Benoit H. Mulsant

Anticholinergic Activity of 107 Medications Commonly Used by Older Adults

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug‐free serum was added to medication and atropine standard‐curve samples. For medications that showed detectable AA, average steady‐state peak plasma and serum concentrations (Cmax) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L‐hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above‐average Cmax values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

Age-related decline in white matter tract integrity and cognitive performance: a DTI tractography and structural equation modeling study.

Age-related decline in microstructural integrity of certain white matter tracts may explain cognitive decline associated with normal aging. Whole brain tractography and a clustering segmentation in 48 healthy individuals across the adult lifespan were used to examine: interhemispheric (corpus callosum), intrahemispheric association (cingulum, uncinate, arcuate, inferior longitudinal, inferior occipitofrontal), and projection (corticospinal) fibers. Principal components analysis reduced cognitive tests into 6 meaningful factors: (1) memory and executive function; (2) visuomotor dexterity; (3) motor speed; (4) attention and working memory; (5) set-shifting/flexibility; and (6) visuospatial construction. Using theory-based structural equation modeling, relationships among age, white matter tract integrity, and cognitive performance were investigated. Parsimonious model fit demonstrated relationships where decline in white matter integrity may explain age-related decline in cognitive performance: inferior longitudinal fasciculus (ILF) with visuomotor dexterity; the inferior occipitofrontal fasciculus with visuospatial construction; and posterior fibers (i.e., splenium) of the corpus callosum with memory and executive function. Our findings suggest that decline in the microstructural integrity of white matter fibers can account for cognitive decline in normal aging.

Diffusion tensor tractography findings in schizophrenia across the adult lifespan

In healthy adult individuals, late life is a dynamic time of change with respect to the microstructural integrity of white matter tracts. Yet, elderly individuals are generally excluded from diffusion tensor imaging studies in schizophrenia. Therefore, we examined microstructural integrity of frontotemporal and interhemispheric white matter tracts in schizophrenia across the adult lifespan. Diffusion tensor imaging data from 25 younger schizophrenic patients (< or = 55 years), 25 younger controls, 25 older schizophrenic patients (> or = 56 years) and 25 older controls were analysed. Patients with schizophrenia in each group were individually matched to controls. Whole-brain tractography and clustering segmentation were employed to isolate white matter tracts. Groups were compared using repeated measures analysis of variance with 12 within-group measures of fractional anisotropy: (left and right) uncinate fasciculus, arcuate fasciculus, inferior longitudinal fasciculus, inferior occipito-frontal fasciculus, cingulum bundle, and genu and splenium of the corpus callosum. For each white matter tract, fractional anisotropy was then regressed against age in patients and controls, and correlation coefficients compared. The main effect of group (F(3,92) = 12.2, P < 0.001), and group by tract interactions (F(26,832) = 1.68, P = 0.018) were evident for fractional anisotropy values. Younger patients had significantly lower fractional anisotropy than younger controls (Bonferroni-corrected alpha = 0.0042) in the left uncinate fasciculus (t(48) = 3.7, P = 0.001) and right cingulum bundle (t(48) = 3.6, P = 0.001), with considerable effect size, but the older groups did not differ. Schizophrenic patients did not demonstrate accelerated age-related decline compared with healthy controls in any white matter tract. To our knowledge, this is the first study to examine the microstructural integrity of frontotemporal white matter tracts across the adult lifespan in schizophrenia. The left uncinate fasciculus and right cingulum bundle are disrupted in younger chronic patients with schizophrenia compared with matched controls, suggesting that these white matter tracts are related to frontotemporal disconnectivity. The absence of accelerated age-related decline, or differences between older community-dwelling patients and controls, suggests that these patients may possess resilience to white matter disruption.

