-generation antipsychotics) in patients with SZ. METHODS: This is a retrospective cohort study using administrative data. Outcome measures included any mental health event (suicide, hospitalization or emergency visit for mental disorders) and physical health event (death other than suicide, hospitalization or emergency visit for physical disorders). Cox proportional hazard models were used to estimate the hazard ratios of the events associated with the use of the different antipsychotic drugs. RESULTS: The cohort included 18 869 adult patients living in the province of Quebec (Canada) with SZ and starting antipsychotic drugs between January 1998 and December 2005. Results show that quetiapine and not using any antipsychotics were associated with an increased risk of mental and physical health events as compared to other drugs. The second finding is the confirmation of better performance of clozapine. The results were robust across sensitivity analyses. CONCLUSION: Both findings call for an international public health and drug agencies surveillance of 'real-world' antipsychotic medication to ensure the optimal choices in treatment guidelines for SZ.

Preventive effect of α-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia.

Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether α-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with α-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. α-Lipoic acid also improved PPI performance in control mice. The reversal effect of α-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage.

White matter injury and autistic-like behavior predominantly affecting male rat offspring exposed to group B streptococcal maternal inflammation.

The impact of the group B streptococcus (GBS)-induced maternal inflammation on offspring's brain has not yet been investigated despite GBS being one of the most frequent bacteria colonizing or infecting pregnant women. According to our hypothesis GBS-induced maternal immune activation plays a role in offspring perinatal brain damage and subsequent neurodisabilities such as autism. Using a new preclinical rat model of maternal inflammation triggered by inactivated GBS, we demonstrated placental, neuropathological and behavioral impacts on offspring. GBS-exposed placentas presented cystic lesions and polymorphonuclear infiltration located within the decidual/maternal side of the placenta, contrasting with macrophagic infiltration and necrotic areas located in the labyrinth/fetal compartment of the placenta after lipopolysaccharide-induced maternal inflammation. Brain damage featured lateral ventricles widening, predominately in the male, reduction of periventricular external capsules thickness, oligodendrocyte loss, and disorganization of frontoparietal subcortical tissue with no glial proliferation. Autistic hallmarks were found in offspring exposed to GBS, namely deficits in motor behavior, social and communicative impairments, i.e. profound defects in the integration and response to both acoustic and chemical signals that are predominant modes of communication in rats. Surprisingly, only male offspring were affected by these combined autistic-like traits. Our results show for the first time that materno-fetal inflammatory response to GBS plays a role in the induction of placental and cerebral insults, remarkably recapitulating cardinal features of human autism such as gender dichotomy and neurobehavioral traits. Unlike other models of prenatal inflammatory brain damage (induced by viral/toll-like receptor 3 (TLR3) or Gram-negative/TLR4), maternal inflammation resulting from GBS/TLR2 interactions induced a distinctive pattern of chorioamnionitis and cerebral injuries. These results also provide important evidence that beyond genetic influences, modifiable environmental factors play a role in both the occurrence of autism and its gender imbalance.

Cognitive effects of antipsychotic dosage and polypharmacy: a study with the BACS in patients with schizophrenia and schizoaffective disorder.

Antipsychotic polypharmacy and high doses have been associated with poorer outcome, longer hospital stays, and increased side effects. The present naturalistic study assessed the cognitive effects of antipsychotics in 56 patients with a diagnosis of schizophrenia or schizoaffective disorder, using the Brief Assessment of Cognition in Schizophrenia (BACS). Antipsychotic daily dose (ADD) was expressed as mg risperidone equivalents/day (RIS eq), using a model based on drug doses from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study for second generation antipsychotics (SGA) and chlorpromazine equivalents for first generation antipsychotics (FGA), with a 1/1 equivalence between haloperidol and risperidone. Increasing age was associated with polypharmacy, FGA prescription and decreasing BACS score. FGA prescription, in turn, predicted a poorer cognitive functioning, independently of age, PANSS subscores and ADD. ADD was associated with decreasing cognitive scores, an effect that remained significant after controlling for age, PANSS or polypharmacy. The detrimental cognitive effects of polypharmacy, in turn, appeared to be mediated by ADD. Different methods of data fitting suggested that ADD above 5-6 mg RIS eq/day were associated with lower BACS scores. Overall, these results show that increasing antipsychotic daily dose is associated with poorer cognitive functioning at doses lower than previously thought, independently of the number of antipsychotic drugs.

Tyrosine kinase inhibitors and cycloheximide inhibit Li+ protection of cerebellar granule neurons switched to non-depolarizing medium.

