The potential of biomarkers for diagnosing insomnia: Consensus statement of the WFSBP Task Force on Sleep Disorders.

OBJECTIVES: Thus far, the diagnosis of insomnia is based on purely clinical criteria. Although a broad range of altered physiological parameters has been identified in insomniacs, the evidence to establish their diagnostic usefulness is very limited. Purpose of this WFSBP Task Force consensus paper is to systematically evaluate a series of biomarkers as potential diagnostic tools for insomnia. METHODS: A newly created grading system was used for assessing the validity of various measurements in establishing the diagnosis of insomnia; these measurements originated from relevant studies selected and reviewed by experts. RESULTS: The measurements with the highest diagnostic performance were those derived from psychometric instruments. Biological measurements which emerged as potentially useful diagnostic instruments were polysomnography-derived cyclic alternating pattern, actigraphy, and BDNF levels, followed by heart rate around sleep onset, deficient melatonin rhythm, and certain neuroimaging patterns (mainly for the activity of frontal and pre-frontal cortex, hippocampus and basal ganglia); yet, these findings need replication, as well as establishment of commonly accepted methodology and diagnostic cut-off points. Routine polysomnography, EEG spectral analysis, heart rate variability, skin conductance, thermoregulation, oxygen consumption, HPA axis, and inflammation indices were not shown to be of satisfactory diagnostic value. CONCLUSIONS: Apart from psychometric instruments which are confirmed to be the gold standard in diagnosing insomnia, six biomarkers emerge as being potentially useful for this purpose.

Differential association of cortisol with visual memory/learning and executive function in Bipolar Disorder.

The association of cortisol with cognition has been understudied in Bipolar Disorder (BD); available evidence is inconsistent while it is unknown whether cortisol's effects vary across neurocognitive domains implicating different brain structures. This study aimed to examine the association of cortisol with two cognitive tasks targeting visual memory and executive function (planning) in BD, related to the hippocampus and prefrontal lobe, respectively. Cambridge Neuropsychological Test Automated Battery (CANTAB) tasks targeting paired associative learning (PAL) and planning (Stockings of Cambridge; SOC) were administered to 60 BD type I patients. Basal serum cortisol was also measured. Higher cortisol was associated with worse performance in PAL, but not SOC, after controlling for gender, education, illness duration and treatment with mood stabilizers. This is the first study to examine the association of cortisol with neurocognitive function in BD while controlling for clinicodemographic and treatment-related factors. We found a significant association of cortisol with hippocampal-related visual memory/learning but not with prefrontal lobe-related executive function, suggesting domain-specific underlying mechanisms of cognitive dysfunction in BD. Future studies should further explore cortisol's brain structure-specific effects on cognitive functioning in BD.

Cortisol to Dehydroepiandrosterone Sulphate Ratio and Executive Function in Bipolar Disorder.

INTRODUCTION: Bipolar disorder (BD) is associated with impairment in cognitive domains such as verbal memory and executive functions. Very few studies have assessed dehydroepiandrosterone sulphate (DHEA-S) in BD and its relation to cognitive functioning despite evidence showing its regulatory effects on glucocorticoid action. The aim of our study was to explore the association of cortisol, DHEA-S, and cortisol to DHEA-S ratio with visuospatial memory and executive functioning in BD. METHODS: Cognitive performance of 60 bipolar I patients and 30 healthy subjects was evaluated by using Cambridge Neuropsychological Test Automated Battery tasks targeting visuospatial memory (spatial recognition memory) and executive functions (planning [Stockings of Cambridge; SOC] and attentional set shifting [ID/ED]). Morning serum cortisol and DHEA-S levels were measured in patients. Main effects of cortisol, DHEA-S, and cortisol/DHEA-S ratio for each neurocognitive task were explored in multiple regression analyses correcting for demographic and clinical parameters as well as treatment-related factors (current use of antipsychotic and mood stabilizer medication). RESULTS: Bipolar patients showed poorer performance than healthy subjects in planning and attentional set shifting but not in visuospatial memory. Cortisol to DHEA-S ratio predicted worse performance in planning (SOC). CONCLUSIONS: This is the first study to assess memory and executive function in BD in relation to DHEA-S and cortisol to DHEA-S ratio. We report an association of cortisol to DHEA-S ratio with worse performance in planning in bipolar I patients, which warrants further investigation.

Sex-related variation of neurocognitive functioning in bipolar disorder: Focus on visual memory and associative learning.

