Glen L. Xiong

Pharmacological strategies for the prevention of Alzheimer’s disease

This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer’s disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual’s risk for developing Alzheimer’s disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 – 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer’s disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer’s disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer’s disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABAB antagonist), TCH 346 (apoptosis inhibitor), Alzhemed™, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug development. Reducing the complexity of prevention trials and gaining regulatory consensus of design is a high priority for the field.

Does meditation enhance cognition and brain plasticity

Meditation practices have various health benefits including the possibility of preserving cognition and preventing dementia. While the mechanisms remain investigational, studies show that meditation may affect multiple pathways that could play a role in brain aging and mental fitness. For example, meditation may reduce stress‐induced cortisol secretion and this could have neuroprotective effects potentially via elevating levels of brain derived neurotrophic factor (BDNF). Meditation may also potentially have beneficial effects on lipid profiles and lower oxidative stress, both of which could in turn reduce the risk for cerebrovascular disease and age‐related neurodegeneration. Further, meditation may potentially strengthen neuronal circuits and enhance cognitive reserve capacity. These are the theoretical bases for how meditation might enhance longevity and optimal health. Evidence to support a neuroprotective effect comes from cognitive, electroencephalogram (EEG), and structural neuroimaging studies. In one cross‐sectional study, meditation practitioners were found to have a lower age‐related decline in thickness of specific cortical regions. However, the enthusiasm must be balanced by the inconsistency and preliminary nature of existing studies as well as the fact that meditation comprises a heterogeneous group of practices. Key future challenges include the isolation of a potential common element in the different meditation modalities, replication of existing findings in larger randomized trials, determining the correct “dose,” studying whether findings from expert practitioners are generalizable to a wider population, and better control of the confounding genetic, dietary and lifestyle influences.

Bupropion for weight reduction

Bupropion is a norepinephrine and dopamine uptake inhibitor that has been available for several years for the treatment of depression and aiding smokers to quit. Although bupropion is not approved for treating obesity, three randomized clinical trials have shown some degree of efficacy for this drug in promoting weight loss in obese patients. The present drug profile provides a review of the pharmacology of bupropion, clinical evidence of efficacy with regard to weight reduction, tolerability and risks, and the current and future role of this drug in the management of obesity.

Transcultural Psychiatry Made Simple—Asynchronous Telepsychiatry as an Approach to Providing Culturally Relevant Care

OBJECTIVE To examine the feasibility and diagnostic reliability of asynchronous telepsychiatry (ATP) consultations in Spanish and ATP consultation with Spanish-to-English translation. SUBJECTS AND METHODS Twenty-four interviews of Spanish-speaking patients were videorecorded by a bilingual clinician who also collected patient history data and gave the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) to each patient. The ATP data (video of the interview and patient history) were forwarded for psychiatric consultation and a diagnostic assessment by the investigators. The ATP data were then examined separately by two Spanish-speaking psychiatrists, before being translated into English and then re-examined by two English-speaking psychiatrists. Agreement between the expert diagnoses of the investigators and the diagnoses from the Spanish consultations, the Spanish-to-English translated consultations, and the SCID-I results was assessed using kappa statistics. RESULTS We found acceptable levels of agreement for major diagnostic groupings among the Spanish- and English-speaking psychiatrists. Kappa values for diagnostic agreement between the expert and the translated consultations, the original language consultations, and the SCID-I were at least 0.52 (percentage agreement, 79%) and higher. CONCLUSIONS ATP consultations in Spanish, and those translated from Spanish to English, are feasible, and broad diagnostic reliability was achieved. The ATP process allows for rapid language translation. This approach could be useful across national boundaries and in numerous ethnic groups. Cross-language ATP may also offer significant benefits over the use of real-time interpreting services and has the potential to improve the quality of care by allowing for the addition of culturally relevant information.

