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INTRODUCTION: The uncertainty regarding the scientific status of psychiatry arises from psychiatry's involvement with some unsolved problems, or put in another way, from its enmeshment in certain points of transition of contemporary science. There is, in primis, the unsolved problem of the relationship between the mind and the body and, moreo- ver, the intricate relationship of connection/disjunction among biology, social science, anthropology, philosophy, etc. To speak about what psychopathology can expect from philosophy is, above all, to immerse oneself in a debate about the conditions of possibility of psychiatry as a science. This debate is especially concerned with the models of knowledge that have, until now, been proposed to psychiatry. Those models oscillate between the Dilthey's paradigms of the "Science of Nature" and the "Science of Spirit".METHODS: It is certain that psychopathology, as already indicated by Jaspers, is a discipline which is among the most involved regard- ing the use of the two different cognitive strategies. The first strategy concerns the concept of "explanation" and its rigid approach to the objective and ultimate cause of the phenomenon. The second strategy is the "comprehensive" approach. This model, which the hermeneutic thought defines "interpretative", theorizes the provisional character, the subjectiveness and the finiteness of every cognitive project.RESULTS: The interest of the authors is orientated towards the hermeneutic side (comprehensive-interpretative) of psychiatry, that which deals with the specificity of every clinical history, with the continuity of sense, and with intrinsic narrative intelligibility of every human event, psychopathological or not.CONCLUSIONS: This approach to psychopathology is based on the statement: "a clinical history is a text which must be interpreted". From this perspective, every clinical history should be perceived as a text to decipher but, above all, as a "text" to listen to, in the persevering expectation that it could disclose its particular "project of world". When speaking about psychiatry, we always face a problem which dominates all the others: the unsolved problem of the relation- ship between typicalness and singularity of subjective events. B.B. Mandelbrot, theorist of "fractals", sums this dilemma up clearly. He suggests that the innumerable variety of the configurations of Nature is a challenge to investigate the morphology of that which is "irregu- lar" in order to discover in it, as far as possible, a rule.

Background: Social adjustment is impaired in depressed patients. The difficulty to adjust to social circumstances has been hypothesized to be one of the causes of depression, as well as a consequence of the disorder. Genetic variation in the serotonin transporter gene has been previously associated with social adjustment levels in patients with mood disorders. Methods: We investigated whether variations on the HTR1A (rs6295) and HTR2A (rs7997012) genes were associated with levels of social adjustment using the Social Adjustment Scale in two samples of depressed patients (total n=156). Results: Patients carrying the GG genotype of the HTR2A-rs7997012 showed better social adjustment in areas of work and family unit bonding. Limitations: These findings did not survive correction for multiple testing and should be interpreted with caution. Conclusion: Our finding is in line with previous observations that have associated the G allele of the HTR2A-rs7997012 with higher rate of antidepressant response. The HTR2A-rs7997012 is worthy of further investigation in studies examining factors that are related to depression course and outcome. (C) 2013 Elsevier B.V. All rights reserved

MAOA and, to a lesser extent, MAOB poly- morphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was com- posed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring fac- tors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI ''anger-out'' subscale) in male suicidal patients compared to controls (p \ 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale (''anger out'') (p = 0.002). Allele frequen- cies of the MAOA rs909525 were associated with suici- dality (p \ 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relation- ship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted.

In the present study, aimed at investigating whether a set of single nucleotide polymorphisms (SNPs) within PTGS2 gene (rs4648276, rs2066826 and rs689466) could be associated with antidepressant response, remission and treatment resistance in a sample of major depression patients, we did not find evidence supporting any of such associations. © 2010 Elsevier Ltd.

Binge-eating (BE) symptoms are relatively common in major depressive disorder (MDD), but their prognostic role is not fully understood. This study compared two groups of patients with MDD experiencing or not BE symptoms to ascertain differences in terms of clinical manifestations, presence of bipolar features, and antidepressant treatment outcomes. The study involved 482 outpatients collected within the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, who were assessed with scales for depressive and hypomanic symptomatology, suicidality, comorbid mental disorders, and childhood traumas. BE symptoms were reported in 95 patients (20%). Patients with MDD experiencing BE symptoms were characterized by higher scores of negative self-outlook ( P = 0.0018), negative outlook of future ( P = 0.0014), irritability ( P = 0.0043), comorbid anxiety disorders (generalized anxiety disorder: P = 0.0006; panic disorder: Plt; 0.0001; social phobia: Plt; 0.0001), obsessive-compulsive disorder ( P = 0.0053), hypomanic symptoms (increased talkativeness: P = 0.0029; reduced need for sleep: P = 0.0171), and suicidality (suicidal propensity: P = 0.0013; suicidal risk: P = 0.0148; lifetime suicidal behavior: P = 0.0052). BE symptoms (OR = 2.02; 95% CI = 1.06-3.84) and depression severity (OR = 1.04; 95% CI = 1.00-1.08) were independently associated with lifetime attempted suicide. The presence of BE symptoms might indicate higher severity of depressive disorder. Suicidal risk is a major issue in these patients, whereas the association between BE and bipolar features needs further research.

Cytochrome P450 genes are involved in the metabolism of antidepressants and could influence treatment response. The aim of this study was to investigate the role of allelic variations of the cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes in antidepressant treatment response and remission rates. Two hundred and seventy-eight patients affected by major depression, responders (N=81) and nonresponders (N=197) to at least one adequate antidepressant treatment, were recruited with a multicentre design for resistant depression and genotyped for all relevant variations. None of the considered metabolic profiles (e.g. poor, intermediate, extensive and ultrarapid metabolizers) was found to be associated with either response or remission rates. In conclusion, the investigated cytochrome genes do not seem to play a major role in antidepressant response in the present sample of depressive patients. Nevertheless, methodological and sample size limitations of this study do not allow definitive conclusions. Int Clin Psychopharmacol 24:250-256 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Several studies investigated possible associations between single nucleotide polymorphisms and the temperament and character inventory (TCI) scores. The possible association between TCI scores and the estrogen receptors 1 (ESR1) polymorphisms, which are expressed in cerebral regions that are involved in the development of temperament and character, has not been investigated yet. The aim of the present study is to investigate possible associations between specific ESR1 polymorphisms and TCI scores. Two hundred eighty-nine healthy subjects and I I I suicide attempters were enrolled in the study. All subjects compiled TCL Rs827421, rs1913474, rs1801132, rs722207, rs974276, and rs910416 in ESR1 were genotyped. Rs722207 was associated with Harm Avoidance (HA) in the healthy sample (P = 0.003). Further associations have been found for two HA subscales, HA2 and HA3, in the healthy sample. Additionally, the haplotype rs722207-rs974276 showed an association with HA (P = 0.0003) and HA2 (P = 0.0002) in the global sample and in healthy volunteers and HA3 showed an association in the global sample. Our study showed a moderate association between ESR1 variants and TCI scores. The main finding concerns the association between rs722207 and HA in the healthy sample. Further research is needed to replicate our findings and to investigate further ESR1 polymorphisms. (C) 2008 Wiley-Liss, Inc

In Italy, although the number of foreign-born residents has grown exponentially, there are no data on mortality risk among migrants who have alcohol use disorders (AUDs). We examined the mortality risk and causes of death for natives and non-natives in a cohort of individuals treated for AUDs in Northern Italy in the period from 01/01/1975 to 31/12/2016. We highlight important characteristics of non-natives compared to Italians: 1) a younger age and a higher proportion of females; 2) a better health status; 3) a better social capital 4) a lower risk of death. We found differences in mortality between the various areas of origin, with a higher risk among participants born in Asia and African countries other than Mediterranean. The excess mortality compared to the reference population (SMRs) was at least three times for Italians and two times for migrants. While the non-native patients with AUDs have in general better health than Italians with AUDs, our results highlighted higher percentage of dropouts from treatment and lower access to Mental Health Services, suggesting that barriers to the access and completion of therapeutic programs still exist.

