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Background: The authors sought to examine the impact of the K-variant of butyrylcholinesterase (BCHE-K) carrier status on age-at-diagnosis of Alzheimer disease (AD) in APOE4 carriers. Methods: Patients aged 50–74 years with cerebrospinal fluid (CSF) biomarker-confirmed AD, were recruited to clinical trial (NCT03186989 since June 14, 2017). Baseline demographics, disease characteristics, and biomarkers were evaluated in 45 patients according to BCHE-K and APOE4 allelic status in this post-hoc study. Results: In APOE4 carriers (N = 33), the mean age-at-diagnosis of AD in BCHE-K carriers (n = 11) was 6.4 years earlier than in BCHE-K noncarriers (n = 22, P <.001, ANOVA). In APOE4 noncarriers (N = 12) there was no observed influence of BCHE-K. APOE4 carriers with BCHE-K also exhibited slightly higher amyloid and tau accumulations compared to BCHE-K noncarriers. A predominantly amyloid, limited tau, and limbic-amnestic phenotype was exemplified by APOE4 homozygotes with BCHE-K. In the overall population, multiple regression analyses demonstrated an association of amyloid accumulation with APOE4 carrier status (P <.029), larger total brain ventricle volume (P <.021), less synaptic injury (Ng, P <.001), and less tau pathophysiology (p-tau181, P <.005). In contrast, tau pathophysiology was associated with more neuroaxonal damage (NfL, P =.002), more synaptic injury (Ng, P <.001), and higher levels of glial activation (YKL-40, P =.01). Conclusion: These findings have implications for the genetic architecture of prognosis in early AD, not the genetics of susceptibility to AD. In patients with early AD aged less than 75 years, the mean age-at-diagnosis of AD in APOE4 carriers was reduced by over 6 years in BCHE-K carriers versus noncarriers. The functional status of glia may explain many of the effects of APOE4 and BCHE-K on the early AD phenotype. Trial registration: NCT03186989 since June 14, 2017 [ABSTRACT FROM AUTHOR]

Many patients with major depressive disorder (MDD) only partially respond, and some have no clinically meaningful response, to current widely used antidepressant drugs. Due to the purported role of dopamine in the pathophysiology of depression, triple-reuptake inhibitors (TRIs) that simultaneously inhibit serotonin (5-HT), norepinephrine (NE) and dopamine reuptake could be a useful addition to the armamentarium of treatments for MDD. A TRI should more effectively activate mesolimbic dopamine-related reward-networks, restore positive mood and reduce potent 5-HT reuptake blockade associated “hypodopaminergic” adverse effects of decreased libido, weight gain and “blunting” of emotions. On the other hand, dopaminergic effects raise concern over abuse liability and TRIs may have many of the cardiovascular effects associated with NET inhibition. Several clinical development programs for potential TRI antidepressants have failed to demonstrate significantly greater efficacy than placebo or standard of care. Successful late-stage clinical development of a TRI is more likely if experimental research studies in the target population of depressed patients have demonstrated target engagement that differentially and dose-dependently improves assessments of reward-network dysfunction relative to existing antidepressants. TRI treatment could be individualized on the basis of predictive markers such as the burden of decreased positive mood symptoms and/or neuroimaging evidence of reward network dysfunction. This review focuses on how the next generation of monoamine-based treatments could be efficiently developed to address unmet medical need in MDD. [ABSTRACT FROM AUTHOR]

Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits. [ABSTRACT FROM AUTHOR]

Restoration of positive mood, in addition to reducing negative mood, is an important treatment goal in the management of depression. The need to restore positive mood states in depressed patients is not adequately addressed by available treatments for major depressive disorder (MDD), suggesting that this mood dimension could be a useful target for drug development. However, for positive mood restoration to become a valid target for antidepressant drug development certain questions should be answered: are symptoms of decreased positive mood phenomenologically distinct from other symptoms of MDD? Should they be considered a distinct aspect of MDD in the diagnostic nomenclature? Is there evidence for differential responsiveness to treatment? Is the underlying pathophysiology understood and different from that of other MDD symptoms? Is low positive mood specific to depression or does it contribute to psychopathology in other disorders? Beyond these basic questions, this review identifies a number of design issues that need to be considered when conducting studies that target improving positive mood. These design issues include (1) what population to study, (2) what line of treatment to target, (3) the appropriateness and validation of methods and measures to evaluate positive mood and its restoration, (4) the role of functional outcome measures in determining success of the treatment, and (5) optimal designs for add-on therapy versus monotherapy agents. [ABSTRACT FROM AUTHOR]

