P.3.c.007 Challenges in treating children and adolescents with antipsychotic agents

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P.3.c. Psychotic disorders and treatment − Treatment (basic)

25 mM, the drug increases the mRNA expression of the genes encoding the molecules involved in the neuregulin 1-ErbB4-PI3K signaling pathway. The mechanism by which clozapine increases the expression of the genes remains unknown. The paper presents the preliminary results of the study. Table: Fold change in the tested genes expression shown as 2−DDCT a . Standard deviations (SD) and p-values are also given. Gene tested

Fold change in the tested genes expression Clozapine 25 mM Clozapine 5 mM Fold change p Fold change p

ERBB4 PIK3CD PIK3R3 PTEN

1.84±0.39 3.19±0.33 6.28±0.65 2.36±0.62

a

DDCT = DCT,

clozapine

− DCT,

0.0082 0.0000 0.0000 0.0017

1.05±0.11 1.04±0.19 1.55±0.21 1.17±0.15

0.7975 0.9076 0.1350 0.2437

control .

References [1] Law, A.J., Wang, Y., Sei, Y., O’Donnell, P., Piantadosi, P., et al., 2012. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110d inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A 109, 12165–12170. [2] Wang, X.D., Su, Y.A., Guo, C.M., Yang, Y., Si, T.M., 2008. Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol 11, 553–561. [3] Pan, B., Huang, X.F., Deng, C., 2011. Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35, 924–930.

P.3.c.006 Effectiveness of paliperidone depot in violent men with co-morbid schizophrenia and dissocial personality disorder R. Mitra1 ° , M. Das1 , F. Larkin1 , C. Ross1 , J. Romero-Urcelay1 1 Broadmoor Hospital, Mental Illness, Crowthorne, United Kingdom Purpose of the study: Paliperidone is licensed as both oral and depot antipsychotic medication for the treatment of schizophrenia. It is a metabolite of risperidone for which there is robust evidence for treatment in schizophrenia. When compliance is a problem for forensic patients often with treatment resistant schizophrenia and poor insight, a depot antipsychotic is a useful option. There is evidence paliperidone is well tolerated with similar efficacy to the risperidone depot but it also has additional practical advantages including a faster onset of action, a smaller needle making it more patient friendly and fewer monthly injections. Whilst there is data for the effectiveness of paliperidone, there is no report for forensic patients and those with co-morbid Personality Disorders. We report a case series of our experience with paliperidone depot in five patients within a UK high secure hospital. All these patients had diagnoses of schizophrenia and Dissocial Personality Disorder and were admitted with histories of violence alongside psychotic symptoms. We evaluated the clinical effectiveness of paliperidone depot and its effect on violence, aggression and personality pathology. Methods: Anonymised patient records were used to formulate Clinical Global Impression (CGI) scores and find incidents of violence and aggression. We looked at the effect on specific personality disorder symptom clusters (Cognitive-Perceptual, ImpulsiveBehavioural dyscontrol and Affective dysregulation) plus their individual engagement in occupational and psychological therapies.

Metabolic parameters including Body Mass Index, glucose and cholesterol as well as prolactin levels were monitored. Results: All five patients showed improvement on the paliperidone depot; there was a significant improvement in the CGI scores plus benefits for patients in the three symptom domains. The three patients that had violent or aggressive incidents in the six months preceding the commencement of the paliperidone, all had a 50% reduction in the number of incidents recorded compared to the six months after. There was no significant effect on any of the metabolic parameters monitored although hyperprolactinaemia (albeit asymptomatic) is a problem. Four of the patients on the depot for longer than 6 months showed improvement in occupational therapy and psychological work engagement. Conclusions: We found in our case series that paliperidone depot was effective in reducing symptoms of schizophrenia and report for the first time that it was also effective in reducing violence and aggression as well as improving personality pathology dimensions in a co-morbid patient. A depot antipsychotic effective in reducing violence in addition to improving psychotic symptoms is significant and promising for the future management of high secure forensic patients. Given the number of patients, this study, as a case series evaluation, should primarily considered as exploratory. Further studies are required over a longer period of time to build up more robust data on the efficacy of this medication and its role in reducing violent behaviour in a High Secure setting.

