Lipopolysaccharide, Immune Biomarkers and Cerebral Amyloid-Beta Deposition in Older Adults With Mild Cognitive Impairment & Major Depressive Disorder.

OBJECTIVE: Inflammatory activation and increased immune response to lipopolysaccharide occur in both depression and cognitive decline and may link these two conditions. We investigated whether lipopolysaccharide (LPS), LPS binding protein (LBP) and peripheral biomarkers of immune response were associated with increased cerebral deposition of amyloid-beta (Abeta) in older adults with mild cognitive impairment (MCI) and remitted major depressive disorder (rMDD). DESIGN: Cross-sectional analysis. SETTING: Five academic health centers in Toronto. PARTICIPANTS: Older adults with MCI with/without rMDD. MEASUREMENTS: We investigated the associations among serum LPS, LBP, biomarkers of inflammatory activation - Interleukin-6 (IL-6), C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1), and cerebral Abeta deposition quantified by positron emission tomography. RESULTS: Among 133 study participants (82 with MCI and 51 with MCI+rMDD) there was no association between LPS (beta - 0.17, p = 0.8) or LBP (beta - 0.11, p = 0.12) and global deposition of Abeta following adjustment for age, gender, and APOE genotype in multivariable regression analyses. LBP was positively correlated with CRP (r = 0.5, p <0.001) and IL-6 (r = 0.2, p = 0.02) but no inflammatory biomarker was associated with Abeta deposition; rMDD was not associated with deposition of Abeta (beta -0.09, p = 0.22). CONCLUSION: In this cross-sectional analysis, we did not find an association among LPS/LBP, immune biomarkers or rMDD and global deposition of Abeta. Future analyses should assess the longitudinal relationships between peripheral and central biomarkers of immune activation, depression and cerebral Abeta deposition.

Antidepressant Augmentation versus Switch in Treatment-Resistant Geriatric Depression.

BACKGROUND: The benefits and risks of augmenting or switching antidepressants in older adults with treatment-resistant depression have not been extensively studied. METHODS: We conducted a two-step, open-label trial involving adults 60 years of age or older with treatment-resistant depression. In step 1, patients were randomly assigned in a 1:1:1 ratio to augmentation of existing antidepressant medication with aripiprazole, augmentation with bupropion, or a switch from existing antidepressant medication to bupropion. Patients who did not benefit from or were ineligible for step 1 were randomly assigned in step 2 in a 1:1 ratio to augmentation with lithium or a switch to nortriptyline. Each step lasted approximately 10 weeks. The primary outcome was the change from baseline in psychological well-being, assessed with the National Institutes of Health Toolbox Positive Affect and General Life Satisfaction subscales (population mean, 50; higher scores indicate greater well-being). A secondary outcome was remission of depression. RESULTS: In step 1, a total of 619 patients were enrolled; 211 were assigned to aripiprazole augmentation, 206 to bupropion augmentation, and 202 to a switch to bupropion. Well-being scores improved by 4.83 points, 4.33 points, and 2.04 points, respectively. The difference between the aripiprazole-augmentation group and the switch-to-bupropion group was 2.79 points (95% CI, 0.56 to 5.02; P = 0.014, with a prespecified threshold P value of 0.017); the between-group differences were not significant for aripiprazole augmentation versus bupropion augmentation or for bupropion augmentation versus a switch to bupropion. Remission occurred in 28.9% of patients in the aripiprazole-augmentation group, 28.2% in the bupropion-augmentation group, and 19.3% in the switch-to-bupropion group. The rate of falls was highest with bupropion augmentation. In step 2, a total of 248 patients were enrolled; 127 were assigned to lithium augmentation and 121 to a switch to nortriptyline. Well-being scores improved by 3.17 points and 2.18 points, respectively (difference, 0.99; 95% CI, -1.92 to 3.91). Remission occurred in 18.9% of patients in the lithium-augmentation group and 21.5% in the switch-to-nortriptyline group; rates of falling were similar in the two groups. CONCLUSIONS: In older adults with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole improved well-being significantly more over 10 weeks than a switch to bupropion and was associated with a numerically higher incidence of remission. Among patients in whom augmentation or a switch to bupropion failed, changes in well-being and the occurrence of remission with lithium augmentation or a switch to nortriptyline were similar. (Funded by the Patient-Centered Outcomes Research Institute; OPTIMUM ClinicalTrials.gov number, NCT02960763.).