Available evidence concerning the side effects experienced by bipolar disorder (BD) patients under naturalistic conditions has been poorly investigated. The aim of this study was therefore to investigate side effects related to major psychotropic drugs in two independent samples of BD patients naturalistically treated with mood stabilizers, antidepressants, antipsychotics and/or anxiolytics. Overall, 3654 patients from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) sample and 282 patients from the Clinical Outcome and Psycho-Education for Bipolar Disorder (COPE-BD) sample were included. The primary outcome measure was the influence of each class of psychotropic drugs under investigation on the emergence of any side effect, as measured with the monitoring form in the STEP-BD study and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale in the COPE-BD study. Secondary outcome measures included the effects of such drugs on psychic, neurologic, autonomic and other side effects. Mood stabilizers and antipsychotics were associated with high rates of side effects in both samples. Furthermore, antipsychotics were specifically associated with psychic side effects, whereas mood stabilizers were specifically associated with neurologic side effects. Our results largely confirm in a naturalistic setting results previously observed in randomized controlled trials focusing on BD patients.

Background: Little is known about the extent to which a family history of major depression (MD) affects residual depressive symptoms in responder and non-responder patients suffering from MD. Methods: Nine hundred eighty-six patients with MD were recruited within the context of a large multicenter project. Information about the family history of MD, as well as about total depressive symptoms and specific depressive clusters, was collected and analyzed. Results: No significant difference was observed in overall depressive symptoms between patients with and those without a family history of MD. However, non-responder patients with a family history of MD showed significantly higher scores in core symptoms as compared with responder patients without a family history of MD. Conclusions: Non-responder MD patients with a positive family history of MD could represent a slightly different sub-group of MD patients with more consistent core depressive symptoms as compared with responder patients without a family history of MD. However, taking into account the retrospective assessment of data, the use of positive or negative family history as a dichotomous indicator of familial loading and the cross-sectional design of the present study, further research is needed to draw more definitive conclusions. (C) 2014 Elsevier Inc. All rights reserved.

Objective: Eating disorders are influenced by both environmental factors and genes. The 5-HTTLPR polymorphism of serotonin transporter gene has been suggested as a good candidate. This meta-analysis was undertaken: (1) to investigate the association between 5-HTTLPR and eating disorders considered as a whole, including anorexia (AN), bulimia (BN), and binge eating disorder (BED); (2) to extend recently reported findings on the association between 5-HTTLPR and AN-BN. Method: PubMed, ISI, and PsycINFO databases were searched for studies published until October 2009. Fifteen studies have been included. Data were analyzed with the Cochrane Collaboration Review Manager Software. Quality of studies and publication bias were assessed. Results: An association between S allele and eating disorders, in particular AN, has been found. Discussion: To be carrier of the 5-HTTLPR S allele seem to represent a risk factor for eating disorders, especially for AN. However, considering the reported high between-study heterogeneity, future studies should focus on more homogeneous endophenotype. (C) 2010 by Wiley Periodicals, Inc

Suicide is one of the leading causes of death among young adults. Both genetic and personality factors plausibly have a role on suicidal behavior. We focused on the catechol-O-methyltransferase gene (COMT) and we performed: a review of studies investigating the association between COMT and both suicidal behavior and personality; a meta-analysis of studies investigating the association between suicidal behavior and COMT rs4680 polymorphism; an association study investigating the link between seven COMT polymorphisms (rs737865, rs5844402, rs5993883, rs4680, rs4633, rs165599 and rs9332377) and both personality traits and suicidal behavior. For the review and the meta-analysis we performed an electronic search to identify studies focused on the association between COMT and both suicidal behavior and personality. The sample of the association study was composed of three groups: 289 German healthy controls, 111 German suicide attempters and 70 Italian mood disorder patients. From the review, the meta-analysis and the association study no relationship emerged between COMT and suicidal behavior. Nevertheless, from both review and association study several links were found between COMT and personality traits. In particular, in the association study we found a significant correlation between rs4633 and Reward Dependence (Temperament and Character Inventory). As secondary results we found an association between rs737865 and Angry Reaction (State-Trait Anger Expression Inventory) and between rs9332377 and Irritability (Questionnaire for Measuring Factors of Aggression). Our findings suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of a COMT role in the modulation of personality traits has been found.

The 5-HT2A receptor is a key modulator of the serotonin pathway. We previously observed a marginal association between 5-HT2A gene variants and antidepressant efficacy in Japanese and Italian population but in the opposite direction. In the present report, we hypothesize that discrepant findings on 5-HT2A gene variants could be due to both the effect of ethnicity and a possible specific effect on some symptom improvement. The sample comprised 203 patients affected by mood disorders and treated for major depression with paroxetine or fluvoxamine. The total depressive scores for all patients were analyzed in previous reports, but symptomatologic clusters were not examined previously. The 21-item Hamilton Rating Scale for Depression (HAM-D) was administered to evaluate depressive symptoms at baseline and bi-weekly over 6 weeks of treatment. All patients were genotyped for the 5-HT2A T102C polymorphism. Compared with patients with the 5-HT2A T and C variants, in the Japanese sample T allele carriers showed selective and slower score reductions than C allele carriers in delusion and activity symptoms; on the other hand, in the Italian sample, C allele carriers showed a slower and selective score reduction compared with T allele carriers in Somatic anxiety, while they did not differ from other patients on the other scores. Despite the limitations of the small sample size and modest significance levels, these findings suggest that response to SSRIs is not a unitary phenomenon and discrepant findings across ethnic groups may be due to differential effects of gene variants. (C) 2007 Elsevier Ireland Ltd. All rights reserved.

The aim of this study is to summarize available knowledge about common genetic, clinical, demographic and psychosocial predictors of response to pharmacotherapy in mood and anxiety disorders. A literature search was carried out by using MEDLINE and references of selected articles. The search included articles published up to March 2008. The main genetic finding concerns the serotonin transporter gene promoter polymorphisms, the long variant of which seems to be related to a positive response to therapy in mood disorders and could also have a role in the treatment of anxiety disorders. Among other predictors, the main factors common to both classes of disorder are comorbid axis II disorders and early onset of illness, which are related to a worse response to therapy and concomitant good physical conditions, absence of earlier treatments, early administration and response to therapies, and higher self-directedness, which is related to a better outcome. Many common predictors have been identified and these seem to be related to features covering the totality of patients that go beyond specific characteristics of single disorders. Possible limitations and suggestions for future research based on a more integrated vision of human complexity are discussed. Int Clin Psychopharmacol 24:1-18 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Introduction: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). Method: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males – 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. Results: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. Conclusions: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition.

