[Long-acting antipsychotics: The QAAPAPLE algorithm review]. / Antipsychotiques à Action Prolongée: Révision de l'algorithme QAAPAPLE.

BACKGROUND: Eight years ago, a committee of experts from 4 Quebec university psychiatry departments has provided the QAAPAPLE algorithm in order to guide clinicians in their use of long-acting antipsychotics (LAAP) for patients with psychotic disorders. OBJECTIVE: Update the QAAPAPLE algorithm. METHODS: Using a qualitative and selective literature review, the experts have focused on several aspects related to the use of LAAP and the relevance of modifying the algorithm: 1) new data on LAAP (including polypharmacy and co-prescription with clozapine, dose frequency/interval); 2) perception and attitude regarding algorithms and evidence; 3) difficulties in implementing algorithms; 4) polypharmacy involving LAAP and co-prescriptions with clozapine; 5) partner patients perspective on the algorithm. RESULTS: Thirteen meta-analysis were published and completed observational studies (including those on national registries), confirming the LAAP benefits. Literature adds specifications about using some drug associations as well as dose frequency and interval. Therefore, scientific advances have been considered to modify the algorithm. CONCLUSION: Interacting with Quebec psychiatrists, we have examined changes in prescription and literature to better understand the use of algorithm. The committee has updated the QAAPAPLE algorithm to guide clinicians in using LAAP along the path of patients with psychosis as early as the first episode and through different clinical settings (including treatment resistance) in order to have a more flexible and user-friendly treatment.

CONTEXTE: Il y a 8 ans, un comité d'experts issus des 4 départements de psychiatrie universitaires québécois a proposé l'algorithme QAAPAPLE visant à guider les cliniciens à l'égard de l'utilisation des APAP pour les patients atteints de troubles psychotiques. OBJECTIF: Faire une mise à jour de l'algorithme QAAPAPLE. MÉTHODES: Grâce à une revue qualitative et sélective de la littérature, les experts se sont intéressés à plusieurs aspects en lien avec l'utilisation des APAP et sur la pertinence de modifier l'algorithme: 1) données nouvelles sur les APAP (incluant polypharmacie et co-prescription avec clozapine, fréquence et intervalle d'administration); 2) perception et attitude sur des algorithmes et données probantes; 3) difficultés d'application des algorithmes; 4) polypharmacie impliquant les APAP et co-prescriptions avec clozapine; 5) avis des patients partenaires sur l'algorithme. RÉSULTATS: 13 méta-analyses ont été publiées et complètent les études observationnelles (incluant celles sur des registres nationaux) confirmant les avantages des APAP. La littérature apporte des précisions quant à l'utilisation de certaines associations médicamenteuses, fréquence et intervalle d'administration. L'algorithme a donc été modifié en tenant compte des avancées scientifiques. CONCLUSION: En interaction avec les psychiatres québécois, nous avons examiné les changements des prescriptions, la littérature, pour mieux comprendre l'utilisation de l'algorithme. Le comité a actualisé l'algorithme QAAPAPLE, pour mieux guider les cliniciens dans l'utilisation des APAP dans la trajectoire des patients atteints de psychoses dès le premier épisode et à travers les différents contextes cliniques (incluant la résistance au traitement) afin de le rendre plus flexible et convivial. IMPLICATIONS CLINIQUES: Les études observationnelles (naturalistes) montrent que les APAP réduisent les rechutes, les ré-hospitalisations et la surmortalité. La palette de fréquence d'injection permet des intervalles de deux semaines à trois mois, ce qui permet un ajustement aux besoins du patient en termes de stabilité clinique et de fréquence des contacts. Les APAP restent une modalité thérapeutique sous-utilisée, un algorithme peut aider à se repérer et donc en faciliter l'utilisation. LIMITES: Le comité a produit une revue de la littérature narrative et systématique, plutôt que quantitative; toutefois, il s'est complètement basé sur les conclusions des méta-analyses. La participation aux sondages reliés à ce projet demeure sous optimale. Le comité n'a pas examiné la littérature concernant les aspects spécifiques reliés à la prescription d'APAP chez les personnes âgées ou les enfants.