P.3.c.007 Challenges in treating children and adolescents with antipsychotic agents A. Simion1 ° , A. Crasan2 , D. Calin1 , M. Muscalu1 , S. Macovei1 Dr. Al. Obregia” Psychiatry Hospital, Child and Adolescent Department, Bucharest, Romania; 2 “Prof. Dr. Al. Obregia” Psychiatry Hospital, Adult Psychiatry Department, Bucharest, Romania 1 “Prof.

Background: Antipsychotic agents are currently employed in the treatment of a great number of psychiatric disorders that affect children and adolescents such as schizophrenia, acute psychotic episodes, bipolar disorder, OCD, severe depression, anxiety disorders, eating disorders and tic disorders. Some of the most commonly used antipsychotic agents used in the treatment of these disorders are olanzapine, aripiprazole, risperidone, quetiapine, levomepromazine and haloperidol [1]. While being of great benefit to the patient, these agents have some restrictive side effects such as weight gain, hiperprolactinemia, extrapyramidal side-effects (dystonia or Parkinsonian movements), sedation or somnolence, neutropenia or agranulocytosis. Objectives: In this analysis we try to identify the main obstacles in administering antipsychotic agents to children and adolescents and also to discuss how best to avoid these obstacles from the initial stages of the treatment and even in later ones. Methods: We have studied several case reports of children admitted to the Child and Adolescent Department ‘Prof. Dr. Alexandru Obregia’ Psychiatric Hospital in Bucharest who have received treatment with antipsychotic agents and were monitored at the clinic for a period of at least 6 months after treatment initiation. Results: We have identified several main factors that exert influence on treatment adherence and, as such, on treatment efficiency. These are both related to the agent itself, such as the appropriateness of a specific agent for treating a certain disorder

P.3.c. Psychotic disorders and treatment − Treatment (basic) or adverse effects leading to discontinuation, and related to how the patient and family perceive the agent and their willingness to adhere to the treatment. Conclusions: Our analysis brought into perspective also the importance the doctor–patient relationship as a positive influence for higher treatment compliance [2]. While the case number is too small for an effective analysis we have identified recurring patterns worthy of further analysis. Patients who undergo treatment with olanzapine have reported insatisfaction with weight gain and, as such, underwent dosage adjustments and even agent replacement [3]. Some patients have, as a result of their disorder, perceived certain agents as harmful without experiencing any side effects and have refused treatment based solely on this perception. References [1] Findling RL, Steiner H, Weller EB (2005). Use of antipsychotics in children and adolescents. The Journal of Clinical Psychiatry [2005, 66 Suppl 7: 29−40]. [2] Arango C (2011) Attenuated psychotic symptoms syndrome: how it may affect children and adolescent psychiatry. Eur Child Adolesc Psychiatry 20(2): 67−70. [3] McGlashan T, Walsh B, Woods S (2010) The Psychosis-risk syndrome. Handbook for diagnosis and follow-up. Oxford University Press, New York.

