Schizophrenia is a debilitating psychiatric condition affecting almost one percent of the US population. Typical antipsychotics (e.g., haloperidol) have been in use for several decades and are generally very effective in treating the emotional and cognitive effects of schizophrenia, but are used as the last line of treatment due to their severe extrapyramidal motor side effects under chronic exposure. The present study was conducted to investigate the role of sex in determining the oromotor side effects of typical antipsychotics via measuring different behavioral dimensions of male and female Sprague-Dawley rats licking sucrose after haloperidol treatment. The results showed a stronger sensitivity in female rats than male rats within total licking responses and inter-lick intervals. The present results suggest closer attention needs to be paid to the role that sexual hormones play in the motor slowing and behavior-reducing effects of antipsychotics.

Amisulpride, a benzamide derivative, is an atypical antipsychotic drug used to treat both schizophrenia and depression. Amisulpride is a selective antagonist at dopamine D2 and D3 receptors and at serotonin 5-HT2B and 5-HT7 receptors and displays an atypical clinical profile with reduced extrapyramidal motor effects. The drug has a chiral center and is a mixture of two optical isomers: (S)-amisulpride and (R)-amisulpride. The present study used a two-lever drug discrimination assay to allow a direct comparison between amisulpride and its two isomers. Additionally, substitution testing was conducted with the typical antipsychotics, atypical antipsychotics, antidepressants, the anxiolytic chlordiazepoxide, several benzamide derivatives, and selective ligands with receptor mechanisms relevant to amisulpride. C57BL/6 mice were trained to discriminate 10 mg/kg rac-amisulpride from vehicle in a two-lever drug discrimination task for food reinforcement in an average of 35.7 sessions (range 6-89). The amisulpride dose-response curve (0.078 – 10.0 mg/kg) yielded an ED50 = 0.64 mg/kg, 95% CI [.47, 0.84 mg/kg]. The isomers fully substituted for amisulpride with a significant left-ward shift in the dose-response curve for (S)-amisulpride as compared to rac-amisulpride and (R)-amisulpride. The benzamide derivatives sulpiride and the (S)-sulpiride isomer fully substituted for amisulpride; tiapride produced partial substitution (76.4% DLR); none of the other tested drugs substituted for rac-amisulpride’s discriminative stimulus. These results showed that the rac-amisulpride stimulus was readily acquired in C57BL/6 mice, and that it has a unique and robust discriminative stimulus that is dose-dependent, time-dependent and stereoselective and is not shared with other antipsychotic or antidepressant drugs.

Introduction: Atypical Antipsychotics (AAPs) are approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder. AAPs are commonly used off-label to treat depression, post-traumatic stress disorder and neuropsychiatric symptoms in dementia due to lack of alternative treatment options and treatment resistance. Concerns for off-label use arise since AAPs increase the risk of cardiovascular events and death. The objectives were 1) describe patterns of RU and costs among off-label AAPs users in a nationally representative population 2) identify prevalence of off-label use in the Medicare population 3) compare RU and costs between off-label AAPs users and non-users with mental health conditions in Medicare. Methods: For the first objective, the Medical Expenditure Panel Survey (MEPS) datasets were used. AAPs users greater than 18 years were identified in this cross-sectional study. Generalized Linear Models (GLM) were used to estimate costs among users and non-users after controlling for age sex, gender, insurance type, marriage status, income and comorbidity index. For the second and third objective, Medicare datasets were used to identify prevalence, RU, and costs of off-label use in Medicare beneficiaries 18 years and older. RU and costs between propensity score matched AAPs user and non-user cohorts were compared in a retrospective cohort study. Results: The adjusted odds of having an office-based outpatient (OR=2.47, 95%CI: 1.55-3.92) or inpatient (OR=1.63, 95%CI: 1.26-2.10) visit were significantly higher among off-label AAPs users. Adjusted office-based visit ($1,943 vs. $1,346), prescription ($4,153 vs. $1,252) and total ($10,694 vs. $4,823) costs were significantly higher among users (p<0.0001). Among Medicare beneficiaries, approximately 37% of AAPs users had no FDA approved diagnosis. The typical off-label user was a white 70-year-old male. Common off-label uses were depression, anxiety and neurotic disorders and dementia. Off-label AAPs users had significantly higher mental health outpatient ($461 vs $297), prescription ($2,349 vs $282) and total ($3,665 vs $1,297) costs per beneficiary than non-users. About 30% of AAPs users had at least one mental health outpatient visit during the year versus 23% of non-users; no significant differences were found in inpatient visits. AAPs non-users had significantly higher all-cause inpatient costs ($6,945 vs. $4,841) per beneficiary (p Conclusion: In a nationally representative population comprising a younger age group AAPs users had higher all-cause RU and total costs than non-users. Off-label prescribing of AAPs continued to be a prevalent practice affecting 37% of Medicare AAPs users. Off-label AAPs users had higher mental health costs but no significant differences in all-cause total health care costs in a Medicare population. Off-label use of AAPs can be a cost-effective option if future research shows off-label use is associated with increased effectiveness, which offsets any additional costs.