[Initiating an antipsychotic drug treatment for schizophrenia: the situation in Quebec, Canada, from 1998 to 2006]. / Amorcer un traitement antipsychotique en schizophrénie : la situation au Québec de 1998 à 2006.

Objectives To describe factors associated with the following characteristics of the first prescription of an antipsychotic drug treatment (ADT): 1) prescribing physician type (psychiatrist vs. general practitioner); 2) second-generation vs. first-generation antipsychotic drug; 3) in conjunction with at least one additional antipsychotic drug (multitherapy); 4) never renewed by the patient.Methods This is a pharmacoepidemiologic study using administrative data from the Régie de l'assurance maladie du Québec (RAMQ), the public healthcare insurer in Quebec, Canada. Available data sample was exhaustive for adults with a diagnosis of schizophrenia who received an ADT under RAMQ drug coverage from 1998 to 2006. We report multiple logistic regression results.Results Among 16,225 patients who met inclusion criteria 46.2% were women and 70% were beneficiaries of governmental financial assistance. Patients who had their ADT prescribed by psychiatrists tended to be younger and were more burdened by their mental illness. Multitherapy was associated with hospitalization with a psychotic disorder as main diagnosis, lower socioeconomic status, and age between 35 and 64. Second-generation antipsychotic use became progressively more prominent during the period under study. Antipsychotic non renewal was correlated with substance use disorders and was less likely to happen following hospitalization with a psychiatric main diagnosis. Conclusions Although this study is subject to the intrinsic limitations of secondary analysis of administrative data, the database available for study was exhaustive within the Quebec healthcare system and included data from both general practice and specialized care, which allowed us to draw a relevant picture of how ADT were initiated for schizophrenia in Quebec, Canada, from 1998 to 2006. This timeframe is especially relevant since the 1990s were marked by the introduction of second-generation antipsychotics in Canada.

Pain perception in schizophrenia: evidence of a specific pain response profile.

OBJECTIVE: Ever since the characterization of schizophrenia, clinicians have noted abnormal pain sensitivity in their patients. The published literature, however, is inconsistent concerning the nature of the change reported. The objective of this study was to characterize the pain response profile of schizophrenic patients by providing both acute and prolonged (i.e., rapidly repeating) painful stimuli to schizophrenic participants and control subjects. PARTICIPANTS: Twelve schizophrenic subjects and eleven controls were included in the final analysis. Diagnosis was made according to Diagnostic and Statistical Manual of mental disorders-4th edition, text revision (DSM-IV-TR) criteria. METHODS: Intermittent, transcutaneous stimulations of the left sural nerve were administered to all participants. Painful sural nerve stimulations provoked a nociceptive flexion reflex response which was measured using an electromyographic recording of the bicep femoris muscle. Pain ratings were obtained using a 0-10 verbal numerical scale. Among schizophrenic participants, the relationship between subjective pain, reflex amplitude, and clinical features was investigated. The Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Subjective Scale to Investigate Cognition in Schizophrenia were used to evaluate clinical features. RESULTS: Compared with controls, schizophrenic subjects showed increased sensitivity to acute pain (i.e., lower pain thresholds; P = 0.019), but decreased subjective pain sensitization (P = 0.027). Group differences in subjective pain sensitization were not accompanied by group differences in nociceptive reflex activity (P = 0.260), suggesting supraspinal origins to the change in pain experienced by schizophrenic subjects. Moreover, positive symptoms correlated negatively with pain threshold values among schizophrenic participants (r = -0.696, P = 0.012), suggesting that distortions of thought and function relate to pain sensitivity in schizophrenic patients. CONCLUSION: Results indicate that schizophrenic subjects present a specific experimental pain response profile, characterized by elevated sensitivity to acute pain but reduced sensitivity to prolonged pain.

