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BACKGROUND Studies show neurological differences between patients with attention-deficit/hyperactivity disorder (ADHD) and healthy controls. Furthermore, it is possible that poor timing is linked with impairments in neural circuitry. This study aimed to test the hypothesis that there is a difference in time perception between adults with severe ADHD symptomatology and adults with no ADHD symptomatology. MATERIAL AND METHODS Previously, we collected data from a more extensive set of participants (n=1518) concerning the prevalence of ADHD in adulthood. We recruited participants from 3 groups defined by increasing ADHD severity out of this participant pool. Each participant was presented with 2 experimental tasks (in counterbalanced order): duration estimation and duration discrimination. RESULTS In general, we did not find any specific differences in time perception related to the severity of ADHD. Regarding duration estimation, we found that the difference between the actual and estimated durations increased with the actual duration (F(1, 7028.00)=2685.38, P0.001). Although the differences between groups were not significant, the group×duration interaction was (F[1, 7028.00]=10.86, P0.001), with a very small effect size (ηp²0.001, 95% CI [0.00, 0.01]). CONCLUSIONS The results suggest that although individuals may demonstrate increased ADHD symptomatology, they may not have objectively more significant difficulties in time perception tasks than their counterparts with mild symptomatology. Nonetheless, time perception should be further studied because, as qualitative research suggests, participants with more severe ADHD symptomatology subjectively perceive more significant differences in time management in real life.

We analyzed activities of complex I, II, III, and IV, and citrate synthase (CS) in patients with major depressive disorder (MDD) or Alzheimer's disease (AD) presenting with or without depression. Associations of these parameters with disease or disease severity were observed in both AD and MDD; however, mean values of mitochondrial parameters were significantly altered in AD but not in MDD. Potential mitochondrial dysfunction in MDD seems not to be caused by disturbed activity of CS or respiratory complexes. In AD, a decrease in the activity of CS and complex IV may cause mitochondrial dysfunction, whereas an increase in activities of other mitochondrial complexes or their ratios to CS may be an adaptive response. The data indicate that comorbid depression in AD is associated with increased complex II activity. The mitochondrial parameters measured can be included in the panel of biomarkers of AD.

Objectives: The bipolar affective disorder (BAD) pathophysiology is multifactorial and has not been fully clarified. Method: We measured selected mitochondrial parameters in peripheral blood components. The analyses were performed for patients suffering from a manic episode during remission and were compared to those performed for healthy controls. BAD was clinically evaluated using well-established diagnostic scales and questionnaires. Mitochondrial respiration was examined in intact and permeabilized blood platelets using high-resolution respirometry. The citrate synthase (CS) and electron transport system (ETS) complex (complex I, II, and IV) activities were examined in platelets. Results: The CS, complex II and complex IV activities were decreased in the BAD patients, complex I activity was increased, and the ratio of complex I to CS was significantly increased. In the intact platelets, respiration after complex I inhibition and residual oxygen consumption were decreased in the BAD patients compared to the healthy controls. In the permeabilized platelets, a decreased ETS capacity was found in the BAD patients. No significant differences were found between BAD patients in mania and remission. Conclusion: Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. We conclude that complex I and its abnormal activity contribute to defects in cellular energy metabolism during a manic episode and that the deficiency in the complex's functioning, but not the availability of oxidative phosphorylation substrates, seems to be responsible for the decreased ETS capacity in BAD patients. The observed parameters can be further evaluated as ‘trait’ markers of BAD.

Schizophrenia is a severe psychiatric disorder characterized by emotional, behavioral and cognitive disturbances, and the treatment of schizophrenia is often complicated by noncompliance and pharmacoresistance. The search for the pathophysiological mechanisms underlying schizophrenia has resulted in the proposal of several hypotheses to explain the impacts of environmental, genetic, neurodevelopmental, immune and inflammatory factors on disease onset and progression. This review discusses the newest insights into the pathophysiology of and risk factors for schizophrenia and notes novel approaches in antipsychotic treatment and potential diagnostic and theranostic biomarkers. The current hypotheses focusing on neuromediators (dopamine, glutamate, and serotonin), neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, and oxidative stress are summarized. Key genetic features, including small nucleotide polymorphisms, copy number variations, microdeletions, mutations and epigenetic changes, are highlighted. Current pharmacotherapy of schizophrenia relies mostly on dopaminergic and serotonergic antagonists/partial agonists, but new findings in the pathophysiology of schizophrenia have allowed the expansion of novel approaches in pharmacotherapy and the establishment of more reliable biomarkers. Substances with promising results in preclinical and clinical studies include lumateperone, pimavanserin, xanomeline, roluperidone, agonists of trace amine-associated receptor 1, inhibitors of glycine transporters, AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitors and cannabidiol. The use of anti-inflammatory agents as an add-on therapy is mentioned.