Defining treatment-resistant schizophrenia and response to antipsychotics: A review and recommendation

Treatment-resistant schizophrenia (TRS) has been defined mainly by severity of (positive) symptoms and response to antipsychotics derived from a relative change in the representative scales (most frequently ≥ 20% decrease in the Positive and Negative Syndrome Scale: PANSS), but these definitions have not necessarily been consistent. Integrating past evidence and real-world practicability, we propose that TRS be defined by at least two failed adequate trials with different antipsychotics (at chlorpromazine-equivalent doses of ≥ 600mg/day for ≥ 6 consecutive weeks) that could be retrospective or preferably include prospective failure to respond to one or more antipsychotic trials. In addition, our proposed criteria require both a score of ≥ 4 on the Clinical Global Impression (CGI)-Severity and a score of ≤ 49 on the Functional Assessment for Comprehensive Treatment of Schizophrenia (FACT-Sz) or ≤ 50 on the Global Assessment of Functioning (GAF) scales to define TRS. Once TRS is established, we propose that subsequent treatment response be defined based on a CGI-Change score of ≤ 2, a ≥ 20% decrease on the total PANSS or Brief Psychiatric Rating Scale (BPRS) scores, and an increase of ≥ 20 points on the FACT-Sz or GAF. While these suggestions provide a pragmatic framework for TRS classification, they need to be tested in future trials.

Nature and course of cognitive function in late-life schizophrenia: A systematic review

OBJECTIVES To systematically review the literature on the nature and course of cognition in late-life schizophrenia (LLS). METHODS We conducted a literature search using Medline. Search terms included schizophrenia, cognition, memory, and other cognitive search terms. We limited our search to age 45 and above. All titles or abstracts were read, and relevant papers were reviewed. Only cross-sectional studies with healthy control groups or longitudinal studies of cognition in LLS are presented in this review. RESULTS We identified 23 publications reporting on cross-sectional studies comparing cognition in subjects with LLS and healthy controls, and 19 publications reporting on cognitive changes during longitudinal follow-up. The cross-sectional reports suggest that patients with LLS are most consistently impaired in executive function, visuospatial ability, and verbal fluency. Impairment has less consistently been observed in memory, attention, and working memory. Longitudinal studies suggest that patients with LLS start to decline cognitively around the age of 65, and that this decline may first affect visuospatial abilities. However, most of these studies have been conducted in institutionalized patients, rather than the typical ambulatory population. Other limitations include small sample sizes, short follow-up periods, and lack of comprehensive neuropsychological assessments. CONCLUSIONS The existing literature suggests that the nature and course of cognition in LLS is heterogeneous. Larger and longer studies using both comprehensive and specific cognitive assessments are needed to understand the causes and consequences of this heterogeneity.

Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA:

[18F]-FEPPA binds to the 18-kDa translocator protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of the PET signal with new generation TSPO PET radioligands are confounded by large interindividual variability in binding affinity. This presents as a trimodal distribution, reflecting high-affinity binders (HABs), low-affinity binder (LAB), and mixed-affinity binders (MABs). Here, we show that one polymorphism (rs6971) located in exon 4 of the TSPO gene, which results in a nonconservative amino-acid substitution from alanine to threonine (Ala147Thr) in the TSPO protein, predicts [18F]-FEPPA total distribution volume in human brains. In addition, [18F]-FEPPA exhibits clearly different features in the shape of the time activity curves between genetic groups. Testing for the rs6971 polymorphism may allow quantitative interpretation of TSPO PET studies with new generation of TSPO PET radioligands.

The role of the corpus callosum in transcranial magnetic stimulation induced interhemispheric signal propagation.

BACKGROUND The corpus callosum, the main interhemispheric connection in the brain, may serve to preserve functional asymmetry between homologous cortical regions. METHODS To test this hypothesis, 30 healthy adult subjects underwent combined transcranial magnetic stimulation (TMS)-electroencephalography procedures. Nineteen of these subjects also completed diffusion tensor imaging and tractography procedures. We examined the relationship between microstructural integrity of subdivisions of the corpus callosum with TMS-induced interhemispheric signal propagation. RESULTS We found a significant inverse relationship between microstructural integrity of callosal motor fibers with TMS-induced interhemispheric signal propagation from left to right motor cortex. We also found a significant inverse relationship between microstructural integrity of genu fibers of the corpus callosum and TMS-induced interhemispheric signal propagation from left to right dorsolateral prefrontal cortex (DLPFC). We then demonstrated neuroanatomic specificity of these relationships. CONCLUSIONS Taken together, our findings suggest that TMS-induced interhemispheric signal propagation is transcallosally mediated and neuroanatomically specific and support a role for the corpus callosum in preservation of functional asymmetry between homologous cortical regions. Delineation of the relationship between corpus callosum microstructure and interhemispheric signal propagation in neuropsychiatric disorders, such as schizophrenia, may reveal novel mechanisms of pathophysiology.

