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.

Coping and Its Relation to PTSD in Greek Firefighters.

Firefighters are exposed continuously to intense stress situations and traumatic incidents, and are at high risk of developing posttraumatic stress disorder (PTSD). Coping mechanisms and behaviors have been examined as factors contributing to PTSD. The strategies that may be used to cope with stress and/or trauma differ between individuals and also between different professions and traumatic events (). Although there is a vast literature on stress and coping processes that exists, very few studies investigated the way individual firefighters cope with trauma. Among several questionnaires that have been used to examine the effects of different types of coping mechanisms after traumatic incidents is the Albert Einstein College of Medicine-Coping Style Questionnaire (AECOM-CSQ; ). In August 2007, large areas in the Peloponnese, Greece, were devastated by wildfires. One month after the event, experienced researchers visited the affected area to provide psychological support and to investigate the psychosocial consequences among the local professional firefighters. One hundred two firefighters that were on duty for the entire period of firefighting (several days) were interviewed using several questionnaires, among them the AECOM-CSQ. Our hypothesis was that firefighters who presented with PTSD would be more inclined toward engaging in avoidance coping mechanisms. A total of 18.6% of the firefighters were found to have PTSD according to ICD-10 criteria. Logistic regression showed that firefighters using the coping mechanisms of minimization and blame were associated with the greater likelihood of PTSD. It seems that specific coping mechanisms used by firefighters immediately after the traumatic event might contribute to the development of PTSD.

A systematic review of non-pharmacological treatments for apathy in dementia.

OBJECTIVE: Apathy is one of the most frequent neuropsychiatric symptoms encountered in dementia. Early diagnosis and timely treatment of apathy in dementia are crucial because apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. DESIGN: Extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies which have investigated the effect of non-pharmacological treatments of apathy in dementia. Quality of the studies was appraised. RESULTS: A total of 1303 records were identified and 120 full-texts assessed. Forty-three unique studies were reviewed. A variety of interventions were found to be effective in reducing apathy in demented patients, particularly when provided in a multidisciplinary manner. However, quantification of the effect was limited by the marked methodological heterogeneity of the studies and the small number of studies where apathy was the primary outcome measure. CONCLUSIONS: Treatment of apathy in dementia is a complex and underexplored field. Certain studies suggest promise for a variety of non-pharmacological interventions. Standardized and systematic efforts primarily focusing on apathy may establish a benefit from individualized treatments for specific disease groups.

Personality characteristics and individual factors associated with PTSD in firefighters one month after extended wildfires.

BACKGROUND: Firefighters participate in activities with intense physical and psychological stress and are constantly at risk to develop various psychopathological reactions. AIMS: To investigate psychological reactions in firefighters one month after devastating wildfires in Greece, during August 2007, which lead to the devastation of large areas and the death of 43 people among whom three were firefighters. METHODS: One month after the wildfires, a joint task force of mental health clinicians was organized in order to provide psychological support and to investigate the psychological consequences of wildfires to firefighters. One hundred and two firefighters, living within the fire-devastated area, who were on duty for the whole period of wildfires were interviewed and assessed with the use of several questionnaires and inventories. RESULTS: Post-traumatic stress disorder (PTSD) was detected in 18.6% of firefighters. Multiple logistic regression found that existence of fear of dying during firefighting, insomnia and increased scores in neuroticism, as well as in depression subscale of the SCL-90, were significantly associated with greater likelihood for having PTSD. Additionally those firefighters who worked permanently had 70% lower probability of having PTSD vs. those seasonally employed. CONCLUSIONS: Insomnia, depressive symptoms, as well as personality characteristics as neuroticism and the perception of fear of imminent death during firefighting operations may precipitate the development of PTSD in firefighters. Within this context, mental health clinicians should be aware that the early detection of these predisposing factors may facilitate the prevention and mitigation of PTSD in firefighters particularly those who are seasonally employed.

Pharmacological and Nonpharmacological Treatment for Apathy in Alzheimer Disease : A systematic review across modalities

OBJECTIVE: Apathy is one of the most frequent neuropsychiatric symptoms encountered in Alzheimer disease (AD). Early diagnosis and timely treatment of apathy in AD seem to be of great importance, since apathy has been associated with poor disease outcome, reduced daily functioning, and caregiver distress. DESIGN: Within this context, we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for studies that have investigated the effect of pharmacological and nonpharmacological treatments of apathy in AD. RESULTS: Acetylcholinesterase inhibitors, gingko biloba, methylphenidate, and a variety of nonpharmacological interventions were found to be successful in reducing apathy in patients with AD. Methodological heterogeneity of the studies and the small amount of studies where apathy was a primary outcome measure are limiting factors to evaluate for group effects. CONCLUSION: Treatment of apathy in AD is a complicated and an underexplored field. Standardized and systematic efforts primarily focused on the study of apathy in AD may establish a benefit from individualized treatment for specific disease groups that would stem from a combination of both pharmacological and nonpharmacological interventions.

