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Objective Genetic variations in the gene encoding zinc finger protein 804A gene (ZNF804A) have been associated with major depression and bipolar disorder. In this work we focused on the potential influence of ZNF804A variations on the risk of developing specific sub-phenotypes as well as the individual response to available treatments. Methods We used two samples of different ethnic origin: a Korean sample, composed by 242 patients diagnosed with major depression and 132 patients diagnosed with bipolar disorder and 326 healthy controls; an Italian sample composed 151 major depression subjects, 189 bipolar disorder subjects and 38 outpatients diagnosed for a primary anxiety disorder. Results Our analyses reported an association of rs1344706 with psychotic phenotype in the cross-diagnostic pooled sample (geno p = 4.15 × 10-4, allelic p = 1.06 × 10-4). In the cross-diagnosis Italian sample but not in the Korean one, rs7597593 was involved with depressive symptoms improvement after treatment (geno p = 0.025, allelic p = 0.007). Conclusion The present study evidenced the role of ZNF804A alterations in symptoms improvement after treatment. Both manic and depressive symptoms seem to be modulated by ZNF804A, though the latter was observed in the bipolar pooled sample only. The role of this factor is likely related to synaptic development and maintenance; however, further analyses will be needed to better understand the molecular mechanics involved with ZNF804A.

Depression affects 7% of the elderly population, and it often remains misdiagnosed or untreated. Peripheral biomarkers might aid clinicians by allowing more accurate and well-timed recognition of the disease. We sought to determine if plasma protein levels predict the severity of depressive symptomatology or distinguish patients from healthy individuals. The severity of depressive symptoms and global cognitive functioning were assessed by the Geriatric Depression Scale (GDS) and Mini-Mental State Examination (MMSE) in 152 elderly subjects, 76 of which with major depressive disorder (MDD). Plasma levels of 24 proteins were measured by multiplexing and analyzed as continuous predictors or dichotomized using the median value. The association between individual plasma proteins and MDD risk or depressive symptoms severity was investigated using multiple logistic and linear regressions including relevant covariates. Sensitivity analyses were performed excluding cognitively impaired individuals or non-acute patients with MDD. After adjusting for possible confounders and false discovery rate (FDR) correction, we found lower Fetuin-A levels in MDD patients vs. controls (pFDR = 1.95 × 10–6). This result was confirmed by the sensitivity and dichotomized analyses. Lower prolactin (PRL) levels predicted more severe depressive symptoms in acute MDD patients (pFDR = 0.024). Fetuin-A is a promising biomarker of MDD in the elderly as this protein was negatively associated with the disorder in our sample, regardless of the global cognitive functioning. Lower PRL levels may be a peripheral signature of impaired neuroprotective processes and serotoninergic neurotransmission in more severely depressed patients.

Objective Genetics factors are likely to play a role in the risk, clinical presentation and treatment outcome in major depressive disorder (MDD). In this study, we investigated the role of three candidate genes for MDD; calcium voltage- gated channel subunit alpha1 C ( CACNA1C ), cholinergic receptor nicotinic alpha 7 subunit ( CHRNA7 ), and mitogen- activated protein kinase 1 ( MAPK1 ). Methods Two-hundred forty-two MDD patients and 326 healthy controls of Korean ancestry served as samples for the analyses. Thirty-nine single nucleotide polymorphisms (SNPs) within CACNA1C , CHRNA7 , and MAPK1 genes were genotyped and subsequently tested for association with MDD (primary analysis) and other clinical features (symptoms' severity, age of onset, history of suicide attempt, treatment outcome) (secondary analyses). Single SNPs, haplotypes and epistatic analyses were performed. Results Single SNPs were not associated with disease risk and clinical features. However, a combination of alleles (haplotype) within MAPK1 was found associated with MDD-status. Secondary analyses detected a possible involvement of CACNA1C haplotype in resistance to antidepressant treatment. Conclusion These data suggest a role for MAPK1 and CACNA1C in MDD risk and treatment resistance, respectively. However, since many limitations characterize the analysis, the results must be considered with great caution and verified.

Despite the fact that the majority of currently available treatment guidelines propose antidepressants as the first-line pharmacological therapy for posttraumatic stress disorder (PTSD), a substantial portion of patients fail to show an adequate response following this type of treatment. In this context, a number of small, open-label studies and randomized controlled clinical trials (RCTs) have found atypical antipsychotics (AAs) to be a beneficial treatment for patients with PTSD. Thus, the present meta-analysis was conducted to enhance the sample size power and further the current understanding of the role of AAs for the treatment of PTSD. An extensive search of several databases identified 12 appropriate RCTs and available data from 9 of these (n ¼ 497) were included in the final meta-analysis. AAs may have potential benefits for the treatment of PTSD as indicated by changes from baseline of the total score on the Clinician Administered PTSD Scale (CAPS; standardized mean difference [SMD] ¼� 0.289, 95% confidence intervals [CIs] ¼� 0.471, � 0.106), P ¼ 0.002). Additionally, AAs were found to be significantly more effective (P < 0.0001) than a placebo in terms of change from baseline for the intrusion sub-score on the CAPS (SMD ¼� 0.373, 95% CIs ¼� 0.568, � 0.178) but there were no significant reductions for the avoidance and hyperarousal sub-symptoms. The responder rate and rate of improvement of depressive symptoms were also significantly higher in the AA group than the placebo group (P ¼ 0.004 and P < 0.0001, respectively). However, the present results should be interpreted carefully and be translated into clinical practice only with due consideration of the limited quality and quantity of existing RCTs included in this analysis.

