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Differential responses to donepezil treatment in patients with Alzheimer’s disease (AD) have been observed in clinical practice. It remains controversial whether, and to what extent, individual variation in the genes responsible for drug metabolism (CYP2D6) or those associated with AD pathogenesis (APOE) modulate the response to donepezil treatment. The aim of this study was to better understand the potential link between donepezil treatment response and CYP2D6 or APOE polymorphisms. We performed a meta-analysis based on data collected from 1266 donepezil-treated AD patients, and evaluated the association of CYP2D6 or APOE polymorphisms with treatment effectiveness. No significant difference was observed in the responder rate of donepezil treatment between the normal function CYP2D6 alleles group and the decreased/non-functional group [odds ratio (OR) 1.34, 95 % confidence interval (CI) 0.5–3.58; p = 0.56]. However, compared with the increased function CYP2D6 alleles group, the normal function group had a better response to donepezil treatment (OR 1.52, 95 % CI 1.14–2.03; p = 0.005). For the specific CYP2D6 single nucleotide polymorphism rs1080985, patients who carried the G allele had a significantly higher risk of poor response to donepezil treatment. After adjusting the data based on APOE genotype, it was observed that only individuals bearing both the APOE-ε4 allele and the rs1080985-G allele showed a significant increase in the frequency of treatment non-response (OR 1.73, 95 % CI 1.07–2.09; p = 0.03). No independent effect of APOE polymorphism on donepezil clinical responses was found (OR 1.08, 95 % CI 0.85–1.38; p = 0.53). Lastly, in a subgroup analysis based on ethnicity, all results remained consistent. The CYP2D6 genotype may be potentially effective for predicting the response to donepezil treatment in AD patients.

Background: Pervasive developmental disorders (PDDs) are severe psychiatric disorders characterized by impairment in social interactions, in verbal and non-verbal communication, and by restricted and stereotyped patterns of interest and behaviour, with onset in the first 3 years of life. The appropriate use of pharmacotherapy can improve some aberrant symptoms and behaviours and increase the person’s response to non-pharmacological interventions. Objective: To describe clinical outcomes, or symptom changes, and adverse effects during naturalistic treatment with aripiprazole monotherapy in children with PDDs and severe behavioural disorders (such as aggression against self and/or others, hostility, hyperactivity, severe impulsiveness). Method: This retrospective naturalistic study included 34 patients (23 males and 11 females, age range 4.5–15 years, mean age 10.2 ± 3.3 years), admitted during 2006–2007, diagnosed according to DSM-IV criteria and followed up for 4–12 months (mean 7.0 ± 3.6 months). Outcome measures were three global measures of clinical and functional impairment and improvement from baseline: the Clinical Global Impression-Severity (CGI-S) and CGI-Improvement (CGI-I) scales; the Children’s Global Assessment Scale (C-GAS); and the Childhood Autism Rating Scale (CARS), a specific measure of PDD symptoms. Results: The mean baseline CGI-S was 5.7 ± 0.8 (markedly ill/severely ill). The mean final dosage of aripiprazole was 8.1 ±4.9 mg/day. At the endpoint, 11 patients (32.4%) were ‘much improved’ or ‘very much improved’ (CGI-I score of 1 or 2), 12 patients (35.3%) were ‘minimally improved’ (CGI-I score of 3) and 10 (29.4%) were ‘unchanged’ or ‘worsened’ (CGI-I score of 4 or 5). C-GAS and CARS scores significantly improved (p <0.0001, effect sizes 0.59 and 0.62, respectively). Nine patients (26.5%) experienced moderate to severe agitation, which was associated with self-injurious behaviours in five of these patients, and five patients presented with sleep disorders. Twelve patients (35.3%) discontinued medication during the follow-up because of lack of efficacy or adverse effects. Conclusions: In these severely impaired children with PDDs, aripiprazole monotherapy was associated with a significant improvement in maladaptive behaviours in one-third of patients. Agitation and insomnia were the most frequent adverse effects. Further controlled studies in larger samples to explore possible predictors of efficacy are warranted.

Several disease-modifying agents (DMAs) are approved for the treatment of multiple sclerosis, including three interferon (IFN)-β products, glatiramer acetate and mitoxantrone. This article reviews the adverse event profiles of these DMAs based on the pivotal phase III trials, and provides practical guidelines for managing adverse effects. In general, the most common adverse events associated with IFNβ therapy are flu-like symptoms, including fever, chills and myalgias, and headache. The flu-like symptoms typically resolve within 24 hours and may be mitigated by over-the-counter anti-inflammatory agents. Adverse events related to glatiramer acetate therapy include injection-site reactions and a systemic reaction consisting of flushing, chest tightness, palpitation, anxiety or dyspnoea. The systemic reaction is transient (30 seconds to 30 minutes) and self-limited. Mitoxantrone may cause nausea, vomiting, alopecia, amenorrhoea and myelosuppression; isolated cases of acute leukaemia and dose-related cardiotoxicity have been reported in the literature. Longer-term tolerability data on mitoxantrone as a treatment for multiple sclerosis are needed. It is important for physicians to counsel patients on DMA-related adverse effects, most of which are transient and of mild-to-moderate severity. Various strategies that can be employed to prevent or manage these adverse effects and lessen their impact on the patient are discussed.