Antipsychotic Treatment of 22q11.2 Deletion Syndrome-Related Psychoses.

In the recent study by Verhoeven and Egger, 2015 and the recent letter to the editor by Boot et al. 2015 an emphasis is given to the best possible pharmacological treatment of 22q11-2 Deletion-Syndrome related psychoses. We would like to present the case of a 23-year old Cypriot patient with 22q11.2 deletion syndrome who fulfilled criteria for treatment resistant schizophrenia (TRS). He was sequentially treated with aripiprazole, risperidone, olanzapine, haloperidol and a combination treatment with olanzapine and haloperidol. Clozapine was the only antipsychotic medication that has improved his condition.

Two Versus One High-Frequency Repetitive Transcranial Magnetic Stimulation Session per Day for Treatment-Resistant Depression: A Randomized Sham-Controlled Trial.

OBJECTIVES: High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has proven antidepressant effects, but the optimal frequency of sessions remains unclear. METHODS: We conducted a 3-week, sham-controlled trial to assess the antidepressant efficacy of 1 active HF-rTMS session per day (A1 group) compared with 2 per day (A2 group) and equivalent sham sessions (once a day, S1 group; twice a day, S2 group) in patients with treatment-resistant major depression with a subsequent 2-week follow-up period. One hundred seventy-seven patients were screened, of whom 105 met eligibility criteria and 98 consented and were randomized. The HF-rTMS (20 Hz) was targeted to the left prefrontal cortex in sessions of approximately 40 trains (2 seconds each) at 100% resting motor threshold with an intertrain interval of 1 minute. Treatment response was defined as a 50% or greater decrease in the Hamilton Depression Rating Scale (HDRS) score and/or Clinician Global Impressions-Severity of Illness (CGI-S) score of 3 or less. Remission was defined as HDRS score less than 8 and/or CGI-S score of 2 or less. RESULTS: Practically none of the subjects in either sham groups achieved remission. Increased odds of remission were present for CGI-S by stimulating twice rather than once per day (odds ratio [OR] = 1.5, P = 0.018), whereas there was a marginal result for HDRS (OR = 3.9, P = 0.066). Patients who had lower baseline HDRS (OR = 0.75, P = 0.014) and CGI-S scores (OR = 0.18, P = 0.001) were more likely to achieve remission. CONCLUSIONS: Twice per day active HF-rTMS might be more effective than once per day active HF-rTMS or sham stimulation.

Insomnia and PTSD one month after wildfires: evidence for an independent role of the "fear of imminent death".

OBJECTIVE: The relationship of insomnia with Post-Traumatic Stress Disorder (PTSD) one month after wildfires and more specifically with the experience of 'fear of imminent death' were investigated. METHODS: Ninety-two randomly chosen victims of wildfires in the Greek province of Ilia, were assessed through a specifically designed semi-structured psychiatric interview comprising of questionnaires and scales to measure psychopathology, as well as psychosocial and environmental parameters. PTSD was set according to ICD-10 research diagnostic criteria, while insomnia was assessed with the Athens Insomnia Scale (AIS). RESULTS: The presence of insomnia was identified in 63.0% of the victims. 46.7% of the participants were diagnosed with PTSD in the first post-disaster month, while 51.1% of the total sample experienced 'fear of imminent death'. The majority of sleep complaints were significantly more frequent in subjects with PTSD. Female gender, PTSD, older age, and 'fear of imminent death' were independently associated with insomnia. CONCLUSIONS: The findings of the present study indicate that the diagnosis of insomnia, as well as, certain specific insomnia complaints were more frequent in female victims of wildfires who have experienced 'fear of imminent death' and have developed PTSD.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with increased body mass index and insulin resistance measures in bipolar disorder and schizophrenia.