Antipsychotic-induced DRD2 upregulation and its prevention by α-lipoic acid in SH-SY5Y neuroblastoma cells.

Most antipsychotic (AP) drugs are dopamine (DA) D2 receptor (DRD2) antagonists and remain the main pharmacological treatment of schizophrenia. Long-term AP use can give rise to tardive dyskinesia. It has been reported that chronic treatment with APs induces DRD2 upregulation and oxidative stress, which have been associated with tardive dyskinesia. We showed previously that H2O2-induced oxidative stress increased DRD2 expression in human SH-SY5Y neuroblastoma cells. We report here the effects of AP drugs on DRD2 expression levels in the same cell line and the effects of the inhibition of oxidative phenomena by (±)-α-lipoic acid treatment. Haloperidol, a first-generation AP, induced an increase in DRD2 protein and mRNA levels, whereas amisulpride, a second-generation AP, had no significant effect. (±)-α-Lipoic acid pretreatment reversed the haloperidol-induced DRD2 upregulation in mRNA and protein levels. Furthermore, haloperidol induced a larger increase of oxidative stress biomarkers (protein carbonylation, lipid peroxidation, and superoxide anion production) than amisulpride. (±)-α-Lipoic acid also attenuated AP-induced oxidative stress. Inhibition of catecholamine synthesis by α-methyl-DL-tyrosine (AMPT) increased DRD2 expression and prevented further increase by APs. Our results suggest that haloperidol-induced DRD2 upregulation is linked to oxidative stress and provide potential mechanisms by which (±)-α-lipoic acid can be considered as a therapeutic agent to prevent and treat side effects related to the use of first-generation APs.

[Long-acting injectable antipsychotics: an expert opinion from the Association des médecins psychiatres du Québec]. / Les antipsychotiques injectables à action prolongée : avis d'experts de l'Association des médecins psychiatres du Québec.

OBJECTIVE: To present points of agreement and disagreement about antipsychotics. Since the appearance of 2nd generation long-acting antipsychotics (LAA), and given the high frequency of noncompliance with antipsychotics in psychotic disorders, LAAs have attracted more interest in psychiatric literature. However,their use is suboptimal, globally, and is also subject to significant national disparities. ln this context,the Association des médecins psychiatres du Québec (AMPQ) has asked for a review of the evidence concerning LAA efficiency and tolerance, and has called for consensual c1inical reflection on the benefits and obstacles of prescribing them, as weil as potential solutions, including administrative and judiciary dimensions. METHODS: The AMPQ established an expert committee, from 4 Quebec universities, which was responsible for preparing the review paper. The committee intended to appropriately provide c1inicians with the different aspects of LAA use. The committee produced a qualitative and selective review. RESULTS: Mean LAA prescription rates observed in Canada are around 6% and data to confirm this are scarce. A 15% to 25% rate could be suggested. CONCLUSION: The committee has submitted the Quebec long-acting antipsychotic algorithm (QAAPAPLE, derived from the French acronym) as a result of the consensus reached by the 4 university psychiatry departments.

[Educational Tools to Improve the Therapeutic Relationship of Psychiatrists and Psychiatric Residents with Patients Suffering from Psychosis: A Systematic Review]. / Outils pédagogiques pour améliorer la relation thérapeutique des psychiatres et résidents en psychiatrie envers les patients souffrant de psychose : revue systématique.

