Advances in the Diagnosis and Management of Psychotic Symptoms in Neurodegenerative Diseases: A Narrative Review.

Background: Approximately 15% of older adults may experience psychotic phenomena. Primary psychiatric disorders that manifest with psychosis (delusions, hallucinations, and disorganized thought or behavior) account for less than half. Up to 60% of late-life psychotic symptoms are due to systemic medical or neurological conditions, particularly neurodegenerative diseases. A thorough medical workup including laboratory tests, additional procedures if indicated, and neuroimaging studies is recommended. This narrative review summarizes current evidence regarding the epidemiology and phenomenology of psychotic symptoms encountered as part of the neurodegenerative disease continuum (including prodromal and manifest stages). Results: Prodromes are constellations of symptoms that precede the onset of overt neurodegenerative syndromes. Prodromal psychotic features, particularly delusions, have been associated with an increased likelihood of receiving a neurodegenerative disease diagnosis within several years. Prompt prodrome recognition is crucial for early intervention. The management of psychosis associated with neurodegenerative diseases includes behavioral and somatic strategies, although evidence is scarce and mostly limited to case reports, case series, or expert consensus guidelines, with few randomized controlled trials. Conclusion: The complexity of psychotic manifestations warrants management by interprofessional teams that provide coordinated, integrated care.

Elevated Mood States in Patients With Parkinson's Disease Treated With Deep Brain Stimulation: Diagnosis and Management Strategies.

OBJECTIVE: Deep brain stimulation (DBS) is an effective surgical treatment for patients with Parkinson's disease (PD). DBS therapy, particularly with the subthalamic nucleus (STN) target, has been linked to rare psychiatric complications, including depression, impulsivity, irritability, and suicidality. Stimulation-induced elevated mood states can also occur. These episodes rarely meet DSM-5 criteria for mania or hypomania. METHODS: The investigators conducted a chart review of 82 patients with PD treated with DBS. RESULTS: Nine (11%) patients developed stimulation-induced elevated mood. Five illustrative cases are described (all males with STN DBS; mean age=62.2 years [SD=10.5], mean PD duration=8.6 years [SD=1.6]). Elevated mood states occurred during or shortly after programming changes, when more ventral contacts were used (typically in monopolar mode) and lasted minutes to months. Four patients experienced elevated mood at low amplitudes (1.0 V/1.0 mA); all had psychiatric risk factors (history of impulse-control disorder, dopamine dysregulation syndrome, substance use disorder, and/or bipolar diathesis) that likely contributed to mood destabilization. CONCLUSIONS: Preoperative DBS evaluations should include a thorough assessment of psychiatric risk factors. The term "stimulation-induced elevated mood states" is proposed to describe episodes of elevated, expansive, or irritable mood and psychomotor agitation that occur during or shortly after DBS programming changes and may be associated with increased goal-directed activity, impulsivity, grandiosity, pressured speech, flight of ideas, or decreased need for sleep and may persist beyond stimulation adjustments. This clinical phenomenon should be considered for inclusion in the bipolar disorder category in future DSM revisions, allowing for increased recognition and appropriate management.

Ages at Onset of Anxiety and Depressive Disorders in Parkinson's Disease.

