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.

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.

Risk of death for veterans on release from prison.

We sought to determine, among veterans released from Washington state prisons from 1999 through 2003, the risk of death from all causes, whether those veterans have faced a higher risk of death than have nonveterans, and whether having VA benefits decreased the risk of death. We linked data from a retrospective cohort study to data from the Veterans Benefit Administration. Mortality rates were compared between veteran and nonveteran former inmates. The crude rate of veteran mortality was 1,195 per 100,000 person-years, significantly higher than that of nonveterans (p < .001), but adjustment for demographic factors demonstrated no significant increased risk. VA benefits were associated with a reduced risk for all-cause deaths (hazard ratio, .376; 95% confidence interval, 0.18-0.79). Veterans share the heightened risk of death after release from prison faced by all released inmates and should be included in efforts to reduce the risks associated with transitioning from prison to the community. VA benefits appear to offer a protective effect, particularly against medical deaths.

Inhibition of the P50 cerebral evoked response to repeated auditory stimuli: results from the Consortium on Genetics of Schizophrenia.

Inhibition of the P50 evoked electroencephalographic response to the second of paired auditory stimuli has been frequently examined as a neurophysiological deficit in schizophrenia. The Consortium on the Genetics of Schizophrenia (COGS), a 7-site study funded by the National Institute of Mental Health, examined this endophenotype in recordings from 181 probands with schizophrenia, 429 of their first degree relatives, and 333 community comparison control subjects. Most probands were treated with second generation antipsychotic medications. Highly significant differences in P50 inhibition, measured as either the ratio of amplitudes or their difference in response to the two stimuli, were found between the probands and the community comparison sample. There were no differences between the COGS sites for these findings. For the ratio parameter, an admixture analysis found that nearly 40% of the relatives demonstrated deficiencies in P50 inhibition that are comparable to the deficit found in the probands. These results indicate that P50 auditory evoked potentials can be recorded across multiple sites and reliably demonstrate a physiological abnormality in schizophrenia. The appearance of the physiological abnormality in a substantial proportion of clinically unaffected first degree relatives is consistent with the hypothesis that deficits in cerebral inhibition are a familial neurobiological risk factor for the illness.

Neuropsychological test performance in soldiers with blast-related mild TBI.

This exploratory study was conducted to increase understanding of neuropsychological test performance in those with blast-related mild traumatic brain injury (mTBI). The two variables of interest for their impact on test performance were presence of mTBI symptoms and history of posttraumatic stress disorder (PTSD). Forty-five soldiers postblast mTBI, 27 with enduring mTBI symptoms and 18 without, completed a series of neuropsychological tests. Seventeen of the 45 met criteria for PTSD. The Paced Auditory Serial Addition Test (Frencham, Fox, & Mayberry, 2005; Spreen & Strauss, 1998) was the primary outcome measure. Two-sided, 2-sample t tests were used to compare scores between groups of interest. Presence of mTBI symptoms did not impact test performance. In addition, no significant differences between soldiers with and without PTSD were identified. Standard neuropsychological assessment may not increase understanding about impairment associated with mTBI symptoms. Further research in this area is indicated.

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.

Suicidality and veterans with a history of traumatic brain injury: precipitants events, protective factors, and prevention strategies.

OBJECTIVES: To increase understanding regarding precipitating and preventative factors of suicidal behavior and to highlight past experiences and recommendations regarding services aimed at suicide prevention among Veterans with a history of traumatic brain injury (TBI). STUDY DESIGN: Qualitative. PARTICIPANTS: Sample of 13 Veterans with a history of TBI, and a history of clinically significant suicidal ideation or behavior. METHOD: In-person interviews were conducted and data were analyzed using a hermeneutic approach. RESULTS: Shared precipitants noted included loss-of-self post-TBI, cognitive sequelae, and psychiatric and emotional disturbances. Common protective factors noted included social supports, a sense of purpose regarding the future, religion and spirituality, and mental health care. Means of improving care were also identified (e.g., increasing the availability of services and mental health professionals' knowledge regarding TBI, providing more structured treatment). CONCLUSIONS: Findings highlight potential areas of importance in the assessment and treatment of suicidal Veterans with a history of TBI. Recommendations regarding means of improving care are also presented.

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.

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.

Family-focused therapy via videoconferencing.

A 30-year-old veteran with a diagnosis of schizoaffective disorder and his mother were referred for family-focused therapy (FFT), an empirically-supported, manual-based treatment. The veteran had had multiple hospitalizations and experienced chronic auditory hallucinations for self-harm. Minor modifications to FFT were made for implementation via videoconferencing (at a bandwidth of 384 kbit/s). This may have enhanced the treatment by making the process of communication and problem-solving more explicit. The course of FFT was successfully completed, and the veteran and family showed a high level of satisfaction with care as well as improved medication adherence, good quality of life, high levels of hope, good interpersonal functioning, and very mild negative and positive psychiatric symptoms. This veteran had previous exposure to telemental health, which may have influenced his willingness to receive tele-FFT and perhaps affected the outcome of the case. The ability to provide this type of service to people in rural areas is important.

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.

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.

Tobacco use and cessation in psychiatric disorders: National Institute of Mental Health report.

The National Institute of Mental Health (NIMH) convened a meeting in September 2005 to review tobacco use and dependence and smoking cessation among those with mental disorders, especially individuals with anxiety disorders, depression, or schizophrenia. Smoking rates are exceptionally high among these individuals and contribute to the high rates of medical morbidity and mortality in these individuals. Numerous biological, psychological, and social factors may explain these high smoking rates, including the lack of smoking cessation treatment in mental health settings. Historically, "self-medication" and "individual rights" have been concerns used to rationalize allowing ongoing tobacco use and limited smoking cessation efforts in many mental health treatment settings. Although research has shown that tobacco use can reduce or ameliorate certain psychiatric symptoms, overreliance on the self-medication hypothesis to explain the high rates of tobacco use in psychiatric populations may result in inadequate attention to other potential explanations for this addictive behavior among those with mental disorders. A more complete understanding of nicotine and tobacco use in psychiatric patients also can lead to new psychiatric treatments and a better understanding of mental illness. Greater collaboration between mental health researchers and nicotine and tobacco researchers is needed to better understand and develop new treatments for cooccurring nicotine dependence and mental illness. Despite an accumulating literature for some specific psychiatric disorders and tobacco use and cessation, many unstudied research questions remain and are a focus and an emphasis of this review.