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1.
Artigo em Inglês | MEDLINE | ID: mdl-33924699

RESUMO

The use of psychotropic medication in children is increasing worldwide. Children with developmental disabilities seem to be prescribed these medications at a higher rate compared to their non-disabled peers. Little is known about prescribing in non-Western, middle-income studies. In Iran, the file records of 1133 children, aged 2 to 17 years, assessed as having autism spectrum disorder (ASD) or an intellectual disability (ID) in Tehran City and Province from 2005 to 2019 were collated, and information from parental reports of medications was extracted. Upwards of 80% of children with ASD and 56% of those with ID were prescribed a psychotropic medication with around one quarter in each group taking two or more medications. The rates were higher among male children showing difficult-to-manage behaviors such as hyperactivity, but less so for children of fathers with higher levels of education. The lack of alternative management strategies may be a significant driver for the use of psychotropic medications in Iran and other Low and Middle Income countries, despite their known side effects, and their failure to address the developmental needs of the children. Rather, multi-disciplinary, behavioral, therapeutic, and educational interventions are required, but these are not available widely in Iran, although a start has been made.


Assuntos
Transtorno do Espectro Autista , Deficiência Intelectual , Adolescente , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/epidemiologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/epidemiologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Irã (Geográfico)/epidemiologia , Masculino , Psicotrópicos/uso terapêutico
2.
Br J Psychiatry ; 218(1): 58-62, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33541472

RESUMO

BACKGROUND: Psychotropics are overprescribed for adults with intellectual disabilities; there are few studies in children and young people. AIMS: To investigate antipsychotic and antidepressant prescribing in children and young people with and without intellectual disabilities, and prescribing trends. METHOD: Scotland's annual Pupil Census, which identifies pupils with and without intellectual disabilities, was record-linked to the Prescribing Information System. Antidepressant and antipsychotic data were extracted. Logistic regression was used to analyse prescribing between 2010 and 2013. RESULTS: Of the 704 297 pupils, 16 142 (2.29%) had a record of intellectual disabilities. Antipsychotic and antidepressant use increased over time, and was higher in older pupils; antipsychotic use was higher in boys, and antidepressant use was higher in girls. Overall, antipsychotics were prescribed to 281 (1.74%) pupils with intellectual disabilities and 802 (0.12%) without (adjusted odds ratio 16.85, 95% CI 15.29-18.56). The higher use among those with intellectual disabilities fell each year (adjusted odds ratio 20.19 in 2010 v. 14.24 in 2013). Overall, 191 (1.18%) pupils with intellectual disabilities and 4561 (0.66%) without were prescribed antidepressants (adjusted odds ratio 2.28, 95% CI 2.03-2.56). The difference decreased each year (adjusted odds ratio 3.10 in 2010 v. 2.02 in 2013). CONCLUSIONS: Significantly more pupils with intellectual disabilities are prescribed antipsychotics and antidepressants than are other pupils. Prescribing overall increased over time, but less so for pupils with intellectual disabilities; either they are not receiving the same treatment advances as other pupils, or possible overprescribing in the past is changing. More longitudinal data are required.


Assuntos
Antipsicóticos , Deficiência Intelectual , Adolescente , Adulto , Idoso , Antidepressivos/uso terapêutico , Antipsicóticos/uso terapêutico , Criança , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Masculino , Razão de Chances , Psicotrópicos/uso terapêutico
3.
Metabolism ; 116: 154463, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33309713

RESUMO

OBJECTIVES: GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1, a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. METHODS: We carried out proteomic analysis and monitored [18F]-fluoro-2-deoxy-d-glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d-Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d-glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. RESULTS: Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [18F]-fluoro-2-deoxy-d-glucose revealed an increased d-glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d-glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy-d-glucose injection. CONCLUSIONS: These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.