Recently, it has been shown that Li+ robustly enhances the survival of cerebellar granule neurons acutely switched to non-depolarizing medium after maturing in vitro, a condition which elicits massive apoptotic death in this cell type. Tyrosine protein phosphorylation is known to underlie the activity of a number of trophic factors. This prompted us to investigate whether specific tyrosine kinase inhibitors could modulate the Li+ protection of cultured granule neurons switched to non-depolarizing medium. Genistein and herbimycin A dose dependently abolished the Li+ effect. Furthermore, this effect was substantially prevented by the translational inhibitor cycloheximide, suggesting that it requires de novo protein synthesis. Overall, these results suggest that Li+ protection of cerebellar granule neurons switched to non-depolarizing medium involves tyrosine kinases and transcriptional activation.

Effects of calcium antagonists on binding of local anesthetics to plasma proteins and erythrocytes in mice.

This study was designed to document possible changes in the binding of bupivacaine (BV), lidocaine (LC) and their main metabolites desbutylbupivacaine (PPX) and monoethylglycinexylydide (MEGX), respectively, to plasma proteins and erythrocytes in mice after acute treatment with the calcium antagonists diltiazem (DZ), nicardipine (NP) and verapamil (VP). A significant plasma protein binding of BV, LC and PPX was measured, whereas no binding could be detected for MEGX. The binding of BV was not modified by DZ, NP and VP, however, the total plasma level was increased in the presence of VP. For PPX a significant increase in total and free plasma levels and a decrease in protein binding were demonstrated after DZ and VP treatment. Concerning LC, a significant increase in total and free plasma levels was documented for DZ, NP and VP suggesting an inhibition of the metabolism of LC by the calcium antagonists. An increased penetration of LC into erythrocytes was also demonstrated which is consistent with the calcium antagonist-induced increase in LC free plasma levels. These effects may contribute in part to the previously observed increase in toxicity of BV by calcium antagonists, but are not likely to be the sole mechanism.

[Efficacy of zuclopenthixol acetate on psychotic anxiety evaluated in an open study]. / Efficacité de l'acétate de zuclopenthixol sur l'anxiété psychotique évaluée lors d'une étude ouverte.

The first scale evaluating psychotic anxiety specifically is the "Psychotic Anxiety Scale": PAS was proposed and validated by O. Blin et al. in 1988. Zuclopenthixol acetate formulation is a both rapid and middle prolonged (2-3 days) acting neuroleptic used to start the treatment in an acute episode of the psychotic illness. It has been established as an effective drug for a broad spectrum of symptoms in schizophrenia and other psychosis, but its "angolytic" effect had never been quantified. It was interesting to study the efficacy of zuclopenthixol acetate on psychotic anxiety with PAS during the first 9 days of hospitalisation of psychotic patients. During the study, the clinical evaluation was made with the Psychotic Anxiety Scale (PAS) for the main criteria; Clinical Global Impression (CGI) and the Nordic side effect scale (UKU) for the secondary criteria. Assessments were performed at days, 0, 1, 3, 4, 6, 7 and 9. Zuclopenthixol acetate was administered at Day 0, Day 3, and Day 6. Protocol allowed an additional injection at D1 in case of insufficient efficacy. Forty six patients were included into this open non comparative multicenter study: 23 patients were male and 23 female. Their mean age (X +/- S) was 32 +/- 10 years, and according to DSM III-R, 28 of them got schizophrenia diagnosis, 13 suffered from brief psychotic disorder and 3 from schizophreniform disorder (diagnosis was missing for two subjects). The mean dosage of zuclopenthixol acetate by injection, foreseen in the protocol, was between 126 to 138 mg. Four patients were treated with high dose: more than 800 mg during the 9 days of the study and 6 patients had 5 injections or more. Between D0 and D9, the total PAS score decreased from 63 (from moderated to severe anxiety) to 25 (absence of anxiety) and the reduction of score was statistically significant from 24 hours after the first injection (p < 0.01). Various items analysis of PAS has showed a statistically significant reduction from 24 hours for all items (p < 0.01) except for physical depersonalisation, inhibition of thought and motor inhibition. Assessment index of therapeutic effect (CGI 2) decreased in a statistically significant way from 72 hours (p = 0.01). Globally, we found a good correlation between Clinical Global Impression and PAS, it was maximal and significant at day 7 (r = 0.87). According to the UKU scale and the investigators, the treatment was well tolerated. The results suggest that zuclopenthixol acetate is an effective and reliable way to initiate neuroleptic treatment with an statistically significant activity in psychotic anxiety from 24 hours.

Red blood cell L-tryptophan uptake in depression: kinetic analysis in untreated depressed patients and healthy volunteers.

