The effect of vortioxetine on anhedonia in patients with schizophrenia.

OBJECTIVE: Anhedonia is a common symptom of depression, but is also a negative symptom of schizophrenia. The purpose of this study was to examine the effects of vortioxetine on anhedonia in patients with schizophrenia. METHODS: A total of 120 patients with schizophrenia in remission who met inclusion criteria were randomized 1:1 by the envelope method into intervention and control groups. All participants in both groups were divided into three subgroups based on the antipsychotic therapy they were receiving (olanzapine, risperidone, or aripiprazole). Vortioxetine was administered to those in the intervention group at a fixed dose of 10 mg per day. The Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), and Chapman Scale for Social and Physical Anhedonia (CSPA) were administered. The study lasted 12 weeks. Participants were assessed twice: At baseline and at the end of the study. Six participants dropped out, with 114 completing the trial. FINDINGS: Vortioxetine treatment had a significant effect on level of physical anhedonia. The treatment interaction was also statistically significant, but with a relatively small effect (F = 3.17, P < .05; η2 = .061). Vortioxetine treatment had a particularly strong effect on the level of social anhedonia. The interaction between the treatment and the type of antipsychotics was also statistically significant with a small effect (F = 5.04, P < 0. 01; η2 = .091). CONCLUSION: The combination of olanzapine and vortioxetine was found to be the best option to reduce symptoms of social and physical anhedonia in these patients with remitted schizophrenia.

Escaping the Long Shadow Cast by Agranulocytosis: Reflections on Clozapine Pharmacovigilance Focused on the United Kingdom.

PURPOSE/BACKGROUND: A recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis. METHODS: Here, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions. FINDINGS/RESULTS: Studies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year. IMPLICATIONS/CONCLUSIONS: The interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

Depression and stress levels in patients with different psychiatric disorders during concurrent early-phase COVID-19 pandemic and earthquake in Croatia.

BACKGROUND: While Croatia shared COVID-19 pandemic with other countries, its capital area was also hit by a 5.6 magnitude earthquake. The simultaneous impact of these two disasters on psychiatric patients is largely unknown, and we addressed those knowledge gaps. METHODS: The cross-sectional study was conducted during the pandemic's first peak, in the aftermath of earthquake, by telephonic survey. Measurements included the Patient Health Questionnaire-9, the Perceived Stress Scale and the semi-structured interview to evaluate the impact of pandemic stress and earthquake. Overall 396 patients with depression and/or anxiety disorders (DAD), 229 participants with schizophrenia spectrum disorders (SSD) and 205 healthy controls were enrolled. RESULTS: Both patient groups had higher depression and stress levels than controls, independent of sex, age and the presence of somatic comorbidity. After controlling for the same covariates, patient groups had higher COVID-19- and earthquake-related fears than controls. In patients with DAD, both fears were greater than among SSD patients. When comparing the two fears, the fear from earthquake was higher in DAD and control groups, whereas in SSD patients there was no such difference. CONCLUSIONS: Patients with DAD were the most vulnerable group during disasters, while earthquake seems to be associated with more fear than the pandemics, at least in DAD patients and healthy individuals. Future longitudinal studies should determine if early psychological support might alleviate stress levels after disasters and prevent further worsening of mental health, particularly among DAD patients.

PTSD, Immune System, and Inflammation.

Posttraumatic stress disorder (PTSD) is a severe trauma and stress-related disorder associated with different somatic comorbidities, especially cardiovascular and metabolic disorders, and with chronic low-grade inflammation. Altered balance of the hypothalamic-pituitary-adrenal (HPA) axis, cytokines and chemokines, C-reactive protein, oxidative stress markers, kynurenine pathways, and gut microbiota might be involved in the alterations of certain brain regions regulating fear conditioning and memory processes, that are all altered in PTSD. In addition to the HPA axis, the gut microbiota maintains the balance and interaction of the immune, CNS, and endocrine pathways forming the gut-brain axis. Disbalance in the HPA axis, gut-brain axis, oxidative stress pathways and kynurenine pathways, altered immune signaling and disrupted homeostasis, as well as the association of the PTSD with the inflammation and disrupted cognition support the search for novel strategies for treatment of PTSD. Besides potential anti-inflammatory treatment, dietary interventions or the use of beneficial bacteria, such as probiotics, can potentially improve the composition and the function of the bacterial community in the gut. Therefore, bacterial supplements and controlled dietary changes, with exercise, might have beneficial effects on the psychological and cognitive functions in patients with PTSD. These new treatments should be aimed to attenuate inflammatory processes and consequently to reduce PTSD symptoms but also to improve cognition and reduce cardio-metabolic disorders associated so frequently with PTSD.