Objetivo: Identificar os medicamentos preferidos no Brasil para tratar o transtorno bipolar e a opinião dos psiquiatras brasileiros sobre a litioterapia. Métodos: Um questionário de múltipla escolha com 14 itens foi desenvolvido para estudar estas questões. Foram enviados 10.059 questionários para psiquiatras brasileiros. Resultados: 820 psiquiatras (8,6%) responderam aos questionários. Lítio foi a medicação de primeira escolha em todas as fases do transtorno. Antipsicóticos foram a segunda escolha no tratamento da mania, superando os anticonvulsivantes. Antidepressivos foram a segunda medicação mais utilizada nos episódios depressivos. Mais de 80% de psiquiatras acreditam que o lítio é um medicamento seguro e de fácil manejo. Características epidemiólogicas como região de origem, alto nível educacional, grande experiência clínica e interesses acadêmicos podem ter influenciado tais resultados. Conclusão: Lítio é o medicamento de primeira linha no tratamento do transtorno bipolar no Brasil, a despeito do que ocorre em outros países. Apesar deste panorama favorável, algumas dificuldades podem ser identificadas como a falta de conhecimento sobre o lítio por profissionais da área de saúde mental e pacientes. / Objective: Identify preferred drugs to treat bipolar disorder in Brazil and the impressions of Brazilian psychiatrits about lithium therapy. Methods: A 14 items multiple-choice questionnaire was developed to answer this issue. Questionnaires were posted to 10,059 Brazilian psychiatrists. Results: 820 psychiatrists (8.6%) have answered the questionnaires. Lithium was the preferred medication used in all phases of the disorder. Antipsychotics were second choice in treatment of mania, overcoming anticonvulsants. Antidepressants were the second more used medication for depressive episode. More than 80% of psychiatrists believe that lithium is a safe drug and there is no difficult to handle with. Epidemiological characteristics such region of origen, high degree, large clinical practice and academic interests may influenced those results. Conclusion: Lithium is the first line drug to treat bipolar disorder in Brazil, despite what occur in others countries. Although this favorable panel, some difficults can be identified as mental health professional and patients\' lack of information about lithium.