Introduction The aims of this systematic review and meta-analysis are to provide a summary of the current literature concerning compulsory treatments in patients with eating disorders (ED) and to understand whether compulsorily and involuntarily treated patients differ in terms of baseline characteristics and treatment outcomes. Methods Relevant articles were identified following the PRISMA guidelines by searching the following terms: “treatment refusal”, “forced feeding”, “compulsory/coercive/involuntary/forced treatment/admission”, “eating disorders”, “feeding and eating disorders”, “anorexia nervosa”, “bulimia nervosa”. Research was restricted to articles concerning humans and published between 1975 and 2020 in English. Results Out of 905 articles retrieved, nine were included for the analyses allowing the comparisons between 242 compulsorily and 738 voluntarily treated patients. Mean body mass index (BMI) was slightly lower in patients compelled to treatments. Mean illness duration, BMI at discharge and BMI variation showed no significant differences between the two groups. Average length of hospitalization was 3 weeks longer among compulsory-treated patients, but this did not result in a higher increase in BMI. No significant risk difference on mortality was estimated (three studies). Conclusions Compulsory treatments are usually intended for patients having worse baseline conditions than voluntary ones. Those patients are unlikely to engage in treatments without being compelled but, after the treatments, albeit with longer hospitalisations, they do achieve similar outcomes. Therefore, we can conclude that forcing patients to treatment is a conceivable option. Level of evidence Level I, systematic review and meta-analysis.

About 20–30% of patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD) and finding new effective treatments for TRD has been a challenge. This study aimed to identify new possible pharmacological options for TRD. Genes in pathways included in predictive models of TRD in a previous whole exome sequence study were compared with those coding for targets of drugs in any phase of development, nutraceuticals, proteins and peptides from Drug repurposing Hub, Drug-Gene Interaction database and DrugBank database. We tested if known gene targets were enriched in TRD-associated genes by a hypergeometric test. Compounds enriched in TRD-associated genes after false-discovery rate (FDR) correction were annotated and compared with those showing enrichment in genes associated with MDD in the last Psychiatric Genomics Consortium genome-wide association study. Among a total of 15,475 compounds, 542 were enriched in TRD-associated genes (FDR p < .05). Significant results included drugs which are currently used in TRD (e.g. lithium and ketamine), confirming the rationale of this approach. Interesting molecules included modulators of inflammation, renin-angiotensin system, proliferator-activated receptor agonists, glycogen synthase kinase 3 beta inhibitors and the rho associated kinase inhibitor fasudil. Nutraceuticals, mostly antioxidant polyphenols, were also identified. Drugs showing enrichment for TRD-associated genes had a higher probability of enrichment for MDD-associated genes compared to those having no TRD-genes enrichment (p = 6.21e-55). This study suggested new potential treatments for TRD using a in silico approach. These analyses are exploratory only but can contribute to the identification of drugs to study in future clinical trials.

Patients suffering from major depression and related pathologies (feeding and eating disorders, obsessive-compulsive disorder, post-traumatic stress disorder, anxiety disorders, etc.) are usually treated with antidepressant agents belonging to several pharmacological and chemical classes; the most recent of these agents are collectively known as “new-generation antidepressants”. In these patients, therapeutic drug monitoring (TDM) with the determination of drug and metabolite blood levels is one of the most useful procedures to optimise and personalise the treatment, enhancing both effectiveness and safety. A new approach is proposed in this study, based on microsampling of both blood and oral fluid by means of volumetric absorptive microsampling (VAMS). This approach makes sampling and storage much simpler and even self- and at-home-sampling possible, while retaining reliability, vastly increasing analyte stability and reducing overall expenses. The microsamples were pretreated by means of microextraction by packed sorbent (MEPS) on C2 sorbent and analysed by liquid chromatography with sequential spectrophotometric and spectrofluorimetric detection (HPLC-UV-FL). Method validation results were satisfactory (extraction yield >84%, precision RSD < 8.9%, stability>85.0% after 3 months). Application to blood and oral fluid VAMS from patients treated with four possible different antidepressants (sertraline, fluoxetine, citalopram and vortioxetine) provided results always in good agreement with those obtained from the corresponding fluid matrices, including the levels of drug metabolites.

Objective: The present study aims at exploring associations between a continuous measure of distorted thought contents and a set of demographic and clinical features in a sample of unipolar/bipolar depressed patients. Methods: Our sample included 1,833 depressed subjects. Severity of mood symptoms was assessed by the 21 items Hamilton Depression Rating Scale (HAM-D). The continuous outcome measure was represented by a delusion (DEL) factor, extracted from HAM-D items and including items: 2 ("Feelings of guilt"), 15 (" Hypochondriasis"), and 20 ("Paranoid symptoms"). Each socio-demographic and clinical variable was tested by a generalized linear model test, having depressive severity (HAM-D score-DEL score) as the covariate. Results: A family history of major depressive disorder (MDD; p=0.0006), a diagnosis of bipolar disorder, type I (p=0.0003), a comorbid general anxiety disorder (p, SCOPUS: ar.j, info:eu-repo/semantics/published

Objective The worldwide phenomenon of an aging population combined with the increasing prevalence of depression in late life are issues that need to be addressed. This study aims to estimate the frequency of depression and subthreshold depression occurring in a sample of cognitively well-functioning, community-dwelling, older Italian adults and to investigate sociodemographic and clinical correlates of depression, exploring gender differences. Methods We used a cross-sectional analyses of survivors in a population-based study (the Faenza Project) that included 359 subjects aged 74 years and older (49.3% women). A modified version of Cambridge Examination for Mental Disorders of Elderly Persons-Revised was administered to all participants. Prevalence rates of depression and 95% confidence intervals (CIs) were estimated according to International Classification of Diseases, Tenth Revision criteria. Statistical analyses were implemented to describe sociodemographic and clinical features associated with depression. Odds ratios were estimated by multivariate logistic regression, and the dependant variable was any type of depression. Results Overall prevalence of depression was 25.1% (95% CI: 20.6–29.6), with no evidence of gender difference. Prevalence of mild, moderate, and severe depression was 16.4% (95% CI: 12.6–20.2), 7.5% (95% CI: 4.8–10.2), and 1.1 (95% CI: –0.4–2.6), respectively. A rate of 5.6% of the population complained of subthreshold depressive symptoms. After age 81, depression occurrence decreased as age increased. The association between depression and functional measures, such as primary activity, mobility, and disability in performing household chores, were stronger in men than in women. Similarly, severely disabling conditions like stroke were more strongly associated with depression in men than in women. Conclusion Our data suggest a disparity between men and women regarding the impact of depression on everyday life. Specific gender differences need to be taken into account for the evaluation of the depression-related burden in late life.