SUICIDE ATTEMPTS ARE ASSOCIATED WITH PERSONALITY DIMENSIONS IN CROATIAN WAR VETERANS WITH POSTTRAUMATIC STRESS DISORDER.

BACKGROUND: Patients with combat-related posttraumatic stress disorder (PTSD) have an increased frequency of suicide ideations, but also a higher risk of suicide attempts. Of all the known predisposing risk factors of suicide attempts in this population, personality dimensions are one of the least investigated. The main aim of this study was to examine if personality traits, namely temperament and character dimensions and trait impulsivity, are associated with suicide attempts in war veterans with PTSD. SUBJECTS AND METHODS: his sample included 178 Croatian male war veterans (mean age 49.20 years) treated for PTSD at the Department of Psychiatry and Psychological Medicine, University Hospital Center Zagreb. These patients were assessed with the M.I.N.I. diagnostic interview and they filled out several self-report scales: the Beck Depression Inventory-Second Edition (BDI-II), the Temperament and Character Inventory-Revised (TCI-R), the Barratt Impulsiveness Scale-11 (BIS-11), and the Satisfaction with Life Scale (SWLS). RESULTS: It was found that 42 (24%) Croatian war veterans with PTSD had a previous suicide attempt. Comparison between the two groups (participants with vs. those without history of suicide attempts) revealed that patients with previous suicide attempts are less educated and more often unemployed, have a longer duration of psychiatric treatment and more psychiatric hospitalizations, and exhibit higher levels of depression and lower life satisfaction. In multivariate logistic regression analyses, temperament dimension Harm Avoidance and character dimension Self-transcendence were unique predictors of suicide attempts, above the influence of age, education level and length of treatment. CONCLUSIONS: Croatian war veterans with PTSD have a substantial risk of suicide attempts. In addition to the role of some sociodemographic and clinical factors, it seems that certain personality dimensions are uniquely associated with suicide behaviours among these individuals.

Utility of Screening Questionnaires to Detect Obstructive Sleep Apnea in Patients with Obesity.

BACKGROUND: Obesity is one of today's most concerning health problems due to increased cardiovascular risk, which is still the leading cause of death. Obstructive sleep apnea syndrome (OSAS) is certainly one of the important risk factors that links obesity and cardiovascular risk. There is a great need to evaluate obstructive sleep apnea (OSA) in obese patients. Today, there are easily available and applicable questionnaires (Epworth Sleepiness Scale (ESS), STOP, STOP-Bang (SBQ), Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI)) that could be very useful in clinical practice for this very purpose. The aim of this paper is to investigate the sensitivity and specificity of the questionnaires for OSA screening in obese patients with and without OSA. PATIENTS AND METHODS: This cross-sectional study was carried out in the tertiary healthcare centre. The following questionnaires were used: ESS, STOP, SBQ, ISI, PSQI. 70 (58 female) adult patients with obesity (body mass index (BMI) > 30 kg/m2) were included. RESULTS: SBQ showed sensitivity of 75%, specificity of 75% at cut-off of 5.5 with the Youden index of 0.5, while PSQI had sensitivity of 78%, specificity of 67% at cut-off of 17.75 with slightly smaller Youden index 0.45. STOP and ESS had a sensitivity of 77% and 75%, respectively but with an even smaller Youden index (0.23 and 0.21), and ISI had the lowest sensitivity of 59% and the lowest Youden index (0.13) of the questionnaires we examined. CONCLUSION: Our study results suggest that SBQ and PSQI are best screening tools in detecting OSA in patients with obesity. Further study of these questionnaires and possible modifications are certainly important for future research.

The Presence of Minor Physical Anomalies of a Hand in Patients with Mental Disorders.

INTRODUCTION: Minor physical anomalies (MPA) are subtle morphological deviations with little to none clinical significance that are developed prenatally and therefore could be an indicator of structural changes in the brain developing at the same time. Aim of this study was to determine whether the MPA of the hand can distinguish psychotic patients from patients with non-psychotic diagnoses as well as from the healthy individuals. SUBJECTS AND METHODS: 100 consecutive patients from the University Hospital Center Zagreb, Department of psychiatry, were included in this case-control study along with 100 healthy control subjects. Investigators examined the dorsal and palmar side of the hand and were blind to the patient's diagnoses previous to the examination. Examined MPA included thenar crease, proximal transverse crease, proximal interphalangeal joint, eponychium of the middle digit, fingernail size and digital flexibility. RESULTS: Results showed significant differences in the quantity of MPA between the patients and the control group, as well as differences between patients with psychosis and the healthy subjects. CONCLUSIONS: Despite the fact that previous studies demonstrated characteristic distribution of specific MPA in schizophrenia, this study did not prove such results. Moreover, this study showed that all the MPA are equally common in both schizophrenia and other psychoses.