Kinetic parameters (Vmax and K(m)) of L-tryptophan (TRP) uptake into red blood cells (RBC) were measured in 72 drug-free depressed inpatients and 35 healthy volunteers. Mean Vmax and K(m) values were not significantly different between patients and volunteers. The frequency distributions of Vmax values, however, largely differed in the two groups: Vmax values were homogeneous in the volunteers while they were widely scattered in the depressed patients. Only 15 out of the 72 depressed patients (21%) had Vmax values within 1 SD from the mean control value. Forty-four percent of the patients (n = 32) had Vmax values above the control mean + 1 SD in 11 patients and above the control mean + 2 SD in 21 patients. Thirty-five depressed patients (n = 25) had Vmax values below the control mean - 1 SD in 8 patients and below the control mean - 2 SD in 17 patients. High and low K(m) values were observed in combination with high and low Vmax values. The alterations in kinetic parameters were neither associated with severity of depression nor with a specific diagnostic subtype of depression. The data show abnormalities in RBC L-TRP uptake in most depressed patients that likely reflect a disturbance in peripheral availability of TRP on which central serotonin synthesis closely depends.

[Chronopharmacology]. / Chronopharmacologie.

Chronopharmacology studies the influence of time of administration of drugs. Numerous studies have report on the influence of time of administration on acute toxicity of drugs. Qualitative and quantitative responses of the organism to drugs have been described in different areas such as anaesthesiology, cardiology, oncology, endocrinology, gastroenterology, obstetrics, neurology, pneumology, psychiatry, rheumatology... in animals and in men. Underlying mechanisms of such variations involve temporal variations of the mode of action of the drug i.e. at the receptor level or temporal modifications of the kinetics of the drug. Absorption, distribution and drug protein binding, metabolism and elimination vary according to the moment of administration of the drug. Chronotherapy consists on the choice of the moment of administration of a drug in order to minimise its side effects and/or to emphasize its therapeutic effects.

Cerebellar lithium toxicity: a review of recent literature and tentative pathophysiology.

Lithium is the archetype of mood stabilizing drugs. Its narrow therapeutic index mostly accounts for the occurrence of acute intoxications. There is, however, growing evidence that lithium can induce long lasting neurological sequelae. These appear to be multifactorial, resulting mainly from overdosage, concomitant neuroleptic treatment, and hyperthermia. The most frequent clinical feature is a permanent cerebellar syndrome. As regards the few pathological data available, there is a striking loss of cerebellar Purkinje cells, which is present in all published neuropathological reports on this condition. It is suggested that lithium, cytokines, and neuroleptics synergize to disrupt calcium homeostasis in Purkinje cells, and to elicit calcium-mediated neurotoxicity. This model might help predict high risk clinical situations and define useful working hypotheses as well.

Circadian phase dependent pharmacokinetics of L-dopa, its main metabolites (3-OMD, HVA, DOPAC) and carbidopa in rats.

This study aims to evaluate whether or not the kinetics of L-dopa, its main metabolites (3-O-methyldopa, 3-OMD, homovanilic acid, HVA and 3,4-dihydroxyphenylacetic acid, DOPAC) and carbidopa, vary according to the 24-hour scale in rats. Four groups of seven adult male Wistar AF EOPS rats were used for these experiments; each group received L-dopa (200 mg.kg-1 ip) and carbidopa (20 mg.kg-1 ip) at 1000, 1600, 2200 or 0400 hours. L-dopa, 3-OMD, DOPAC, HVA and carbidopa were simultaneously determined by specific ion-pair reversed-phase high performance liquid chromatography with electrochemical detection. A temporal variation of the kinetics of both L-dopa and carbidopa was demonstrated with higher plasma clearance and lower area under concentration curve after the administration at 2200 hours. Moreover, a temporal variation of the metabolism of L-dopa was indirectly documented by temporal variation in kinetics of 3-OMD, DOPAC and HVA.

Effects of clonidine pretreatment on the local anaesthetic activity of bupivacaine in mice.

This study was designed to document possible changes in bupivacaine local anaesthetic activity in mice after a single injection of clonidine (0.1 or 1 mgkg-1, i.p.). The local anaesthetic activity was evaluated during 60 min, according to a previously reported technique, using sciatic nerve blockade by injection of bupivacaine in the area of the sciatic nerve. Clonidine pretreatment modified the local anaesthetic activity of bupivacaine dose-dependently. The time of recovery was higher for clonidine-pretreated mice (40.00 +/- 7.24 min, 0.1 mgkg-1 clonidine: 50.0 +/- 9.35 min, 1 mgkg-1 clonidine) compared with controls (27.22 +/- 1.21 min, P = 0.02). The maximal effect (Emax) was significantly lower for the pretreated group (1.15 +/- 0.13 units, 0.1 mgkg-1; 1.35 +/- 0.09 units, 1 mgkg-1) compared with the control group (1.72 +/- 0.13, P = 0.01). Our data indicate a significant decrease in the duration of anaesthetic activity of bupivacaine in clonidine-pretreated mice.

A prospective study of depression in French patients with Parkinson's disease. The Depar study.