Factors Associated With Initiation of Antidepressant Medication in Adults With Type 1 and Type 2 Diabetes: A Primary Care Retrospective Cohort Study in Ontario, Canada.

OBJECTIVES: Depression in patients with diabetes mellitus is common and associated with poorer outcomes. This study aims to identify demographic, socioeconomic and medical factors associated with the initiation of antidepressant medication after a diagnosis of diabetes in adult patients without a previous prescription for antidepressants. We also examined frequency of primary care visits in the year after antidepressant initiation compared with the year before treatment began. METHODS: This was a retrospective cohort study using routinely collected electronic medical record data spanning January 2011 to December 2019 from the University of Toronto Practice-based Research Network (UTOPIAN) Data Safe Haven. Our primary outcome was a first prescription for an antidepressant in patients with diabetes. We used a mixed-effects logistic regression model to identify sociodemographic and medical factors associated with this event. RESULTS: Among 22,750 patients with diabetes mellitus, 3,055 patients (13.4%) began taking an antidepressant medication. Increased odds of antidepressant initiation were observed in younger patients (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.39 to 2.26), females (OR, 1.60; 95% CI, 1.46 to 1.7), those receiving insulin treatment (OR, 1.59; 95% CI, 1.43 to 1.78) and cases of polypharmacy (OR, 3.67; 95% CI, 3.29 to 4.11). There was an increase in the mean number of primary care visits from 4.6 to 5.9 per year after antidepressant initiation. CONCLUSIONS: In patients with diabetes, age, sex and medical characteristics were associated with the initiation of antidepressants. These patients accessed primary care more frequently. Screening and prevention of depression, particularly in these subgroups, could reduce its personal and systemic burdens.

Sex-specific associations between lifetime diagnosis of bipolar disorder and cardiovascular disease: A cross-sectional analysis of 257,673 participants from the UK Biobank.

BACKGROUND: Sex is seldom considered as a potential moderator of the impact of bipolar disorder (BD) on cardiovascular disease (CVD) risk. We aimed to characterize the sex-specific association of CVD and BD using data from the UK Biobank. METHODS: In a cross-sectional analysis, we compared the odds ratio between women and men with BD for seven CVD diagnoses (coronary artery disease, myocardial infarction, angina, atrial fibrillation, heart failure, stroke, and essential hypertension) and four cardiovascular biomarkers (arterial stiffness index, low-density lipoprotein, C-reactive protein, and HbA1c) in 293 participants with BD and 257,380 psychiatrically healthy controls in the UK Biobank. RESULTS: After adjusting for age, we found a two- to three-fold stronger association among women than among men between BD and rates of coronary artery disease, heart failure, and essential hypertension, with a significant sex-by-diagnosis interactions. The association remained significant after controlling for self-reported race, education, income, and smoking status. After controlling for potential confounders, there was no significant association between sex and any cardiovascular biomarkers. LIMITATIONS: These analyses could not disentangle effects of BD from its treatment. CONCLUSIONS: Our results underscore the importance of incorporating sex and mental illness in risk estimation tools for CVD, and improving screening for, and timely treatment of, CVD in those with BD. Future research is needed to better understand the contributors and mechanisms of sex differences related to CVD risk in BD.

Atorvastatin lowers serum calcium levels in lithium-users: results from a randomized controlled trial.

