Apathy as a Treatment Target in Alzheimer's Disease: Implications for Clinical Trials.

Apathy is one of the most prevalent, stable and persistent neuropsychiatric symptom across the neurocognitive disorders spectrum. Recent advances in understanding of phenomenology, neurobiology and intervention trials highlight apathy as an important target for clinical intervention. We conducted a comprehensive review and critical evaluation of recent advances to determine the evidence-based suggestions for future trial designs. This review focused on 4 key areas: 1) pre-dementia states; 2) assessment; 3) mechanisms/biomarkers and 4) treatment/intervention efficacy. Considerable progress has been made in understanding apathy as a treatment target and appreciating pharmacological and non-pharmacological apathy treatment interventions. Areas requiring greater investigation include: diagnostic procedures, symptom measurement, understanding the biological mechanisms/biomarkers of apathy, and a well-formed approach to the development of treatment strategies. A better understanding of the subdomains and biological mechanisms of apathy will advance apathy as a treatment target for clinical trials.

Diagnostic criteria for apathy in neurocognitive disorders.

INTRODUCTION: Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed. METHODS: The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019. RESULTS: The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies. DISCUSSION: These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Electroconvulsive Therapy in a Patient With a Recent Subarachnoid Hemorrhage.

The safety of electroconvulsive therapy (ECT) is improving with advances in anesthesia and ECT technique. There are published case reports of successful treatment of depression in patients who were once considered at high medical risk. Recent cerebral hemorrhage is one of the conditions considered to significantly increase the risk of ECT treatment. Literature search did not indicate any case reports of ECT treatment in patients with recent subarachnoid hemorrhage. We report the successful ECT treatment of depression in an older man who had developed a subarachnoid hemorrhage after a suicide attempt by ingestion of antifreeze.

Varenicline and P50 auditory gating in medicated schizophrenic patients: a pilot study.

Most schizophrenic patients have a deficit in auditory sensory gating that appears to be mediated by the alpha-7 nicotinic receptor. This pilot study examines the effects of varenicline, an alpha-7 agonist, on the P50 auditory evoked potential in six schizophrenic patients. The study was canceled because of concerning side effects consistent with those reported by the FDA. However, in this small group of subjects, varenicline did not consistently enhance P50 auditory gating.

Sensitivity and specificity of the Beck Depression Inventory-II in persons with traumatic brain injury.

OBJECTIVES: Our objective was to examine the Beck Depression Inventory-II (BDI-II) in a traumatic brain injury (TBI) sample using a receiver operating characteristic (ROC) curve to determine how well the BDI-II identifies depression. An ROC curve allows for analysis of the sensitivity and specificity of a diagnostic test using various cutoff points to determine the number of true positives, true negatives, false positives, and false negatives. DESIGN: This was a secondary analysis of data gathered from an observational study. We examined BDI-II scores in a sample of 52 veterans with remote histories of TBI. SETTING: This study was completed at a Veterans Affairs (VA) Medical Center. PARTICIPANTS: Participants were veterans eligible to receive VA health care services. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Outcome measures included the BDI-II and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IV). RESULTS: We generated an ROC curve to determine how well the BDI-II identifies depression using the SCID-IV as the criterion standard for diagnosing depression, defined here as a diagnosis of major depressive disorder. Results indicated a cutoff score of at least 19 if one has a mild TBI or at least 35 if one has a moderate or severe TBI. These scores maximize sensitivity (87%) and specificity (79%). CONCLUSIONS: Clinicians working with persons with TBI can use the BDI-II to determine whether depressive symptoms warrant further assessment.

An exploratory study of neuroimaging, neurologic, and neuropsychological findings in veterans with traumatic brain injury and/or posttraumatic stress disorder.