Objectives This systematic review identifies the literature on educational tools specifically targeting 2 of the keys competencies that a psychiatrist must acquire according to the Royal College of Physicians and Surgeons of Canada: the therapeutic relationship and empathy, in the context of psychosis. Method This review was carried out in the Medline databases via Ovid, PsycInfo (EBSCO) and Scopus using combinations of terms associated with therapeutic tools, empathy, residents in psychiatry, psychiatrists and psychosis. Two independent reviewers reviewed 1169 titles and abstracts, and retained 5 articles. Results All of the articles analyzed explore communication skills, in particular communication skills training, and 3 of the articles focus on one of its adaptations in psychiatry: ComPsych. It focuses on the announcement of the diagnosis and prognosis of schizophrenia through 5 areas of expertise: the meeting agenda, identification, questionnaire, organization of information and empathetic communication. These studies use role plays, standardized simulated patients, videos and feedback. An improvement in confidence regarding the prognosis is noted although the improvement obtained is inconsistent depending on the modalities used. A fourth article used the TEMPO model (Training to enhance psychiatrist communication with patients with psychosis) which resembles the ComPsych model, but includes, among other things, the use of real patients. TEMPO is also based on the Self-Repair measurement, a tool that determines how well a person strives to speak in a way that is understandable and acceptable to the listener in a conversation in general and in a psychiatric encounter. In the study, an improvement in the therapeutic relationship (moderate effect) by both psychiatrists and patients was observed. The last article provides a randomized controlled trial protocol for Shared decision making Plus (SDM-Plus) training in physician-patient interaction with an emphasis on shared and explicit decision-making. One module is for doctors, the other for patients. Conclusion Although many educational manuals and the Royal College of Physicians and Surgeons of Canada stress the role and importance of establishing a positive therapeutic relationship, this systematic review of the literature shows that there are only a limited number of studies on this subject, and they have low statistical power. It is therefore necessary to continue research on this field and to develop new educational tools. Here we make some recommendations.

From QAAPAPLE 1 to QAAPAPLE 2: how do we move from one algorithm to another one with Long Acting Antipsychotics (LAIs).

BACKGROUND: In 2011, the authors published an algorithm summarizing practice guidelines related to the use of long-acting antipsychotics (LAIs) called the Québec Algorithme Antipsychotique à Action Prolongée (QAAPAPLE), and proposed that it be revised every 5-10 years to update it according to most recent scientific knowledge. Therefore, a re-evaluation of the algorithm was conducted to determine which recommendations were still relevant and which needed modification. METHODS: The authors conducted a two-fold approach: a review of the literature to include new evidence since 2011 (controlled trials, meta-analyses, and practice guidelines); and a participatory component involving electronic surveys, conferences, encounters with opinion leadres, and patients' representatives. RESULTS: Overall, prescribers tended to make decisions based on personal experience and conversations with colleagues rather than consulting evidence-based guidelines. To test if the algorithm was useful worldwide, it was presented in the United Arab Emirates, where the feedback was in agreement with the algorithm and its limitations. CONCLUSIONS: Since its initial publication, the QAAPAPLE algorithm has been updated to guide clinicians on the use of LAIs. The new algorithm has also been assessed outside Canada to test its generalizability worldwide, and indicated its flexibility, efficiency, and user-friendliness in order to guide clinicians on the use of LAIs.

Human evidence of a supra-spinal modulating role of dopamine on pain perception.

BACKGROUND: Over the last decades, remarkable progresses have been accomplished regarding the understanding of the neurophysiologic and neuropharmacological bases of pain. A growing preclinical literature supports a role for substance P, endogenous opioids, glutamate, serotonin, and norepinephrine in pain perception. Recently, a series of studies explored the function of dopamine in pain perception, which we review here, while focusing on human studies. METHODS: The literature was screened using electronic databases. RESULTS: We found evidence from genetics, brain imaging, neuropsychiatry, and pharmacology of an involvement of dopamine in pain processing. Using positron emission tomography and molecular genetics, studies have been performed in healthy volunteers and patients suffering from chronic pain conditions, showing a key role of dopamine in pain perception. Moreover, abnormal pain perception has been documented in neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, where dopamine has a pathophysiological role. Lastly, pharmacological studies have shown that dopaminergic drugs (antipsychotics, antiparkinsonian drugs, atypical antidepressants, psychostimulants) modify pain perception. DISCUSSION: Although there is growing evidence supporting a role of dopamine in pain perception, the mechanisms by which dopamine influences pain processing remains to be determined. On the basis of preliminary findings, we put forth the hypothesis that dopamine is involved in endogenous pain modulation systems, and further discuss the implications of this hypothesis for the understanding of the physiopathology of chronic pain disorders associated with dysfunctional endogenous pain modulation systems.