Assuntos
Desoxiglucose/farmacologia , Glicólise/efeitos dos fármacos , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Transtornos da Memória/prevenção & controle , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células Cultivadas , Desoxiglucose/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Glucose/metabolismo , Inibidores de Dissociação do Nucleotídeo Guanina/deficiência , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/genética , Camundongos , Camundongos Knockout
4.
BMJ Case Rep ; 13(12)2020 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-33310825

RESUMO

Histamine is involved in various physiological functions like sleep-wake cycle and stress regulation. The histamine N-methyltransferase (HNMT) enzyme is the only pathway for termination of histamine neurotransmission in the central nervous system. Experiments with HNMT knockout mice generated aggressive behaviours and dysregulation of sleep-wake cycles. Recently, seven members of two unrelated consanguineous families have been reported in whom two different missense HNMT mutations were identified. All showed severe intellectual disability, delayed speech development and mild regression from the age of 5 years without, however, any dysmorphisms or congenital abnormality. A diagnosis of mental retardation, autosomal recessive 51 was made. Here, we describe a severely mentally retarded adolescent male born from second cousins with a homozygous mutation in HNMT. His phenotypic profile comprised aggression, delayed speech, autism, sleep disturbances and gastro-intestinal problems. At early age, regression occurred. Treatment with hydroxyzine combined with a histamine-restricted diet resulted in significant general improvement.


Assuntos
Histamina N-Metiltransferase/genética , Homozigoto , Deficiência Intelectual/genética , Mutação , Agressão/fisiologia , Encéfalo/metabolismo , Histamina/metabolismo , Histamina N-Metiltransferase/metabolismo , Humanos , Hidroxizina/uso terapêutico , Deficiência Intelectual/dietoterapia , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/metabolismo , Masculino , Sono/fisiologia , Resultado do Tratamento , Adulto Jovem
5.
Pediatrics ; 146(5)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33093139

RESUMO

Autism spectrum disorder (ASD) is the most common disability-causing neurodevelopmental disorder in childhood. Although inborn errors of metabolism (IEM) are rare causes of ASD, they are significant for several reasons, including implications in genetic counseling and determination of prognosis. In this article, we present a 6-year-old boy who presented to us with ASD and was diagnosed with creatine transporter deficiency. Physical and neurologic examination of this patient had not previously raised suspicion of IEM, but twin pregnancy, prematurity, NICU stay due to necrotizing enterocolitis, transient infantile hypotonia, gross-motor delay, breath-holding spells, and a single febrile seizure complicated the history. MRI revealed mild T2-hyperintensity in posterior periventricular white matter. Further evaluation with magnetic resonance spectroscopy, which showed a decreased creatine peak, led to diagnostic investigations for disorders of creatine metabolism, revealing increased urinary creatine:creatinine ratio and a de novo, novel hemizygous frameshift variant in SLC6A8 Clinicians are advised to maintain a high index of suspicion for IEM and to evaluate patients with ASD for syndromic features. Although current guidelines from relevant organizations differ in their recommendations regarding the necessity and the extent of metabolic screening in ASD, there is a growing trend toward screening for treatable IEM. In this case report, we present challenges and pitfalls in the diagnostic journey for creatine transporter deficiency and underline the significance of a thorough history and physical examination in the evaluation of a child with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Encefalopatias Metabólicas Congênitas/genética , Creatina/deficiência , Doenças em Gêmeos/genética , Mutação da Fase de Leitura , Retardo Mental Ligado ao Cromossomo X/genética , Proteínas do Tecido Nervoso/genética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/deficiência , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encefalopatias Metabólicas Congênitas/diagnóstico , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Criança , Creatina/genética , Creatinina/metabolismo , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/tratamento farmacológico , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Retardo Mental Ligado ao Cromossomo X/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/genética , Espectroscopia de Prótons por Ressonância Magnética
6.
Rev Med Suisse ; 16(708): 1786-1789, 2020 Sep 30.
Artigo em Francês | MEDLINE | ID: mdl-32997447

RESUMO

Behavioral disorders in people with developmental and intellectual disability are frequent but their management is rarely taught. This article is to help primary physicians prescribe drug treatment. We will also discuss the key elements of two of the most commonly used classes of drugs, taking into account the patient's co-morbidities, contraindications and the main side effects.