Os transtornos do espectro autista (TEA) são distúrbios neuropsiquiátricos bastante comuns, graves, e que propiciam grande impacto social e financeiro. A identificação de vias moleculares e processos celulares alterados que são compartilhados pelos pacientes, mesmo que estes apresentem causas etiológicas distintas, pode contribuir de forma significativa para o entendimento de sua patofisiologia desses transtornos. Ainda, a identificação destas vias pode propiciar o desenvolvimento de abordagens terapêuticas mais eficientes, uma vez que o uso de medicamentos nos TEA ainda é inadequado, envolvendo baixa melhora funcional e diversos efeitos colaterais, como o ganho excessivo de peso e anormalidades metabólicas associadas. Neste trabalho, selecionamos como uma primeira abordagem o estudo da via de sinalização PI3K-mTOR em pacientes com TEA não-sindrômico, via esta envolvida com diversos aspectos do desenvolvimento e funcionamento neuronal, assim como com a patofisiologia de síndromes monogênicas que apresentam alta prevalência de TEA em seu quadro clínico. Foram utilizadas como modelo experimental in vitro células-tronco mesenquimais provenientes de polpa de dente decíduo (SHEDs) de pacientes e indivíduos controles. Os resultados aqui obtidos sugerem a importância da desregulação da via PI3K/mTOR na patofisiologia de uma parcela importante dos casos de TEA não-sindrômico. Ainda, observamos que as células dos pacientes com alterações nessa via de sinalização apresentam maior capacidade proliferativa, e que a modulação deste fenótipo alterado por meio do uso concomitante de inibidores de PI3K e mTOR nas células de um destes pacientes sugere esta via como um alvo promissor para o desenvolvimento de novas abordagens terapêuticas para estes pacientes. Em seguida, na tentativa de desvendar os mecanismos subjacentes aos efeitos metabólicos adversos associados com o uso de antipsicóticos prescritos para o tratamento de pacientes com TEA, investigamos os efeitos destes psicofármacos sobre a biologia do tecido adiposo humano. Foram utilizadas como modelos in vitro células-tronco (ADSCs) e adipócitos maduros derivados de tecido adiposo humano de indivíduos controles. Os resultados obtidos sugerem que a ação direta dos antipsicóticos com alta propensão ao ganho de peso (como a olanzapina e a clozapina) sobre a proliferação, diferenciação, e o metabolismo do tecido adiposo humano parece não constituir um mecanismo importante associado ao ganho de peso apresentado pelos pacientes, e que a ação desses medicamentos sobre os sistemas centrais que regulam o peso e o metabolismo deve ser o mecanismo principal levando aos efeitos metabólicos adversos. Juntos, os resultados gerados neste trabalho podem, de certa forma, contribuir para da farmacoterapia dos TEA / Autism spectrum disorders (ASD) are common neuropsypchiatric disorders, which has serious social and economic impacts. Identification of common molecular and cellular processes altered in patients, despite the underlying genetic heterogeneity, can contribute significantly to our understanding of the disease pathophysiology and can help to develop more effective treatments, since available pharmacotherapy for ASD is inefficient and frequently associated with adverse side effects, such as weight gain and metabolic disturbances. Here, we used patient-derived Stem cells from Human Exfoliated Deciduous teeth (SHEDs) as an intro model system to investigate whether non-syndromic ASD patients show altered regulation of PI3K/mTOR signaling pathway, which is involved in multiple aspects of neuronal development and physiology, and in the pathogenesis of monogenic syndromes that share features with ASD. Our results suggest that dysregulation of PI3K/mTOR-linked networks play an important role in the pathogenesis of a subgroup of non-syndromic ASD. In addition, we found enhanced proliferative capacity in cells with altered PI3K/mTOR activity, which was rescued in one of these patients through combined pharmacological inhibition of both PI3K and mTOR kinase activity, suggesting that PI3K-mTOR signaling is a promising target for the development of new therapeutic approaches for these individuals. Next, in an attempt to better understand the mechanisms underlying the metabolic side effects of the antipsychotics prescribed for ASD treatment, we investigated the effects of some of these drugs on the biology of human adipose tissue using as in vitro model systems human adipose-derived stem cells (ADSCs) and mature adipocytes. Our results suggest that a direct and potent effect of antipsychotics with high weight gain liability (such as clozapine and olanzapine) on cell proliferation, differentiation, and metabolism of human adipose tissue is not an important mechanism by which these drugs induce metabolic disturbances. Consequently, our results suggest that these side effects may mainly reflect the action of these drugs on central pathways involved in weight control and metabolism. Together, our results can, to some extent, contribute to improving pharmacotherapy of ASD