Comparative psychometric properties of the BACS and RBANS in patients with schizophrenia and schizoaffective disorder.

OBJECTIVES: There has been a recent impetus to develop short and portable instruments for the cognitive assessment of patients with schizophrenia in clinical settings, but direct comparative data are lacking. The objectives of the present study were to compare the psychometric properties of two such batteries, the BACS (Brief Assessment of Cognition in Schizophrenia) and the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status). METHODS: The French version of the BACS and the RBANS was administered to 36 patients with schizophrenia and schizoaffective disorder, and 14 healthy controls. A subgroup of patients was also tested with a standard battery (WAIS-III). RESULTS: Both instruments were easily administrable. Internal consistency was satisfying (global scale reliability alphas of 0.90 for the BACS, and 0.87 for the RBANS), although some sub-scores from the RBANS decreased the overall consistency of the instrument. BACS and RBANS composite scores were highly correlated to verbal, non-verbal and total WAIS-III scores (BACS: r=0.727, 0.865 and 0.857, respectively; RBANS: r=0.843, 0.747 and 0.875, respectively). Patients underperformed controls by a magnitude of 1.81 SD (BACS), and 0.78 SD (RBANS), after adjusting for education. Both batteries showed good test-retest reliability, except for three sub-scores from the RBANS. CONCLUSION: The psychometric properties and ease of use of the BACS and the RBANS were overall satisfying. The BACS demonstrated better internal consistency and test-retest reliability than the RBANS and was nominally more sensitive to diagnosis.

Case report: clozapine given in the context of chemotherapy for lung cancer.

BACKGROUND: Despite the frequent use of the antipsychotic medication, clozapine, in chronic treatments of psychiatric patients, there is limited clinical evidence available to guide clinicians in the problematic situation of a chemotherapy-induced blood dyscrasia. OBJECTIVE: To perform a literature review and add a case report to the available clinical evidence. METHOD: We gathered evidence through literature searches on Medline and with the assistance of a medical information specialist from Novartis who searched their internal database. We also report the case of a patient maintained on clozapine treatment despite full-dose chemotherapy (cisplatin and etoposide) for an extensive lung cancer. RESULT: The searches returned seven clinically relevant references. These references do not establish a synergistic effect of clozapine and chemotherapy on blood counts. However, it has been shown that clozapine exposure activates common apoptotic pathways shared with anticancer drugs. CONCLUSION: Although the meagre clinical evidence precludes drawing any general conclusion as to the safety of maintaining clozapine administration during chemotherapy, it does not point to an obvious worsening of the haematological outcomes.

Increased left prefrontal activation during staring/mutism episodes in a patient with resistant catatonic schizophrenia: a near infrared spectroscopy study.

OBJECTIVE: To present the first near infrared spectroscopy (NIRS) study of a patient with resistant catatonic schizophrenia during residual episodes of catatonia-related symptoms. BACKGROUND: Functional imaging studies generally point to a decreased cortical activation in catatonic patients, with the notable exception of increased orbitofrontal/medial prefrontal activity elicited by negative stimuli. METHODS: Cortical activity of the left anterior prefrontal area was recorded with a Techen 4 x 4 NIRS apparatus. Four episodes of staring/mutism were recorded and averaged. Compared with normal activity, these episodes were characterized by increased cortical activation. CONCLUSIONS: Within its methodologic limitations, the present observation suggests that increased anterior prefrontal activation in catatonic patients is not specific to negative stimuli. Known functions of the anterior prefrontal cortex such as self monitoring, reallocation of attention, or conflict resolution might underlie these findings. These also attest to the potential of NIRS for functional imaging of vulnerable subjects.