Assuntos
Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/psicologia , Comportamento Problema/psicologia , Comorbidade , Humanos , Deficiência Intelectual/complicações
7.
Expert Opin Pharmacother ; 21(15): 1897-1913, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32692263

RESUMO

INTRODUCTION: ADHD causes significant distress and functional impairment in multiple domains of daily life. Therefore, diagnosis and treatment are important to improve the quality of life of people. The pharmacotherapy for ADHD is well established but needs systematic evaluation in Intellectual Disability (ID) populations. AREAS COVERED: This paper reviews the ADHD pharmacological treatment in people with ID using the PRISMA guidance for scoping reviews to help identify the nature and strength of evidence. EXPERT OPINION: In the last 20 years, seven randomized controlled trials have evaluated pharmacotherapies for ADHD in people with ID; five looking at methylphenidate. Generally, studies were underpowered; all but two had less than 25 participants. Of the two larger trials one was single blinded and therefore open to bias. Only two used a parallel-group method, the remainder were mostly short crossover trials; not ideal when measuring behavioral and psychological parameters which are long standing. The remaining evidence is made up of observational studies. Methylphenidate and atomoxetine, particularly at higher doses, have shown clear benefits in people with ID. Most people with ID tolerated ADHD medications well. Benefits were seen in behavioral and/or cognitive domains. The evidence base is limited, though promising, for dexamfetamine, clonidine, and guanfacine.


Assuntos
Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Clonidina/uso terapêutico , Dextroanfetamina/uso terapêutico , Deficiência Intelectual/tratamento farmacológico , Metilfenidato/uso terapêutico , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Criança , Cognição/efeitos dos fármacos , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/psicologia , Guias de Prática Clínica como Assunto , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
8.
Nat Commun ; 11(1): 480, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980599

RESUMO

Mutations in the actively expressed, maternal allele of the imprinted KCNK9 gene cause Birk-Barel intellectual disability syndrome (BBIDS). Using a BBIDS mouse model, we identify here a partial rescue of the BBIDS-like behavioral and neuronal phenotypes mediated via residual expression from the paternal Kcnk9 (Kcnk9pat) allele. We further demonstrate that the second-generation HDAC inhibitor CI-994 induces enhanced expression from the paternally silenced Kcnk9 allele and leads to a full rescue of the behavioral phenotype suggesting CI-994 as a promising molecule for BBIDS therapy. Thus, these findings suggest a potential approach to improve cognitive dysfunction in a mouse model of an imprinting disorder.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Histonas/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Hipotonia Muscular/genética , Hipotonia Muscular/metabolismo , Canais de Potássio/genética , Animais , Comportamento Animal , Benzamidas , Encéfalo/metabolismo , Anormalidades Craniofaciais/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Técnicas de Silenciamento de Genes , Impressão Genômica , Inibidores de Histona Desacetilases/farmacologia , Humanos , Deficiência Intelectual/tratamento farmacológico , Locus Cerúleo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hipotonia Muscular/tratamento farmacológico , Mutação , Fenótipo , Fenilenodiaminas/farmacologia , Canais de Potássio/deficiência , Canais de Potássio/metabolismo , Regulação para Cima/efeitos dos fármacos
9.
Eur J Med Genet ; 63(1): 103625, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30711678

RESUMO

We set out to investigate whether a de-novo paradigm could explain genetic causes of chronic ultra-refractory epilepsy, with onset later than the typical age for the epileptic encephalopathies. We performed exome sequencing on nine adult patients with MRI-negative epilepsy and no preceding intellectual disability. All had an onset of seizures after five years old and had chronic ultra-refractory epilepsy defined here as having failed more than six anti-epileptic drugs and currently experiencing ≥4 disabling seizures per month. Parents were sequenced to identify de-novo mutations and these were assessed for likelihood of pathogenicity based on the American College of Medical Genetics and Genomics (ACMG) criteria. We confirmed the presence of functional and predicted-damaging de-novo mutations in 3/9 patients. One of these pathogenic de-novo mutations, in DNM1L, was previously reported in a patient with severe epilepsy and chronic pharmacoresistance adding to the evidence for DNM1L as an epilepsy gene. Exome sequencing is a successful strategy for identifying de-novo mutations in paediatric epileptic encephalopathies and rare neurological disorders. Our study demonstrates the potential benefit of considering ultra-refractory epilepsy patients with later onset for genetic testing. Identifying genetic mutations underpinning severe epilepsy of unknown aetiology may provide new insight into the underlying biology and offers the potential for therapeutic intervention in the form of precision medicine in older patients.