Este trabalho apresenta a continuidade da avaliação farmacológica do derivado Nfenilpiperazínico LASSBio-579 em busca de um novo candidato a antipsicótico de segunda geração. Em estudos anteriores, demonstramos que LASSBio-579 base livre é um potencial candidato a antipsicótico atípico capaz de modular três diferentes sistemas neurotransmissores envolvidos na patofisiologia da esquizofrenia: a neurotransmissão dopaminérgica, serotonérgica e glutamatérgica; entretanto, LASSBio-579 na forma de cloridrato apresenta baixa biodisponibilidade. Neste trabalho avaliamos inicialmente a ação de LASSBio-579.HCl. -ciclodextrina, proposto como alternativa para melhorar a biodisponibilidade. Porém, quando avaliado no modelo de escalada induzida por apomorfina, preditivo de atividade antipsicótica, essa preparação não foi efetiva. Assim, seguimos a avaliação farmacodinâmica com LASSBio-579 base livre, utilizando modelos preditivos de atividade antipsicótica, em camundongos. Neste trabalho foram realizados ainda ensaios in vitro, onde se avaliou a ação de LASSBio-579 sobre a viabilidade celular, captação de glutamato e secreção de proteína S100B, utilizando-se para isso fatias hipocampais de ratos tratadas de forma aguda com LASSBio-579 nas concentrações de 0,1; 1,0; 10 e 20μM. / This study presents the continuity of the pharmacological evaluation of the Nphenilpiperazine derivative LASSBio-579, searching a new second generation antipsychotic compound. In previous studies we have demonstrated that LASSBio- 579 in form of base is a potential atypical antipsychotic able to modulate three different neurotransmitter systems involved in the pathophysiology of schizophrenia: dopaminergic, glutamatergic and serotonergic. However, LASSBio-579 hydrochloride has low bioavailability. In this study we evaluated LASSBio-579.HCl. -cyclodextrin, prepared with the aim of increasing oral bioavailability, in the apomorphine induced climbing in mice, which is a model predictive of antipsychotic activity; and it was not effective. Thus, we continue the study with LASSBio-579 in form of base by testing it in others mice models predictive of antipsychotic activity. In this study, also were made in vitro studies performed in hippocampal acute slices which demonstrated that LASSBio-579 induced a glutamate uptake inhibition and also inhibited the S100B protein secretion.

Objetivo: Identificar os medicamentos preferidos no Brasil para tratar o transtorno bipolar e a opinião dos psiquiatras brasileiros sobre a litioterapia. Métodos: Um questionário de múltipla escolha com 14 itens foi desenvolvido para estudar estas questões. Foram enviados 10.059 questionários para psiquiatras brasileiros. Resultados: 820 psiquiatras (8,6%) responderam aos questionários. Lítio foi a medicação de primeira escolha em todas as fases do transtorno. Antipsicóticos foram a segunda escolha no tratamento da mania, superando os anticonvulsivantes. Antidepressivos foram a segunda medicação mais utilizada nos episódios depressivos. Mais de 80% de psiquiatras acreditam que o lítio é um medicamento seguro e de fácil manejo. Características epidemiólogicas como região de origem, alto nível educacional, grande experiência clínica e interesses acadêmicos podem ter influenciado tais resultados. Conclusão: Lítio é o medicamento de primeira linha no tratamento do transtorno bipolar no Brasil, a despeito do que ocorre em outros países. Apesar deste panorama favorável, algumas dificuldades podem ser identificadas como a falta de conhecimento sobre o lítio por profissionais da área de saúde mental e pacientes. / Objective: Identify preferred drugs to treat bipolar disorder in Brazil and the impressions of Brazilian psychiatrits about lithium therapy. Methods: A 14 items multiple-choice questionnaire was developed to answer this issue. Questionnaires were posted to 10,059 Brazilian psychiatrists. Results: 820 psychiatrists (8.6%) have answered the questionnaires. Lithium was the preferred medication used in all phases of the disorder. Antipsychotics were second choice in treatment of mania, overcoming anticonvulsants. Antidepressants were the second more used medication for depressive episode. More than 80% of psychiatrists believe that lithium is a safe drug and there is no difficult to handle with. Epidemiological characteristics such region of origen, high degree, large clinical practice and academic interests may influenced those results. Conclusion: Lithium is the first line drug to treat bipolar disorder in Brazil, despite what occur in others countries. Although this favorable panel, some difficults can be identified as mental health professional and patients\' lack of information about lithium.