VASCULAR RISK FACTORS AND COGNITIVE DECLINE AMONG ELDERLY MALE TWINS

Background: Studies investigating the association between cardiovascular risk factors and cognitive decline report discrepant outcomes. The co-twin control method improves on traditional case-control approaches by controlling for within-twin pair similarities of genetic and early environmental influences. Objective: To examine the association of diabetes, hypertension, hypercholesterolemia, and elevated body mass index (BMI) (>30 kg/m2), individually and combined, with cognitive decline over a 12-year period in members of the National Academy of Sciences-National Research Council Twin Registry of World War II male veterans. Methods: Modified Telephone Interview for Cognitive Status (TICS-m) was administered four times at approximately 4-year intervals from 1990 to 2002 as part of an epidemiologic study of dementia. Self-report medical information was collected from 1996 to 2002. We examined the difference in cognitive decline within twin pairs discordant for the vascular risk factors while controlling for baseline TICS-m, education, smoking, and alcohol history. Results: Among twin pairs discordant for diabetes (n = 177), the diabetic twins declined an average of almost 1 point more than their nondiabetic co-twins (p = 0.018) at the last screening time point. Further analyses showed that this was in large part due to greater decline among older men (age 76 to 84 years). Cognitive change was not significantly different between members of pairs discordant for hypertension (n = 326), hypercholesterolemia (n = 282), or elevated BMI (n = 166). Conclusion: Based on this study of twin pairs who share similar genetic and early environmental risks for cardiovascular risk factors, diabetes is associated with greater cognitive decline, particularly among the oldest individuals.

Health Status and Depression Remission in Patients with Chronic Heart Failure: Patient-Reported Outcomes from the SADHART-CHF Trial

Background—Depression is a common comorbidity in heart failure and is strongly associated with increased mortality, morbidity, and reduced health status. Whether depression treatment may result in improvement of health status in heart failure patients with comorbid depression remains unknown. Methods and Results—The Sertraline Against Depression and Heart Disease in Chronic Heart Failure study randomized 469 participants with chronic heart failure (left ventricular ejection fraction 45% and New York Heart Association class II) and major depressive disorder based on Diagnostic Statistics Manual fourth edition criteria to sertraline or placebo for 12 weeks. The Kansas City Cardiomyopathy Questionnaire, 36-Item Short-Form Health Survey, and 6-minute walk test were used to assess health status. Health status changes between treatment arms and remission status were evaluated adjusting for baseline variables and treatment assignment. The final Hamilton Depression Rating Scale scores were 3.50±2.08 and 12.97±4.33 in the remission and nonremission groups, respectively (P value=0.0001). Of 469 total participants, 378 (80.6%) completed the 6-minute walk test and 285 (70.1%) completed Kansas city cardiomyopathy questionnaire and 36-item short-form health survey, at baseline and at week 12. Depression remission was significantly associated with higher improvements in Kansas City Cardiomyopathy Questionnaire subscale scores (P<0.001) except on the Self-Efficacy (P=0.18) and Symptom Stability (P=0.91). On the 36-Item Short-Form Health Survey, depression remission was associated with significant improvement in subscales of the physical and mental component summary except the Pain Index (P=0.34). The 6-minute walk test improved more in depression remission compared with nonremission group (difference from baseline: 63.51±238.78 versus 16.24±115.70 m, P=0.03). Conclusions—Patients with heart failure whose depressive symptoms remitted had significantly greater improvement in physical function, social function, and quality of life.

Safety of Selective Serotonin Reuptake Inhibitor Use Prior to Coronary Artery Bypass Grafting

Selective serotonin reuptake inhibitors (SSRIs) have been shown to increase bleeding risks. This study examined the association of perioperative coronary artery bypass grafting (CABG) bleeding risks and SSRI use prior to CABG.

Statins and Cognition: What Can We Learn from Existing Randomized Trials?

BACKGROUND Statins are being developed as treatments for Alzheimers dementia based on evidence from preclinical and observational studies. However, cholesterol plays an integral role in cell membrane signal transduction and suboptimal cholesterol level could potentially impair neuronal function. Additionally, results of observational nonrandomized studies may have been affected by treatment bias. METHODS We performed a systematic literature review in MEDLINE from January 1966 to July 2004 and included published prospective, randomized, and placebo-controlled human studies that examined the cognitive effects of statins. RESULTS Nine studies with sample sizes ranging from 22 to 20,000 and duration of 3 weeks to 5 years, met criteria for review. Study populations and cognitive outcomes varied. Four studies were >6 months or longer. Overall, none of these studies reported finding a positive benefit for any statin on cognition in non-demented subjects although there was inconsistent evidence for acute cognitive worsening in some studies. CONCLUSION While statins intuitively have appeal for the prevention or treatment of dementia, any conclusions about their efficacy should await more definitive evidence from on-going prospective clinical trials.