Disease-specific assessments are not currently available for patients with Parkinson's disease dementia (PDD). This study evaluated the criterion-related validity and test-retest reliability of the Alzheimer's Disease Assessment scale cognitive subscale (ADAS-cog) in terms of sensitivity for differentiation between mild and moderate severity impairment in PDD. Six other dementia rating scales and cognitive tests were also examined. A total of 113 patients with PDD or Alzheimer disease were recruited into this 4-week, multicenter study, segregated into 2 severity groups based on Mini-Mental State Examination (MMSE) score. Mean ADAS-cog scores showed a statistically significant separation between mild and moderate severity patients in both dementias (P < .001). For the ADAS-cog, test-retest Spearman correlation coefficients were significant for each dementia type and severity. This study demonstrated the criterion-related validity and test-retest reliability for ADAS-cog in patients with PDD and strong correlations with MMSE. This supports the validity of previous results obtained with these measures in studies of patients with PDD. [ABSTRACT FROM AUTHOR]

The effects of rivastigmine versus placebo in Parkinson's disease dementia (PDD) patients with elevated or normal/low plasma homocysteine were determined. In this prospective analysis of a 24-week, randomly assigned, placebo-controlled study of rivastigmine in PDD, subpopulations comprised patients with plasma homocysteine ≥14 μmol/L (elevated) or <14 μmol/L (normal/low). Coprimary outcomes were the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Alzheimer Disease Cooperative Society-Clinical Global Impression of Change (ADCS-CGIC). Secondary outcomes included additional measures of cognition, including attention and executive function, daily function, and neuropsychiatric symptoms. Adverse events (AEs) were monitored. In total, 342 of 541 patients provided samples for analysis, from which 72% had elevated plasma homocysteine. Hyperhomocysteinemic patients showed treatment differences (rivastigmine vs. placebo) of 4.0 on ADAS-cog and 0.7 on ADCS-CGIC (both P < 0.01), and significant treatment differences on secondary outcomes. Rivastigmine- and placebo-treated hyperhomocysteinemic patients (16.5% and 14.6%) discontinued the study because of AEs. Patients with normal/low homocysteine showed no treatment differences on primary or secondary outcomes (1.4 on the ADAS-cog and 0.1 on ADCS-CGIC, both P = ns); 16.7% and 10.3% rivastigmine- and placebo-treated patients discontinued because of AEs. Elevated homocysteine was associated with greater rivastigmine treatment differences than normal/low homocysteine. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Parkinson's disease dementia (PDD) and Alzheimer's disease (AD) are both characterized by cognitive abnormalities, neuropsychiatric symptoms, and cholinergic deficits. We reviewed data from large, placebo-controlled clinical trials conducted with rivastigmine in patients with PDD and AD to evaluate similarities and differences in response to treatment. In placebo groups, AD patients appeared to show more rapid cognitive decline than those with PDD. Treatment effects (rivastigmine versus placebo) on cognitive performance over 6 months were quantitatively similar in both populations, but qualitatively different: in AD, cognitive abilities were stabilized by rivastigmine compared to declines in placebo groups, whereas in PDD symptomatic improvements above baseline drove treatment effects while placebo patients had limited change. On activities of daily living, stabilization (rather than improvement) was observed in both dementia types. A more aggressive course of placebo decline, and greater treatment differences (rivastigmine versus placebo), were seen in sub-populations of both PDD and AD patients with hallucinations at baseline. The safety and adverse event profiles were comparable in the two populations. In conclusion, the magnitude of effect with rivastigmine versus placebo is quantitatively comparable in patients with AD and PD, but the treatment effect tended to be one of stabilization in AD, while in PDD improvements over baseline were seen. In both populations, hallucinations may identify patients who are likely to be more treatment-responsive. [ABSTRACT FROM AUTHOR]