Second-generation antipsychotics (SGA) have been associated with risk of stroke in elderly patients, but the molecular and genetic background under this association has been poorly investigated. The aim of the present study was to prioritize a list of genes with an SGA altered expression in order to characterize the genetic background of the SGA-associated stroke risk. Genes with evidence of an altered expression after SGA treatments in genome-wide investigations, both in animals and men, were identified. The Genetic Association Database (GAD) served to verify which of these genes had a proven positive association with an increased stroke risk, and along with it each evidence was tested and recorded. Seven hundred and forty five genes had evidence of a change of their expression profile after SGA administration in various studies. Nine out of them have also been significantly related to an increased strokes risk. We identified and described nine genes as potential candidates for future genetic studies aimed at identifying the genetic background of the SGA-related stroke risk. Further, we identify the molecular pathways in which these genes operate in order to provide a molecular framework to understand on which basis SGA may enhance the risk for stroke.

Early antidepressant response (2nd week) has been reported as the result of a true antidepressant effect and a predictor of subsequent stable response. With the purpose to study the clinical profile of early response/remission (2nd week) compared to late response/remission (4th-6th weeks), two independent major depressive disorder (MDD) samples (the Sequenced Treatment Alternatives to Relieve Depression or STAR*D n=1922 and an Italian sample n=171) were investigated. Patients were treated with citalopram in the STAR*D while in a naturalistic setting in the Italian sample. Depressive symptomatology was assessed by the Hamilton Depressive Rating Scale weekly in the Italian sample and biweekly by the Quick Inventory of Depressive Symptomatology Clinician Rated in the STAR*D. Logistic regression was used to investigate possible predictors of early response and the Bonferroni correction was applied. In the STAR*D, higher levels of baseline core depressive symptoms (Bech subscale) were associated with early response (p=0.00017), as well as lower baseline insomnia (p=0.003) and higher work and social functioning (p=0.001). In the Italian sample none of these variables were associated with the phenotype, but a non significant trend of lower baseline quality of life (p=0.078) was observed in late remitters. In the STAR*D late responders reported higher levels of antidepressant induced side effects, especially difficulty in sleeping (p=5.68e-13), with a non significant trend in the same direction in the Italian sample (p=0.09). The identification of late versus early antidepressant responders at the beginning of the treatment may be useful to guide therapeutic choices in clinical settings.

We previously investigated a sample of psychotic patients acutely ill and acutely treated with haloperidol in the search for genetic predictors of response at PANSS scores during the first month of treatment. In the present work we extend the analysis to a wider panel of genetic variations including SNPs harbored by genes whose products are involved in molecular pathways consistent with the latest results of genome-wide association studies (GWAS) of antipsychotic efficacy. 96 Patients were investigated. The results were replicated in an independent sample of bipolar manic patients treated with antipsychotics (n tot=470, the sample was retrieved from the STEP-BD). Outcomes were the PANSS variation through time in the first sample, and changes of mania symptomatology at any two consecutive observations in the public available STEP-BD replication sample. A list of variations harbored by AKAP13, CACNA1, GRIK4 and GRIA1 were found to be significantly associated with outcome in both samples (different set of variations for each sample). Results did not survived multiple testing in the original sample but were replicated in both samples. This finding stresses the relevance of the glutamatergic system and regulatory molecular cascades in antipsychotic response. Nonetheless, the level of significance and the indirect and incomplete replication mandate cautiousness and further replication.

OBJECTIVE: The aim of this literature review was to assess the effects of Animal-Assisted Interventions (AAI) on elderly patients with dementia or various psychiatric disorders. METHODS: We conducted a comprehensive literature search using the online PubMed network of the US National Library of Medicine & National Institutes of Health, Embase, PsycINFO, with the purpose of investigating AAI effects on cognitive functions, mood, and behaviour. RESULTS: A total of 18 articles on dementia and 5 on psychiatric disorders were included in the present review. AAI were found to have positive influences on demented patients by reducing degree of agitation and by improving degree and quality of social interaction. Few studies have assessed the effects of AAI on mood, and even fewer have assessed its consequences on cognitive functions. The results that are available indicate a positive effect on communication and coping ability, but none on cognitive performance. A substitute pet robot yielded encouraging results, but its use requires further investigation. The few studies conducted for elderly patients presenting a variety of psychiatric diagnoses produced controversial findings. CONCLUSIONS: In spite of the encouraging results of AAI, much more research examining the issue of optimal AAI duration, frequency of sessions, and suitable target group is needed.

Alzheimer's disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-alpha; IL-6; IFN-gamma) and low plasma levels of cyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). Plasma B12 levels were measured by radioligand binding assay. Basal and PMA-stimulated levels of IFN-gamma, TNF-alpha, and IL-6 were measured by ELISPOT (PBMC culture supernatant). 47 patients were genotyped for APOE. Ten patients (18%) had their B12 levels below < 250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features; their MMSE scores were lower (14.7 vs 19.6 p=0.03) but not after adjustment for disease duration. A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml vs 976 p< 0.01); this association was confirmed after controlling for age of onset and APOE genotype. In conclusion, low B12 level is associated with greater production of IL-6 in peripheral blood mononuclear cells. Further research is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in the pathophysiology of AD.

Response to pharmacological treatments is moderated by both genetic and environmental factors. The contribution of such factors is relatively small and complex interactions are likely to be involved. Serotonin transporter gene (SLC6A4) is a major candidate gene associated to response to antidepressant treatment. Moreover, the 5-HTTLPR polymorphism has been associated with anxiety-related traits such as neuroticism and harm avoidance (HA), which are known to influence the risk to develop mood disorders and response to treatments. In the present study we aimed to investigate the interaction between 3 SLC6A4 variants and HA on medium term antidepressant response in a sample of depressed bipolar-spectrum patients followed for 12 months. Contrary to expectations, SLC6A4 variants did significantly influence neither the course of depressive symptoms nor HA scores. However, a significant interaction was observed between HA and 5-HTTLPR genotype. Indeed, a high HA impaired outcome in patients carrying the L(G)/S or the S/S genotype more than in L(A)/L(A) patients. Though a number of limitations characterize the present study, our results indicate HA as a potential moderator of the effect of 5-HTTLPR on the outcome of depression. Given that many factors may influence response to pharmacological treatments, studies that consider personality and other individual characteristics are warranted also in pharmacogenetic investigations.

Objective:Genetic factors are largely implicated in predisposing to schizophrenia. Environmental factors contribute to the onset of the disorder in individuals at increased genetic risk. Cognitive deficits have emerged as endophenotypes and potential therapeutic targets for schizophrenia because of their association with functional outcome. The aims of this review were to analyse the joint effect of genetic and environmental (G×E) factors on liability to schizophrenia and to investigate relationships between genes and cognitive endophenotypes focusing on practical applications for prevention and rehabilitation.Methods:Medline search of relevant studies published between 1990 and 2008.Results:In schizophrenia, examples of G×E interaction include the catechol-O-methyl transferase (COMT) (Val158Met) polymorphism, which was found to moderate the onset of psychotic manifestations in response to stress and to increase the risk for psychosis related to cannabis use, and neurodevelopmental genes such as AKT1 (serine-threonine kinase), brain-derived neurotrophic factor (BDNF), DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate receptor 3), which were associated with development of schizophrenia in adulthood after exposure to perinatal obstetric complications. Neurocognitive deficits are recognised as core features of schizophrenia that facilitate the onset of the disorder and have a great impact on functional outcome. Neurocognitive deficits are also endophenotypes that have been linked to a variety of genes [COMT, neuregulin (NRG1), BDNF, Disrupted-In-Schizophrenia 1 (DISC1) and dysbindin] conferring susceptibility to schizophrenia. Recently, it has emerged that cognitive improvement during rehabilitation therapy was under control of COMT (Val158Met) polymorphism.Conclusion:This review could indicate a pivotal role of psychiatric genetics in prevention and rehabilitation of schizophrenic psychoses.