Seventy-two veterans with traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), or both participated in assessment procedures to evaluate between group differences. Half the sample was randomly selected for magnetic resonance imaging (MRI). Neurologic examinations were conducted using the Neurologic Rating Scale (NRS). Neuropsychological measures included the Paced Auditory Serial Addition Test (PASAT), Rey Auditory Verbal Learning Test (RAVLT), Conners' Continuous Performance Test II (CPT II), and Halstead Impairment Index (HII) including the Booklet Category Test (BCT). Data were analyzed using linear regression. Participants with moderate/ severe TBI were significantly more likely to have trauma-related imaging findings, and more severe TBI predicted lower scores on the NRS. No significant between-group differences were identified on the HII, PASAT, RAVLT, or CPT II. TBI group performance was significantly better on the BCT. More severe TBI predicted abnormal imaging findings and lower NRS scores. Hypothesized between-group differences on neuropsychological measures were not supported.

Utility of the trauma symptom inventory for the assessment of post-traumatic stress symptoms in veterans with a history of psychological trauma and/or brain injury.

Correspondence of three core Trauma Symptom Inventory (TSI) posttraumatic stress disorder (PTSD) scales (Intrusive Experiences, Defensive Avoidance, and Anxious Arousal) and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-IV) PTSD module were examined among 72 veterans with traumatic brain injury (TBI), PTSD, or both conditions. Subjects were classified into PTSD only, TBI only, or co-occurring PTSD and TBI groups based on TBI assessment and SCID-IV PTSD diagnosis. Linear regression was used to model TSI T-Scores as a function of group. Scores on all three scales significantly differed between the TBI and PTSD groups (PTSD only and co-occurring PTSD and TBI) in the expected direction. Study findings indicate that despite the potential overlap of symptoms between PTSD and TBI, the TSI appears to be a useful measure of trauma-related symptoms in veterans who may also have a TBI, particularly mild TBI. Limitations and areas for future research are discussed.

Suicide among incarcerated veterans.

Both veterans and jail/prison inmates face an increased risk of suicide. The incarcerated veteran sits at the intersection of these two groups, yet little is known about this subpopulation, particularly its risk of suicide. A Pubmed/Medline/PsycINFO search anchored to incarcerated veteran suicide, veteran suicide, suicide in jails/prisons, and veterans incarcerated from 2000 to the present was performed. The currently available literature does not reveal the suicide risk of incarcerated veterans, nor does it enable meaningful estimates. However, striking similarities and overlapping characteristics link the data on veteran suicide, inmate suicide, and incarcerated veterans, suggesting that the veteran in jail or prison faces a level of suicide risk beyond that conferred by either veteran status or incarceration alone. There is a clear need for a better characterization of the incarcerated veteran population and the suicide rate faced by this group. Implications for clinical practice and future research are offered.

Psychiatric hospitalization and veterans with traumatic brain injury: a retrospective study.

OBJECTIVE: To determine risk factors for psychiatric hospitalization after traumatic brain injury (TBI) in veterans. SUBJECTS AND PROCEDURES: Medical records of 96 veterans with histories of TBI (17 mild, 33 moderate, and 46 severe) were reviewed for information concerning psychiatric history, including hospitalization and substance misuse. RESULTS: Subjects with a history of problematic drug and alcohol use had a significantly higher probability of psychiatric hospitalization than those without such a history. Gender, age, problematic alcohol use without problematic drug use, injury severity, time since injury, years of follow-up, and a history of psychiatric symptoms (including those attributed to general medical conditions) were not identified as significant risk factors. Ninety-one veterans (95%) had a history of psychiatric difficulty. In addition, the probability of post-TBI problematic drug and alcohol use, given a pre-TBI history of such use, was significantly higher than the probability given no history. CONCLUSIONS: Veterans with problematic drug and alcohol use are at increased risk for psychiatric hospitalization after TBI. In addition, the likelihood of problematic post-TBI drug and alcohol use was significantly greater for those with a preinjury history. Ninety-five percent of veterans in the current sample endorsed lifetime histories of psychiatric difficulty. These findings highlight the need for evidence-based means of psychiatric and/or substance abuse treatment of those with a history of TBI.