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia.

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.

A Load to Find Clinically Useful Biomarkers for Depression.

Depression is heterogeneous and complex disease with diverse symptoms. Its neurobiological underpinning is still not completely understood. For now, there are still no validated, easy obtainable, clinically useful noninvasive biomarker(s) or biomarker panel that will be able to confirm a diagnosis of depression, its subtypes and improve diagnostic procedures. Future multimodal preclinical and clinical research that involves (epi)genetic, molecular, cellular, imaging, and other studies is necessary to advance our understanding of the role of monoamines, GABA, HPA axis, neurotrophins, metabolome, and glycome in the pathogenesis of depression and their potential as diagnostic, prognostic, and treatment response biomarkers. These studies should be focused to include the first-episode depression and antidepressant drug-naïve patients with large sample sizes to reduce variability in different biological and clinical parameters. At present, metabolomics study revealed with high precision that a neurometabolite panel consisting of plasma metabolite biomarkers (GABA, dopamine, tyramine, kynurenine) might represent clinically useful biomarkers of MDD.

Biomarkers of Depression Associated with Comorbid Somatic Diseases.

Depression is heterogeneous clinical entity with different clinical symptoms, that imply diverse biological underpinning, different molecular substrates and pathways. Besides different psychiatric comorbidities, depression is frequently interrelated with somatic diseases. Multi-morbidities, i.e. somatic diseases associated with depression, reduce quality of life, worsen clinical picture and increase mortality. The most frequent somatic diseases co-occurring with depression are cardiovascular and metabolic diseases. Vulnerable individuals will develop depression, and the goal in modern research and in precision/personalized medicine is to determine vulnerability factors associated with development of depression and to find easy available biomarkers of depression, especially comorbid with somatic diseases. This mini-review aimed to describe the latest published data (from 2015-20120) considering biomarkers of depression related to somatic diseases. Biomarkers related to inflammatory processes, atherosclerosis, imbalance of the hypothalamic-pituitary-adrenal axis, autonomic nerve system, sympathetic and parasympathetic nervous system, heart rate variability and endothelial dysfunction could improve the understanding of the underlying biological mechanisms of the common pathways of depression comorbid with somatic diseases. These targeted biomarkers might be used to reduce the symptoms, improve the treatment of these interrelated diseases, and decrease the morbidity and mortality.

Symptom continuum reported by affective disorder patients through a structure-validated questionnaire.

BACKGROUND: Affective disorders, such as major depressive (MDD), bipolar I (BD I) and II (BD II) disorders, are overlapped at a continuum, but their exact loci are not clear. The self-reports from patients with affective disorders might help to clarify this issue. METHODS: We invited 738 healthy volunteers, 207 individuals with BD I, 265 BD II, and 192 MDD to answer a 79 item-MATRIX about on-going affective states. RESULTS: In study 1, all 1402 participants were divided random-evenly and gender-balanced into two subsamples; one subsample was used for exploratory factor analysis, and another for confirmatory factor analysis. A structure-validated inventory with six domains of Overactivation, Psychomotor Acceleration, Distraction/ Impulsivity, Hopelessness, Retardation, and Suicide Tendency, was developed. In study 2, among the four groups, MDD scored the highest on Retardation, Hopelessness and Suicide Tendency, whereas BD I on Distraction/ Impulsivity and Overactivation. CONCLUSION: Our patients confirmed the affective continuum from Suicide Tendency to Overactivation, and described the different loci of MDD, BD I and BD II on this continuum.

Temperament, Character, and Subjective Well-Being in Croatian War Veterans Suffering From Posttraumatic Stress Disorder.

Subjective well-being is decreased in war-affected populations. However, no previous research has investigated the role of temperament and character dimensions in life satisfaction among war veterans with posttraumatic stress disorder (PTSD). This study enrolled 148 Croatian male war veterans being treated for combat-related PTSD. The participants completed the Beck Depression Inventory-Second Edition, Satisfaction with Life Scale, and Temperament and Character Inventory-Revised. Two multivariate regression analyses with life satisfaction as a dependent variable and temperament and character dimensions, respectively, as predictor variables, were performed. Temperament dimensions harm avoidance and novelty seeking as well as character dimensions self-directedness and cooperativeness were unique predictors of life satisfaction, while controlling for the influence of depressive symptoms, education level, and employment status. Given the influence of personality dimensions on life satisfaction, the routine assessment of these dimensions might help to establish the individually tailored treatment among war veterans with PTSD.