Clinical outcome of alcoholism may be partly under genetic control. The serotonergic system is involved in alcohol intake, and it has been widely investigated in alcohol dependence. Recently, attention has been focused on the neuronal tryptophan hydroxylase 2 gene (TPH2). TPH2 variants have been consistently associated with anxiety-related traits; since anxiety is critical for alcohol dependence treatment, in the present paper we investigated 9 SNPs within the THP2 gene in anxiety symptoms during the detoxification procedure. The sample comprised 68 alcohol-dependent patients who where evaluated with the Hamilton Rating Scale for Anxiety, before and after the detoxification procedure. Other psychopathological indicators of outcome, such as depression and anxiety sub-features were also investigated. We did not observe a role for TPH2 variants in the efficacy of treatment in relieving anxiety and other psychopathological symptoms. However, a haplotype that included the promoter rs4570625 polymorphism (associated with anxiety-related traits in previous studies) showed an association with the severity of anxiety symptoms on admission. This preliminary finding, although obtained on a small sample, may provide further support for a role of the TPH2 gene in emotional behaviors. Furthermore, the present study suggests the possible functional significance of the promoter rs4570625 polymorphism. The present preliminary results are of interest in alcoholism, given that comorbidity with anxiety represents a critical problem in treatment settings and response to detoxification.

The incidence or recurrence of major depression is greatly increased in women during the transition to and after menopause and hormonal changes occurring during these periods are thought to play an important role in depressive recurrence. It has been also suggested that a chronic hypoestrogenic state may reduce the response to antidepressant drugs, but whether or not, and the extent to which hormonal changes related to menopause influence the response to antidepressant drugs, is yet to be determined. Thirty-nine female patients (n=17 in pre-menopause; n=22 in post-menopause) with major depressive disorder (MDD) based on DSM-IV criteria, who were not on hormonal replacement therapy, participated in the study in order to prospectively evaluate the effect of menopausal status and its hormonal correlates on the effectiveness of antidepressant treatment for 6weeks. The Hamilton Depression Rating Scale-17 item (HAMD), the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression Severity scale (CGI-S) were administered at baseline, week 1, week 3, and week 6. The CGI-I scale was also assessed at weeks 1, 3, and 6. After controlling for age, age at onset, baseline symptom severity, antidepressant dosage and hormonal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), post-menopausal women showed a poor response to antidepressants over 6weeks of treatment, compared to the response of pre-menopausal women. Old age and high levels of FSH were also associated with the efficacy of antidepressants in post-menopausal women. In conclusion, sex hormones are known to interact with serotonergic, noradrenergic and dopaminergic systems. Despite methodological limitations, our study suggests that menopausal status and old age are predictors of a poor response to antidepressant treatment. Furthermore, the FSH may interfere with the mechanism of action of the antidepressant agents. Hence, larger, randomized and controlled trials are warranted to expand our understanding of this area.

Childhood attention deficit hyperactivity disorder (ADHD) symptomatology persists in a substantial proportion of cases into adult life. ADHD is highly heritable but the etiology of ADHD is complex and heterogeneous, involving both genetic and non-genetic factors. In the present article we analyzed the influence of both genetics and adverse life events on severity of ADHD symptoms in 110 adult ADHD patients. Subjects were genotyped for the norepinephrine transporter (NET), the catechol-O-methyltransferase (COMT), the serotonin transporter promoter polymorphism (SERTPR) and the more rare A/G variant within SERTPR. Three main outcomes were obtained: (1) adverse events showed a small but positive correlation with current ADHD severity; (2) NET, COMT and the A/G variant within SERTPR were not associated with ADHD severity; (3) taking into account stressors, the long (L) SERTPR variant showed a mild effect on ADHD, being associated with an increased severity, particularly as regard affective dysregulations; on the other hand, in subjects exposed to early stressors, it showed a protective effect, as compared to the short (S) variant. In conclusion, our data support the role of environmental factors in adult ADHD symptomatology. SERTPR may be involved in some features of the illness and act as a moderator of environmental influences in ADHD. © 2008 Wiley-Liss, Inc.

Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic. In this field, accurate understanding of genetics, which per se is a non-controllable risk factor, may help clinicians to prevent life-threatening side effects. So far, a number of genes have been associated with arrhythmia: SCN5A, SCN4B, CACNL1AC, KCNH2, KCNQ1, KCNE1, ANK2, ALG10, KCNJ2, KCNE2, RYR2, KCND3, KCND2, ACE, NOS1AP, CASQ2 and Rad. These genes represent good candidates for the definition of a genetic pro-arrhythmic profile. A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed. Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics. A list of relevant rare mutations within the selected genes is presented, together with a complete list of Tag SNPs covering the whole genetic sequence. The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. The selected variants, both mutations and polymorphisms, may help in defining a next-to-come genetic assessment to be performed before drug prescription in order to improve drug safety.

Dysbindin gene (DTNBP1) has been associated with schizophrenia, but literature findings are inconsistent, and further analyses are required. This study is aimed to investigate if a set of DTNBP1 variations might influence clinic psychotic phenotype or treatment response in a sample of 240 Korean schizophrenic in-patients. Four variants have been selected (rs3213207; rs1011313; rs16876759; rs2619522) on the basis of previous findings of association with schizophrenia, bipolar disorder and antidepressant response. Single marker analysis gave marginal results. Haplotype analysis identified a significant association between A–A (rs3213207(A/G), rs1011313(A/G)) haplotype and lower PANSS total and positive scores at baseline ( p = 0.01; 0.02) and at discharge ( p = 0.008; 0.005). Covariate analysis revealed a more stable significant association between A–A haplotype and baseline scores. These results suggest a protective effect of A–A haplotype on psychotic positive symptoms at baseline.

Dysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.

Variants at the gene encoding for the 5-hydrosytryptamine (serotonin) receptor 2A (HTR2A) have been associated with many psychiatric disorders such as schizophrenia, mood disorders, attention deficit hyperactivity disorder, suicide, anxiety disorders, obsessive-compulsive disorder, eating disorders, and Alzheimer's disease. The studied SNPs differ across studies, in the present review we focused on available evidence with the aim of identifying the overall phenotypic profile of HTR2A variant carriers. We then extensively analyzed all SNPs of the HTR2A gene with criteria of frequency, haplotype blocks, previous evidence, functionality in order to obtain a list of suitable SNPs for future studies that properly cover all possible genetic control of the HTR2A gene. Genetic association studies report conflicting and generally negative results. Most replicated data suggest C allele of the 102 T/C and Tyr452 variants as risk factor for psychosis and antipsychotic response, but the number of not replicating studies does not allow to draw any definite conclusion. Moreover their impact as risk factors is very small. In the other investigated psychiatric fields, evidence shows no involvement or at least a small and not replicated role for HTR2A gene variants. Conflicting and negative results could be due to a real marginal role of this receptor gene variants, or it could be caused by a lack of gene coverage of investigated SNPs. We suggest a wider investigation of the HTR2A gene to better understand its role in psychiatric disorders, preferably complemented with the use of proteomic or metabolomic approaches.

Background: According to the self-medication hypothesis, individuals with depression and anxiety disorders use alcohol to control their symptoms and subsequently become dependent. Conversely, alcohol dependence disorder (ADD) can cause or exacerbate psychiatric disorders. This study analyzed the characteristics of depression and social phobia secondary to ADD. (1) What is their functional impact? (2) Are they independent or associated conditions? (3) Do they completely remit in abstinent individuals? (4) Is the remission of one disorder associated with the remission of the other disorder? Methods: Sixty-four inpatients with ADD were evaluated with depression and anxiety disorder scales upon admission to hospital and after 5 weeks of detoxification. Results: Baseline comparisons differentiated patients with a Hamilton Rating Scale for Depression (HDRS) score >35 (n = 50; 78%) from those with an HDRS score ≤35 by higher levels of generalized anxiety and lower global functioning. Patients with generalized social phobia [Leibowitz Social Anxiety Scale (LSAS) score >60: n = 20; 31.2%] were not distinguishable from those with an LSAS score ≤60 by depressive and anxiety disorder symptoms. In postdetoxification assessment, patients who remitted from depression (HDRS score Conclusions: Depression and social phobia secondary to ADD are independent conditions that do not completely remit after cessation of drinking. Specific treatments are needed to reduce residual depressive and anxiety symptoms in abstinent alcoholics.

Substance P is involved in the modulation of depression, anxiety, and suicidal-related behaviors. We studied gene variants of Tachykinin Receptor 1 (TACR1—rs3771810, rs3771825, rs726506, rs1477157) in 167 German suicide attempters (affective spectrum n = 107, schizophrenia spectrum n = 35, borderline personality disorder n = 25), 92 Caucasian individuals who committed suicide and 312 German healthy subjects. Single markers and haplotype analysis in relation to suicidal behaviors (suicide attempters/completers) did not reveal any significant association. The rarest rs3771825 T allele however showed a marginal association with higher Reactive Aggression scores on the Questionnaire for Measuring Factors of Aggression (FAF) (F = 9.86, df = 1; P = 0.0017). Haplotype analyses confirmed the finding. Violence or impulsivity of suicide attempt and State-Trait Anger Expression Inventory (STAXI) scores were not associated with gene variants. In conclusion, our study suggests that TACR1 gene variants have no major influence on suicidal behavior but may modulate aggression features. © 2007 Wiley-Liss, Inc.

Background: This study aims to detect the impact of stroke on the occurrence of dementia and cognitive impairment/no dementia (CIND) in different age, sex, and education groups. Methods: Persons with dementia (DSM-III-R) or CIND were identified by a two-phase study design among 7,930 persons from the population-based Faenza Community Aging Study. Results: Subjects with a history of stroke had increased risk of both dementia [risk ratio (RR) = 3.7; 95% confidence interval (CI) = 3.1–4.4] and CIND (RR = 1.7, 95% CI = 1.4–2.2). These associations were stronger in the younger-old (61–74 years) than in the older-old (75+ years), and among higher-educated (4+ years) than lower-educated (0–3 years of schooling) persons. Dementia and CIND prevalence among stroke subjects was similar to the prevalence detected among subjects 10 years older but without a history of stroke. In stroke subjects, dementia prevalence became higher than CIND prevalence 10 years earlier than in non-stroke subjects. A combined effect for dementia due to a history of stroke, increasing age, and decreasing years of schooling was detected. Conclusions: Stroke is a strong risk factor for dementia among younger-old and higher-educated subjects; in the presence of a stroke, dementia onset might occur about 10 years earlier, possibly by accelerating the progression from CIND to dementia.

OBJECTIVE: Antidepressant drug efficacy is partially under genetic control and a number of gene variants have been associated with antidepressants efficacy over the last few years. In the search for further genes influencing antidepressant response we focused on the dysbindin gene (dystrobrevin-binding-protein 1, DTNBP1). BASIC METHODS: One hundred and four Korean inpatients affected by major depressive disorder were treated with various antidepressants at standard therapeutic daily doses and rated with the 10-items Montgomery-Asberg Depression rating scale (MADRS) at baseline and discharge. Five DTNBP1 variants (rs3213207 A/G, rs1011313 C/T, rs2005976 G/A, rs760761 C/T and rs2619522 A/C) were analysed for all patients. RESULTS: Rs2005976 was found to be significantly associated with final MADRS scores, with the rarest A allele associated with higher final scores (P=0.00055), rs760761 also showed a significant association (P=0.0058) and rs2619522 showed a positive trend (P=0.025). Markers were not significantly associated with Clinical Global Impression Scale scores. Five marker haplotypes were mildly associated with MADRS final scores but when considering the block composed of the three single nucleotide polymorphisms individually associated with response (rs2005976, rs760761 and rs2619522), results were more marked (P=0.0096), with the more frequent G-C-A haplotype associated with a positive outcome. CONCLUSIONS: Despite limitations due to the sample size and the mild antidepressant response, we observed a significant association between DTNBP1 variants and antidepressant response.

The serotonin system modulates affective, cognitive and behavioral processes. A key molecular structure of this system, the serotonin transporter (SERT) gene, has been associated with many human behaviors, both normal and pathological. This article aim is a comprehensive overview of the human behavioral features influenced by SERT gene variants and to suggest some comprehensive hypotheses. In particular, the SERTPR insertion/deletion polymorphism has been related to hippocampal volume and amygdala response and it has been found to influence anxiety-related personality traits and anxiety disorders; in mood disorders it showed some influences on age at onset, periodicity, illness recurrence, rapid cycling, antidepressants response and depressive reaction to stressful life events. Psychosomatic disorders, suicide, alcoholism, smoking, eating disorders, attention deficit hyperactivity disorders and autism have been also found to be related to SERTPR variants. SERT gene variants seem therefore to modulate a wide range of aspects in both normal and affected individuals, many of which are possibly due to indirect correlations between such human features.

Objective The aim of this study is to investigate the association between depression and frequent attendance in elderly primary care patients. Moreover, we compare the prevalence and clinical characteristics of frequent attenders (FAs) in the elderly and the nonelderly patients. Methods This nationwide, cross-sectional, two-phase epidemiological study involved 191 primary care physicians (PCPs) and 1896 patients aged 14 and over. We consider FAs those subjects attending PCP practice more than once a month in the last 6 months. Screening for psychiatric disorders was conducted by using the General Health Questionnaire-12. Subsequently, probable cases were assessed by the PCPs with the WHO ICD-10 Checklist for Depression. Results Prevalence value of frequent attendance was 22.4% in the elderly. Depression was associated with frequent attendance in the elderly even after controlling for physical illness and unexplained somatic complaints. The risk for being an FA was more than twofold in the elderly than in the nonelderly (cOR=2.58; 95% confidence interval, 1.97–3.37). Considering subjects without medical illness, depression increased the risk of being an FA fivefold among the elderly and threefold among the nonelderly. Conclusion Frequent attendance in primary care is associated with depressive disorder in the elderly. Depression seems to play a more important role in determining frequent attendance in the elderly patients in respect to the nonelderly.

Objective The authors examined the impact of very early dementia and symptoms of depression on functional disability in a community-based group of 216 elderly people with low-to-moderate education level. Methods The combined effect of very early dementia and symptoms of depression on functional disability was assessed with a logistic-regression model in which functional disability was the dependent variable. The same model was repeated with each item on the Instrumental Activities of Daily Living scale as the dependent variable. Results Very early dementia alone was strongly associated with functional disability, and this association tripled in subjects with both very early dementia and symptoms of depression. In fact, whereas subjects with very early dementia had an 11-fold higher risk than normal persons for disability, subjects with both very early dementia and symptoms of depression showed a 37-fold higher risk for functional dependence. Conclusions Elderly people who suffer from very early dementia and who also have symptoms of depression are at very high risk for functional disability and have a great need for accurate diagnostic assessment. If confirmed, the results are relevant for prevention because people who suffer from very early dementia and have symptoms of depression may be a suitable target group for intervention before the development of severe disability.

Objective: To evaluate the age, gender and education distribution of both cognitive impairment and dementia in the whole old age range of the elderly (from 61 years of age and over). Subjects and Methods: The study population consisted of all subjects born in 1930 or before, living in the municipality of Faenza and Granarolo, Italy (n = 7,930). A two-phase study design was implemented, by using the Mini-Mental State Examination and Global Deterioration Scale as screening instruments. The DSM-III-R diagnostic criteria were used for the clinical diagnosis of dementia. A subject was classified as affected by cognitive impairment, no dementia (CIND) if he/she scored 2 or more standard deviations lower than the corrected mean MMSE score. Results: The prevalences of dementia and CIND were 6.5 per 100 (95% CI 5.9–7.0) and 5.1 per 100 (95% CI 4.6–5.6), respectively. The prevalence of CIND was higher than that of dementia in the youngest old groups (61–74 years), both in men and women, whereas the opposite pattern was present among the older old (75+). In the older age groups, dementia prevalence increased exponentially with age, while CIND prevalence was more stable. There was not a substantial gender difference in CIND prevalence in all ages. Only in the subpopulation of higher educated subjects, women had a higher prevalence of both dementia and CIND than men. Lower educated subjects had a higher prevalence of both dementia and CIND. When compared to higher educated persons, subjects without any schooling had odds ratios of 10.9 (CI 7.0–16.7) and 16.7 (CI 11.2–25.0) for dementia and CIND, respectively. Conclusions: Cognitive impairment is very common in the younger old ages (under 70 years of age), whereas dementia becomes predominant after 75 years of age. Both conditions are strongly related to the educational level.

Recently, microarray technology is reshaping the molecular biology, given the high number of fields of application like, gene expression analysis, rapid sequencing of DNA, mapping of allelic variation, identification polymorphisms. It is a recently developed technique, which allows analysing thousands of genes in a very short time. Due to the powerful nature of this genetic approach, the number of researches using microarray technology boosted in the last years (less than ten papers from 1995 to 1997, up to approximately one thousand in the following 5 years -PubMed). Nevertheless, in spite of the promising fields of application, many drawbacks need to be carefully considered before generalizing the results obtained with this new technology. In fact, up to now a number of drawbacks have been described in the use of DNA microarray: many errors of incorporation during the manufacturing of the chips, loss of splicing variants, variable reliability of differential expression data, low specificity of cDNA microarray probes, discrepancy in fold change calculation for a given gene and so on. In spite of all those troubles, there is no doubt that this new promising technology could give an overall idea of gene organization and expression and might contribute to understanding the molecular mechanisms involved in processes as disease diagnosis or drug discovery (Pharmacogenetics and Pharmacogenomics). The goal of the present review is to suggest a targeted use of DNA chip technology in the field of pharmacogenetics (with the example of antidepressants), suggesting the inclusion of only those genes, possibly candidates, through a step by step analysis of the pathways involved in the pharmacological action of antidepressants. Received on: 02-03-2004 - Accepted on: 30-06-2004

Literature data consistently show different prevalence estimates of dementia when different classification systems are used in the same population. Very few data are available for the oldest old of the elderly. We investigated the occurrence of dementia among 34 nonagenarians and centenarians according to four classification systems: the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-III-R) and fourth edition (DSM-IV), the World Health Organization’s International Classification of Diseases, 10th revision (ICD-10), and the Cambridge Examination for Mental Disorders of the Elderly (CAMDEX). Cognitive functioning, work, social function and independence in activities of daily living were evaluated by using an extensive neuropsychological examination. The prevalence (95% CI) of dementia was the following: 47.1% (95% CI 30.3–63.8) with the DSM-III-R criteria, 41.2% (95% CI 24.6–57.7) with the DSM-IV criteria, 29.4% (95% CI 14.1–44.7) with the ICD-10 criteria and 38.2% (95% CI 21.9–54.6) with the CAMDEX. The factors that best predicted disagreement between DSM-III-R and DSM-IV were calculation impairment and the presence or absence of personality changes. DSM-III-R and ICD-10 were differentiated by the weight given to executive functions that all have to be impaired according to ICD-10, whereas progressive deterioration differentiated CAMDEX from DSM-III-R. It should be noted that although the DSM-III-R diagnoses differ by a factor of 1.6 times from the ICD-10 and 1.2 times from the CAMDEX diagnoses, we are speaking about dementia, which is very frequent in nonagenarians and centenarians. Moreover, with regard to public health, an estimation of the number of subjects who will lose their autonomy is rather more useful and informative than simple prevalence figures of dementia by itself. In this light, classification systems, such as the ICD-10, that do not include impairment of social function as a criterion for assessing dementia become less adequate.

Background:In clinical practice, Second Generation Antipsychotics (SGAs) are often used as first-line treatment for the Behavioral and Psychological Symptoms of Dementia (BPSD) in older adults due to their fewer neurological adverse events and similar effectiveness compared with First Generation Antipsychotics (FGAs). SGAs, however, are associated with more severe metabolic side effects (weight gain, hyperglycemia, diabetes risk, and hyperlipidemia) than FGAs are. In general, older patients, especially those affected by dementia, are at increased risk for malnutrition, and tend to have lower basal metabolism and reduced liver and kidney function. However, little is known about the metabolic side effects of antipsychotic drugs in this population.Methods:A comprehensive review of the literature published between January 1996 and December 2012 investigating the metabolic side effects related to FGAs and SGAs use in old patients affected by dementia.Results:Antipsychotic drugs currently used to treat BPSD in subjects with mild to moderate dementia are associated with weight gain. Currently, there are insufficient data to support a causal relationship between the use of FGAs and SGAs and changes in glucose homeostasis or lipid metabolism in older persons affected by severe dementia (MMSE Conclusion:A possible association between antipsychotic drugs use and weight gain might exist, in particular in subjects with mild to moderate dementia whereas no significant effects are demonstrated regarding glucose homeostasis and lipid metabolism. The antipsychotic drugs potential for causing metabolic abnormalities in older patients requires further specifically designed studies. Clinicians must be aware of this possibility even if the shorter periods of treatment administered in late-life might not be as harmful as it is in younger individuals.

Among the several genes associated with late-onset Alzheimer’s disease (LOAD), recently, Sirtuin genes have roused a growing interest because of their involvement in metabolic homeostasis and in brain aging. Particularly SIRT2 gene has been associated with Alzheimer’s disease (AD) as well as with mood disorders. The aim of this study is to investigate the possible associations between Sirtuin 2 gene (SIRT2) rs10410544 polymorphism and AD as well as depression in AD. In addition, we performed some exploratory analyses to investigate possible associations between the rs10410544 genotype and clinical features. We investigated these associations in two independent samples: the first one was composed of 275 Greek inhabitants and 117 patients; the second sample counted 181 Italian people and 43 patients. All patients were affected by LOAD. We failed to find any association between rs10410544 genotype and AD in the two samples. On the other hand, we found an association between the single nucleotide polymorphism (SNP) and depressive symptomatology (in the total sample p = 0.002), which was modulated by the tumor necrosis factor (TNF) values. Particularly, TT genotype seems to be protective versus depression. Finally, in the exploratory analyses, we found that the TT genotype was associated with earlier AD onset and a longer duration of the illness. In conclusion, we confirmed the association between SIRT2 gene and mood disturbances, although in AD patients. Further, we provided evidence that the TT genotype may be protective versus depressive symptoms, allowing an easier and thus earlier diagnosis of AD. This awareness may lead to a more detailed approach to these patients concerning diagnosis and therapy.

The present study explores whether ankyrin repeat and kinase domain containing 1 (ANKK1) and dopamine receptor D2 (DRD2) variants could predict efficacy and tolerability of haloperidol in the treatment of psychotic patients. We also attempted to replicate findings in a group of schizophrenic patients from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) study. Eighty-eight acutely psychotic patients were genotyped for 9 ANKK1 and 27 DRD2 SNPs. Treatment efficacy and tolerability were assessed using the Positive and Negative Symptoms Scale and the Udvalg for Kliniske Undersogelser side effects rating scales, respectively. Multivariate analyses were employed to test possible influences of single-nucleotide polymorphisms on clinical and safety variables. Analysis of haplotypes was also performed. Outcomes in the replication sample were response versus nonresponse and the presence versus absence of motor side effects at 1 month of treatment. rs2242592 within ANKK1 gene and rs1124493 within DRD2 gene were associated with clinical improvement (p = 0.008 and p = 0.001, respectively). Results were confirmed in the allelic analysis. Three haplotype blocks, one among ANKK1 and two among DRD2 gene were associated with better clinical improvement. Our results were not replicated in the CATIE sample, although rs11604671, which is in strong linkage disequilibrium with rs2242592, was associated with response in the replication sample. Our findings support a possible role of ANKK1 and DRD2 variability on haloperidol efficacy. However, due to the discrepancies between the results in the two samples, our results need further validation.

Quetiapine has been proposed for depression in bipolar patients but a quantitative analysis is lacking. In the present paper, we review and meta-analyze available data about the short-term and long-term efficacy and tolerability of quetiapine for the depressive phase of bipolar disorder or bipolar depression. A literature research was carried out using three electronic databases. Studies providing measures of efficacy and tolerability of quetiapine, either as monotherapy or as augmentation, for bipolar depression were considered. Seven short-term studies and four maintenance studies were included. Short-term studies suggested that patients treated with quetiapine monotherapy were significantly more likely than patients treated with placebo and further active comparators to achieve higher response and remission rates as well as more clinical improvements at the endpoint. Such benefits were significant from the first weeks of treatment onward. Maintenance studies suggested that the combination of quetiapine and mood stabilizers was significantly better than placebo plus mood stabilizers for the prevention of both depressive and manic relapses. Quetiapine was generally well tolerated. Furthermore, several clinical variables moderated outcomes under investigation. In conclusion, quetiapine could have some advantages over traditional treatments for the treatment of bipolar depression.

It was suggested that the gene encoding for sorLa, (SORL1) may affect Alzheimer's disease (LOAD) through a female-specific mechanism. The aims of this study were to confirm the role of gender in modulating the association between SORL1 and LOAD and to ascertain the influence of SORL1 on cognitive impairment, neuropsychiatric symptoms (BPSD) and secretion of pro-inflammatory cytokines. Ninety six outpatients with LOAD and 120 unrelated controls were genotyped for APOE and three SNPs at the 5' end of SORL1(intron 6): SNP 8 (rs668387); SNP 9 (rs68902); SNP 10 (rs641120). Clinical evaluation was made with the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). ELISPOT assays were used to measure pro-inflammatory cytokine (TNF-alpha; IL-6; IL-1beta; IFN-gamma) production in peripheral blood mononuclear cell (PBMC) supernatant from AD patients. SORL1 SNPs were not associated with LOAD in overall sample. Instead the G-alleles at SNPs 9 (p=0.015) and 10 (p=0.015) and the CGG haplotype (p=0.02) were associated with LOAD in the women subgroup. The TAA haplotype was marginally protective in AD patients being associated with lower BPSD scores (p=0.01). The same haplotype was also associated with higher IL-1beta (p=0.01) production. These genetic effects were not modified by APOE4 allele and controlled for illness duration and treatment. In conclusion, SORL1 does not appear to be a major risk factor for LOAD. Its contribution could be underestimated in our small sample. Sex-specific factors could modulate the association between SORL1 and AD. The influence of SORL1 variants on production of inflammatory cytokines warrants further investigation.

OBJECTIVE: The aim of this study was to evaluate the association between vision and hearing impairment and depressive-anxiety syndrome in a large population participating in the Faenza Project, Northern Italy. METHOD: The study population consisted of 7389 participants not affected by dementia, 4408 (59.7%), of whom were women, mean age ± standard deviation (±SD) 71.9 (±7.7) years. Information about previous or current psychiatric symptoms, including sleeping and eating habits, non-verbal language and ability in activity of daily living was used to investigate depressive and anxiety syndrome. A semi-structured interview was administered to survey the presence of sensory impairment. Logistic regression analyses were used to evaluate the association between sensory impairment and depressive-anxiety syndrome estimating Odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: The prevalence of vision and hearing impairment was 1.4% and 0.2%, respectively, with an increasing trend in people aged 75+ years (p < 0.001). The prevalence of depressive syndrome was higher among vision-impaired participants (20.2% vs. 9.3%, p < 0.001), especially women (22.9%) and persons aged 75+ years (22.1%). The prevalence of anxiety syndrome was higher in the hearing-impaired group (25.0% vs. 11.0%, p = 0.09). Vision-impaired participants, especially women and participants aged 75+ years had have a twofold higher probability to have depressive syndrome (OR = 2.03, 95% CI = 1.21-3.38), and hearing-impaired individuals showed an increased probability of presenting anxiety syndrome (OR = 2.71, 95% CI = 0.86-8.55), although these results were not statistically significant. CONCLUSION: This study's findings suggest that sensory impairment in older adults can increase their probability of experiencing depressive and anxiety syndrome. Correction of these deficits could improve the quality of life in this population.