Inflammation Markers and Major Depressive Disorder in Patients With Chronic Heart Failure: Results From the Sertraline Against Depression and Heart Disease in Chronic Heart Failure Study.

Background Major depressive disorder (MDD) and chronic heart failure (CHF) have in common heightening states of inflammation, manifested by elevated inflammation markers such as C-reactive protein. This study compared inflammatory biomarker profiles in patients with CHF and MDD to those without MDD. Methods The study recruited patients admitted to inpatient care for acute heart failure exacerbations, after psychiatric diagnostic interview. Patients with Beck Depression Inventory (BDI) scores lower than 10 and with no history of depression served as the nondepressed reference group (n = 25). MDD severity was defined as follows: mild (BDI 10-15; n = 48), moderate (BDI 16–23; n = 51), and severe (BDI ≥ 24; n = 33). A Bio-Plex assay measured 18 inflammation markers. Ordinal logistic models were used to examine the association of MDD severity and biomarker levels. Results Adjusting for age, sex, statin use, body mass index, left ventricular ejection fraction, tobacco use, and New York Heart Association class, the MDD overall group variable was significantly associated with elevated interleukin (IL)-2 (p = .019), IL-4 (p = .020), IL-6 (p = .026), interferon-&ggr; (p = .010), monocyte chemoattractant protein 1 (p = .002), macrophage inflammatory protein 1&bgr; (p = .003), and tumor necrosis factor &agr; (p = .004). MDD severity subgroups had a greater probability of elevated IL-6, IL-8, interferon-&ggr;, monocyte chemoattractant protein 1, macrophage inflammatory protein 1&bgr;, and tumor necrosis factor &agr; compared with nondepressed group. The nondepressed group had greater probability of elevated IL-17 (p < .001) and IL-1&bgr; (p < .01). Conclusions MDD in patients with CHF was associated with altered inflammation marker levels compared with patients with CHF who had no depression. Whether effective depression treatment will normalize the altered inflammation marker levels requires further study. Trial Registration: ClinicalTrials.gov NCT00078286.

Clozapine induced gastrointestinal hypomotility: A potentially life threatening adverse event. A review of the literature

OBJECTIVE The haematological and cardiac complications of clozapine have been well documented. Recent evidence from pharmacovigilance databases suggests that gastrointestinal (GI) complications are the leading cause of clozapine related deaths. This review aims to describe clinical features along with preventative and treatment options. METHOD A review of MEDLINE via PubMed searching for all articles published up to February of 2016. Inclusion criteria were articles that provided clinical or epidemiological information relating to the diagnosis, outcome, management or pathophysiology of clozapine related gastrointestinal disorders in humans. RESULTS Three large case series were identified with 104 cases, 20 of these reported clinical details. A further 52 cases reports were included. Median age was 40, with 79% being male, mean daily clozapine dose was 453 mg. Mortality was 38% with survivors being younger (39 vs. 42), on lower daily doses (400 mg vs. 532 mg), more likely to be female (32% vs. 6%). Four patients were re-challenged with clozapine following CIGH, two suffered a recurrence. CONCLUSION Risk factors for CIGH appear to be older age, male gender, patients in the first four months of treatment, co-prescription of constipating agents, higher daily dose of clozapine, and previous CIGH. Risk factors for death were older age and male gender. Patients receiving clozapine should be counselled about the dangers of constipation and to report new GI symptoms. Once severe CIGH has occurred clozapine should be halted and reviewed with bowel symptoms managed promptly. Re-challenging with clozapine may present substantial risks due to the severity of CIGH and a paucity of evidence. From the available evidence a treatment strategy has been proposed. Further prospective data regarding CIGH are needed to allow a better assessment of the scale of the problem with the development and testing of treatment strategies.