A review of "suicidal intent" within the existing suicide literature.

The results of a systematic literature review that investigated suicide intent are presented. Of the 44 relevant articles identified, 17 investigated the relationships between various suicide risk factors and suicide intent and 25 publications investigated the relationships between suicide intent and various suicide outcomes. Despite recent advancements in the definition and nomological validity of suicide intent, a high degree of variability in the empirical measurement and analysis of suicide intent was found. Such variability limits future research related to measuring suicidal risk and outcomes, reporting suicide intent, or the meaningful comparison of diagnostic approaches or treatments across multiple studies.

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

A normative zone of RPE ratings for use during graded exercise testing.

The purposes of this investigation were to identify a zone of normality for ratings of perceived exertion (RPE) and to compare the RPE responses in patients with coronary artery disease to this zone. The zone was generated from RPE estimated during the last minute of each stage of a Bruce treadmill test in 44 normal adult men. RPE were regressed against the corresponding MET level for each exercise stage. The zone was established as the 95% confidence interval (CI) spanning the average RPE vs MET regression line. RPE estimated during the last 1.0 min. of a Bruce or Modified Balke treadmill test administered to adult men (n=37) with coronary artery disease were compared to the 95% CI zone. A total of 19 (51%) of the coronary artery disease patients estimated RPE during a progressively incremented treadmill test that were above the zone, indicating a comparatively greater than normal perception of strain for a given metabolic stress. The presently generated zone provides a practical use of RPE in the interpretation of clinical exercise tests.

Elevated Plasma Aß42 in Cognitively Impaired Individuals Taking ACE Inhibitor Antihypertensives.

BACKGROUND/RATIONALE: Accumulating evidence suggests that the use of angiotensin-converting enzyme inhibitor (ACE-I) medication protects against cognitive decline in the elderly patients. We investigated whether ACE-I use was associated with higher plasma levels of amyloid-ß (Aß), possibly indicating improved Aß clearance from brain to blood. METHODS: We measured and compared plasma concentrations of Aß42, Aß40, and creatinine in cognitively impaired individuals with amnestic mild cognitive impairment, probable Alzheimer's disease (AD) dementia, and mixed probable AD/vascular dementia. RESULTS: Plasma Aß42 levels and Aß42/Aß40 ratios of participants taking ACE-Is (n = 11) significantly exceeded ( t = 3.1, df = 19, P = .006; U = 24, P = .029, respectively) those not taking ACE-Is (n = 10). CONCLUSIONS: This study is the first to show an association between ACE-I use and increased plasma Aß42 level and Aß42/Aß40 ratio in cognitively impaired individuals. Future investigations should assess whether a possible ACE-I-induced increase in plasma Aß42 indicates improved Aß42 clearance from brain that contributes to protection from cognitive decline.

Baseline neurocognitive deficits in the CATIE schizophrenia trial.

Neurocognition is moderately to severely impaired in patients with schizophrenia. However, the factor structure of the various neurocognitive deficits, the relationship with symptoms and other variables, and the minimum amount of testing required to determine an adequate composite score has not been determined in typical patients with schizophrenia. An 'all-comer' approach to cognition is needed, as provided by the baseline assessment of an unprecedented number of patients in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial. From academic sites and treatment providers representative of the community, 1493 patients with chronic schizophrenia were entered into the study, including those with medical comorbidity and substance abuse. Eleven neurocognitive tests were administered, resulting in 24 individual scores reduced to nine neurocognitive outcome measures, five domain scores and a composite score. Despite minimal screening procedures, 91.2% of patients provided meaningful neurocognitive data. Exploratory principal components analysis yielded one factor accounting for 45% of the test variance. Confirmatory factor analysis showed that a single-factor model comprised of five domain scores was the best fit. The correlations among the factors were medium to high, and scores on individual factors were very highly correlated with the single composite score. Neurocognitive deficits were modestly correlated with negative symptom severity (r=0.13-0.27), but correlations with positive symptom severity were near zero (r<0.08). Even in an 'all-comer' clinical trial, neurocognitive deficits can be assessed in the overwhelming majority of patients, and the severity of impairment is similar to meta-analytic estimates. Multiple analyses suggested that a broad cognitive deficit characterizes this sample. These deficits are modestly related to negative symptoms and essentially independent of positive symptom severity.