BACKGROUND Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer's disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. MATERIAL AND METHODS A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. RESULTS Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ε4 allele of APOE. CONCLUSIONS Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ε4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ε4 allele.

BACKGROUND This real-world study aimed to investigate the use of the Alcohol Use Disorders Identification Test (AUDIT) in men admitted to a psychiatric hospital. MATERIAL AND METHODS The AUDIT questionnaire (10 items) was consecutively administered for a period of 3 years to male patients admitted to a psychiatric hospital (n=636). Laboratory blood tests of biochemical parameters were measured as biomarkers of alcohol consumption. Data were evaluated using linear models with mixed effects in the case of continuous dependent variables and logistic regression models with mixed effects in the case of categorical dependent variables. RESULTS We found that 45.3% of the patients had a high risk of alcohol consumption or alcohol dependence and 54.7% had a low risk of alcohol consumption. The ICD-10 diagnoses of alcohol-related disorders (F1x), psychotic disorders (F2x), affective disorders (F3x), neurotic and psychosomatic disorders (F4x) were statistically significantly associated with total AUDIT score (P

Martina Zvéřová,1 Jana Hroudová,1,2 Zdeněk Fišar,1 Hana Hansíková,3 Lucie Kališová,1 Eva Kitzlerová,1 Alena Lambertová,1 Jiří Raboch1 1Department of Psychiatry, First Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague 2, Czech Republic; 2Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 00 Prague 2, Czech Republic; 3Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague 2, Czech Republic Background: Mitochondrial dysfunctions are implicated in the pathophysiology of mood disorders. We measured and examined the following selected mitochondrial parameters: citrate synthase (CS) activity, electron transport system (ETS) complex (complexes I, II, and IV) activities, and mitochondrial respiration in blood platelets. Patients and methods: The analyses were performed for 24 patients suffering from a depressive episode of bipolar affective disorder (BD), compared to 68 patients with MDD and 104 healthy controls. BD and unipolar depression were clinically evaluated using well-established diagnostic scales and questionnaires. Results: The CS, complex II, and complex IV activities were decreased in the depressive episode of BD patients; complex I and complex I/CS ratio were significantly increased compared to healthy controls. We observed significantly decreased complex II and CS activities in patients suffering from MDD compared to controls. Decreased respiration after complex I inhibition and increased residual respiration were found in depressive BD patients compared to controls. Physiological respiration and capacity of the ETS were decreased, and respiration after complex I inhibition was increased in MDD patients, compared to controls. Increased complex I activity can be a compensatory mechanism for decreased CS and complex II and IV activities. Conclusion: We can conclude that complex I and its abnormal activity contribute to the defects in cellular energy metabolism during a depressive episode of BD. The observed parameters could be used in a panel of biomarkers that could selectively distinguish BD depression from MDD and can be easily examined from blood elements. Keywords: affective disorder, biomarker, oxidative phosphorylation, mitochondrial enzyme, platelet

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis and a common occurrence of comorbid diseases such as depression. It is accepted that the presence of the ε4 allele of the gene that encodes apolipoprotein E (APOE) is the strongest genetic risk factor for the development of sporadic AD. Melatonin, cortisol, homocysteine, and prolactin are presumed to be risk factors or biomarkers for stress- and age-related disorders. Objective: The interplay between the APOE genotype and plasma biomarkers was examined in patients with AD presenting with or without depression to contribute to understanding the interdependence of various molecular mechanisms in the pathophysiology of AD. Method: The APOE genotype and morning plasma melatonin, cortisol, homocysteine, and prolactin concentrations were measured in 85 patients with AD and 44 elderly controls. Results: A significant association between AD and the allele (ε4) or genotype (ε3/ε4 or ε4/ε4) frequencies of APOE was confirmed. Plasma homocysteine and cortisol levels were significantly increased in patients with AD compared to those in controls, independent of the presence of comorbid depressive symptoms or the severity of dementia. Significantly lower plasma melatonin concentration was found in patients with AD but not in controls, who were noncarriers of the APOE ε4 allele, regardless of the presence of depression or the severity of dementia in AD. Conclusion: Our findings indicate the existence of a little-known specific APOE-mediated mechanism that increases the plasma melatonin level in a subgroup of patients with AD who are carriers of the APOE ε4 allele.

