Andreea L. Seritan

Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers

OBJECTIVE The authors studied the lifetime prevalence of DSM-IV-TR psychiatric disorders in a population of adults with the fragile X premutation. METHOD The Structured Clinical Interview for DSM-IV was conducted, from 2007-2008, in 85 individuals with the fragile X premutation, 47 with the fragile X-associated tremor/ataxia syndrome (FXTAS; 33 male, 14 female; mean age = 66 years) and 38 without FXTAS (16 male, 22 female; mean age = 52 years). Lifetime prevalence for mood and anxiety disorders among carriers with and without FXTAS was compared to available age-specific population estimates from the National Comorbidity Survey Replication (NCS-R). RESULTS Among participants with FXTAS, 30 (65%) met lifetime DSM-IV-TR criteria for a mood disorder; 24 (52%) met lifetime DSM-IV-TR criteria for an anxiety disorder. Among the non-FXTAS participants, there were 15 instances of lifetime mood disorder (42%) and 18 of lifetime anxiety disorder (47%). When compared to age-specific NCS-R data, the lifetime prevalences of any mood disorder (P < .0001), major depressive disorder (P < .0001), any anxiety disorder (P < .0001), panic disorder (P = .006), specific phobia (P = .0003), and posttraumatic stress disorder (P = .004) were significantly higher in participants with FXTAS. The lifetime rates of social phobia in individuals with the premutation without FXTAS were significantly higher than NCS-R data (P = .001). CONCLUSIONS This sample of carriers of the fragile X premutation had a notably high lifetime risk of mood and anxiety disorders. Mood and anxiety disorders may be part of the clinical phenotype of the fragile X premutation conditions, especially in carriers with FXTAS. Clinicians encountering these patients are advised to consider FXTAS as a neuropsychiatric syndrome as well as a neurologic disorder.

Treatment of fragile X-associated tremor ataxia syndrome (FXTAS) and related neurological problems.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurological disorder that affects older adult carriers, predominantly males, of premutation alleles (55 to 200 CGG repeats) of the fragile X (FMR1) gene. Principal features of FXTAS are intention tremor, ataxia, parkinsonism, cognitive decline, and peripheral neuropathy; ancillary features include, autonomic dysfunction, and psychiatric symptoms of anxiety, depression, and disinhibition. Although controlled trials have not been carried out in individuals with FXTAS, there is a significant amount of anecdotal information regarding various treatment modalities. Moreover, there exists a great deal of evidence regarding the efficacy of various medications for treatment of other disorders (eg, Alzheimer disease) that have substantial phenotypic overlap with FXTAS. The current review summarizes what is currently known regarding the symptomatic treatment, or potential for treatment, of FXTAS.

Neuropathological, clinical and molecular pathology in female fragile X premutation carriers with and without FXTAS

Fragile X‐associated tremor/ataxia syndrome (FXTAS) is an adult‐onset neurodegenerative disorder associated with premutation alleles of the fragile X mental retardation 1 (FMR1) gene. Approximately 40% of older male premutation carriers, and a smaller proportion of females, are affected by FXTAS; due to the lower penetrance the characterization of the disorder in females is much less detailed. Core clinical features of FXTAS include intention tremor, cerebellar gait ataxia and frequently parkinsonism, autonomic dysfunction and cognitive deficits progressing to dementia in up to 50% of males.

Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): Comparison with Alzheimer's disease†

Neurocognitive deficits in fragile X‐associated tremor/ataxia syndrome (FXTAS) involve attentional control, working memory, executive functioning, and declarative and procedural learning. To date, no studies comparing FXTAS with other dementias have been done. We characterize the dementia in FXTAS, comparing it with Alzheimers disease. Retrospective chart review of 68 adults (50 men, 18 women) with FXTAS. 20 men with FXTAS dementia were matched by age, gender, and education to patients with mild Alzheimers dementia (AD). Neuropsychological measures were compared between the two groups: Boston Naming Test (BNT), phonemic fluency (Controlled Oral Word Association Test), digit span forward (DSF) and backward (DSB). Comparisons were based on analysis of covariance and t‐tests to assess significant differences between groups. 50% of men with FXTAS and no women were cognitively impaired. On mean scores of verbal fluency (22.83 in FXTAS vs. 28.83 in AD, P = 0.112), working memory (DSB, 4.80 in AD vs. 5.41 in FXTAS, P = 0.359), and language (BNT, 48.54 in AD vs. 54.20 in FXTAS, P = 0.089), there were no significant differences. Digit span forward, measuring attention, was significantly higher in subjects with FXTAS dementia (8.59, vs. 7.10 in AD, P = 0.010). Individuals with FXTAS have significant cognitive deficits, on the order of those in AD although the cognitive profiles in these dementias are not similar. Further research is needed to outline the neuropsychiatric profile in FXTAS and the correlation of genetic markers with the progression and severity of cognitive loss.

Self-reported anxiety, depressive, and vasomotor symptoms: a study of perimenopausal women presenting to a specialized midlife assessment center.