OBJECTIVE: Parkinson's disease (PD) is a quintessential neuropsychiatric condition in which anxiety and depressive symptoms are common and may precede motor manifestations. The authors explored the ages at onset of anxiety and depressive disorders among patients with PD evaluated by psychiatrists at a deep brain stimulation center. METHODS: Psychiatric diagnoses and ages at onset were collected via clinical interviews. The ages at PD diagnosis were ascertained by chart review. Onset ages for anxiety and depressive disorders (overall and for specific disorders) were compared with patients' ages at PD diagnosis by using t tests. Onset ages for major depressive disorder (MDD), generalized anxiety disorder (GAD), and panic disorder were compared with typical onset ages in the general population by using the sign test. A total of 108 patients (66.7% men; age 63.7 years [SD=8.9]) were included in the analysis. RESULTS: Anxiety and depressive disorders occurred significantly earlier than PD diagnoses. Among patients whose anxiety and depression predated motor symptoms, the mean age at onset of anxiety disorders was 25.6 years earlier, and the mean age at onset of depressive disorders was 17.6 years earlier compared with the mean age at PD diagnosis (both p values <0.0001). Median onset ages for MDD (p<0.0001), GAD (p=0.0002), and panic disorder (p=0.0005) were significantly higher than typical median onset ages in the general population. CONCLUSIONS: These results may indicate that neurodegenerative changes are present in parts of the brainstem reticular core and limbic system before motor circuits are affected to a degree that causes motor symptoms. Psychiatrists should be mindful that onset of MDD, GAD, and panic disorder after age 45 might signal a neurodegenerative movement disorder such as PD.

Risk Factors for Cognitive Impairment in Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disease with motor, psychiatric, and cognitive manifestations that occurs in carriers of the fragile X mental retardation 1 ( FMR1) gene premutations. This was a retrospective chart review of 196 individuals (127 men and 69 women) with FXTAS. Forty-six (23%) participants were cognitively impaired, of whom 19 (10%) had dementia. Risk factors for dementia were examined (CGG repeat size; alcohol, benzodiazepine, and opioid use; diabetes; hyperlipidemia; hypertension; hypothyroidism; obesity; sleep apnea; surgeries with general anesthesia; depression; family history of dementia). Thirteen individuals with FXTAS and dementia were then compared to 13 cognitively intact individuals matched on age, gender, and FXTAS stage. CGG repeat size was significantly higher (mean = 98.5, standard deviation [SD] = 22.2) in the dementia group, compared to the cognitively intact group (mean = 81.6, SD = 11.5; P = .0256). These results show that CGG repeat size is a risk factor for FXTAS dementia.

From Industry to Generativity: The First 12 Years of the Association for Academic Psychiatry Master Educator Program.

OBJECTIVE: This study presents a mixed-methods evaluation of the first 12 years of the Association for Academic Psychiatry (AAP) Master Educator (ME) program, developed in 2003 to help academic psychiatrists hone their skills as educators. Participants attend two 3-h workshops at the annual meeting, organized in 3-year cycles, for a total of 18 h. Core topics include assessment, curriculum design, and program evaluation. METHODS: Overall session rating scores from 2003 to 2014 were analyzed using descriptive statistics. A 20-question survey was sent to 58 program graduates in October 2014, exploring participant perspectives on the impact of the ME program on their careers and on the educational programs they were affiliated with. Survey responses were analyzed quantitatively (for multiple choice questions) and qualitatively (for open-ended questions). RESULTS: The mean overall session scores ranged between 4.1 and 4.9 (on a Likert-type scale of 1-5) for each 3-year cycle. Twenty-nine graduates completed the survey (50 % response rate). Survey responses indicated a positive perception of the impact of the ME program on participants' careers. Most respondents noted improvement in their teaching methods and curriculum development skills and being able to link educational theory with their individual practices. There was a significant increase in perceived confidence, leadership, and further contributions to their educational milieu. Fifteen (52 %) participants also reported generative behaviors that directly impacted others, such as developing new programs, enhancing existing programs at their institutions, or contributing to national educational efforts. CONCLUSION: The AAP ME program has demonstrated significant benefit over its 12 years of existence. This program represents one strategy to sustain and grow an international community of like-minded educators working to develop their own and future generations' skills in providing high-quality education in psychiatry.

Psychiatric disorders among women with the fragile X premutation without children affected by fragile X syndrome.