OBJECTIVES: We tested the hypothesis that a common functional variant in brain-derived neurotrophic factor (BDNF), Val66Met, which has been shown to be associated with increased body mass index (BMI) in schizophrenia (SCZ) and schizoaffective disorder (SAD), is also associated with antipsychotic-induced weight gain in bipolar disorder (BPD). Association of Val66Met with other metabolic measures, including high- and low-density cholesterol, triglycerides, total cholesterol, fasting blood glucose, and hemoglobin A1c, was also tested. METHODS: This was a 12-month, prospective, randomized trial of two atypical antipsychotic drugs (APDs) with moderate (risperidone) or high (olanzapine) risk to cause weight gain. Subjects were diagnosed as having BPD (n = 90) and SCZ or SAD (n = 76). RESULTS: BMI was significantly greater in all diagnoses for Met66 allele carriers at six months (p = 0.01). Met66 carriers with BPD showed a greater increase in the triglycerides/high-density (HDL) cholesterol ratio (p = 0.01), a key marker for metabolic syndrome related to insulin resistance, and log-triglycerides (p = 0.04), after three or six months of treatment. Met66 carriers had the greatest increase in log-triglycerides (p = 0.03) and triglycerides/HDL cholesterol ratio after three months of treatment with risperidone (p = 0.003), and the highest BMI at six months (p = 0.01). CONCLUSIONS: The positive association of BNDF Val66Met with high BMI values replicates previous findings in patients with SCZ and indicates the BDNF Val66Met genotype as a potential risk factor for obesity and insulin resistance measures in patients with BPD receiving antipsychotics as well.

A review of neuroimaging findings of apathy in Alzheimer's disease.

BACKGROUND: Apathy is one of the most frequent "behavioral and psychological signs and symptoms of dementia" (BPSD) encountered in Alzheimer's disease (AD). There is a growing interest in the early diagnosis of apathetic elderly patients in the community since apathy has been associated with reduced daily functioning, caregiver distress, and poor outcome. The generalization of neuroimaging techniques might be able to offer help in this domain. METHODS: Within this context we conducted an extensive electronic search from the databases included in the National Library of Medicine as well as PsychInfo and Google Scholar for neuroimaging findings of apathy in AD. RESULTS: Neuroimaging findings lend support to the notion that frontal-subcortical networks are involved in the occurrence of apathy in AD. CONCLUSIONS: Longitudinal studies comparing patients and normal individuals might allow us to infer on the association between apathy and neurodegenerative diseases and what can brain imaging markers tell us about the characterization of this association, thus revealing disease patterns, helping to distinguish clinically distinct cognitive syndromes, and allowing predictions.

Association of gut dysbiosis with first­episode psychosis (Review).

The gut­microbiota­brain axis is a complex bidirectional communication system linking the gastrointestinal tract to the brain. Changes in the balance, composition and diversity of the gut­microbiota (gut dysbiosis) have been found to be associated with the development of psychosis. Early­life stress, along with various stressors encountered in different developmental phases, have been shown to be associated with the abnormal composition of the gut microbiota, leading to irregular immunological and neuroendocrine functions, which are potentially responsible for the occurrence of first­episode psychosis (FEP). The aim of the present narrative review was to summarize the significant differences of the altered microbiome composition in patients suffering from FEP vs. healthy controls, and to discuss its effects on the occurrence and intensity of symptoms in FEP.

A Systematic Review of Pharmacological Interventions for Apathy in Aging Neurocognitive Disorders.

OBJECTIVE: Apathy, a frequent neuropsychiatric symptom in aging neurocognitive disorders, has been associated with cognitive decline and functional disability. Therefore, timely provision of pharmacological interventions for apathy is greatly needed. DESIGN: A systematical literature review of existing studies was conducted up to 30 May 2023 in several databases (PubMed, PsychInfo, Cochrane, Google Scholar, etc.) that included randomized controlled trials (RCTs) and meta-analyses assessing pharmacological treatments for apathy in aging neurocognitive disorders. The quality of the studies was appraised. RESULTS: In patients with Alzheimer's Disease (AD), donepezil, galantamine, rivastigmine, methylphenidate, and gingko biloba were proven efficacious for apathy, while rivastigmine, cognitive enhancer IRL752 and piribedil were found to be beneficial in patients with Parkinson's Disease (PD) and agomelatine in patients with Frontotemporal Dementia (FD). The extensive proportion of RCTs in which apathy was used as a secondary outcome measure, along with the considerable methodological heterogeneity, did not allow the evaluation of group effects. CONCLUSIONS: Pharmacological interventions for apathy in aging neurocognitive disorders are complex and under-investigated. The continuation of systematic research efforts and the provision of individualized treatment for patients suffering from these disorders is vital.

Investigating environmental parameters involved in psychosis etiopathology. Translation and test-retest reliability of four scales.