HTR1A, HTR1B, HTR2A, HTR2C and HTR6 Gene Polymorphisms and Extrapyramidal Side Effects in Haloperidol-Treated Patients with Schizophrenia.

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to examine molecular associations of HTR1A, HTR1B, HTR2A, HTR2C and HTR6 gene polymorphisms with acute EPS in 229 male schizophrenia patients, following two weeks of haloperidol monotherapy. The Simpson-Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS) were used to evaluate EPS severity. Genotyping was performed using real-time PCR, following extraction of blood DNA. Significant acute EPS appeared in 48.03% of schizophrenia patients. For the rs13212041 HTR1B gene polymorphism, affecting microRNA regulation of HTR1B gene expression, a higher frequency of TT carriers was found among haloperidol-treated patients with akathisia when compared to the group without akathisia symptoms. In comparison to C-allele carriers, patients carrying the TT genotype had higher akathisia severity, as determined by the SAS, BARS and ESRS scales. These molecular findings suggest potential involvement of 5-HT1B receptors in akathisia development following haloperidol treatment, as well as possible epigenetic mechanisms of serotonergic modulation associated with antipsychotic-induced EPS.

Remission Is not Associated with DRD2 rs1800497 and DAT1 rs28363170 Genetic Variants in Male Schizophrenic Patients after 6-months Monotherapy with Olanzapine.

BACKGROUND: Symptomatic remission is an achievable goal in the treatment of schizophrenia. The type of antipsychotic medication and particular genetic variants of the dopaminergic system might be associated with remission. Potential pharmacogenetic markers of the treatment response to antipsychotic medication are missing. This study assessed the possible association between dopamine receptor type 2 (DRD2 rs1800497) and dopamine transporter (DAT1 rs28363170) gene variants with symptomatic remission in schizophrenia. SUBJECTS AND METHODS: Olanzapine (5-20 mg/d) monotherapy was administered for 6 months to 150 male Caucasian subjects with schizophrenia. Remission was evaluated according to "Remission in Schizophrenia Working Group" criteria. Genotyping was performed by PCR-RFLP. RESULTS: Symptomatic remission was found in 31% of patients. DRD2 rs1800497 and DAT1 rs28363170 gene variants were not significantly associated with symptomatic remission. The limitations are a relatively small sample size of patients with schizophrenia (N=150), especially of group with symptomatic remission (N=45). However, the study had moderate but adequate sample sizes for most of the comparisons. Only two dopaminergic polymorphisms were analyzed, and plasma concentration of olanzapine was not determined. CONCLUSION: These results revealed a lack of association between DRD2 rs1800497 and DAT1 rs28363170 genetic variants and symptomatic remission in male patients treated with olanzapine, suggesting that these genetic variants could not be used to predict symptomatic remission to olanzapine monotherapy. Negative results should be further confirmed or rejected in the larger samples, including haplotype analyses, to detect clinically useful and easy obtainable pharmacogenetic markers that might predict therapeutic response or remission in schizophrenia.

Utilization of somatic healthcare in Croatian patients with schizophrenia spectrum disorder, major depression, PTSD and the general population.

BACKGROUND: Utilization of somatic healthcare services is highly predictive of the development of chronic physical illnesses and increased mortality risks. The objective of this study was to assess the differences in healthcare utilization among patients with schizophrenia spectrum disorders (SSD), major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) and the general population in Croatia. METHODS: We enrolled 566 Croatian participants from the general population, 282 with SSD, 178 with MDD, and 86 with PTSD. The primary outcome was a self-reported specialist consultation for non-psychiatric (e.g., somatic) causes within the previous 12 months. RESULTS: Although SSD patients with chronic physical illnesses were significantly more often hospitalized for physical illness than the general population, the proportion of patients who had a specialist consultation were equal in SSD and the general population. MDD and PTSD patients had significantly higher adjusted odds for specialist consultation than the general population and SSD patients (MDD compared to SSD: OR = 2.14; 95% CI 1.27-3.59; PTSD compared to SSD: OR = 2.03; 95% CI 1.00-4.10). CONCLUSIONS: SSD patients' utilization of somatic healthcare is equal to the general population, despite their increased healthcare needs. However, their utilization is lower than in MDD and PTSD patients and, therefore, probably not adequate. TRIAL REGISTRATION: The study protocol was registered at ClinicalTrials.gov ( NCT02773108 ) on May 16, 2016.