Assuntos
Dinaminas/genética , Epilepsia/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Adolescente , Idade de Início , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Criança , Epilepsia/diagnóstico por imagem , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Exoma/genética , Feminino , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/patologia , Masculino , Mutação , Sequenciamento Completo do Exoma
10.
Medicine (Baltimore) ; 98(51): e18075, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31860957

RESUMO

RATIONALE: Dyke-Davidoff-Masson syndrome (DDMS) is a rare syndrome commonly occurring in children and characterized by cerebral hemiatrophy, hypertrophy of the skull, epilepsy, and mental retardation. However, few have been reported in China, especially in teenagers. This case investigated its possible cause and explored a relative effective solution. PATIENT CONCERNS: A 24-year-old female came to department having experienced recurrent seizures for 12 years. DIAGNOSIS: DDMS was diagnosed from its manifestations, biochemistry indexes, and imaging (computed tomography angiography, magnetic resonance venography, and so on). INTERVENTIONS: Several drugs are used to treat the disease, including valproate, carbamazepine, topiramate, and ginkgo biloba extract. OUTCOMES: Under the medicine treatment of magnesium valproate with carbamazepine, the patient experienced partial seizures approximately once per month that lasted 30 to 60 seconds each without any complications observed during a follow-up period of 24 months. CONCLUSION: The imaging and clinical features of DDMS in this teenager were similar to those in classic infantile-onset cases. A potential cause of the disease could be brain trauma, which impaired the middle cerebral artery and reduced cerebral blood supply, leading to epilepsy and hemiatrophy. LESSONS: It was concluded early diagnosis and pharmacotherapy are the keys to preventing intellectual decline in DDMS patients. Moreover, the combination of magnesium valproate and carbamazepine could significantly reduce the frequency and duration of seizures, despite not eliminating them completely.


Assuntos
Encefalopatias/diagnóstico por imagem , Deficiência Intelectual/diagnóstico , Imageamento por Ressonância Magnética/métodos , Convulsões/diagnóstico , Convulsões/tratamento farmacológico , Encefalopatias/tratamento farmacológico , Carbamazepina/uso terapêutico , China , Doença Crônica , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Prognóstico , Recidiva , Medição de Risco , Índice de Gravidade de Doença , Síndrome , Tomografia Computadorizada por Raios X/métodos , Ácido Valproico , Adulto Jovem
12.
BMC Cancer ; 19(1): 1040, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31684896

RESUMO

BACKGROUND: The longevity for people with intellectual disability (ID) has significantly increased in developed countries during the past decades. Consequently, the incidence of cancer is expected to increase in this group. The aim of the present study was to investigate the prescription of pain medication in older cancer patients with intellectual disability (ID) compared to older patients in the general population, surviving or living with a cancer diagnosis. METHODS: This Swedish national registry-based study, included people with ID aged 55 years or older in 2012, and alive at the end of that year (ID cohort, n = 7936). For comparisons, we used a referent cohort, one-to-one matched with the general population by year of birth and sex (gPop cohort, n = 7936). People with at least one diagnosis of cancer during 2002-2012 were identified using the Swedish National Patient Register, resulting in 555 cancer patients with ID and 877 cancer patients from the general population. These two cohorts of cancer patients were compared with respect to prescription of pain medication for the period 2006-2012. Outcome data were aggregated so that each patient was categorized as either having or not having at least one prescription of each investigated drug group during the study period, and relative risks (RRs) for prescription were estimated for prescription in the ID cohort vs the gPop cohort. RESULTS: Cancer patients with ID were less likely than cancer patients in the gPop cohort to have at least one prescription of COX inhibitors (RR 0.61) and weak opioids (RR 0.63). They were, however, more likely to be prescribed paracetamol (RR 1.16), antidepressants (RR 2.09), anxiolytics (RR 2.84), and "other hypnotics, sedatives, and neuroleptics" (RR 1.39). No statistically significant differences between the two cohorts were found for strong opioids, antiepileptics, tricyclic antidepressants, or hypnotics and sedatives. CONCLUSION: In the studied cohort of older people surviving or living with cancer, prescriptions for pain-treatment was less common in patients with ID compared to the general population. These results may suggest that pain is not sufficiently treated among cancer patients with ID, a situation that most likely would compromise the quality of life in this group.