First Episode Psychosis (FEP) emergence and clinical outcome might be attributed to various parameters, wherein gene - environment interaction plays a pivotal role in. Four specified psychometric tools, that have been used for the evaluation of possible environmental, social and psychological parameters involved in the etiopathology and clinical course of psychosis are the following: Social Environment Assessment Tool (SEAT), Discrimination (DISC), Brief Core-Schema Scales (BCSS) and Life-Threatening Events-Brief Life-Events Questionnaire (LTE-Q). These tools were used in the Athens-FEP Study assessment schedule, which investigates the gene-environment interaction among patients presenting with FEP. The goal of the present study is to present them in regard to their content, their use in international literature, their translation in Greek, and their test-retest reliability. SEAT, DISC and BCSS were provided to the Athens FEP Study by the European Network of National Schizophrenia Network studying Gene-Environment interactions (EUGEI) research project. LTE-Q was already translated into Greek and was selected as befitting the purposes of the FEP-Study. The EUGEI instruments were translated into Greek language by two independent translators for each instrument. All translators were qualified in the administration of the English version of the scales after being trained online through a comprehensive work-package training set provided by the EUGEI. The principal investigator of the Athens-FEP project checked and approved the final versions of the questionnaires. The four tools were administered to 32 subjects, all diagnosed with FEP, participating in the Athens-FEP project. Intraclass correlation coefficients (ICCs) were used to assess the agreement between scores of the four questionnaires after first and second administration. The scales were administered to our subjects twice, with an intermediate period of three weeks between the first and second administrations, by three qualified researchers. There was a statistically significant agreement for almost all measurements of the four questionnaires, except for the frequency dimension of DISC. Agreement between those measurements was very high (ICCs>0.8). Our study is an indication that the Greek versions of the psychometric tools are reliable, although a more thorough test of their psychometric properties is needed. All four questionnaires have unique properties that differentiate them from other similar tools. Moreover, the DISC is the only discrimination scale translated into Greek. More importantly, the translated questionnaires are part of a broad, well-established research package of psychometric tools, suitable for the evaluation of environmental risk factors potentially involved in early psychosis, which might represent a valuable scientific resource in the Greek research field.

Clozapine, neutropenia and Covid-19: should clinicians be concerned? 3 months report.

BACKGROUND: Clozapine is among the most effective antipsychotics used for treatment resistant schizophrenia. Adverse reactions to clozapine include neutropenia. In March 2020, at the start of the Coronavirus -19 pandemic, clinicians raised concerns regarding continuation of antipsychotic treatment, and specifically of clozapine, in patients with coronavirus disease. We aimed here at providing a short report focusing on the association between neutropenia and clozapine in a case series of psychiatric inpatients diagnosed with COVID-19. PATIENTS & METHODS: We retrospectively inspected data of 10 patients on clozapine, admitted to Highgate Mental Health Centre, Camden & Islington NHS Foundation Trust, between March and July 2020; selection was based on their COVID-19 positive PCR test. We used a linear regression model to estimate whether there was a significant drop in the neutrophil count during SARS-CoV-2 infection.The analysis was done in R using a linear regression to the origin. RESULTS: Data were collected on 10 patients, of which 7 were males. During COVID-19 infection, neutrophils' count (ANC) was 4.13 â€‹× â€‹109/l (SD â€‹= â€‹2.70) which constituted a significant drop from a baseline value of 5.2 â€‹× â€‹109/l (SD â€‹= â€‹2.24). The mean relative reduction in ANC was -0.2729 (SD â€‹= â€‹0.1666). The beta value of 0.8377 obtained with the linear regression showed that ANC values during SARS-CoV-2 infection were 83.77% of the baseline ANC showing that within the two time points there was a decrease of 16.23%. The linear regression had a pvalue â€‹= â€‹8.96 â€‹× â€‹10-8 and an adjusted R2 of 95.94% which shows that the variability of the data is very well explained by the model. We also compared baseline ANC with ANC values approximately a month after resolution of the infection and results indicate that ANC values return to a 95% of baseline. CONCLUSIONS: Clinicians should bear in mind that a significant drop in neutrophils' count may occur in patients taking clozapine and affected from a SARS-CoV-2 infectionand that this drop is only transitory.

Perceived social stigma, self-concept, and self-stigmatization of patient with schizophrenia.