BACKGROUND: Although lithium is considered the gold-standard treatment for bipolar disorder (BD), it is associated with a variety of major endocrine and metabolic side effects, including parathyroid hormone (PTH) dependent hypercalcemia. Aside from surgery and medication discontinuation, there are limited treatments for hypercalcemia. This paper will assess data from a randomized controlled trial (RCT). METHODS: This is a secondary analysis of an RCT that explored the effects of atorvastatin (n = 27) versus placebo (n = 33) on lithium-induced nephrogenic diabetes insipidus (NDI) in patients with BD and major depressive disorder (MDD) using lithium (n = 60), over a 12-week period. This secondary analysis will explore serum calcium levels and thyroid stimulating hormone (TSH) measured at baseline, week 4, and week 12. RESULTS: At 12-weeks follow-up while adjusting results for baseline, linear regression analyses found that corrected serum calcium levels were significantly lower in the treatment group (mean (M) = 2.30 mmol/L, standard deviation (SD) = 0.07) compared to the placebo group (M = 2.33 mmol/L, SD = 0.07) (ß = - 0.03 (95% C.I.; - 0.0662, - 0.0035), p = 0.03) for lithium users. There were no significant changes in TSH. CONCLUSION: In lithium users with relatively normal calcium levels, receiving atorvastatin was associated with a decrease in serum calcium levels. Although exciting, this is a preliminary finding that needs further investigation with hypercalcemic patients. Future RCTs could examine whether atorvastatin can treat PTH dependent hypercalcemia due to lithium and other causes.

Impact of standardizing care for agitation in dementia using an integrated care pathway on an inpatient geriatric psychiatry unit.

OBJECTIVES: This study examined the effectiveness of an integrated care pathway (ICP), including a medication algorithm, to treat agitation associated with dementia. DESIGN: Analyses of data (both prospective and retrospective) collected during routine clinical care. SETTING: Geriatric Psychiatry Inpatient Unit. PARTICIPANTS: Patients with agitation associated with dementia (n = 28) who were treated as part of the implementation of the ICP and those who received treatment-as-usual (TAU) (n = 28) on the same inpatient unit before the implementation of the ICP. Two control groups of patients without dementia treated on the same unit contemporaneously to the TAU (n = 17) and ICP groups (n = 36) were included to account for any secular trends. INTERVENTION: ICP. MEASUREMENTS: Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory Questionnaire (NPIQ), and assessment of motor symptoms were completed during the ICP implementation. Chart review was used to obtain length of inpatient stay and rates of psychotropic polypharmacy. RESULTS: Patients in the ICP group experienced a reduction in their scores on the CMAI and NPIQ and no changes in motor symptoms. Compared to the TAU group, the ICP group had a higher chance of an earlier discharge from hospital, a lower rate of psychotropic polypharmacy, and a lower chance of having a fall during hospital stay. In contrast, these outcomes did not differ between the two control groups. CONCLUSIONS: These preliminary results suggest that an ICP can be used effectively to treat agitation associated with dementia in inpatients. A larger randomized study is needed to confirm these results.

Technology-enabled collaborative care for youth with early psychosis: Results of a feasibility study to improve physical health behaviours.

AIM: Psychotic disorders are associated with excess morbidity and premature mortality. Contributing factors include tobacco smoking, low physical activity, and poor nutrition. This study tested a Technology-Enabled Collaborative Care model to improve health behaviours among youth with early psychosis. METHODS: A feasibility study among youth (ages 16-29) with early psychosis in Ontario, Canada. Participants were randomized to either a health coach supervised by a virtual care team (high intensity, n = 29), or self-directed learning (low intensity, n = 23) for 12 weeks. The primary outcome was participant engagement, defined as self-perceived benefit of changing health behaviours. Secondary outcomes were measures of health behaviours and programme-use metrics. RESULTS: Engagement was higher for high intensity participants for physical activity (adjusted group difference in change at 24 weeks = 3.4, CI95% = 1.9-4.9, p < .001) and nutrition (adjusted difference = 2.9, CI95% = 1.2-4.6, p = .001). No change was observed in health behaviours. Sixty two percent of participants completed 6 or more of the 12 weekly remote individualized health coaching sessions. Nine (39%) low intensity and 12 (41%) high intensity participants completed the final follow-up. CONCLUSIONS: Personalized health coaching for youth with psychosis is feasible and may have sustained benefits. However, retention with this population for 12 weeks is challenging.

Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.

OBJECTIVES: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study. DESIGN: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed. SETTING: Community-based multi-centered study based in Toronto across 5 academic sites. PARTICIPANTS: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls. MEASUREMENTS: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores. RESULTS: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD. CONCLUSIONS: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.

An update on antidepressant pharmacotherapy in late-life depression.