The evaluation and treatment of depression is an important component of the management of individuals with Parkinson’s disease. This review summarises current knowledge on the epidemiology, pathophysiology and treatment of depression in Parkinson’s disease. Limited information is available regarding the pathophysiology of depression in Parkinson’s disease and the effectiveness of treatment. Selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) are commonly used but more information is needed regarding their tolerability and antidepressant efficacy in patients with Parkinson’s disease, and their effect on motor function. Antidepressants can interact with selegiline (deprenyl) to cause the ‘serotonin syndrome’, although retrospective chart reviews indicate that this is rare. While several case reports have noted worsening parkinsonian motor features with SSRI use, open-label prospective studies have not substantiated these findings. Further double-blind, prospective studies would be valuable to further evaluate the tolerability and efficacy of antidepressants in Parkinson’s disease.

Opioid use disorder (OUD) is a significant health problem in the United States and many other countries. A combination of issues, most notably increased prescription of opioid analgesics, has resulted in climbing rates of opioid abuse and overdose over the last decade. This ongoing epidemic has produced a growing population of patients requiring treatment for OUD. Medications such as methadone and buprenorphine have well documented success rates in treating the disorder compared with placebo. However, significant percentages of the population still fail to maintain abstinence or reduce illicit opioid use while using such medications. Genetic variation may play a role in this variability in outcome through pharmacokinetic or pharmacodynamic effects on OUD medications, or by affecting the rate of negative side effects and adverse events. This review focuses on the existing literature on the pharmacogenetics of OUD treatment, with specific focus on medication metabolism, treatment outcomes, and adverse events.

Thyrotropin-releasing hormone (TRH; protirelin) is the smallest known peptide hormone. It has central effects, unrelated to its endocrine effects, via an action at the pituitary-thyroid axis. TRH has been used successfully to treat children with neurological disorders including intractable epilepsy. The effectiveness of TRH, and an analogue of the peptide (DN-1417), has been reported as both add-on and monotherapy in the treatment of progressive myoclonic epilepsy, West syndrome, Lennox-Gastaut syndrome, complex partial seizures, severe myoclonic epilepsy in infancy, and early infantile epileptic encephalopathy. No serious adverse effects have been reported. TRH may, thus, be considered to be a possible treatment for intractable epilepsy, especially for children with West syndrome and Lennox-Gastaut syndrome. However, it should be noted that the studies were not placebo-controlled or double-blind in design, and most were performed in Japan (the peptide has not been widely studied as a treatment for epilepsy in other countries). The relatively prolonged duration of action of TRH may indicate that the mechanism of its anticonvulsant action differs from that of other anticonvulsant drugs. It is likely that TRH contributes to the plasticity of the seizure network, in analogy to its known trophic effect on spinal motoneurons. Additional research is required to further elucidate the mechanism of action of TRH in children who have epilepsy that is refractory to conventional treatment, and further efforts should be made to develop more potent and selective TRH analogues for neurological disorders.

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice. It affects approximately 6% of persons over 65 years of age and is independently associated with a 4-to 5-fold higher risk of ischaemic stroke and a 2-fold higher risk of death. Randomized controlled trials have shown that treatment with adjusted-dose oral vitamin K antagonists (primarily warfarin with a target international normalized ratio [INR] of 2.0–3.0) reduces the relative risk of ischaemic stroke by two-thirds (an approximately 3% reduction in annual absolute risk), but is associated with a 0.2% excess annual absolute risk of intracranial haemorrhage (ICH). However, in ‘real world’ studies, the risk reductions in ischaemic stroke with warfarin have been significantly lower (25–50% relative risk reduction) than in selected trial samples. Moreover, more than 90% of patients enrolled in the sentinel trials were White/European. This raises the question of whether the beneficial results of warfarin can be extrapolated to persons of colour. Important differences in stroke risk profile and responsiveness to warfarin exist across racial/ethnic groups, such that one cannot assume a priori that there is a net benefit of warfarin therapy for AF patients of all racial/ethnic groups. Among patients with ischaemic stroke, AF is more likely to be implicated as the cause of stroke in the White population than in other racial/ethnic groups. Furthermore, AF may be a stronger predictor of ischaemic stroke among the White population than in Black or Hispanic/Latino populations. Approximately one-third of strokes in AF patients are noncardioembolic. Warfarin has been shown to be ineffective in preventing recurrent noncardioembolic strokes. Many persons of colour with AF have other risk factors that predispose them to noncardioembolic stroke, which may partially explain why warfarin has been reported to be less efficacious in preventing strokes in non-White patients with AF, even after adjustment for co-morbidities and anticoagulation monitoring. Notably, the background incidence of ICH is higher in Black, Hispanic and Asian patients than in White patients. Any greater than expected increases in bleeding secondary to anticoagulation may potentially offset any benefit gained from cardioembolic stroke reduction, although this has not been fully resolved. Finally, there are racial/ethnic differences in the prevalence of certain polymorphisms in genes that influence warfarin pharmacokinetics and pharmaco-dynamics (e.g. cytochrome P450 2C9 and vitamin K epoxide reductase). The Asian population generally appear to require the lowest daily dose of warfarin to maintain a given INR target, with the White population requiring an intermediate daily dose and the Black population requiring the highest daily dose. These differences must be taken into account when administering warfarin in order to minimize the risk of under-or over-anticoagulation. In summary, warfarin is highly effective in preventing ischaemic strokes in White patients with AF at a modestly higher risk of ICH. Whether the same net clinical benefit extends to persons of colour is unproven. Given the rapidly changing demographic nationally and internationally, additional research is needed to resolve this important question.