Background Cortisol is presumed to be a risk factor for stress- and age-related disorders, such as depressive disorder and Alzheimer’s disease (AD). The aim of this study was to investigate the association of plasma cortisol concentration with AD in presence or absence of comorbid depressive symptoms. Material/Methods Plasma cortisol concentration was measured in 80 AD patients (35 of them with depressive symptoms), 27 elderly depressive patients without AD, and 37 elderly controls. Results Compared to controls, a significant increase of mean plasma cortisol was found in AD patients but not in depressive patients. Plasma cortisol was positively correlated with cognitive impairment in AD patients. We confirmed a U-shaped association between plasma cortisol and major depression and a linear association between plasma cortisol and AD without depressive symptoms. Significantly increased relative risk of disease in people with high plasma cortisol was found for AD with depressive symptoms and for AD with mild dementia. Conclusions Plasma cortisol reflects the degree of cognitive impairment in AD rather than the severity of comorbid depression. We confirmed that both hypercortisolemia and hypocortisolemia are associated with depressive disorder. Significant association between high plasma cortisol and AD was found, supporting the use of high plasma cortisol as a component of a panel of biochemical markers for AD with depressive symptoms as well as AD in the early stage of dementia development.

Elevated homocysteine is associated with a variety of diseases, including Alzheimer's disease (AD) and depressive disorder. This study was designed to detect an association between plasma homocysteine and AD with or without co-morbid depressive symptoms.Plasma homocysteine concentrations were measured in 85 AD patients (36 of them with depressive symptoms), 33 non-AD patients with a depression diagnosis and 44 healthy controls, all aged above 50 years.Positive correlation between age and homocysteine was confirmed. Significantly higher mean plasma homocysteine was found in AD patients, but not in depressive patients, when compared with controls. We confirmed significant correlation between homocysteine concentration and the degree of cognitive impairment in AD patients. There was no incremental effect of concurrent depressive symptoms on homocysteine concentration in AD patients.The association of high homocysteine with degree of cognitive impairment or stage of dementia in AD indicate potential role of high plasma homocysteine as a biomarker of the disease and/or indicator of brain damage during the progression of AD dementia.

Background Glycogen synthase kinase-3β (GSK3β), cAMP-response element‐binding protein (CREB) and brain-derived neurotrophic factor (BDNF) play critical roles in neuronal survival, synaptic plasticity and memory and participate in the pathophysiology of both depressive disorder and Alzheimer's disease (AD). Methods This study was designed to determine the association of GSK3β activity, CREB activity and BDNF concentration in peripheral blood of patients with AD with or without depressive symptoms and in depressive patients without AD. GSK3β activity in platelets, CREB activity in lymphocytes and BDNF concentration in plasma, platelet-rich plasma or platelets were measured in 85 AD patients (36 of whom displayed co-morbid depressive symptoms), 65 non-AD patients with depressive disorder and 96 healthy controls. AD patients were clinically assessed for stage of dementia, cognitive impairment and severity of depressive symptoms. Depressive patients were clinically assessed for severity of depression. Results We observed increased CREB activity and GSK3β activity in AD with depressive symptoms or in AD at mild stage of dementia. Decreased BDNF concentration was found in platelet-rich plasma of AD patients at moderate to severe stages of dementia or in AD without depressive symptoms. An association was revealed of the severity of cognitive impairment with the increase of GSK3β in the platelets of AD patients with mild dementia. In depressive patients, a lower concentration of phosphorylated GSK3β was associated with a higher severity of depression. Association was confirmed between severity of depression, CREB activation, and BDNF concentration in drug-naive depressive patients. Conclusion Our data demonstrated that AD is accompanied by increased CREB activity in lymphocytes and a decreased concentration of BDNF in platelet-rich plasma. The decreased BDNF concentration appears to correlate with moderate to severe stages of dementia in AD. Observation of decreased phosphorylation of GSK3β in platelets of both AD patients with depressive symptoms and depressive patients after treatment confirms the role of increased GSK3β activity in the pathophysiology of both AD and depressive disorder. Associations were confirmed between AD and platelet GSK3β activity, lymphocyte CREB activity and plasma BDNF. CREB activity and platelet BDNF concentration seems to be related to depressive disorder.

Recent evidences include mitochondrial dysfunctions in pathophysiology of mood disorders. We examined association between depressive disorders and mitochondrial respiration using both intact and permeabilized blood platelets. In intact platelets, physiological respiration, maximal capacity of electron transport system and respiratory rate after complex I inhibition were decreased in depressive patients, who reached partial remission, compared to healthy controls. Respiratory rates were unchanged in several respiratory states in permeabilized platelets. Results indicate that changes in respiratory rate in intact platelets can be used as biological marker of depressive disorder. The hypothesis that decreased mitochondrial respiratory rate participate in pathophysiology of depression was supported.