Improved p50 auditory gating with ondansetron in medicated schizophrenia patients.

OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the alpha-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.

M50 sensory gating predicts negative symptoms in schizophrenia.

Impaired auditory sensory gating is considered characteristic of schizophrenia and a marker of the information processing deficit inherent to that disorder. Predominance of negative symptoms also reflects the degree of deficit in schizophrenia and is associated with poorer pre-morbid functioning, lower IQ, and poorer outcomes. However, a consistent relationship between auditory sensory gating and negative symptoms in schizophrenia has yet to be demonstrated. The absence of such a finding is surprising, since both impaired auditory gating and negative symptoms have been linked with impaired fronto-temporal cortical function. The present study measured auditory gating using the P50 event related potential (ERP) in a paired-click paradigm and capitalized on the relative localization advantage of magnetoencephalography (MEG) to assess auditory sensory gating in terms of the event related field (ERF) M50 source dipoles on bilateral superior temporal gyrus (STG). The primary hypothesis was that there would be a positive correlation between lateralized M50 auditory sensory gating measures and negative symptoms in patients with schizophrenia. A standard paired-click paradigm was used during simultaneous EEG and MEG data collection to determine S2/S1 sensory gating ratios in a group of 20 patients for both neuroimaging techniques. Participants were administered the Schedule for the Assessment of Negative Symptoms (SANS), the Positive and Negative Symptom Scale (PANSS), and the Calgary Depression Scale for Schizophrenia. Consistent with previous reports, there was no relationship between ERP P50 sensory gating and negative symptoms. However, right (not left) hemisphere ERF M50 sensory gating ratio was significantly and positively correlated with negative symptoms. This finding is compatible with information processing theories of negative symptoms and with more recent findings of fronto-temporal abnormality in patients with predominantly negative symptoms.

Improving clinical trials: American Society of Clinical Psychopharmacology recommendations.

The major purpose of this American Society of Clinical Psychopharmacology-sponsored meeting was to identify strategies for more efficiently detecting clinical drug effects, thus reducing the economic and scientific risks of investigating new chemical entities in psychiatric disorders. The meeting consisted of presentations and discussions by experts who repeatedly had difficulty pursuing scientific, public health--relevant goals. Many approaches to improving the detection of potentially beneficial agents were reviewed. In this article, we discuss technically feasible study improvements. The scope of inquiry included identifying means of shifting institutional and regulatory assumptions and processes, even to the point of seeking appropriate national incentives.

Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia.

BACKGROUND: The alpha7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) has been implicated as a candidate gene for schizophrenia, and for an auditory sensory processing deficit found in the disease, by both genetic linkage at 15q14 and biochemical data. The expression of CHRNA7 is reduced in several brain regions in schizophrenic subjects compared with control subjects. This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects. METHODS: Single-strand conformation polymorphism analysis and DNA sequencing were used for mutation screening of the core promoter in the CHRNA7 gene. The sample included subjects from 166 schizophrenic families and 165 controls. Controls had no evidence of current or past psychosis and had auditory evoked potentials recorded. RESULTS: Multiple polymorphic patterns were identified in the CHRNA7 core promoter in both schizophrenic and control subjects. Functional analysis of polymorphisms indicated that transcription was reduced. The prevalence of functional promoter variants was statistically greater in schizophrenic subjects than in the controls. Presence of an alpha7 promoter polymorphism in controls was associated with failure to inhibit the P50 auditory evoked potential response. CONCLUSIONS: Although linkage disequilibrium with other genetic alterations cannot be excluded, the CHRNA7 core promoter variants, found in this study, may contribute to a common pathophysiologic feature of schizophrenia.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.