The advent of community-based mental health care in Greece emphasized clinicians' need to understand patients' attitudes and their experience of their illness. A 42-item self-administered questionnaire (Self-Stigmatization Questionnaire) with flexible format was designed and administered to 150 outpatients with schizophrenia who fulfilled the criteria for inclusion in the vocational rehabilitation program where the study took place. The patients participated voluntarily. Multivariate regression models were applied to each item to assess the degree of patients' self-stigmatization experience as well as the effect of potential factors such as age, sex, psychopathologic condition, hospitalization, and duration of illness. The options selected by the patients revealed stigmatized attitudes in most items. The odds of selecting these options were mainly influenced by the severity of the patients' psychopathologic condition and the duration of illness and less by sex, age, and hospitalization.

Insomnia and its correlates in a representative sample of the Greek population.

BACKGROUND: Insomnia is a major public health concern affecting about 10% of the general population in its chronic form. Furthermore, epidemiological surveys demonstrate that poor sleep and sleep dissatisfaction are even more frequent problems (10-48%) in the community. This is the first report on the prevalence of insomnia in Greece, a southeastern European country which differs in several socio-cultural and climatic aspects from the rest of European Community members. Data obtained from a national household survey (n = 1005) were used to assess the relationship between insomnia symptoms and a variety of sociodemographic variables, life habits, and health-related factors. METHODS: A self-administered questionnaire with questions pertaining to general health and related issues was given to the participants. The Short Form-36 (Mental Health subscale), the Athens Insomnia Scale (AIS) as a measure of insomnia-related symptoms, and the International Physical Activity Questionnaire (IPAQ) were also used for the assessment. RESULTS: The prevalence of insomnia in the total sample was 25.3% (n = 254); insomnia was more frequent in women than men (30.7% vs. 19.5%) and increased with age. Multiple regression analysis revealed a significant association of insomnia with low socio-economical status and educational level, physical inactivity, existence of a chronic physical or mental disease and increased number of hospitalizations in the previous year. CONCLUSIONS: The present study confirms most findings reported from other developed countries around the world regarding the high prevalence of insomnia problems in the general population and their association with several sociodemographic and health-related predisposing factors. These results further indicate the need for more active interventions on the part of physicians who should suspect and specifically ask about such symptoms.

Amisulpride for the treatment of very-late-onset schizophrenia-like psychosis.

BACKGROUND: Although schizophrenia affects all age groups, late or very-late-onset schizophrenia-like psychosis has not been well studied and various treatment issues remain unresolved. The objective of the present study was to evaluate the efficacy and safety of amisulpride monotherapy in a diagnostically homogeneous group of elderly patients without cognitive impairment suffering from very-late-onset schizophrenia. METHODS: Twenty-six patients of mean age 76.2 +/- 5.8 years, fulfilling both the recent consensus criteria for very late-onset schizophrenia-like psychosis and the DSM-IV-TR criteria for schizophrenia, were assessed by the Brief Psychiatric Rating Scale, the Clinical Global Impression Scale and the Positive and Negative Syndrome Scale at baseline and five weeks following amisulpride (50-200 mg/day) administration; also, the presence of abnormal movements was evaluated with the Simpson-Angus Scale, the Barnes Akathisia Scale, and the Abnormal Involuntary Movement Scale. RESULTS: A highly significant (p < 0.001) improvement on all measures of psychotic symptomatology was observed in all patients. Amisulpride was very well tolerated by the patients and no clinically significant adverse effects were observed. Scores on all abnormal movement scales did not differ significantly prior to and after amisulpride treatment. CONCLUSION: Preliminary results indicate that amisulpride appears to be an efficacious and safe atypical antipsychotic for the treatment of very-late-onset schizophrenia-like psychosis.

Larger variability of saccadic reaction times in schizophrenia patients.

Slower mean reaction time (RT), known as psychomotor slowing, is well documented in patients with schizophrenia. Fewer studies have shown increased variability of RT in these patients suggesting a basic difference in the distribution of RT. In this study median RT and its variability were measured for visually guided saccades performed by 53 patients and 1089 control subjects. Then average cumulative RT distributions were derived for each group and the RT distribution for each group was modeled using a decision signal rising linearly to a threshold signaling the beginning of the visually guided saccade. There was a small increase in the median RT for patients while their RTs were much more variable from trial to trial leading to a difference in the average RT distribution of the patient group. The model application led to the conclusion that this difference in the distribution of RT for patients could be attributed to a basic difference in information processing leading to the decision to move the eyes to the visually presented target. This information-processing difference could be the result of a difference in the build-up of neuronal activity involved in the generation of visually guided saccades in the frontal cortex.