Introduction: Clinically important depressive symptoms that occur in adults over age 60 are often termed late-life depression (LLD). LLD poses challenges for treating clinicians in both detection and treatment. Antidepressants are the most common first-line treatment approach. Older adults are at an increased risk of adverse effects because of polypharmacy.Areas covered: This article summarizes the challenges and approaches when using pharmacotherapy in LLD with a focus on newer data that have become available during the last five years. While no new antidepressants have become available during this period, a review of the literature summarizes advances in the knowledge of the adverse effects associated with various antidepressants and on the potential contribution of pharmacogenetic tools when prescribing antidepressants to older patients.Expert opinion: During the past 5 years, most of the literature relevant to the pharmacotherapy of MDD in older patients has focused on adverse effects. In particular, the effects of antidepressants on cognition and bone are emerging as important areas for clinical attention and further investigation. There is also an emerging literature on the potential role of pharmacogenetic testing in patients with MDD, though recommendations for use in older adults await larger studies that demonstrate its efficacy and cost-effectiveness.

Predictors of change in suicidal ideation across treatment phases of major depressive disorder: analysis of the STAR*D data.

The effects of common antidepressants on suicidal ideation (SI) is unclear. In the landmark STAR*D trial antidepressants were effective for Major Depressive Disorder (MDD) in early treatment phases, but less effective in later phases. The effects of antidepressants on SI across the entire sample of the STAR*D trial has never been investigated. We performed a secondary analysis of the STAR*D data with the primary outcome of change in score on the suicide item (item three) of the Hamilton Rating Scale for Depression (HRSD17) across all four study levels. We used descriptive statistics and logistic regression analyses. Pearson correlation was used for change in SI versus change in depression (HRSD16). Reduction in mean (SD) SI was greater in levels one: 0.29 (±0.78) (p < 0.001) and two: 0.26 (±0.88) (p < 0.001) than in levels three: 0.16 (±0.92) (p = 0.005) and four: 0.18 (±0.93) (p = 0.094). A history of past suicide attempts (OR 1.72, p = 0.007), comorbid medical illness (OR 2.23, p = 0.005), and a family history of drug abuse (OR 1.69, p = 0.008) were correlated with worsening of SI across level one. Treatment with bupropion (OR 0.24, p < 0.001) or buspirone (OR 0.24, p = 0.001) were correlated with lowering of SI across level two. Improvement in SI was correlated with improvement in overall depression (HRSD16) at level one: r(3756) = 0.48; level two: r(1027) = 0.38; level three: r(249) = 0.31; and level four: r(75) = 0.42 (p < 0.001 for all levels). Improvement in SI is limited with pharmacotherapy in patients with treatment-resistant depression. Treatments with known anti-suicidal effects in MDD, such as ECT, should be considered in these patients.

Technology-enabled collaborative care for youth with early psychosis: A protocol for a feasibility study to improve physical health behaviours.

AIM: Individuals with psychotic disorders have poorer health outcomes and die earlier due to cardiovascular diseases when compared to healthy populations. Contributing factors include low levels of physical activity, poor nutrition and tobacco smoking. Currently, patients navigate a fragmented health-care system to seek physical and mental health services, often without access to evidence-based health promotion interventions, especially in non-academic settings or rural areas, increasing client barriers at the individual and provider level. To address these gaps, we wish to test the feasibility and impact of a Technology-Enabled Collaborative Care for Youth (TECC-Y) model to improve healthy behaviours among youth with early psychosis. The model addresses geographical barriers and maldistribution of physical and mental health care. METHODS: A randomized controlled trial, including youth (ages of 16-29) with early psychosis (diagnosed in the past 5 years) residing in Ontario, Canada. Our primary outcome is client engagement. Secondary outcomes include smoking status, physical health and nutrition. Participants are randomly assigned to either a health coach supervised by a virtual care team, or a self-directed learning group (e-platform with psychoeducational materials). Assessments are conducted at baseline, 6, 12 and 24 weeks. RESULTS: This paper presents the protocol of the study. Recruitment commenced in August 2018. This study was registered on 16 July 2018 on clinicaltrials.gov (Registry ID: NCT03610087). CONCLUSIONS: TECC-Y will determine if a technology-based collaborative care model engages youth with early psychosis, and whether this will be associated with changes in smoking, physical health and nutrition.