Treatment resistant schizophrenia and response to antipsychotics: A review

BACKGROUND There remains a lack of agreement regarding criteria for treatment-resistant schizophrenia (TRS) and definition of response. METHOD A literature search was conducted to identify clinical studies of antipsychotics in TRS using PubMed, EMBASE and PsycINFO (last search 31 July 2011). Psychopharmacological studies with the number of participants of ≥ 40 were evaluated in terms of definitions for TRS and subsequent treatment response. RESULTS Thirty-three studies of antipsychotics in TRS were reviewed. TRS has been defined mainly by severity in symptoms. Many studies based TRS with at least 2 failed adequate antipsychotic trials (at chlorpromazine equivalent doses of ≥ 1000 mg/day for ≥ 6 weeks), but some studies adopted prospective treatment arm to be certain of sample refractoriness. Treatment response has been defined by a relative change in the representative scales (most commonly ≥ 20% decrease in the Positive and Negative Syndrome Scale), but it sometimes included the absolute criteria such as post-treatment score of ≤ 35 in the Brief Psychiatric Rating Scale or Clinical Global Impression-severity score of ≤ 3 (mild or less severe). Social functioning has not been a primary outcome measure in past pivotal trials, and other important domains of the illness such as cognition and subjective perspectives have not been incorporated into definitions of treatment resistance or response. However, adopting various assessment scales can be time-consuming and complicated, with an additional possibility of disagreement among raters. CONCLUSION Defining outcomes in schizophrenia is a challenging task. It is imperative that the field agrees on how this population is better defined and what constitutes treatment response.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

BACKGROUND Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Sensitivity of Older Patients to Antipsychotic Motor Side Effects: A PET Study Examining Potential Mechanisms

OBJECTIVE It is generally held that the elderly are more sensitive to motor side effects of antipsychotics, although the mechanisms for such an effect are not fully understood. The objective of this study was to examine whether this sensitivity is due to a central pharmacokinetic (i.e., higher occupancy for a given plasma level) or pharmacodynamic (i.e., greater functional effects for a given occupancy) effect. DESIGN Cross-sectional. SETTING Centre for Addiction and Mental Health, Toronto, Ontario, Canada. PARTICIPANTS Thirteen subjects aged 50 (mean +/- standard deviation age: 62 +/- 9 years) with schizophrenia or schizoaffective disorder who were receiving risperidone. MEASUREMENTS Dopamine D2 binding potential in the striatum, using [C]raclopride positron emission tomography scan. D2 receptor occupancy was calculated, using age-corrected measure from healthy individuals and region of interest analysis. RESULTS The authors observed the expected nonlinear relationship between total risperidone and 9-hydroxyrisperidone plasma level and striatal D2 receptor occupancy. The estimated plasma level of risperidone plus 9-hydroxyrisperidone associated with 50% maximal receptor occupancy was 7.3 ng/mL, which is similar to what has been reported in younger patients. However, extrapyramidal side effects (EPS) were observed in seven subjects at D2 occupancy of 34%-79%, occupancy levels that are lower than previously reported for younger patients in whom EPS are rare at occupancies lower than 80%. CONCLUSION The observation of greater functional effect (EPS in this case) for a given drug occupancy than the younger patients supports a pharmacodynamic mechanism for age-related antipsychotic drug sensitivity. This finding has important implications for dosing of antipsychotics in older patients with schizophrenia.