Objective: Involuntary treatment in mental health care is a sensitive but rarely studied issue. This study was part of the European Evaluation of Coercion in Psychiatry and Harmonization of Best Clinical Practice (EUNOMIA) project. It assessed and compared the use of coercive measures in psychiatric inpatient facilities in ten European countries. Methods: The sample included 2,030 involuntarily admitted patients. Data were obtained on coercive measures (physical restraint, seclusion, and forced medication). Results: In total, 1,462 coercive measures were used with 770 patients (38%). The percentage of patients receiving coercive measures in each country varied between 21% and 59%. The most frequent reason for prescribing coercive measures was patient aggression against others. In eight of the countries, the most frequent measure used was forced medication, and in two of the countries mechanical restraint was the most frequent measure used. Seclusion was rarely administered and was reported in only six countries. A diagnosis of schizophrenia and more severe symptoms were associated with a higher probability of receiving coercive measures. Conclusions: Coercive measures were used in a substantial group of involuntarily admitted patients across Europe. Their use appeared to depend on diagnosis and the severity of illness, but use was also heavily influenced by the individual country. Variation across countries may reflect differences in societal attitudes and clinical traditions. (Psychiatric Services 61: 1012-1017, 2010)

Antipsychotic medication and early relapse warning signs detection are the cornerstone of relapse prevention in schizophrenia spectrum disorders. Many patients do not use antipsychotic medication because of lack of information about its preventive effects and the risk of relapse. We introduce PREDUKA--PREventive EDUcational programme for relapse prevention. The goal of the programme is to deliver the information about schizophrenia to patients and their relatives. 178 patients and 252 relatives (118 mothers and 51 fathers) took part in 25 one-day psychoeducational programmes in 6 centres in the Czech Republic between January 2008 and June 2009 and anonymously fulfilled a short questionnaire. Patients and relatives assessed the programme with an average mark 1.4 (1 best, 5 worst). 49.4% patients and 49.0% relatives had received enough information about psychotic disorders during their hospitalization. Moreover 94.1% patients and 95.7% relatives confirmed acquiring new information on how to live with psychosis as a result of PREDUKA programme. 59.6% patients and 73.8% relatives were interested in ITAREPS - Information Technology Aided Relapse Prevention Programme. Mothers were significantly more interested (82.2%) than fathers (62.2%) (p = 0.031). Expressed high interest of patients and their relatives in both programmes indicates their readiness to become active and competent partners in the long-term treatment of schizophrenia spectrum disorders.

SummaryAims – To analyse factors that differentiate patients who attend follow-up assessments versus those who do not, and to identify predictors for drop-out within the context of the European Day Hospital Evaluation Study (EDEN-Study). Methods – The EDEN-Study, a multi-center RCT comparing acute psychiatric day care with inpatient care, required re-assessment of patients at discharge, 3 and 12 months after discharge. Follow-up rates varied between 54.0% and 99.5%. Socio-demographic and clinical characteristics of patients who did and did not attend follow-up were analysed using uni- and multivariate statistical methods. Results – Univariate analyses showed differences between patients regarding study site, treatment setting, living situation, employment, age, psychopathological symptoms and treatment satisfaction. They were not confirmed in multivariate analyses thus meaningful predictors of drop-out could not be identified. Conclusions – Results emphasize the general need to compare patients re-assessed and not re-assessed in terms of their most relevant socio-demographic and clinical variables to assess the generalizability of results.Declaration of Interest: EDEN (Psychiatric day hospital treatment: An alternative to inpatient treatment, being cost-effective and minimizing post-treatment needs for care? An evaluative study in European countries with different care systems) was funded by the European Commission (Quality of Life and Management of Living Resources Programme: QLG4-CT-2000-01700). Additional national grants supporting the project were provided by Roland-Ernst-Stiftung für Gesundheitswesen and the Faculty of Medicine at the Dresden University of Technology, the National Health Service Executive Organization and Management Programme, the Polish National Committee of Scientific Affairs, and the Slovak Ministry of Education. Pfizer Pharmaceutical Company supported travel and accommodation for EDEN project meetings.

Depressive disorders and cardiovascular disease are inter-connected by a whole range of pathophysiological mechanisms. Three biological mechanisms are fundamental: activation of the hypothalamus-hypohysis-adrenal axis with a subsequent increase in sympathetic-adrenal system activity, decrease in vagal tone with a decrease in heart rate variability, and alterations of thrombogenesis with increased platelet aggregability. Behavioural mechanisms and psycho-social factors are also integral to this common pathophysiology. Recently, research has focused mainly on studying various forms of stress, as well as changes and possibilities of influencing the autonomous vegetative system. Temporal aspects of the incidence and development of depressive episodes in relation to cardiovascular disease and subsequent cardiovascular morbidity and mortality are being studied, as well as general mortality risk factors. These findings are important for clinical practice. It is evident that in patients with untreated depressive disorder, the risk of developing cardiovascular disease is significantly higher than in patients suffering from a depressive disorder being treated with anti-depressants. From the data published so far, it may be surmised that depressive disorders in patients with cardiovascular disease may be reliably and safely treated with anti-depressants that act as inhibitors of serotonin re-uptake.