Prolactin and Estrogen Levels in Postmenopausal Women Receiving Aripiprazole Augmentation Treatment for Depression.

BACKGROUND: Antipsychotic drugs are well established to alter serum prolactin levels, often resulting in adverse effects including amenorrhea, galactorrhea, osteoporosis, and loss of libido. There is growing preclinical evidence that prolactin-elevating drugs can instigate the progression of precancerous lesions to breast cancer and that genes activated by prolactin are associated with the development and proliferation of breast cancer. Current guides advise a cautious approach (weighing risks and benefits) to the administration of prolactin-elevating antipsychotic drugs in women with a previously detected breast cancer. Aripiprazole is known to be a prolactin-sparing antipsychotic; however, data regarding its effects on prolactin and estrogens in postmenopausal women are lacking. METHODS: We examined serum hormone levels in n = 66 women who participated in a randomized, double-blind, placebo-controlled, multicenter trial of aripiprazole (high and low doses) added to an antidepressant in adults older than 60 years. Aripiprazole or placebo tablets were administered for 12 weeks as an augmentation strategy in venlafaxine-treated women. The primary outcomes were the difference in prolactin and estrogen levels. RESULTS: There was no significant effect of aripiprazole treatment on prolactin or estrogen levels, including in models that divided groups into low and high doses: prolactin (P = 0.075), estrone (P = 0.67), and estradiol (P = 0.96). CONCLUSIONS: Aripiprazole addition to an antidepressant did not alter serum estrogens or prolactin. These findings may be relevant in the treatment of some postmenopausal women with depression.

Contributions of cholinergic receptor muscarinic 1 and CYP1A2 gene variants on the effects of plasma ratio of clozapine/N-desmethylclozapine on working memory in schizophrenia.

BACKGROUND: Clozapine has heterogenous efficacy in enhancing working memory in schizophrenia. We have previously hypothesized that this is due to opposing effects of clozapine and its metabolite, N-desmethylclozapine, at the muscarinic M1 receptor and demonstrated that a lower clozapine/N-desmethylclozapine ratio is associated with better working memory than clozapine or N-desmethylclozapine levels alone. AIMS: In this study, we expanded the above hypothesis to explore whether genetic variation in the cholinergic receptor muscarinic 1 gene, encoding the M1 receptor, affects the relationship between clozapine/N-desmethylclozapine and working memory. Further, we explored whether CYP1A2 gene variants affect the ratio of clozapine/N-desmethylclozapine and by this, working memory performance. METHODS: We evaluated two functionally significant single nucleotide polymorphisms, rs1942499 and rs2075748, in cholinergic receptor muscarinic 1, with the haplotype T-A associated with lower transcriptional activity than the haplotype C-G. Further, we examined CYP1A2 *1F, with *1F/*1F conferring high inducibility in the presence of smoking. RESULTS: In a sample of 30 patients with schizophrenia on clozapine monotherapy, clozapine/N-desmethylclozapine was correlated with working memory only in non-carriers of the haplotype T-A of the cholinergic receptor muscarinic 1 gene. Interaction of CYP1A2 genotype and smoking status significantly affected clozapine concentrations, but there were no significant effects of CYP1A2 genotype and smoking status on the relationship between clozapine/N-desmethylclozapine on working memory. CONCLUSIONS: Our finding that the relationship between clozapine/N-desmethylclozapine and working memory is specific to patients with potentially higher transcription of M1 receptor (i.e. non-carriers of the haplotype T-A of cholinergic receptor muscarinic 1) supports a cholinergic mechanism underlying this relationship.

COVID-19 and persons with substance use disorders: Inequities and mitigation strategies.

The COVID-19 pandemic disproportionately disrupts the daily lives of marginalized populations. Persons with substance use disorders are a particularly vulnerable population because of their unique social and health care needs. They face significant harm from both the pandemic itself and its social and economic consequences, including marginalization in health care and social systems. Hence, we discuss: (1) why persons with substance use disorders are at increased risk for infection with COVID-19 and a severe illness course; (2) anticipated adverse consequences of COVID-19 in persons with substance use disorders; (3) challenges to health care delivery and substance use treatment programs during and after the COVID-19 pandemic; and (4) the potential impact on clinical research in substance use disorders. We offer recommendations for clinical, public health, and social policies to mitigate these challenges and to prevent negative outcomes.