Bipolar disorder (BD) is associated with cognitive deficits in attention, verbal memory and executive functions. However, only few studies have examined sex effects on cognition despite their clinical relevance. Given that visual memory/ learning has been understudied the aim of our study was to investigate sex-related variation in cognition (executive functions and visual memory/ learning) in BD. Cognitive performance of 60 bipolar-I patients and 30 healthy controls was evaluated by using CANTAB battery tasks targeting spatial memory (SRM), paired associative learning (PAL) and executive functions. We fitted a multivariate analysis of covariance (MANCOVA), followed by task-specific ANCOVAs. A significant diagnosis by sex interaction effect was detected (MANCOVA); specifically, diagnosis-specific sex effects were found for SRM and PAL, as healthy males outperformed healthy females but this pattern was attenuated in BD patients. Patients' clinicodemographic characteristics, current psychopathology or medication status did not differ across sexes and were, therefore, unlikely to explain detected sex effects. Our study is one of few studies to assess sex-related variation in cognition in BD and the first to record a diagnosis-specific sex effect for two tasks of visuo-spatial memory/ learning, indicating that sex-related variation in healthy subjects is disrupted in BD.

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.

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.

Clinical and treatment-related predictors of cognition in bipolar disorder: focus on visual paired associative learning.

Bipolar disorder (BD) is associated with impairment in cognitive domains such as verbal memory and executive functions. However, visual paired associative learning (PAL) has been far less researched. Neurocognitive dysfunction in BD patients has been related to several clinical factors, but data on the effect of medication are relatively scarce and inconsistent. The aim of our study was to explore the effect of clinical and treatment-related parameters on executive functions and visual memory/learning, including PAL, in BD. Cognitive performance of 60 bipolar I patients and 30 healthy subjects was evaluated by using CANTAB battery tasks targeting spatial recognition memory, PAL and executive functions (set shifting, planning, inhibitory control). Bipolar patients showed poorer performance in PAL, set shifting, planning and inhibitory control than healthy subjects; however, only differences in PAL and planning survived correction for multiple comparisons. Number of previous manic episodes and illness duration predicted worse performance in set shifting and PAL, respectively, whereas current treatment with valproate predicted better performance in PAL. This is one of the first studies to assess clinical and treatment-related predictors of PAL in BD. We report a possibly beneficial effect of valproate on PAL, which warrants further investigation.

The development of the Athens Emotional States Inventory (AESI): collection, validation and automatic processing of emotionally loaded sentences.

OBJECTIVES: The development of ecologically valid procedures for collecting reliable and unbiased emotional data towards computer interfaces with social and affective intelligence targeting patients with mental disorders. METHODS: Following its development, presented with, the Athens Emotional States Inventory (AESI) proposes the design, recording and validation of an audiovisual database for five emotional states: anger, fear, joy, sadness and neutral. The items of the AESI consist of sentences each having content indicative of the corresponding emotion. Emotional content was assessed through a survey of 40 young participants with a questionnaire following the Latin square design. The emotional sentences that were correctly identified by 85% of the participants were recorded in a soundproof room with microphones and cameras. A preliminary validation of AESI is performed through automatic emotion recognition experiments from speech. RESULTS: The resulting database contains 696 recorded utterances in Greek language by 20 native speakers and has a total duration of approximately 28 min. Speech classification results yield accuracy up to 75.15% for automatically recognizing the emotions in AESI. CONCLUSIONS: These results indicate the usefulness of our approach for collecting emotional data with reliable content, balanced across classes and with reduced environmental variability.

Sleep EEG and spindle characteristics after combination treatment with clozapine in drug-resistant schizophrenia: a pilot study.

PURPOSE: Clozapine is an atypical neuroleptic agent, effective in treating drug-resistant schizophrenia. The aim of this work was to investigate overall sleep architecture and sleep spindle morphology characteristics, before and after combination treatment with clozapine, in patients with drug-resistant schizophrenia who underwent polysomnography. METHODS: Standard polysomnographic techniques were used. To quantify the sleep spindle morphology, a modeling technique was used that quantifies time-varying patterns in both the spindle envelope and the intraspindle frequency. RESULTS: After combination treatment with clozapine, the patients showed clinical improvement. In addition, their overall sleep architecture and, more importantly, parameters that quantify the time-varying sleep spindle morphology were affected. Specifically, the results showed increased stage 2 sleep, reduced slow-wave sleep, increased rapid eye movement sleep, increased total sleep time, decreased wake time after sleep onset, as well as effects on spindle amplitude and intraspindle frequency parameters. However, the above changes in overall sleep architecture were statistically nonsignificant trends. CONCLUSIONS: The findings concerning statistically significant effects on spindle amplitude and intraspindle frequency parameters may imply changes in cortical sleep EEG generation mechanisms, as well as changes in thalamic pacing mechanisms or in thalamo-cortical network dynamics involved in sleep EEG generation, as a result of combination treatment with clozapine. SIGNIFICANCE: Sleep spindle parameters may serve as metrics for the eventual development of effective EEG biomarkers to investigate treatment effects and pathophysiological mechanisms in schizophrenia.

