The role of comorbid anxiety in exercise and depression trials: Secondary analysis of the SMILE-II randomized clinical trial.

OBJECTIVES: To explore the anxiolytic effects of a 4-month randomized, placebo-controlled trial of exercise and antidepressant medication in patients with major depressive disorder (MDD), and to examine the potential modifying effects of anxiety in treating depressive symptoms. MATERIALS AND METHODS: In this secondary analysis of the SMILE-II trial, 148 sedentary adults with MDD were randomized to: (a) supervised exercise, (b) home-based exercise, (c) sertraline, or (d) placebo control. Symptoms of state anxiety measured by the Spielberger Anxiety Inventory were examined before and after 4 months of treatment. Depressive symptoms were assessed by the Hamilton Depression Rating Scale (HAMD) and Beck Depression Inventory-II (BDI-II). Analyses were carried out using general linear models. RESULTS: Compared to placebo controls, the exercise and sertraline groups had lower state anxiety scores (standardized difference = 0.3 [95% CI = -0.6, -0.04]; p = 0.02) after treatment. Higher pretreatment state anxiety was associated with poorer depression outcomes in the active treatments compared to placebo controls for both the HAMD (p = .004) and BDI-II (p = .02). CONCLUSION: Aerobic exercise as well as sertraline reduced symptoms of state anxiety in patients with MDD. Higher levels of pretreatment anxiety attenuated the effects of the interventions on depressive symptoms, however, especially among exercisers. Patients with MDD with higher comorbid state anxiety appear to be less likely to benefit from exercise interventions in reducing depression and thus may require supplemental treatment with special attention to anxiety.

Donepezil Treatment in Patients With Depression and Cognitive Impairment on Stable Antidepressant Treatment: A Randomized Controlled Trial.

OBJECTIVE: Depression and cognitive impairment are often comorbid in older adults, but optimal treatment strategies remain unclear. In a two-site study, the efficacy and safety of add-on donepezil versus placebo were compared in depressed patients with cognitive impairment receiving stable antidepressant treatment. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in older adults with depression and cognitive impairment (https://clinicaltrials.gov/ct2/show/NCT01658228; NCT01658228). Patients received open-label antidepressant treatment for 16 weeks, initially with citalopram and then with venlafaxine, if needed, followed by random assignment to add-on donepezil 5-10 mg daily or placebo for another 62 weeks. Outcome measures were neuropsychological test performance (Alzheimer's Disease Assessment Scale-Cognitive subscale [ADAS-Cog] and Selective Reminding Test [SRT] total immediate recall) and instrumental activities of daily living (Functional Activities Questionnaire). RESULTS: Of 81 patients who signed informed consent, 79 patients completed the baseline evaluation. Open antidepressant treatment was associated with improvement in depression in 63.93% responders by week 16. In the randomized trial, there were no treatment group differences between donepezil and placebo on dementia conversion rates, ADAS-Cog, SRT total immediate recall, or FAQ. Neither baseline cognitive impairment severity nor apolipoprotein E e4 genotype influenced donepezil efficacy. Donepezil was associated with more adverse effects than placebo. CONCLUSION: The results do not support adjunctive off-label cholinesterase inhibitor treatment in patients with depression and cognitive impairment. The findings highlight the need to prioritize discovery of novel treatments for this highly prevalent population with comorbid illnesses.

Dissecting the gene dose-effects of the APOE ε4 and ε2 alleles on hippocampal volumes in aging and Alzheimer's disease.

OBJECTIVE: To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer's Disease (AD). MATERIALS AND METHODS: We analyzed MR and genetic data on 662 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database-198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects-looking for dose-dependent effects of the ε4 and ε2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model. RESULTS: There was a dose-dependent effect of the ε4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)-in both cases, each allele accounted for loss of >150 mm(3) (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen's d = -0.16 and -0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the ε2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume-an approximately 20% per allele volume increase as compared to CN with no ε2 alleles (Cohen's d = 0.23). CONCLUSION: Though no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging.