Correction to: Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

The following authors have double affiliations: Stefania Boccia, Marco Di Nicola and they should read.

Psychiatric disorders and SLC6A4 gene variants: possible effects on alcohol dependence and alzheimer's disease.

Serotoninergic system is one of the most important neurotransmission systems investigated in the field of psychiatry. Extensive evidence reveals how alterations of this system, and especially of the SLC6A4 gene, may be associated with psychiatric disorders. In this study we aimed to evaluate the pleiotropic nature of SLC6A4 alterations and their association with the overall risk of brain diseases rather than disorder-specific. SLC6A4 variants, namely 5HTTLPR, STin2, rs2066713, rs25531, rs4251417, rs6354 and rs7224199 were investigated in 4 independent cohorts of subjects with specific psychiatric disorders, including Alcohol dependence disorder (ALC), Alzheimer disease (ALZ), Schizophrenia (SCZ) and Bipolar disorder (BPD). Other variables (biochemical parameters and Psychiatric scales scores) were also tested for association. SLC6A4 polymorphisms are not associated with the risk of developing major psychiatric disorders (SCZ and BPD); however some signals were detected in ALC (HTTLPR pd = 9.25 × 10-03, pr = 7.24 × 10-03; rs2066713 pd = 6.35 × 10-08; rs25531 pd = 2.95 × 10-02; rs4251417 pd = 2.46 × 10-03), and ALZ (rs6354 pr = 1.22 × 10-02; rs7224199 pd = 1.00 × 10-08, pr = 2.65 × 10-02) cohorts. Some associations were also observed on exploratory analyses. Our findings did not reveal any major influence on SCZ and BPD development; On the other hand, some alteration of the SLC6A4 sequence were associated with an increased risk of ALC and ALZ disorders, suggesting common pathways. The results of this study should be carefully interpreted since it suffers of some inherent limitations (e.g. cohort size, slight ethnic heterogeneity). Further analyses may provide better detail on the molecular processes behind SLC6A4 alterations.

Alzheimer's Disease and Neurotransmission Gene Variants: Focus on Their Effects on Psychiatric Comorbidities and Inflammatory Parameters.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder accounting for 60-70% of dementia cases. Genetic origin accounts for 49-79% of disease risk. This paper aims to investigate the association of 17 polymorphisms within 7 genes involved in neurotransmission (COMT, HTR2A, PPP3CC, RORA, SIGMAR1, SIRT1, and SORBS3) and AD. METHODS: A Greek and an Italian sample were investigated, for a total of 156 AD subjects and 301 healthy controls. Exploratory analyses on psychosis and depression comorbidities were performed, as well as on other available clinical and serological parameters. RESULTS: AD was associated with rs4680 within the COMT gene in the total sample. Trends of association were found in the 2 subsamples. Some nominal associations were found for the depressive phenotype. rs10997871 and rs10997875 within SIRT1 were nominally associated with depression in the total sample and in the Greek subsample. rs174696 within COMT was associated with depression comorbidity in the Italian subsample. DISCUSSION: Our data support the role of COMT, and particularly of rs4680, in the pathogenesis of AD. Furthermore, the SIRT1 gene seems to modulate depressive symptomatology in the AD population.

Temperament and character influence on depression treatment outcome.

BACKGROUND: personality features have been repeatedly associated with depression treatment outcome in Major Depressive Disorder (MDD), however conclusive results are still lacking. Moreover, as for Bipolar Disorder (BD), results are only few and preliminary. AIM: the aim of the present study was to perform an exploratory investigation of the influence of personality traits as assessed by the Temperament and Character Inventory (TCI), on principal depression treatment outcomes (non remission, non response and resistance). METHODS: 743 mood disorders patients (455 MDD (61.24%) and 288 BD (38.76%)) were recruited in the context of 6 European studies. Generalized logit models were performed to test the effects of TCI dimensions on treatment outcomes, considering possible confounders such as age, gender and education. Positive results were controlled for comorbidities (anxiety and substance use disorders) as well. RESULTS: MDD Non-Remitters showed high Harm Avoidance (HA) and Self Transcendence (ST) (p = 0.0004, d = 0.40; p = 0.007, d = 0.36 respectively) and low Persistence (P) and Self Directedness (SD) (p = 0.05; d = 0.18; p = 0.002, d = 0.40, respectively); MDD Non-Responders showed a slightly different profile with high HA and low Reward Dependence (RD) and SD; finally, MDD Resistants showed low RD, P and Cooperativeness (C). In BD patients, only higher HA in non response was observed. LIMITATIONS: the retrospective cross-sectional design, the TCI assessment regardless of the mood state and the small number of bipolar patients represent the main limitations. CONCLUSION: specific TCI personality traits are associated with depression treatment outcome in MDD patients. The inclusion of such personality traits, together with other socio-demographic and clinical predictors, could ameliorate the accuracy of the prediction models available to date.

Major Depression and the Degree of Suicidality: Results of the European Group for the Study of Resistant Depression (GSRD).

Background: This European multicenter study aimed to elucidate suicidality in major depressive disorder. Previous surveys suggest a prevalence of suicidality in major depressive disorder of ≥50%, but little is known about the association of different degrees of suicidality with socio-demographic, psychosocial, and clinical characteristics. Methods: We stratified 1410 major depressive disorder patients into 3 categories of suicidality based on the Hamilton Rating Scale for Depression item 3 (suicidality) ratings (0=no suicidality; 1-2=mild/moderate suicidality; 3-4=severe suicidality). Chi-squared tests, analyses of covariance, and Spearman correlation analyses were applied for the data analyses. Results: The prevalence rate of suicidality in major depressive disorder amounted to 46.67% (Hamilton Rating Scale for Depression item 3 score ≥1). 53.33% were allocated into the no, 38.44% into the mild/moderate, and 8.23% into the severe suicidality patient group. Due to the stratification of our major depressive disorder patient sample according to different levels of suicidality, we identified some socio-demographic, psychosocial, and clinical variables differentiating from the patient group without suicidality already in presence of mild/moderate suicidality (depressive symptom severity, treatment resistance, psychotic features, add-on medications in general), whereas others separated only when severe suicidality was manifest (inpatient treatment, augmentation with antipsychotics and benzodiazepines, melancholic features, somatic comorbidities). Conclusions: As even mild/moderate suicidality is associated with a failure of achieving treatment response, adequate recognition of this condition should be ensured in the clinical practice.

Arterial Hypertension and Health-Related Quality of Life.

PURPOSE: To investigate the effect of awareness of arterial hypertension on quality of life in hypertensive patients in Greece. MATERIALS AND METHODS: This was a prospective observational study that included 189 aware hypertensive patients on treatment with antihypertensive therapy. Patients were ambulatory men or women ≥18 years old, with diagnosed essential hypertension. The administration and fulfillment of the questionnaires was given at the outpatient hypertensive clinic starting with the SF-36 and continuing with the BDI-I test. RESULTS: The mean BDI score was 9.9 ± 6.9, and 58, 25, 8.9, and 7.3% were identified as without, with minimal, moderate, and 0.8% with severe depression, respectively. The mean score for physical component summary (PCS-36) was 48.9 ± 7.6, and the mean score for mental component summary (MCS-36) was 46.0 ± 10.6. The stage of hypertension was not an independent predictor for any of the SF-36 dimensions. Dippers had not different levels of health-related quality of life (HRQOL) as compared with non-dippers. LV hypertrophy was associated with lower scores on bodily pain (p < 0.05) and kidney failure was associated with lower scores on general health perception (p < 0.05). Female gender, increased age, and the presence of COPD were independently associated with lower physical and mental health scores (p < 0.05). Score on BDI independently correlated with all dimensions of SF-36, indicating that greater depression levels are associated with lower levels of HRQOL. CONCLUSION: The stage as well as awareness of arterial hypertension does not affect physical and mental health. The fact that arterial hypertension per se is not a symptomatic disease may explain these results at least in patients with uncomplicated hypertension.

Medical students' attitudes to mental illnesses and to psychiatry before and after the psychiatric clerkship: Training in a specialty and a general hospital.

Medical students' attitudes to mental illnesses and psychiatry may be reshaped during the psychiatric training, with important implications in their future practice of the profession. Therefore, the present study set out to explore the impact of the psychiatric clerkship in students' attitudes, while taking into consideration the site of their practical training. To this end, a total of 678 final-year medical students were recruited. Students completed a self-reported questionnaire entailing the Attitudes to Psychiatry scale, the Attitudes to Mental Illness scale and the Greek Social Distance scale before and after their placement. Findings indicate that the psychiatric clerkship had a positive effect in reducing stigma towards both psychiatry and mental illnesses, with the effect being more pronounced in the general hospital with respect to the former, while in the specialty hospital was more marked regarding the latter. A further exploration of the determinants of change revealed that the improvement discerned in the general hospital was only among those without professional experience of mental illnesses. Therefore, the psychiatric clerkship may exert a substantial influence on shaping favourable attitudes towards mental illnesses and psychiatry; however, other elements should also be taken into consideration, if the clerkship is to tackle stigma in healthcare.

Adolescent gambling in greater Athens area: a cross-sectional study.

PURPOSE: Problem gambling in adolescents has recently emerged as a pressing public health concern. In this context and in light of the pervasive financial crisis in Greece, the present study aimed to explore adolescents' gambling involvement in Athens region to estimate the prevalence of its problematic form and to identify its risk/protective factors. METHODS: A total of 2141 students were recruited from a representative sample of 51 schools located in greater Athens area. The presence of problem gambling was assessed through the use of the DSM-IV-MR-J questionnaire. Data were collected in the form of a self-reported questionnaire during one school hour. RESULTS: Results indicate that 1-year prevalence of high severity problem gambling was found to be 5.6%. Regarding the risk factors for problem gambling; male gender, parental engagement with gambling activities, living without the parents, low grades at school, foreign nationality and the referent absence of availability of food in the household, increased the risk of suffering from the disorder. CONCLUSION: Gambling behavior among adolescents constitutes a problem in Greece and highlights the need for designing and implementing appropriate preventive interventions, especially amid the ongoing financial crisis.

Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in Alzheimer's disease.

INTRODUCTION: With the increase of the population's average age, Alzheimer's disease (AD) is becoming one of the most disabling diseases worldwide. Recently, neurodevelopment processes have been involved in the AD etiopathogenesis. Genetic studies in this field could contribute to our knowledge and suggest new molecular targets for possible treatments. METHODS: Our primary aim was to investigate the associations among single nucleotide polymorphisms (SNPs) within neurodevelopment related genes (BDNF, ST8SIA2, C15orf32, NCAPG2, ESYT2, WDR60, LOC154822, VIPR2, GSK3B, NR1I2, ZNF804A, SP4) and AD. A number of exploratory analyses was also performed to evaluate the associations with the presence of behavioral and psychiatric symptoms of dementia (BPSD), as well as with variations in hematological parameters. Two independent samples were investigated, one of 228 Greek subjects and one sample of 229 Italian subjects, including 156Alzheimer's Disease patients CE patients and 301 healthy controls. All patients were affected by late onset AD (LOAD). RESULTS: None of the analyzed SNPs was associated with AD in our samples. In the exploratory analyses, several genetic variants were associated with inflammation parameters in the Greek sample and in the merged one, suggesting a relationship among these genes and the modulation of inflammation and the immune response. Other exploratory analyses showed associations among several SNPs and psychiatric symptomatology in the Greek sample, suggesting a possible modulation of these variants on psychiatric comorbidities in AD. CONCLUSIONS: Although we failed to find a direct relationship between AD and the genetic variants investigated, possible connections with inflammation and psychiatric symptoms were suggested.

Suicide in Greece 1992-2012: A time-series analysis.

BACKGROUND AND AIMS: Since 2008, Greece has entered a long period of economic crisis with adverse effects on various aspects of daily life. In this frame, it is quite important to examine the suicide trends in Greece. METHOD: Our analysis covered the period 1992-2012. 2012 was the last year for which official suicide data were available. The inclusion of data for pre-crisis period enabled us to assess trends in suicide preceding the economic crisis, starting in 2008. Trends in sex- and age-adjusted standardized suicide rates (SSR) were analyzed using joinpoint regression. RESULTS: Total SSR presented statistically significant annual decrease of 0.89% (95% confidence interval (CI): -1.7, -0.1) during the period 1992-2008. After 2009, the trend in total SSR increased statistically significant annual increase (12.48%; 95% CI: 0.3%, 26.1%). SSR in males presented an initial period of modest annual decrease (-0.84%; 95% CI: -1.6%, -0.1%), during the period 1992-2008. After 2009, an annual increase by 9.25% (95% CI: 2.7%, 16.3%) was revealed. No change in female SSR trend was observed during the studied period. CONCLUSION: According to the results of this study, there is clear evidence of an increase in the overall SSR and male SSR in Greece during the period of the current financial crisis.

Anxiety and depression among Greek men with primary erectile dysfunction and premature ejaculation.

BACKGROUND: Erectile dysfunction (ED) and premature ejaculation (PE) are the two most prevalent sexual disorders among males associated with significant distress and impairment in quality of life. The aim of this study was to investigate the prevalence of anxiety and depression symptoms among patients with primary ED and PE. METHODS: A sample of 57 men (ED = 31; PE = 26) were compared to 25 male outpatients with anxiety disorder (AD) and 25 healthy controls. Principal assessment measures included the State-Trait Anxiety Inventory (STAI) and the Beck Depression Inventory (BDI). RESULTS: Greater levels of STAI state anxiety were reported among the ED, PE, and AD groups as compared to healthy controls. In contrast ED and AD groups scored higher than controls on the STAI trait anxiety and BDI, but PE scores were not different from healthy controls in both measures. CONCLUSIONS: The study findings suggest that both primary ED and PE are conditions associated with significant state anxiety; however, PE appears to be less associated with trait anxiety and depression compared to ED, a finding that corroborates the recent acknowledgement of PE as a more biologically based condition. Limitations and potential clinical implications are also discussed.

What to expect from a third step in treatment resistant depression: A prospective open study on escitalopram.

OBJECTIVES: Only few studies investigated treatment strategies for treatment resistant depression (TRD). The objective of this multicentre study was to evaluate TRD patients who did not respond to at least two antidepressants. METHODS: A total of 417 patients, who failed to respond to a previous retrospectively assessed antidepressant (AD1), were firstly included in a 6-week venlafaxine treatment (AD2); secondly, those who failed to respond were treated for further 6 weeks with escitalopram (AD3). RESULTS: Out of 417 patients who had failed to respond to previous treatment (AD1), 334 completed treatment with venlafaxine to prospectively define TRD. In the intent to treat (ITT) population in the first phase of the trial (AD2), responders to venlafaxine were 151 (36.21%) out of which remitters were 83 (19.90%). After phase one, 170 non-responders, defined as TRD, were included in the second phase and 157 completed the course. Of the 170 ITT entering the second phase (AD3), responders to escitalopram were 71 (41.76%) out of which remitters were 39 (22.94%). After the third treatment, patients showed a dropout rate of 7.65% and a rate of presence of at least one serious adverse event of 19.18%. CONCLUSIONS: Relevant rates of response and remission may be observed after a third line treatment in patients resistant to two previous treatments. A relevant limitation of this study was represented by the design: naturalistic, non-randomized, open-label, without a control sample and with unblinded raters.

Quality of life in schizophrenia spectrum disorders: associations with insight and psychopathology.

Therapeutic interventions in chronic mental illness face the important challenge to pursuit the quality of life (QOL) of patients. Insight into chronic mental illness, though a prerequisite for treatment adherence and a positive therapeutic outcome, has shown adverse associations with subjective QOL. This study aims to explore the contribution of psychopathological symptoms on the ambiguous role of insight on QOL. Seventy-two outpatients with schizophrenia spectrum disorders were assessed using the positive and negative syndrome scale, the scale to assess unawareness of mental disorder, and the WHOQOL-100 instrument for the assessment of quality of life. Insight was found to associate inversely with quality of life. Among psychopathological symptoms, depressive symptoms were the strongest negative contributor on QOL. Mediation analysis revealed that the effects of awareness of the consequences of illness on QOL were largely mediated by depressive symptoms (full mediation for the effect on physical and psychological domain and partial mediation for the effect on independence and environment domain of the QOL). Our results suggest that the inverse relationship between insight and subjective quality of life is partially mediated by depressive symptoms. We discuss theoretical and therapeutic implications of the findings, in conjunction with similar recent research data.

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.

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.

Suicidal behavior in a patient with burning mouth syndrome.

Introduction. Chronic pain of the oral cavity is a long-term condition and like all other types of chronic pain is associated with numerous comorbidities such as depression or anxiety. Case Presentation. This is a case of a 93-year-old patient suffering from chronic oral cavity pain who repeatedly stabbed his palate due to ongoing local pain, over the last few months, which he could not further tolerate. The patient was suffering from depression and also a diagnosis of "burning mouth syndrome" (BMS) was made. Discussion. Burning mouth syndrome (BMS) is characterized by a burning sensation in the tongue or other oral sites. BMS has high psychiatric comorbidity but can occur in the absence of psychiatric diagnosis. Patients with multiple forms of pain must be considered as potential candidates for underdiagnosed depression (major) and suicidal thoughts.

Comorbid attention-deficit/hyperactivity disorder in adult psychiatric outpatients with depressive or anxiety disorders.

BACKGROUND: There are very few studies reporting on the prevalence and the contribution of not previously diagnosed ADHD in the clinical picture of other psychiatric disorders. The aim of our study is to determine the prevalence and clinical correlates of comorbid attention deficit/hyperactivity disorder (ADHD) in adult psychiatric outpatients with depressive or anxiety disorders. METHODS: During a 6-month period, 114 outpatients with depressive or anxiety disorders were evaluated for ADHD diagnosis. Assessment included interviews with both patient and relatives/friends and the use of a daily diary. Moreover, the patients completed the self-report scales Beck Depression Inventory (BDI), Spielberger's Anxiety Inventory (STAI), and the Symptom Checklist-90-R Rating Scale (SCL-90-R). RESULTS: A total of 22 out of 114 patients (19.3%) received an ADHD diagnosis for the first time in their life. Comorbid ADHD compared to non ADHD patients scored significantly higher (p < 0.05) for depression (BDI), state and trait anxiety (STAI) and in the following SCL-90-R factors: Positive Symptoms Distressing Index, Positive Symptoms Index, Somatization, Obsessive Compulsive, Depression, Anxiety, and Hostility. CONCLUSIONS: ADHD might go unrecognized among psychiatric outpatients. Patients with depressive or anxiety disorder reporting more severe symptomatology should be carefully screened for possible comorbid adult ADHD.

Cytokines, diabetes mellitus and psychopathology: a challenging combination.

OBJECTIVES: The aim of this study was to investigate the association of IL-6, IL-12, and TNF-α with trait and state psychological factors in type 2 diabetic patients. DESIGN: Patients were divided in two groups. Group A consisted of 86 controlled diabetic patients (HbA1c<7) and the Group B consisted of 45 uncontrolled diabetic patients (HbA1c ≥ 7). SETTINGS: During the initial phase of the study (T0), blood samples were taken for measuring IL-6, IL-12 and TNF-α serum levels as well as a battery of psychometric instruments. One year later (T1), the uncontrolled diabetic patients were re-evaluated with the use of the same psychometric instruments and with the identical blood analysis. RESULTS: The average values of tnf-α were significantly different among controlled (7.73 ± 5.51) and uncontrolled patients (9.29 ± 4.52) at a significance level of 5% (p=0.009). Controlled diabetic patients show a statistically significant relationship between IL-6 and neuroticism (rp=0.303, p=0.010), and between IL-12 and psychotism, (rsp=0.382, p=0.001). Controlled diabetic patients show a statistically significant relationship between IL-12 and the act out hostility (rsp=-0.307, p=0.009). The scores of the psychometric tests differ significantly between the first and second evaluation. Acting out hostility and the direction of hostility increased when HbA1c values fell below the threshold of 7, while the total hostility index, as well as all other scales, dropped when patients controlled their metabolic profile. CONCLUSIONS: The present results provide evidence that IL-6, IL-12 and TNF-α are closely related to the course and treatment of type 2 diabetes.