Assuntos
Analgésicos/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Deficiência Intelectual/epidemiologia , Neoplasias/epidemiologia , Dor/tratamento farmacológico , Sistema de Registros/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Sobreviventes de Câncer , Estudos de Coortes , Feminino , Humanos , Deficiência Intelectual/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Suécia/epidemiologia
14.
BMJ Open ; 9(11): e032861, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31780594

RESUMO

OBJECTIVES: Understanding patient and carer perspectives is essential to improving the quality of medication prescribing. This study aimed to explore experiences of psychotropic medication use among people with intellectual disability (ID) and their carers, with a focus on how medication decisions are made. DESIGN: Thematic analysis of data collected in individual semistructured interviews. PARTICIPANTS AND SETTING: Fourteen adults with ID, 12 family carers and 12 paid carers were recruited from specialist psychiatry services, community groups, care providers and training organisations in the UK. RESULTS: People with ID reported being highly compliant with psychotropic medication, based on a largely unquestioned view of medication as important and necessary, and belief in the authority of the psychiatrist. Though they sometimes experienced medication negatively, they were generally not aware of their right to be involved in medication decisions. Paid and family carers reported undertaking a number of medication-related activities. Their 'front-line' status and longevity of relationships meant that carers felt they possessed important forms of knowledge relevant to medication decisions. Both groups of carers valued decision-making in which they felt they had a voice and a genuine role. While some in each group described making joint decisions about medication with psychiatrists, lack of involvement was often described. This took three forms in participants' accounts: being uninformed of important facts, insufficiently included in discussions and lacking influence to shape decisions. Participants described efforts to democratise the decision-making process by gathering information, acting to disrupt perceived power asymmetries and attempting to prove their credibility as valid decision-making partners. CONCLUSIONS: Stakeholder involvement is a key element of medication optimisation that is not always experienced in decisions about psychotropic medication for people with ID. Forms of shared decision-making could be developed to promote collaboration and offer people with ID and their carers greater involvement in medication decisions.


Assuntos
Cuidadores/psicologia , Tomada de Decisão Compartilhada , Família/psicologia , Deficiência Intelectual/tratamento farmacológico , Participação do Paciente , Psicotrópicos/uso terapêutico , Adulto , Idoso , Inglaterra , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Papel Profissional , Psiquiatria , Pesquisa Qualitativa
15.
South Med J ; 112(8): 428-432, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375839