This study analyzed the associative properties of nicotine in a conditioned place preference (CPP) paradigm in adolescent rats neonatally treated with quinpirole (NQ) or saline (NS). NQ produces dopamine D2 receptor supersensitivity that persists throughout the animal's lifetime, and therefore has relevance towards schizophrenia. In two experiments, rats were ip administered quinpirole (1mg/kg) or saline from postnatal day (P)1–21. After an initial preference test at P42–43, animals were conditioned for eight consecutive days with saline or nicotine (0.6mg/kg free base) in Experiment 1 or saline or nicotine (1.8mg/kg free base) in Experiment 2. In addition, there were NQ and NS groups in each experiment given the antipsychotic haloperidol (0.05mg/kg) or clozapine (2.5mg/kg) before nicotine conditioning. A drug free post-conditioning test was administered at P52. At P53, the nucleus accumbens (NAc) was analyzed for glial cell-line derived neurotrophic factor (GDNF). Results revealed that NQ enhanced nicotine CPP, but blunted the aversive properties of nicotine. Haloperidol was more effective than clozapine at blocking nicotine CPP in Experiment 1, but neither antipsychotic affected nicotine conditioned place aversion in Experiment 2. NQ increased accumbal GDNF which was sensitized in NQ rats conditioned to nicotine in Experiment 1, but the aversive dose of nicotine reduced GDNF in NQ animals in Experiment 2. Both antipsychotics in combination with the aversive dose of nicotine decreased accumbal GDNF. In sum, increased D2 receptor sensitivity influenced the associative properties and GDNF response to nicotine which has implications towards pharmacological targets for smoking cessation in schizophrenia.

Schizophrenia is a chronic mental disorder affecting millions worldwide. It has no known cure. Current pharmaceutical treatments have shown efficacy in only one of the three symptom clusters of schizophrenia, providing little or no benefit in the other two. Furthermore, the current standard-of-care drugs, known as atypical antipsychotics, carry risks of severe side effects affecting multiple body systems. Most patients opt to discontinue drug therapy within two years of initiation due to lack of efficacy and/or preponderance of adverse effects. Previous findings have shown that chronic usage of atypical antipsychotics causes a 5-HT2A-dependent upregulation of histone deacetylase 2 (HDAC2), which in turn leads to downregulation of metabotropic glutamate receptor 2 (mGluR2), a G protein-coupled receptor with an important role in synaptic plasticity. The present study aims to characterize the extent to which this downregulation leads to specific functional outcomes, and in doing so, may help identify new targets for more effective treatment of schizophrenia.

For over a century, there have been suggestions of a link between what is currently called bipolar disorder and cardiovascular mortality. In the contemporary epidemiological literature, this risk has been confirmed and approximates twice that expected based on age and gender. To date, however, this information has come primarily from clinical samples, which carry considerable risk of selection bias. The studies contained in this dissertation sought to assess this relationship using methods less vulnerable to selection bias and to determine the role that course of illness and treatments for illness may play in the development of vascular disease. In a nationally representative sample, we confirmed a link between mood disorders and vascular disease, which was particularly pronounced in women with bipolar disorder. In subsequent studies, a dose-response relationship between the duration of clinically significant hypomanic or manic symptoms and both cardiovascular mortality and endothelial function was seen. While medication exposure did not appear related to mortality or endothelial function, first generation antipsychotics were associated with arterial stiffness, an effect apparently mediated by elevations in blood pressure. In cross-sectional samples, our data suggests that vasculopathy is not present early in the course of bipolar disorder although is much greater than expected later in the course of illness. This dissertation purports that vasculopathy develops over the long-term course of bipolar disorder, is proportional to symptom burden, and is influenced by health behaviors and treatments. These findings may provide opportunities for clinicians and those afflicted to intervene to address this excess risk of vascular morbidity and mortality.