Several studies have demonstrated increased rates of anxiety and depressive disorders among female carriers of the fragile X premutation. However, the majority of these studies focused on mothers of children with fragile X syndrome, who experience higher rates of parenting stress that may contribute to the emergence of these disorders. The present study compared psychiatric symptom presentation (utilizing measures of current symptoms and lifetime DSM-IV Axis I disorders) in 24 female carriers without affected children (mean age = 32.1 years) to 26 non-carrier women from the community (mean age = 30.5 years). We also examined the association between CGG repeat size (adjusted for X activation ratio) and mRNA, with severity of psychiatric symptoms. Women with the premutation reported significantly elevated symptoms of anxiety, depression, interpersonal sensitivity, obsessive-compulsiveness, and somatization relative to controls during the past week. Carriers had significantly higher rates of lifetime social phobia (42.3%) compared to controls (12.5%); however, this comparison did not remain significant after multiple comparison adjustment. Rates of other psychiatric disorders were not significantly elevated relative to controls, though it should be noted that lifetime rates among controls were much higher than previously published population estimates. Although the sample is relatively small, the study of this unique cohort suggests the premutation confers risk for mood and anxiety disorders independent of the stress of parenting children with FXS. Screening for psychiatric disorders in women with the premutation, even before they become parents, is important and highly encouraged. © 2016 Wiley Periodicals, Inc.

The office of student wellness: innovating to improve student mental health.

OBJECTIVE: Despite increasing mental health needs among medical students, few models for effective preventive student wellness programs exist. METHODS: This paper describes a novel approach developed at the University of California (UC) Davis School of Medicine: the Office of Student Wellness (OSW). RESULTS: Improved access and mental health service utilization have been documented, with over half of all students receiving support and clinical care. UC Davis student satisfaction mean scores on the Association of American Medical Colleges Graduation Questionnaire wellness questions have reached or exceeded national average over the last 4 years, since the OSW was founded. CONCLUSIONS: This program may serve as a blueprint for other medical schools in developing effective student wellness programs.

Phenotypes of hypofrontality in older female fragile X premutation carriers.

OBJECTIVE: 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). METHODS: Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years). RESULTS: Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, whereas only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P300 measures correlated with executive function and information processing speed. INTERPRETATION: The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.

Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): a brain potential study.

Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.

Helping psychiatry residents cope with patient suicide.

OBJECTIVE: Every clinical specialty has its own high risk patient challenges that threaten to undermine their trainees' professional identity, evolving sense of competence. In psychiatric training, it is patient suicide, an all-too frequently encountered consequence of severe mental illness that may leave the treating resident perplexed, guilt-ridden, and uncertain of their suitability for the profession. This study evaluates a patient suicide training program aimed at educating residents about patient suicide, common reactions, and steps to attenuate emotional distress while facilitating learning. METHODS: The intervention was selected aspects of a patient suicide educational program, "Collateral Damages,"-video vignettes, focused discussions, and a patient-based learning exercise. Pre- and post-survey results were compared to assess both knowledge and attitudes resulting from this educational program. Eight psychiatry residency training programs participated in the study, and 167 of a possible 240 trainees (response rate = 69.58 %) completed pre- and post-surveys. RESULTS: Knowledge of issues related to patient suicide increased after the program. Participants reported increased awareness of the common feelings physicians and trainees often experience after a patient suicide, of recommended "next" steps, available support systems, required documentation, and the role played by risk management. CONCLUSIONS: This patient suicide educational program increased awareness of issues related to patient suicide and shows promise as a useful and long overdue educational program in residency training. It will be useful to learn whether this program enhances patient care or coping with actual patient suicide. Similar programs might be useful for other specialties.

Online Mindfulness-Based Cognitive Therapy for People with Parkinson's Disease and Their Caregivers: a Pilot Study.