The 5α-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia.

Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5α-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved.

Assessment of malondialdehyde levels in schizophrenia: a meta-analysis and some methodological considerations.

Oxidative stress has long been suggested to participate in the pathophysiology of schizophrenia. Most of the published data on the subject rely on malondialdehyde levels assessment through thiobarbituric acid reactive substances (TBARS), despite significant methodological concerns. The present paper reports on a meta-analysis of studies published up to July 2006. Relevant studies were identified through PubMed search and the References section of experimental and review papers on the subject. Studies were retained for analysis if they provided adequate methods description, controls and subjects numbers, means and standard deviations. Using a random effect model, an effect size of 1.22 (CI: 0.64-1.80) was found, with significant bias and high heterogeneity. Inspection of the bias assessment plot suggested a lower value in the order of d approximately 0.5, in line with the results of the larger studies. The heterogeneity of the results appeared to be unrelated to assay type or biological sample. However a meta-regression analysis suggested an association, at trend level, between the precision-weighted effect size and the proportion of drug-free patients, which might therefore account for some of the heterogeneity.

Mitochondrial Dysfunction in Schizophrenia: Determination of Mitochondrial Respiratory Activity in a Two-Hit Mouse Model.

Schizophrenia is a chronic mental illness in which mitochondrial dysfunction has been suggested. Our laboratory recently developed a juvenile murine two-hit model (THM) of schizophrenia based on the combination of gestational inflammation, followed by juvenile restraint stress. We previously reported that relevant behaviors and neurochemical disturbances, including oxidative stress, were reversed by the antioxidant lipoic acid (LA), thereby pointing to the central role played by oxidative abnormalities and prompting us to investigate mitochondrial function. Mitochondrial activity was determined with the MitoXpress® commercial kit in two schizophrenia-relevant regions (prefrontal cortex (PFC) and striatum). Measurements were performed in state 3, with substrates for complex I- and complex II-induced respiratory activity (IRA). We observed an increase in complex I IRA in the PFC and striatum in both sexes but an increase in complex II activity only in males. LA treatment prevented this increase only in complex II IRA in males. Expression levels of the different respiratory chain complexes, as well as fission/fusion proteins and protein carbonylation, were unchanged. In conclusion, our juvenile schizophrenia THM shows an increase in mitochondrial activity reversed by LA, specifically in complex II IRA in males. Further investigations are required to determine the mechanisms of these modifications.

A two-hit model of suicide-trait-related behaviors in the context of a schizophrenia-like phenotype: Distinct effects of lithium chloride and clozapine.

Schizophrenia patients show a high rate of premature mortality due to suicide. The pathophysiological mechanisms of these suicidal behaviors in schizophrenia do not appear to involve serotonergic neurotransmission as found in the general population. Our aim was to develop an in vivo model of schizophrenia presenting suicide-trait-related behaviors such as aggressiveness, impulsivity, anxiety and helplessness. We opted for a two-hit model: C57BL/6 dams were injected with polyI:C on gestational day 12. The pups were submitted to social isolation for 4weeks after weaning. During the last week of social isolation and 30min before behavioral testing, the mice received vehicle, lithium chloride or clozapine. Lithium chloride is well known for its suicide preventive effects in the non-schizophrenic population, while clozapine is the antipsychotic with the best-established suicide preventive effect. The two-hit model induced several schizophrenia-related and suicide-trait-related behaviors in male, but not female, mice. Additionally, lithium chloride improved prepulse inhibition, aggressiveness, impulsivity and anxiety-like behavior in socially isolated mice only, whereas clozapine prevented behavioral abnormalities mainly in mice prenatally exposed to polyI:C and submitted to isolated rearing. The distinct effects of lithium chloride and clozapine suggested that mice prenatally exposed to polyI:C and submitted to social isolation presented a distinct phenotype from that of mice submitted to social isolation only. Because diagnosing suicidal risk in patients is a challenge for psychiatrists given the lack of specific clinical predictors, our in vivo model could help in gaining a better understanding of the mechanisms underlying suicidal behavior in the context of schizophrenia.