P.3.c.008 Immediate early and constitutive genes expression in antipsychotic switching paradigm: from clinical practice to animal model F. Marmo1 ° , E.F. Buonaguro1 , G. Latte1 , F. Iasevoli1 , A. De Bartolomeis1 1 University of Naples ‘Federico II’, Neuroscience Reproductive and Odontostomatologic Science, Naples, Italy Switching from one antipsychotic to another with different receptor profile is a common clinical practice when patients show poor or no treatment response or intolerable adverse effects. Switching could be a potentially destabilizing event because it could lead to rebound and withdrawal phenomena. Neuroimaging studies highlighted morphological and molecular changes after longterm administration in brain regions affected by antipsychotics, resulting in unexpected clinical outcome [1]. Mimicking a clinical practice, in this study we investigate the effect of chronic treatment with an atypical antipsychotic amisulpride, after first treatment with a high affinity D2 antagonist, haloperidol, on immediate early genes expression, Homer1a and Arc, and constitutive genes Homer1b and Psd-95. We have choosen amisulpride as second antipsychotic because, despite its high affinity to D2 receptor, it has demonstrated to behave clinically as an atypical antipsychotics [e.g. a low potential to cause extrapyramidal symptoms (EPS)] and devoid of any significant affinity to other receptor, with the exception of D3 receptor [2]. Moreover amisulpride induced a pattern of Homer1a expression mainly impacting medial striatal subregions, compared to haloperidol [3]. We treated Male Sprague-Dawley rats with haloperidol (0.8 mg/kg) or vehicle for the first 15 days (n = 18); from 16th day rats were switched to vehicle, haloperidol or amisulpride (n = 6) and received daily treatment for 15 days more. Animals were injected intraperitoneally (i.p.) and sacrificed by decapitation 90 minutes after the last administration. We analyzed Homer1a, Arc, Homer1b and Psd-95 expression by mean ISHH. For statistic analysis we used One Way Anova and Tukey-Kramer post hoc test

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to evaluate intergroups differences and then we used Two Way Analysis of Variance to highlighted an effect of first treatment or second treatment or the interaction between them. Haloperidol first treatment prevents amisulpride second treatment to induce Homer1a in dorsal and medial striatal subregions (p < 0.05). In the cortex haloperidol first treatment prevents amisulpride to induce Homer1a (p < 0.05). In the medial striatal subregions, haloperidol first treatment enhances Arc induction by amisulpride second treatment (p < 0.05). Moreover, in the lateral striatal subregions Arc expression level induced by haloperidol depends on treatment length (p < 0.05). In the cortex no Arc induction was detected (p < 0.05). In the striatum Homer1a and Arc expression was significantly affected by the second chronic treatment (p < 0.05). In the dorsolateral caudateputamen Homer1a expression was also affected by the combination of the first and the second chronic treatment (p < 0.05). In the striatum amisulpride enhanced Homer1b expression when preceded by haloperidol administration (p < 0.05). In dorsolateral and ventromedial subregions a first treatment effect on Homer1b expression was detected; in the striatum an interaction between first and second treatment effect was highlighted (p < 0.05). No changes in Psd-95 expression were detected in striatum and in the cortex (p < 0.05). In this animal model a first chronic treatment with a D2 blocker, haloperidol, affects PSD genes expression induced by a second chronic treatment with amisulpride. These data suggest that prolonged D2 R blockade may prime the effect on gene expression of a second antipsychotic compound that, even if a D2 R antagonist, has different receptor profile and is considered to behave as an atypical antipsychotic. References [1] Buckley PF. Receptor-binding profiles of antipsychotic: clinical strategies when switching between agents. J Clin Psychiatry, 2007; 68 Suppl 6:5−9. [2] Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B. Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther. 1997 Jan; 280(1): 83−97. [3] de Bartolomeis A, Marmo F, Buonaguro EF, Rossi R, Tomasetti C, Iasevoli F. Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. Eur Neuropsychopharmacol, 2013 Nov; 23(11):1516−29.

P.3.c.009 Effects of antipsychotics on the glutathione and antioxidative enzymes in the brain of rats treated perinatally with phencyclidine T. Stojkovic1 ° , M. Velimirovic1 , T. Nikolic1 , G. Jevtic1 , N. Petronijevic1 1 Institute of Medical and Clinical Biochemistry School of Medicine University of Belgrade, Belgrade, Serbia Antagonists of N-methyl-D-aspartate (NMDA)-type glutamate receptors, such as phencyclidine (PCP) and ketamine, uniquely reproduce psychotic symptoms and cognitive disturbances similar to those in schizophrenia. PCP administration may elicit some behavioral symptoms of schizophrenia in animals, including deficits in spatial learning and working memory, hyperlocomotion, and alter sensorimotor gating. These findings, along with other evidence of glutamatergic neuronal dysfunction in schizophrenia, have contributed to the development of PCP animal model of schizophrenia. Previous data suggest redox dysregulation in this disease. It is proposed that an imbalance between production