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized.

OBJECTIVE: Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. METHODS: This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalence of falls and fall-related injuries). RESULTS: To date, 396 participants have been randomized. The authors report on four challenges: 1) engagement and recruitment; 2) increasing polypharmacy in older adults, resulting in potentially hazardous scenarios; 3) reporting adverse events and procedure standardization across sites; and 4) dissemination of results. CONCLUSION: Solutions to these challenges, including early inclusion of stake holders, will inform future pragmatic studies in older adults with depression.

Unilateral and bilateral repetitive transcranial magnetic stimulation for treatment-resistant late-life depression.

BACKGROUND: The management of late-life depression is challenged by high rates of treatment-resistance and adverse effects, along with medical comorbidities and polypharmacy. Together with the limited data on managing treatment-resistant depression in older adults, there is a need for investigating the efficacy of nonpharmacological treatment strategies. Repetitive transcranial magnetic stimulation (rTMS) is one modality that may better serve this patient population. METHODS: The present study examines data from two previous clinical trials (NCT00305045 and NCT01515215) to explore the efficacy of bilateral and unilateral high-frequency left-sided (HFL) rTMS in older adults suffering from treatment-resistant depression. A total of 43 adults aged 60 or older with a current major depressive episode were randomized to bilateral sequential, unilateral HFL, or sham. Bilateral sequential stimulation involved low-frequency (1 Hz) right dorsolateral prefrontal cortex (DLPFC) stimulation followed immediately by high-frequency (10 Hz) left DLPFC. The unilateral condition was HFL stimulation alone, and the placebo condition was either HFL or sequential bilateral form of sham. The primary outcome was remission of depression. RESULTS: Participants receiving bilateral rTMS experienced greater remission rates (40%) compared with unilateral (0%) or sham (0%) groups. Response to rTMS in the Hamilton Depression Rating Scale scores similarly favored the efficacy of bilateral rTMS. CONCLUSION: This study suggests that sequential bilateral treatment may be an optimal form of rTMS when used for treatment-resistant depression in older adults. Further large-scale comparative effectiveness trials of bilateral rTMS in this population are warranted.

Pharmacogenetic guidelines and decision support tools for depression treatment: application to late-life.

Late-life depression (LLD) is a major depressive disorder that affects someone after the age of 60 years. LLD is frequently associated with inadequate response and remission from antidepressants, in addition to polypharmacy. Pharmacogenetics offers a promising approach to improve clinical outcomes in LLD via new discoveries determining the genetic basis of response rates and side effects, as well as the development of tailored pharmacogenetic-based decision support tools. This invited review evaluates the LLD pharmacogenetic evidence base and the extent to which this was incorporated into existing commercial decision support tools and clinical pharmacogenetic guidelines.

Anticholinergic Burden and Cognition in Older Patients With Schizophrenia.

OBJECTIVE: Older individuals with schizophrenia are at risk of being treated with anticholinergic medications due to the prevalence of medical comorbidities and polypharmacy. High anticholinergic burden impairs cognition and is a risk factor for Alzheimer's dementia. Thus, we assessed the impact of anticholinergic burden on Alzheimer's dementia-related and schizophrenia-related cognitive functions in older patients with schizophrenia. METHODS: Anticholinergic burden was measured using the Anticholinergic Cognitive Burden scale (ACB) in 60 community-dwelling patients aged ≥ 50 years who met DSM-IV criteria for schizophrenia between May 2007 and November 2011. Cognitive domains affected early in the course of Alzheimer's dementia were assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) Alzheimer's Dementia Battery and the Repeatable Battery for the Assessment of Neuropsychological Status. Two CANTAB tests of executive function were used to assess deficits common in schizophrenia. Regression analyses were used to assess the relationships between anticholinergic burden and cognition. A receiver operating characteristic curve was constructed to determine an ACB cutoff score to identify those at risk of cognitive impairment. RESULTS: ACB scores were associated with spatial working (P = .04) and immediate (P = .004) memory and visuospatial ability (P = .02) and showed a trend toward association with impaired learning (P = .06), but were not associated with attention, executive function, language, or reaction time. An ACB cutoff score of ≤ 1.5 can detect cognitive impairment with a sensitivity of 90.3% and specificity of 48.3%. CONCLUSIONS: High anticholinergic burden contributes to specific cognitive deficits in older individuals with schizophrenia that resemble those commonly observed early in the course of Alzheimer's dementia. The ACB is a potentially useful screening tool that can help identify patients at risk of developing anticholinergic-related cognitive impairment.