RESUMO

OBJECTIVES: Individuals with intellectual disabilities (IDs) are at increased risk for low bone mass and fragility fractures, and those who are nonambulatory may be at even higher risk. Patients with IDs often are vitamin D deficient, but there is little information concerning how vitamin D treatment of patients with IDs affects markers of bone formation and resorption. METHODS: We performed a retrospective analysis of 23 institutionalized individuals with IDs who were the subject of a performance improvement continuing medical education project designed to reduce risk for fracture by optimizing serum vitamin D levels. Patients were divided into those with normal weight-bearing (NWB) physical activity (15 patients: 14 men, 1 woman) and those with low weight-bearing (LWB) physical activity (8 patients: 7 men, 1 woman). All of the subjects received 50,000 IU of vitamin D3 weekly for 4 to 8 weeks, followed by a maintenance dose of 50,000 IU monthly for 3 to 6 months. Bone turnover markers (type 1 cross-linked C-telopeptide [CTX], type 1 N-terminal propeptide [P1NP], and parathyroid hormone [PTH]) and 25(OH)-vitamin D levels were measured before and after vitamin D supplementation. RESULTS: At baseline, there were no significant differences in the serum levels of 25OH-D, PTH, P1NP, or CTX between the two groups (NWB and LWB). Vitamin D levels were increased to a higher value in LWB subjects than in NWB subjects (61 ± 4.1 vs 48.4 ± 2.2 ng/mL, P < 0.001). Vitamin D treatment suppressed PTH (20.5% ± 14.3% vs 31.4% ± 7.7%, P = not significant) and P1NP (33.0% ± 6.2% vs 29.4% ± 6.9%, P = not significant) similarly in both groups. Although CTX levels declined by 26.4% ± 5.3% (P = 0.0002) in NWB individuals (as anticipated), vitamin D supplementation resulted in an unexpected 25.8% ± 8% increase (P = 0.01) in CTX in LWB individuals, suggesting osteoclast activation. CONCLUSIONS: Although high-dose vitamin D appeared to suppress osteoclast activity in NWB adults with IDs, the increase in serum CTX levels in those with LWB activity implies activation of osteoclasts that could exacerbate their unique low bone mass and increase fracture risk. The results support the use of a lower-dose vitamin D regimen in this patient group with LWB.


Assuntos
Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/prevenção & controle , Exercício Físico/fisiologia , Deficiência Intelectual/complicações , Deficiência Intelectual/tratamento farmacológico , Vitamina D/farmacologia , Suporte de Carga/fisiologia , Adulto , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/etiologia , Reabsorção Óssea/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vitaminas/farmacologia , Adulto Jovem
16.
Med Hypotheses ; 131: 109289, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31443780

RESUMO

Mental retardation is a progressive condition in Down syndrome: intelligence starts to decline linearly within the first year. This phenomenon could be related to the overproduction of a toxic compound, hydrogen sulfide. Indeed, a gene located on chromosome 21 controls the production of cystathionine-ß-synthase, an enzyme involved in hydrogen sulfide production in the central nervous system. It has recently been demonstrated that excess cystathionine-ß-synthase levels are needed and sufficient to induce cognitive phenotypes in mouse models of Down syndrome. Thus, two therapeutic options might be used in Down syndrome patients: the use of a specific cystathionine ß-synthase inhibitor and the use of an effective antidote to reduce hydrogen sulfide toxicity. Prenatal treatment of Down syndrome fetuses is also suggested.


Assuntos
Cistationina beta-Sintase/fisiologia , Síndrome de Down/psicologia , Sulfeto de Hidrogênio/antagonistas & inibidores , Deficiência Intelectual/terapia , Ácido Amino-Oxiacético/uso terapêutico , Animais , Benserazida/uso terapêutico , Encéfalo/metabolismo , Cromossomos Humanos Par 21/genética , Cobamidas/uso terapêutico , Cistationina beta-Sintase/antagonistas & inibidores , Cistationina beta-Sintase/genética , Modelos Animais de Doenças , Progressão da Doença , Dissulfiram/uso terapêutico , Síndrome de Down/genética , Inibidores Enzimáticos/uso terapêutico , Dosagem de Genes , Humanos , Sulfeto de Hidrogênio/metabolismo , Recém-Nascido , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/genética , Camundongos , Mitocôndrias/metabolismo , Ratos , Nitrito de Sódio/uso terapêutico , Especificidade da Espécie , Tiossulfatos/metabolismo
17.
J Psychopharmacol ; 33(11): 1395-1406, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31423939

RESUMO

PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are common, co-occurring developmental disorders and are frequently associated with sleep problems. This study aimed to assess the effectiveness and tolerability of agomelatine as a pharmacotherapy for sleep problems in ASD adults with ID. METHOD: A randomised, crossover, triple-blind, placebo-controlled clinical trial, with two three-month periods of treatment starting with either agomelatine or placebo and a washout period of two weeks. Ambulatory circadian monitoring (24 hours/7 days) evaluated total sleep time (TST) as the primary outcome variable. RESULTS: Participants (N=23; 35±12 years old; 83% male) had a median of three (interquartile range (IQR) 1-4) co-morbidities and were taking a median of five (IQR 2-7) prescribed drugs. Before agomelatine or placebo treatment, all subjects presented with insomnia symptoms, including sleep latency (100% abnormal, 55±23 minutes) or TST (55% abnormal, 449±177 minutes), and 66% had circadian rhythm sleep-wake abnormalities with rhythm phase advancements according to the M5 sleep phase marker values. During the three-month agomelatine treatment, night TST significantly increased by a mean of 83 minutes (16% abnormal, 532±121 minutes), together with a phase correction (M5 1:45±2:28 hours vs. 3:15±2:20 hours), improving sleep stability in wrist temperature rhythm (0.43±0.29 vs. 0.52±0.18 AU). Adverse events were mild and transient. CONCLUSIONS: Agomelatine was effective and well tolerated for treating insomnia and circadian rhythm sleep problems present in adults with ASD and ID.


Assuntos
Acetamidas/administração & dosagem , Transtorno do Espectro Autista/tratamento farmacológico , Hipnóticos e Sedativos/administração & dosagem , Deficiência Intelectual/tratamento farmacológico , Transtornos do Sono-Vigília/tratamento farmacológico , Acetamidas/efeitos adversos , Adulto , Transtorno do Espectro Autista/complicações , Ritmo Circadiano , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Deficiência Intelectual/complicações , Masculino , Pessoa de Meia-Idade , Transtornos do Sono-Vigília/etiologia , Fatores de Tempo , Adulto Jovem
18.
BMJ Open ; 9(7): e028125, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366646

RESUMO

OBJECTIVES: To describe factors associated with initiating antipsychotics and patterns of persistence to antipsychotic therapy in a large cohort of adults with intellectual and developmental disabilities. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Adults with intellectual and developmental disabilities (IDD) in Ontario. OUTCOME MEASURES: We used multivariable logistic regression to investigate patient characteristics associated with antipsychotic initiation. Patient characteristics studied included sociodemographic characteristics, measures of clinical comorbidity and health service use. RESULTS: Among 39 244 individuals eligible for this study, 6924 (17.6%) initiated an antipsychotic over the accrual window, of whom 1863 (26.9%) had no psychiatric diagnosis in the prior 2 years. A number of factors were significantly associated with antipsychotic initiation, including male gender, residence in a group home, prior use of benzodiazepines, antidepressants or cognitive enhancers, a recent emergency department visit or mental health hospitalisation and a visit to a psychiatrist or family physician in the prior 90 days. In a secondary analysis, the association between antipsychotic initiation and age, prior diagnosis of diabetes or myocardial infarction and polypharmacy differed slightly on the basis of whether an individual had a previously diagnosed psychiatric disorder. CONCLUSIONS: Factors associated with the initiation of an antipsychotic differ according to the presence of a psychiatric diagnosis. Given the long duration of antipsychotic use in this population, future research is needed to understand the appropriateness of antipsychotic initiation among adults with IDD and the safety implications of long-term use of these products.


Assuntos
Antipsicóticos/uso terapêutico , Deficiências do Desenvolvimento/tratamento farmacológico , Deficiências do Desenvolvimento/epidemiologia , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/epidemiologia , Transtornos Mentais/epidemiologia , Adolescente , Adulto , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Masculino , Transtornos Mentais/terapia , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Ontário/epidemiologia , Fatores de Proteção , Fatores de Risco , Adulto Jovem
19.
Pharm Res ; 36(9): 137, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332533

RESUMO

PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 µM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.


Assuntos
Di-Hidropiridinas/farmacologia , Reposicionamento de Medicamentos/métodos , Hiperventilação/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Canal de Potássio KCNQ1/antagonistas & inibidores , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Teorema de Bayes , Células CHO , Cricetulus , Di-Hidropiridinas/química , Facies , Células HEK293 , Humanos , Canal de Potássio KCNQ1/metabolismo , Aprendizado de Máquina , Bloqueadores dos Canais de Potássio/química , Bibliotecas de Moléculas Pequenas/química , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química
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