To investigate the prevalence and symptomatology of depression in Parkinson's disease (PD), we have studied 506 unselected patients attending the neurology services in French general hospitals during a 5 month period defined for prospective inclusion. 246 patients (48.6%) were suspected of depression according to different methods of evaluation and 168 (33.2%) were defined as definite or probable depression. According to the Montgomery and Asberg scale, 46 cases (9%) had a severity score suggestive of major depression. As a function of the cut-off score defined for severity, these patients represented from 23.2 to 43.7% of the depressive population with PD. There was no significant difference between depressed and non depressed PD patients as a function of the patient's current age or age at onset of PD. A significantly higher rate of depression was found among women with PD. A past history of depression was a risk factor for mood disorder after onset of PD. The severely depressed patients had a significantly longer duration of PD and a higher score of cognitive impairment than mildly or moderately depressed and non depressed patients with PD. Depressed patients had a significantly more advanced stage of disability than non-depressed patients with PD.

Omega-conotoxin sensitive calcium channels in cerebellar granule cells are not coupled to [3H]glutamate release.

We have studied the biochemical and functional aspects of omega-conotoxin GVIA (omega-CgTx)-sensitive calcium channels in cerebellar granule cells in vitro. 125I-omega-Conotoxin GVIA (125I-omega-CgTx) binding sites were detected in intact cultured cerebellar granule cells and binding parameters were measured (Bmax: 134 fmol/mg protein; kinetic association constant kappa: 3.10(6) M-1.s-1). [3H]Glutamate release was assessed under different release paradigms (namely release triggered by calcium, voltage, and sodium channel agonists) and different times (15 s and 2 min). However, in all cases, [3H]glutamate release was found to be completely insensitive to omega-CgTx. Conversely, voltage-dependent release was inhibited in a dose-dependent fashion by cadmium chloride, with total inhibition at 10(-4) M. These results indicate that N-type calcium channels are not involved in glutamate secretion from granule neurons.

[Plasma MHPG, peripheral noradrenergic marker and hormonal plasma levels of cortisol-T3-T4-TSH in depressive syndromes]. / Contribution á l'étude du MHPG plasmatique marqueur noradrénergique périphérique et des taux plasmatiques hormonaux de cortisol-T3-T4-TSH dans les syndromes dépressifs.

Based on the hypocatecholaminergic hypothesis in the depressive syndromes, this survey on 30 depressed patients compared to 21 control patients, attempts to state exactly the potential interactions between the noradrenergic system and the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid neuroendocrine axis. The biological indices used during this survey are: total plasmatic MHPG, the basic plasmatic cortisol, the thyroid hormones T3, T4, free T4, and the TSH. The results of this survey reveal a significative increase of the basic plasmatic cortisol among the depressed patients, including dysthymics, a decrease of the plasmatic MHPG during major depressions, and a significant fall of the total T3 among depressed men, as well as some correlations between the different axes, the interpretation of which remains "ticklish".

[Recurrent psychiatric manifestations during malaria prevention with mefloquine. A case report]. / Manifestations psychiatriques récidivantes lors d'une prophylaxie antipaludique par méfloquine. A propos d'un cas.

The authors report the case of a 22 years old woman without psychiatric antecedent who started a prophylaxis with mefloquine for a journey in a chloroquino resistant area. The first tablet induced an acute psychiatric syndrome which lasted five days; the second tablet induced the recidive of the psychiatric data and a suicide attempt by drowning.

[Changes in the kinetics of erythrocyte membrane transport of tryptophan in depression]. / Modifications des cinétiques du transport membranaire érythrocytaire du tryptophane dans les dépressions.

The initial rate of L-tryptophan uptake into human red cells as a function of its concentration in the medium was measured in a group of 8 depressed patients hospitalized included 2 bipolar disorders (296.5x, DSM III), 3 major depressions, single episode or recurrent (296.3x and 296.2x, DSM III) and 3 dysthymic disorders (300.40x, DSM III), which were out of antidepressive treatment, with age ranging from 34 to 64 years compared to a group of 11 healthy volunteers with age ranging from 23 to 54 ans. Kinetic constants were measured at 37 degrees C on red cells incubated with tritiated L-tryptophan and cold L-tryptophan over the concentration range 0.1 to 10 mM. The maximum velocity (Vmax) of the saturable transport is severely lowered in a significant manner in the patients compared to controls (mean +/- s.e.m. = 48.9 +/- 5.5 mumol/l cells/min and 92.0 +/- 14 which represents 47% in decrease). In return, the Michaelis constant is unaffected. The linear component of tryptophan transport, which corresponds to the participation of nonspecific transport systems, is not modified. The possible incidence of such a deficit in the plasmatic reserve of tryptophan in depressed patients on the central availability of serotonin synthesis precursor is postulated.