Immunological biomarkers associated with brain structure and executive function in late-life depression: exploratory pilot study.

OBJECTIVE: Several immunological biomarkers are altered in late-life major depressive disorder (LLD). Immunological alterations could contribute to LLD's consequences, but little is known about the relations between specific immunological biomarkers and brain health in LLD. We performed an exploratory pilot study to identify, from several candidates, the specific immunological biomarkers related to important aspects of brain health that are altered in LLD (brain structure and executive function). METHODS: Adults (n = 31) were at least 60 years old and had major depressive disorder. A multiplex immunoassay assessed 13 immunological biomarkers, and we examined their associations with structural MRI (grey matter volume and white matter hyperintensity volume (WMH)) and executive function (Color-Word Interference and Trail-Making tests) measures. RESULTS: Vascular endothelial growth factor (VEGF) and the chemokine eotaxin had significant negative associations with grey matter volume (VEGF: n = 31, r = -0.65; eotaxin: n = 29, r = -0.44). Tumor necrosis factor alpha (TNF-α) had a significant positive relationship with WMHs (n = 30, r = 0.52); interferon-γ (IFN-γ) and macrophage inflammatory protein-1α (MIP-1α) were also significantly associated with WMHs (IFN-γ: n = 31, r = 0.48; MIP-1α: n = 29, r = 0.45). Only eotaxin was associated with executive function (set-shifting performance as measured with the Trail-making test: n = 33, r = -0.43). CONCLUSIONS: Immunological markers are associated with brain structure in LLD. We found the immunological correlates of grey and white matter differ. Prospective studies are needed to evaluate whether these immunological correlates of brain health increase the risk of LLD's consequences. Eotaxin, which correlated with both grey matter volume and set-shifting performance, may be particularly relevant to neurodegeneration and cognition in LLD. Copyright © 2016 John Wiley & Sons, Ltd.

The Impact of Sertraline Co-Administration on the Pharmacokinetics of Olanzapine: A Population Pharmacokinetic Analysis of the STOP-PD.

BACKGROUND AND OBJECTIVE: Clinical evidence and expert opinion support using a combination of an antipsychotic and an antidepressant when treating major depression with psychotic features. We characterized the impact of sertraline co-administration on olanzapine clearance in psychotic depression using population pharmacokinetic methods. METHODS: The Study of Pharmacotherapy for Psychotic Depression (STOP-PD) randomized 259 participants to olanzapine plus placebo or olanzapine plus sertraline. Olanzapine was started at 2.5-5 mg/day and sertraline at 25-50 mg/day. Doses were increased to a maximum of 20 mg/day for olanzapine and 200 mg/day for sertraline. Up to four olanzapine concentration samples were collected during the 12-week trial and 12-week continuation phase. We used NONMEM (Version VII) for population pharmacokinetic analysis, assessing effects of the covariates sex, African American origin, smoking, age, and sertraline co-administration. RESULTS: Population pharmacokinetic analysis comprised 336 samples from 175 individuals. The structural model published by Bigos et al. was sufficient to describe the olanzapine data adequately: a one-compartment model with first-order absorption and elimination, using an additive residual error structure with the absorption rate constant fixed to 0.5. Sertraline co-administration significantly increased olanzapine apparent clearance (p < 0.005) by 25-35 % depending on the patient characteristics included. Male sex was associated with a significantly increased clearance. Age and race did not have a significant impact on clearance. CONCLUSIONS: Contrary to expectations from the knowledge of cytochrome P450 interactions, sertraline increased olanzapine apparent clearance. Plausible explanations include patients treated with sertraline having poorer adherence to olanzapine, or the impact of sertraline inhibition of transporters resulting in increased intracellular concentrations and thus access to metabolizing enzymes.