Anxiety and depression are common non-motor symptoms of Parkinson's disease (PD). Caregivers of people with PD may experience severe caregiver burden. This study explored the feasibility and potential benefits of an online mindfulness-based cognitive therapy (MBCT) intervention for improving anxiety and depressive symptoms in people with PD and their caregivers (ClinicalTrials.gov NCT04469049, 7/8/2020). People with PD or parkinsonism and anxiety and/or depressive symptoms and caregivers of people with PD participated in one of three online MBCT groups. Demographic variables, pre- and post-MBCT behavioral measures (GAD-7, PHQ-9, Five Facet Mindfulness Questionnaire - FFMQ-15, Caregiver Self-Assessment Questionnaire - CSAQ), and satisfaction surveys were collected. Descriptive statistics were used to summarize data. Pre- and post-MBCT behavioral scores were compared using mixed-effect models. Fifty-six potential participants were assessed for eligibility. Twenty-eight entered MBCT groups; all but one completed the intervention. The overall sample analyzed (22 people with PD, 4 caregivers) showed significant GAD-7 and PHQ-9 score reductions and FFMQ-15 total and observing and non-reactivity subscale score increases (all p's < 0.05). Participants with PD and anxiety symptoms (n = 14) had a significant GAD-7 score reduction; those with PD and depressive symptoms (n = 12) had a significant PHQ-9 score reduction (both p's < 0.05). Participants with PD also had a significant FFMQ-15 observing subscale score increase (p < 0.05). The caregiver sample was too small to be analyzed separately. Online MBCT is feasible (as measured by high attendance, completion rate, and participant satisfaction) and may be effective in improving anxiety and depressive symptoms in people with PD.

Abnormal N400 word repetition effects in fragile X-associated tremor/ataxia syndrome.

Fragile X-associated tremor/ataxia syndrome, a neurodegenerative disorder associated with premutation alleles (55-200 CGG repeats) of the FMR1 gene, affects many carriers in late-life. Patients with fragile X-associated tremor/ataxia syndrome typically have cerebellar ataxia, intranuclear inclusions in neurons and astrocytes, as well as cognitive impairment. Dementia can also be present with cognitive deficits that are as severe as in Alzheimer's disease, however frontosubcortical type impairment is more pronounced in fragile X-associated tremor/ataxia syndrome. We sought to characterize the P600 and N400 word repetition effects in patients with fragile X-associated tremor/ataxia syndrome, using an event-related potential word repetition paradigm with demonstrated sensitivity to very early Alzheimer's disease. We hypothesized that the fragile X-associated tremor/ataxia syndrome-affected participants with poor declarative verbal memory would have pronounced abnormalities in the P600 repetition effect. In the event-related potential experiment, subjects performed a category decision task whilst an electroencephalogram was recorded. Auditory category statements were each followed by an associated visual target word (50% 'congruous' category exemplars, 50% 'incongruous' nouns). Two-thirds of the stimuli (category statement-target word pairs) were repeated, either at short-lag (approximately 10-40 s) or long-lag (approximately 100-140 s). The N400 and P600 amplitude data were submitted to split-plot analyses of variance. These analyses of variance showed a highly significant reduction of the N400 repetition effect (F = 22.5, P < 0.001), but not of the P600 repetition effect, in mild fragile X-associated tremor/ataxia syndrome (n = 32, mean age = 68.7, mean Mini-Mental State Examination score = 26.8). Patients with fragile X-associated tremor/ataxia syndrome had significantly smaller late positive amplitude (550-800 ms post-stimulus onset) to congruous words (P = 0.04 for group effect). Reduced P600 repetition effect amplitude was associated with poorer recall within fragile X-associated tremor/ataxia syndrome patients (r = 0.66) and across all subjects (r = 0.52). Larger P600 amplitude to new congruous words also correlated significantly with higher free recall scores (r = 0.37, P < 0.01) across all subjects. We found a correlation between the amplitude of late positivity and CGG repeat length in those with fragile X-associated tremor/ataxia syndrome (r = 0.47, P = 0.006). Higher levels of FMR1 mRNA were associated with smaller N400s to incongruous words and larger positive amplitudes (between 300 and 500 ms) to congruous words. In conclusion, event-related potential word repetition effects appear sensitive to the cognitive dysfunction present in patients with mild fragile X-associated tremor/ataxia syndrome. Their more severe reduction in N400 repetition effect, than P600, is in contrast to the reverse pattern reported in amnestic mild cognitive impairment and incipient Alzheimer's disease (Olichney et al., 2008).