Neuroprotective effects of hypothermia in inflammatory-sensitized hypoxic-ischemic encephalopathy.

BACKGROUND: Despite the recent introduction of hypothermia as a mandatory standard of care, the incidence of neonatal encephalopathy in full-term newborns and its devastating neuro-behavioral outcomes continues to be a major individual, familial and social issue. Neonatal encephalopathy is mainly due to the compounding and interacting effects of hypoxia-ischemia and inflammation resulting from placental and other perinatal infections. It is unclear why hypothermia is effective in alleviating neonatal encephalopathy in some, but not all, full-term newborns. However, newborns exposed to inflammatory-sensitized hypoxia-ischemia seem to have less therapeutic benefit from hypothermia than those exposed to hypoxia-ischemia alone. OBJECTIVES: To clarify this uncertainty, we tested the efficacy of hypothermia in a double-hit model of neonatal encephalopathy induced by inflammatory-sensitized hypoxia-ischemia. METHODS: Using a rat preclinical model of endotoxin plus hypoxia-ischemia-induced neonatal encephalopathy of term newborns, we assessed the following in pups exposed (or not) to hypothermia: the extent of brain injuries and the expressions of molecules implicated in neural cell death, namely: pro-inflammatory cytokines, matrix metalloproteinase-9, antioxidant enzymes, as well as receptor-interacting protein-3. RESULTS: Hypothermia was neuroprotective on inflammatory-sensitized hypoxia-ischemia-induced penumbra, but not core, brain injuries. This beneficial effect was associated with a hypothermia-induced increase of antioxidant enzymes (superoxide dismutase-1, glutathione peroxidase-1), but was not associated with any variations of the other inflammatory mediators tested, namely: interleukin-1ß, interleukin-1 receptor antagonist, tumor necrosis factor-α and matrix metalloproteinase-9. CONCLUSION: Hypothermia is neuroprotective against inflammatory-sensitized hypoxia-ischemia possibly through a hypothermia-induced increase of antioxidant enzymes. This neuroprotective effect seems to be independent of the interleukin-1 system.

Implication of the ERK/MAPK pathway in antipsychotics-induced dopamine D2 receptor upregulation and in the preventive effects of (±)-α-lipoic acid in SH-SY5Y neuroblastoma cells.

Chronic administration of antipsychotics (APs) has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We previously showed that haloperidol, a first-generation AP, exerted a more robust increase in D2R expression than amisulpride, a second-generation AP and that (±)-α-lipoic acid pre-treatment reversed the AP-induced D2R upregulation. We also demonstrated that the Akt/GSK-3ß/ß-catenin pathway is involved in the control of D2R expression levels, but is unlikely implicated in the preventive effects of (±)-α-lipoic acid since co-treatment with haloperidol and (±)-α-lipoic acid exerts synergistic effects on Akt/GSK-3ß activation. These findings led us to examine whether the ERK/MAPK signaling pathway may be involved in D2R upregulation elicited by APs, and in its reversal by (±)-α-lipoic acid, in SH-SY5Y human neuroblastoma cells. Our results revealed that haloperidol, in parallel with an elevation in D2R mRNA levels, induced a larger increase of ERK (p42/p44) phosphorylation than amisulpride. Pre-treatment with the selective ERK inhibitor U0126 attenuated haloperidol-induced increase in D2R upregulation. Furthermore, (±)-α-lipoic acid prevented AP-induced ERK activation. These results show that (1) the ERK/MAPK pathway is involved in haloperidol-induced D2R upregulation; (2) the preventive effect of (±)-α-lipoic acid on haloperidol-induced D2R upregulation is in part mediated by an ERK/MAPK-dependent signaling cascade. Taken together, our data suggest that (±)-α-lipoic acid exerts synergistic effects with haloperidol on the Akt/GSK-3ß pathway, potentially involved in the therapeutic effects of APs, and antagonism of ERK activation and D2R upregulation, potentially involved in tardive dyskinesia and treatment resistance.