Religiosity and Severity of Symptoms in Croatian Patients With Major Depressive Disorder or Schizophrenia.

We examined and compared the relationship between religiosity and symptom severity in patients with major depressive disorder (MDD) rated by the Hamilton Depression Rating Scale) and schizophrenia (rated by the Positive and Negative Syndrome Scale). The Duke University Religion Index, the Santa Clara Strength of Religious Faith (SCSORF) questionnaire, and the Brief Religious Coping scale scores were similar between patients with MDD (n = 50) and patients with schizophrenia (n = 50). In patients with MDD, higher organizational religious activity (ORA) (estimate = 2.28, 95% confidence interval [CI] = 0.37-4.19; p = 0.020) and higher negative religious coping (estimate = 0.43, 95% CI = 0.03-0.84; p = 0.037) were independently associated with more severe symptoms. In patients with schizophrenia, higher ORA was associated with lower negative symptoms (estimate = -1.99, 95% CI = -3.94 to -0.03; p = 0.046). Higher SCSORF was associated with lower ORA in both patient subsets, and thus indirectly with milder symptoms in patients with MDD and with more severe negative symptoms in patients with schizophrenia. The relationship between religiosity and symptom severity apparently differs in patients with MDD and those with schizophrenia.

Genetic Markers in Psychiatry.

Psychiatric disorders such as addiction (substance use and addictive disorders), depression, eating disorders, schizophrenia, and post-traumatic stress disorder (PTSD) are severe, complex, multifactorial mental disorders that carry a high social impact, enormous public health costs, and various comorbidities as well as premature morbidity. Their neurobiological foundation is still not clear. Therefore, it is difficult to uncover new set of genes and possible genetic markers of these disorders since the understanding of the molecular imbalance leading to these disorders is not complete. The integrative approach is needed which will combine genomics and epigenomics; evaluate epigenetic influence on genes and their influence on neuropeptides, neurotransmitters, and hormones; examine gene × gene and gene × environment interplay; and identify abnormalities contributing to development of these disorders. Therefore, novel genetic approaches based on systems biology focused on improvement of the identification of the biological underpinnings might offer genetic markers of addiction, depression, eating disorders, schizophrenia, and PTSD. These markers might be used for early prediction, detection of the risk to develop these disorders, novel subtypes of the diseases and tailored, personalized approach to therapy.

Cognitive deficit in schizophrenia: an overview.

Depressive mood, anxiety, delusions, hallucinations and behavioral disturbances have been traditionally recognized as leading symptoms of mental disorders. However, cognitive symptoms went under-recognized or declined. Today there is robust evidence that cognitive dysfunction is present in the majority of mental disorders and is also related to impairments in the functioning of the persons with mental illness. It is proposed that aberrant brain neuronal network connectivity, arising from interplay of genetic, epigenetic, developmental and environmental factors, is responsible for cognitive decline. In schizophrenia, dysfunctions in working memory, attention, processing speed, visual and verbal learning with substantial deficit in reasoning, planning, abstract thinking and problem solving have been extensively documented. Social cognition - the ability to correctly process information and use it to generate appropriate response in situations, is also impaired. The correlation of cognitive impairment with functional outcome and employment, independent living and social functioning has emphasized the need for development of the treatments specific to cognition. It is considered that brain neuroplasticity allows for re-modulating and compensating the impairment process which could give opportunity to improve cognitive functions. Therefore, there is a need for comprehensive clinical assessment and follow-up of cognitive decline in mental illness. Implementation of specific treatment strategies addressing cognitive decline in mental illness, like new drugs, distinct cognitive-behavioural therapy, psychoeducation, social skills training and remediation strategies should be strongly indorsed targeting recovery and reduction of disability due to mental illness.

Anhedonia in Schizophrenia: Mini-Review.

The perception of reward exerts a powerful influence on human behavior. While anhedonia might occur in healthy individuals, its prevalence and severity are much higher in psychiatric patients, particularly those with depression and schizophrenia. Anhedonia is a negative symptom, and presumably a trait marker in schizophrenia. Recent research confirmed that anhedonia is a complex construct, consisting of anticipatory, consummatory, and reward learning components. In general, schizophrenia patients show anticipation deficits, and a substantial portion of them have physical (PA) and social anhedonia (SA). The relationship between anhedonia and psychopathology appears bidirectional. While gene-environment interactions affect reward circuity, anhedonia modulates clinical features, such as suicidality and nicotine consumption. Future clinical research employing longitudinal designs may shed more light on the dynamics and treatment of anhedonia in schizophrenia.

Integration of complementary biomarkers in patients with first episode psychosis: research protocol of a prospective follow up study.

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.