Baseline heartbeat perception accuracy and short-term outcome of brief cognitive-behaviour therapy for panic disorder with agoraphobia.

BACKGROUND: Increased heartbeat perception accuracy (HBP-accuracy) may contribute to the pathogenesis of Panic Disorder (PD) without or with Agoraphobia (PDA). Extant research suggests that HBP-accuracy is a rather stable individual characteristic, moreover predictive of worse long-term outcome in PD/PDA patients. However, it remains still unexplored whether HBP-accuracy adversely affects patients' short-term outcome after structured cognitive behaviour therapy (CBT) for PD/PDA. AIM: To explore the potential association between HBP-accuracy and the short-term outcome of a structured brief-CBT for the acute treatment of PDA. METHOD: We assessed baseline HBP-accuracy using the "mental tracking" paradigm in 25 consecutive medication-free, CBT-naive PDA patients. Patients then underwent a structured, protocol-based, 8-session CBT by the same therapist. Outcome measures included the number of panic attacks during the past week, the Agoraphobic Cognitions Questionnaire (ACQ), and the Mobility Inventory-Alone subscale (MI-alone). RESULTS: No association emerged between baseline HBP-accuracy and posttreatment changes concerning number of panic attacks. Moreover, higher baseline HBP-accuracy was associated with significantly larger reductions in the scores of the ACQ and the MI-alone scales. CONCLUSION: Our results suggest that in PDA patients undergoing structured brief-CBT for the acute treatment of their symptoms, higher baseline HBP-accuracy is not associated with worse short-term outcome concerning panic attacks. Furthermore, higher baseline HBP-accuracy may be associated with enhanced therapeutic gains in agoraphobic cognitions and behaviours.

Indoleamine 2,3-dioxygenase and immune changes under antidepressive treatment in major depression in females.

BACKGROUND/AIM: Indoleamine 2, 3-dioxygenase (IDO) induction has been suggested as a mechanism by which immune activation affects tryptophan metabolism and serotonin synthesis in major depressive disorder (MDD). We investigated IDO and changes in inflammatory mediators in patients with MDD undergoing effective treatment. PATIENTS AND METHODS: Forty female patients with MDD and 40 controls were recruited. Serum IDO was assessed by enzyme-linked immunosorbent assay (ELISA). We also determined tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), C-reactive protein (CRP) and serotonin concentrations. RESULTS: Patients' baseline concentrations of IDO and immune mediators were higher and serotonin concentrations were lower compared to controls. IDO and TNFα concentrations decreased under treatment and IDO changes were positively correlated with patient improvement. IFNγ and CRP concentrations remained unchanged. Serotonin concentration tended to increase. CONCLUSION: IDO might play an important role in the pathophysiology of MDD. Moreover, antidepressant therapy might reduce IDO production through an IFNγ-independent pathway. Finally, peripheral concentration of IDO assessed by ELISA might be a useful marker of MDD.

Differences in EEG delta frequency characteristics and patterns in slow-wave sleep between dementia patients and controls: a pilot study.

PURPOSE: To evaluate the modifications of EEG activity during slow-wave sleep in patients with dementia compared with healthy elderly subjects, using spectral analysis and period-amplitude analysis. METHODS: Five patients with dementia and 5 elderly control subjects underwent night polysomnographic recordings. For each of the first three nonrapid eye movement-rapid eye movement sleep cycles, a well-defined slow-wave sleep portion was chosen. The delta frequency band (0.4-3.6 Hz) in these portions was analyzed with both spectral analysis and period-amplitude analysis. RESULTS: Spectral analysis showed an increase in the delta band power in the dementia group, with a decrease across the night observed only in the control group. For the dementia group, period-amplitude analysis showed a decrease in well-defined delta waves of frequency lower than 1.6 Hz and an increase in such waves of frequency higher than 2 Hz, in incidence and amplitude. CONCLUSIONS: Our study showed (1) a loss of the dynamics of delta band power across the night sleep, in dementia, and (2) a different distribution of delta waves during slow-wave sleep in dementia compared with control subjects. This kind of computer-based analysis can highlight the presence of a pathologic delta activity during slow-wave sleep in dementia and may support the hypothesis of a dynamic interaction between sleep alteration and cognitive decline.