Objective: The aim of this study was to examine the association of vasomotor symptoms (VMS) with anxiety and/or depressive symptoms in perimenopausal women. Methods: A retrospective chart review of 487 women 40 to 64 years old seen during October 2004 to December 2006 in the Womens Midlife Assessment Program at the University of California, Davis, was performed. Of these, 395 women were included in the analysis: 58 (15%) were premenopausal, 199 (50%) were perimenopausal, and 138 (35%) were postmenopausal. VMS bothersomeness was represented by converting Likert-scale ratings for hot flashes and night sweats to scores and adding them into an overall score. Multiple logistic regression models were used to quantify the association of self-reported anxiety and/or depressive symptoms with VMS bothersomeness. Results: Thirty-one (53%) premenopausal, 131 (66%) perimenopausal, and 69 (50%) postmenopausal women reported anxiety and/or depressive symptoms. Perimenopausal and postmenopausal women reporting anxiety and/or depressive symptoms had significantly higher VMS bothersomeness scores (2.2 ± 1.7 and 2.2 ± 1.9, respectively) than did women who did not report these symptoms (1.7 ± 1.7 and 1.6 ± 1.7, respectively; both P values < 0.05). Women experiencing more bothersome VMS were significantly more likely to report anxiety and/or depressive symptoms (odds ratio, 1.5; P < 0.01). Perimenopausal women were significantly more likely to report anxiety and/or depressive symptoms than were postmenopausal women (odds ratio, 1.9; P < 0.01). Both associations remained significant after restricting the analyses to women not taking hormone therapy or psychotropics. Conclusions: VMS bothersomeness was associated with self-reported anxiety and/or depressive symptoms, showing the importance of screening for anxiety and mood changes during perimenopause.

Memantine for Fragile X-Associated Tremor/Ataxia Syndrome: A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE Memantine, an uncompetitive N-methyl-d-aspartate receptor antagonist, is currently approved by the US Food and Drug Administration for the treatment of moderate to severe Alzheimers disease. Anecdotal reports have suggested that memantine may improve neurologic and cognitive symptoms of individuals with the neurodegenerative disease fragile X-associated tremor/ataxia syndrome (FXTAS); however, its efficacy and safety in this population have not been assessed in a controlled trial. METHOD Individuals with FXTAS aged 34-80 years were enrolled in a randomized, double-blind, placebo-controlled, 1-year trial between September 2007 and August 2012. Inclusion required definite, probable, or possible FXTAS in clinical stages 1-5 according to previously published criteria. Primary outcome measures were the Behavioral Dyscontrol Scale (BDS) score and CATSYS intention tremor severity. RESULTS Ninety-four participants were randomized from 205 screened; of those, 43 and 45 started treatment with memantine (titrated to 10 mg twice daily) and placebo, respectively. Thirty-four participants receiving memantine and 36 receiving placebo completed the 1-year endpoint assessment (n = 70). Intention-to-treat analysis showed no improvement with respect to intention tremor severity (mean [SD] values with memantine vs placebo: 1.05 [0.73] vs 1.89 [2.19], P = .047) or BDS score (16.12 [5.43] vs 15.72 [3.93], P = .727) at follow-up. Post hoc analyses of participants with early FXTAS (stage ≤ 3), those with late FXTAS (stage > 3), and those in different age groups (≤ 65 years and > 65 years) also indicated no significant improvement. More frequent mild adverse events were observed in the placebo group, while more frequent moderate adverse events occurred in the memantine group (P = .007). CONCLUSION This randomized, double-blind, placebo-controlled trial of memantine for individuals with FXTAS showed no benefit compared to placebo with respect to the selected outcome measures. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00584948.

Clinician-Educator Tracks for Residents: Three Pilot Programs

ObjectiveOver the past 30 years, clinician-educators have become a prominent component of medical school faculties, yet few of these individuals received formal training for this role and their professional development lags behind other faculty. This article reviews three residency tracks designed to build skills in teaching, curriculum development and assessment, education research, and career development to meet this need.MethodsThe residency clinician educator tracks at University of Michigan, Baylor College of Medicine, and University of California Davis are described in detail, with particular attention to their common elements, unique features, resource needs, and graduate outcomes.ResultsCommon elements in the tracks are faculty mentorship, formal didactics, teaching opportunities, and an expectation of scholarly productivity. Essential resources include motivated faculty, departmental support, and a modest budget. Favorable outcomes include a high percentage of graduates in clinical faculty positions, teaching programs created by the residents, positive effects on recruitment, and enhancement of faculty identity as clinician educators.ConclusionClinician-educator tracks in residency present a viable means to address the training needs of clinical track faculty. The programs described in this article provide a model to assist other departments in developing similar programs.

Memantine Effects on Verbal Memory in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): a Double-Blind Brain Potential Study

Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer’s disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.

Ages of Onset of Mood and Anxiety Disorders in Fragile X Premutation Carriers

OBJECTIVE FMR1 premutation carriers of both genders have a high lifetime prevalence of anxiety and depressive disorders, however little is known regarding the onset ages of these conditions. This study compared onset ages of mood and anxiety disorders in premutation carriers with typical onset ages of the same disorders in the general population. METHODS Eighty-one premutation carriers (42% men; average age 62, SD 10) with and without FXTAS completed the Structured Clinical Interview for DSM-IV-TR. Onset ages of mood and anxiety disorders were compared to the corresponding typical population onset ages using the signed rank test. RESULTS Overall median onset ages of MDD (46 years old, p < 0.0001), panic disorder (40 years old, p = 0.0067), and specific phobia (11.5 years old, p = 0.0003) were significantly higher in premutation carriers compared to the general population. Median MDD onset ages in male carriers (52 years old) and those with FXTAS (49.5 years old) were significantly higher relative to the general population (median 32, both p < 0.0001). Tremor and ataxia emerged significantly later than MDD and the anxiety disorders studied. CONCLUSION Depressive and anxiety disorders in premutation carriers have a later onset compared to the general population, but precede the onset of motor symptoms. This may be due to progressive mRNA toxicity in the limbic system, white matter changes leading to neuronal dysconnectivity, and interaction with environmental factors. Psychosocial factors may be protective. Further research is needed to understand the full spectrum of psychiatric phenotypes in FMR1 premutation carriers.

Phenotypes of hypofrontality in older female fragile X premutation carriers.

To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X‐associated tremor/ataxia syndrome (FXTAS).