The pathophysiology of Alzheimer’s disease is complex and involves several different biochemical pathways. These include defective β-amyloid (Aβ) protein metabolism, abnormalities of glutamatergic, adrenergic, serotonergic and dopaminergic neurotransmission, and the potential involvement of inflammatory, oxidative and hormonal pathways. Consequently, these pathways are all potential targets for Alzheimer’s disease treatment and prevention strategies. Currently, the mainstay treatments for Alzheimer’s disease are the cholinesterase inhibitors, which increase the availability of acetylcholine at cholinergic synapses. Since the cholinesterase inhibitors confer only modest benefits, additional non-cholinergic Alzheimer’s disease therapies are urgently needed. Several non-cholinergic agents are currently under development for the treatment and/or prevention of Alzheimer’s disease. These include anti-amyloid strategies (e.g. immunisation, aggregation inhibitors, secretase inhibitors), transition metal chelators (e.g. clioquinol), growth factors, hormones (e.g. estradiol), herbs (e.g. Ginkgo biloba), nonsteroidal anti-inflammatory drugs (NSAIDs, e.g. indomethacin), antioxidants, lipid-lowering agents, antihypertensives, selective phosphodiesterase inhibitors, vitamins (E, B12, B6, folic acid) and agents that target neurotransmitter or neuropeptide alterations. Neurotransmitter receptor-based approaches include agents that modulate certain receptors (e.g. nicotinic, muscarinic, α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid [AMPA], γ-aminobutyric acid [GABA], N-methyl-D-aspartate [NMDA]) and agents that increase the availability of neurotransmitters (e.g. noradrenergic reuptake inhibitors). Of these strategies, the NMDA receptor antagonist memantine is in the most advanced stage of development in the US and is already approved in Europe as the first treatment for moderately severe to severe Alzheimer’s disease. Memantine is proposed to counteract cellular damage due to pathological activation of NMDA receptors by glutamate. Results with Ginkgo biloba have been mixed. Data for neurotrophic therapies and vitamin E (tocopherol) appear promising but require confirmation. NSAIDs and conjugated estrogens have not proven to be of value to date for the treatment of Alzheimer’s disease. Statins may have a potential role in reducing the risk or delaying the onset of Alzheimer’s disease, although this has yet to be confirmed in randomised trials. There are currently no data to support the use of statins as a treatment for dementia. This article provides an update on the current status of selected agents, focusing primarily on those agents with the most extensive clinical evidence at present.

Rối loạn trầm cảm và lo âu là những hình thức bệnh tâm thần rất phổ biến, được coi là rối loạn liên quan đến stress vì một số dạng sự kiện cuộc sống căng thẳng thường kích hoạt triệu chứng của chúng. Yếu tố giải phóng corticotropin (CRF) là một neuropeptide dài 41 axit amin tham gia vào việc trung gian hóa các phản ứng thần kinh nội tiết, tự động và hành vi đối với stress, và các nghiên cứu lâm sàng cung cấp bằng chứng cho vai trò của CRF trong sự phát triển của rối loạn trầm cảm và lo âu. Hai phân loại thụ thể CRF đã được xác định cho đến nay - thụ thể CRF1 và thụ thể CRF2. Các mô hình tiền lâm sàng cung cấp bằng chứng về vai trò của thụ thể CRF1 trong việc kích hoạt phản ứng stress. Dữ liệu từ những thí nghiệm này gợi ý rằng việc đối kháng hoạt động của thụ thể CRF1 có thể cung cấp một liệu pháp dược lý hiệu quả cho các rối loạn tâm thần liên quan đến stress. Bài tổng quan này làm nổi bật những tiến bộ đến nay trong việc phát triển các thuốc đối kháng thụ thể CRF1 như là liệu pháp dược lý tiềm năng cho rối loạn trầm cảm và lo âu. Mặc dù cần có thêm nghiên cứu để điều tra đầy đủ về hiệu quả và hồ sơ an toàn của các thuốc đối kháng thụ thể CRF1 như là các thuốc ứng viên cho những rối loạn này, nhưng kết quả từ các thí nghiệm tiền lâm sàng và các thử nghiệm lâm sàng là hứa hẹn. Việc phát triển thêm các hợp chất này là cần thiết.