Education in mental health promotion and its impact on the participants' attitudes and perceived mental health.

BACKGROUND: Although the promotion of mental health (MHP) through education and training is widely accepted, there is scarce evidence for its effectiveness in the literature from outcome studies worldwide. The present study aimed to assess the effect of a three-semester MHP educational program on the recipients' opinions towards mental illness and on their own self-assessed health. METHODS: Respondents were 78 attendees who completed the assessment battery at the first (baseline) and the last session (end) of the training course. They were primary care physicians or other professionals, or key community agents, working in the greater Athens area. The course consisted of 44 sessions (4 h each), over a 3-semester period, focusing on the principles and methods of mental health promotion, the main aspects of major psychiatric disorders, and on relevant to health skills. Assessment instruments included the Opinion about Mental Illness (OMI) scale and the General Health Questionnaire (GHQ-28). RESULTS: The mean scores of three OMI factors, that is, social discrimination, social restriction and social integration, and the two GHQ-28 subscales, that is, anxiety/insomnia and social dysfunction, were significantly improved by the end of the training course. CONCLUSIONS: The results of this study provide evidence, with limitations, for the short-term effectiveness of the implemented educational MHP program on an adult group of recipients-key agents in their community. Because interventions for strengthening positive opinions about mental illness and enhancing self-assessed health constitute priority aims of mental health promotion, it would be beneficial to further investigate the sustainability of the observed positive changes. In addition it would be useful to examine (a) the possible interplay between the two outcome measures, that is, the effect of opinions of recipients about mental health on their perceived health, and (b) the applicability of this intervention in individuals with different sociodemographic profiles.

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.

Independent component analysis for source localization of EEG sleep spindle components.

Sleep spindles are bursts of sleep electroencephalogram (EEG) quasirhythmic activity within the frequency band of 11-16 Hz, characterized by progressively increasing, then gradually decreasing amplitude. The purpose of the present study was to process sleep spindles with Independent Component Analysis (ICA) in order to investigate the possibility of extracting, through visual analysis of the spindle EEG and visual selection of Independent Components (ICs), spindle "components" (SCs) corresponding to separate EEG activity patterns during a spindle, and to investigate the intracranial current sources underlying these SCs. Current source analysis using Low-Resolution Brain Electromagnetic Tomography (LORETA) was applied to the original and the ICA-reconstructed EEGs. Results indicated that SCs can be extracted by reconstructing the EEG through back-projection of separate groups of ICs, based on a temporal and spectral analysis of ICs. The intracranial current sources related to the SCs were found to be spatially stable during the time evolution of the sleep spindles.

Depressive symptomatology in high school students: the role of age, gender and academic pressure.

To clarify the prevalence of depressive symptomatology in high school students in Athens and to evaluate risk factors for depressive symptomatology the CES-D scale was administered to 713 students (age 15-18). Demographic, school performance and extracurricular activities data were collected. A high prevalence (26.2%) of depressive symptomatology (CES-D cut-off score >28) was found. Regression analysis showed depressive symptomatology to be associated to gender (girls had higher scores than boys), school record (students with a better record had lower scores) and the interaction of gender and grade (males were found to have higher depressive symptomatology scores as they grew older).

Physical activity may promote sleep in cardiac patients suffering from insomnia.

Data obtained from a national household survey in Greece (n=1005) were used to assess the relationship between physical activity and insomnia in a group of subjects suffering from several major disabling physical illnesses. A self-administered questionnaire with questions pertaining to general health and related issues was given to the participants. The Short Form-36, the Athens Insomnia Scale (AIS), and the International Physical Activity Questionnaire (IPAQ) were included in the assessment. Half (49.5%) of the participants had moderate or vigorous physical activity and 33.4% had a chronic somatic disease. The prevalence of insomnia in the total sample was 25.3% (n=254); subjects having moderate or vigorous physical activity were 56% less likely to have insomnia in univariate analysis. Multiple analysis revealed a significant interaction of physical activity with heart failure or myocardial ischemia (OR=0.054, 95% CI: 0.003-0.95), indicating that subjects having moderate or vigorous physical activity and heart failure or myocardial ischemia had lower odds for having insomnia compared to individuals with heart problems and low physical activity levels. Consequently, cardiac patients suffering from insomnia seem to benefit from physical exercise. Since sleep disorders are quite frequent in cardiac patients and may result in both physical and psychological complications which deteriorate even further their quality of life and health, our results need replication in this particularly vulnerable population.