α-Lipoic acid interaction with dopamine D2 receptor-dependent activation of the Akt/GSK-3ß signaling pathway induced by antipsychotics: potential relevance for the treatment of schizophrenia.

Chronic administration of antipsychotics has been associated with dopamine D2 receptor (D2R) upregulation and tardive dyskinesia. We have previously shown that haloperidol, a first-generation antipsychotic (FGA), exerted an increase in D2R expression and oxidative stress and that (±)-α-lipoic acid reversed its effect. Previous studies have implicated the Akt/glycogen synthase kinase-3ß (GSK-3ß) signaling pathway in antipsychotic action. These findings led us to examine whether the Akt/GSK-3ß pathway was involved in D2R upregulation and oxidative stress elicited by antipsychotics and, in (±)-α-lipoic acid-induced reversal of these phenomena, in SH-SY5Y cells. Antipsychotics increased phosphorylation of Akt and GSK-3ß, and additive effects were observed with (±)-α-lipoic acid. GSK-3ß inhibitors reversed haloperidol-induced overexpression of D2R mRNA levels but did not affect haloperidol-induced oxidative stress. Sustained antipsychotic treatment increased ß-arrestin-2 and D2R receptor interaction. Regarding Akt/GSK-3ß downstream targets, antipsychotics increased ß-catenin levels, whereas (±)-α-lipoic acid induced an elevation of mTOR activation. These results suggest (1) that the effect of antipsychotics on the Akt/GSK-3ß pathway in SH-SY5Y cells is reminiscent of their in vivo action, (2) that (±)-α-lipoic acid partially synergizes with antipsychotic drugs (APDs) on the same pathway, and (3) that the Akt/GSK-3ß signaling cascade is not involved in the preventive effect of (±)-α-lipoic acid on antipsychotics-induced D2R upregulation.

Combination of prenatal immune challenge and restraint stress affects prepulse inhibition and dopaminergic/GABAergic markers.

Gestational immune challenge with the viral-like antigen poly I:C is a well-established neurodevelopmental model of schizophrenia. However, exposure to inflammation during early life may sensitize the developing brain to secondary insults and enhance the central nervous system vulnerability. To gain a better understanding of the pathophysiology of schizophrenia, we thus developed a two-hit animal model based on prenatal poly I:C immune challenge followed by restraint stress in juvenile mice. C57BL/6 gestational mice were intraperitoneally injected with poly I:C or saline at gestational day 12. Pups were then submitted or not, to restraint stress for 2h, for three consecutive days, from postnatal days 33 to 35. Prepulse inhibition (PPI) of acoustic startle response is commonly used to assess sensorimotor gating, a neural process severely disrupted in patients with schizophrenia. Our results revealed that the combination of prenatal immune challenge with poly I:C followed by a restraint stress period was able to induce a PPI disruption in 36-day-old pups, as opposed to each insult applied separately. PPI deficits were accompanied by dopaminergic and GABAergic abnormalities in the prefrontal cortex and striatum. Indeed, measurements of cortical and striatal dopamine D2 receptor (D2R) mRNA and protein levels revealed that the combination of gestational exposure to poly I:C and postnatal restraint stress induced an increase in D2R protein and mRNA levels. Likewise, the combination of both insults reduced the mRNA and protein expression levels of the 67 kDa form of glutamic acid decarboxylase (GAD67), in those two brain regions. To our knowledge, this two-hit animal model is the first in vivo model reporting PPI deficits at pubertal age. This two-hit animal model may also help in studying innovative therapies dedicated to the treatment of schizophrenia, especially in its early phase.