Rationale. Seasonal affective disorder (SAD) is a relatively common cyclical depressive illness characterized by seasonal depressions during winter. The disorder is commonly responsive to light therapy, but antidepressant drug efficacy has not been definitely established. Serotonin selective re-uptake inhibitors are potentially efficacious treatments for SAD. Objectives. The objective of this study was to evaluate the efficacy, tolerability and safety of sertraline treatment for SAD. Methods. One hundred and eighty seven outpatients with seasonal pattern recurrent winter depression (DSM-III-R defined) and a minimum 29-item Hamilton depression scale (SIGH-SAD version) score of 22 were randomized to 8 weeks treatment with either sertraline or placebo in a double-blind, multi-country, multi-center, parallel-group, flexible dose (50–200 mg once daily) study. Efficacy was investigated using physician and patient-rated scales measuring depression, anxiety and symptoms characteristic of seasonal affective disorder. Results. Sertraline produced a significantly greater response than placebo at endpoint as measured by changes in the 29-item and 21-item Hamilton depression scales, the clinical global impression (CGI) severity scale, the Hamilton anxiety scale, and the hospital anxiety and depression scale. The proportion of sertraline-treated subjects achieving a response on the CGI improvement rating (ratings of 1 or 2) at endpoint (last observation carried forward) was significantly greater than that of the placebo group. Overall sertraline was well tolerated with the most frequent placebo adjusted adverse events, being nausea, diarrhea, insomnia and dry mouth. Adverse events were mostly mild to moderate and transient. Conclusions. Sertraline pharmacotherapy has been demonstrated to be an effective and well-tolerated therapy for out patients with SAD. As such, sertraline offers an important pharmacological option in the clinical management of this condition. [ABSTRACT FROM AUTHOR]

Evaluates the efficacy, safety and tolerability of selective serotonin reuptake inhibitor, sertraline in the treatment of social phobia. Efficacy and tolerance of the drug in patients with symptoms of the illness; Comparison of the rate of response to sertraline to placebo-controlled studies; Evidence of the consistent improvement of the patients.

Abstract: Retrospective data are presented to support a spectrum of early Alzheimer’s disease (AD) along a continuum defined by gender and genotype. The putative neurodegenerative mechanisms driving distinct phenotypes at each end of the spectrum are glial hypoactivity associated with early failure of synaptic cholinergic neurotransmission and glial overactivation associated with loss of neural network connectivity due to accelerated age-related breakdown of myelin. In early AD, male butyrylcholinesterase K-variant carriers with one or two apolipoprotein ɛ4 alleles have prominent medial temporal atrophy, synaptic failure, cognitive decline, and accumulation of aggregated beta-amyloid peptide. Increasing synaptic acetylcholine in damaged but still functional cholinergic synapses improves cognitive symptoms, whereas increasing the ability of glia to support synapses and to clear beta-amyloid peptide might be disease-modifying. Conversely, chronic glial overactivation can also drive degenerative processes and in butyrylcholinesterase K-variant negative females generalized glial overactivation may be the main driver from mild cognitive impairment to AD. Females are more likely than males to have accelerated age-related myelin breakdown, more widespread white matter loss, loss of neural network connectivity, whole brain atrophy, and functional decline. Increasing extracellular acetylcholine levels blocks glial activation, reduces myelin loss and damage to neural network connectivity, and is disease-modifying. Between extremes characterized by gender, genotype, and age, pathophysiology may be mixed and this spectrum may explain much of the heterogeneity of amnestic mild cognitive impairment. Preservation of the functional integrity of the neural network may be an important component of strengthening cognitive reserve and significantly delaying the onset and progression of dementia, particularly in females. Prospective confirmation of these hypotheses is required. Implications for future research and therapeutic opportunities are discussed. [Copyright &y& Elsevier]