The gene coding for the catechol-O-methyltransferase (COMT) and the one coding for the dopamine receptor 2 (DRD2) have been linked with major depression (MD) and with the response to antidepressants in several studies. However, contrasting findings have been reported as well. The aim of the present study is, therefore, to investigate possible influences of rs4680 within COMT and rs6276 within DRD2, analyzed both individually and in combination, on the diagnosis and clinical outcomes in a sample of Korean MD patients treated with antidepressants.Totally, 184 Korean in-patients suffering from MD treated with either paroxetine or venlafaxine and 220 healthy control subjects were included in the present study. Depression severity was assessed by means of the Hamilton Rating Scale for Depression.We were not able to find any association between the two variants under investigation and diagnosis of MD, as well as with antidepressant response.Although limited by several factors, including the small sample size and the impossibility to extend our findings to patients treated with different antidepressants, the results of our study provide support to the notion that these variants might not play a major role in the etiology and clinical outcomes of MD.

Quetiapine fumarate extended release (XR) has been approved for treatment of schizophrenia and bipolar disorder. Quetiapine may have antidepressant effects through effects on 5-HT(2A) receptor, 5-HT(1A) receptor, dopamine receptor, glutamate receptor and norepinephrine transporter. Recently, 7 large-scale randomized, double-blind, placebo (2-studies with active comparator)-controlled clinical trials have demonstrated that quetiapine XR has clinically meaningful efficacy as monotherapy and adjunct therapy to antidepressants for the treatment of adult patients with major depressive disorder (MDD). In such clinical trials, quetiapine XR was generally well tolerated, although weight gain and changes in metabolic parameters, consistent with the known profile of quetiapine, were observed in some patients. As of December 2009, the United States Food and Drug Administration has approved quetiapine XR for the adjunct treatment of MDD. From the data of currently available clinical trials, this review provides an overview of the data and clinical implications for quetiapine XR in the treatment of MDD to enhance clinicians understanding of the use of quetiapine XR in the treatment of MDD.

Epistasis, the interaction between genes, is a topic of current interest in molecular and quantitative genetics. We have further studied a previously investigated sample of 187 major depressive disorder (MDD) patients, 171 bipolar disorder (BD) patients, and 288 controls, and tried to analyze the interaction between a set of variations of independent genes: the trace amine receptor 6 (rs4305745, rs8192625, rs7452939, rs6903874, and rs6937506) and the heat shock protein 70 (rs562047, rs1061581, rs2227956). The multifactor dimensionality reduction (MDR) method was applied and the covariates associated with diagnosis were also controlled. A significant predictive value of specific interactions between genotypes located in the investigated genes was found. We then report preliminary evidence that the epistasis between trace amine receptor 6 and heat shock protein 70 variations may compose a risk profile for major mood disorders. The level of statistical significance (P

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.

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.

Posttraumatic stress disorder (PTSD) is a prevalent and disabling mental illness. Small studies found atypical antipsychotics (AAs) to be beneficial in the treatment of patients with PTSD regardless of psychotic symptoms who are unresponsive to conventional pharmacological treatments such as serotonin selective reuptake inhibitors. This study reports the results of a meta-analysis of existing randomized, double-blind, placebo-controlled clinical trials (RCTs) of AAs as a monotherapy or augmentation therapy for the treatment of patients with PTSD. Seven RCTs were identified through extensive scans of databases, which included PubMed, MedLine, the National PTSD Center Pilots database, PsycINFO, Cochrane Central Register of Controlled Trials, and the Abstracts Library of the American Psychiatric Association with predefined inclusion criteria. Dichotomous and continuous measures were performed using a fixed effects model, heterogeneity was assessed, and subgroup analyses were done. Data from seven RCTs involving a total of 192 PTSD patients (102 randomized to AAs and 90 randomized to placebo) were analyzed. The results show that AAs may have a beneficial effect in the treatment of PTSD, as indicated by the changes from baseline in Clinician Administered PTSD Scale total scores [standardized mean difference (SMD)=-0.45, 95% confidence interval (CI) (-0.75, -0.14), P=0.004]. In addition, the overall SMD of the mean changes in the three Clinician Administered PTSD Scale subscores was statistically significant (P=0.007) between AAs and placebo groups, favoring AAs over placebo (SMD=-0.27, 95% CI=-0.47, -0.07). In particular, the symptom of 'intrusion' was mainly responsible for this significance. Clinical significance of the results, however, should be carefully interpreted and translated into clinical practice, given that the quality and availability of currently existing RCTs included in the analysis.

Despite the availability of different classes of drugs for the treatment of depressive and anxiety disorders, there are a number of clinically significant unmet needs, such as a high prevalence of treatment resistance, partial response, subsyndromal symptomatology, recurrence and relapse. With the approval of atypical antipsychotics, which are associated with a lower adverse effect burden than typical antipsychotics, consideration of their off-label use for the treatment of affective disorders and various other psychiatric disorders has become a viable option. However, consideration should be given to the US FDA black box warning indicating that atypical antipsychotics may increase mortality risk, particularly in the elderly population with dementia-related psychosis. There has been much conjecture about the utility of these atypical drugs to facilitate traditional antidepressant therapy, either in combination (from the initiation of therapy) or as adjunctive therapy (in the case of partial/incomplete response). Nevertheless, at present, available evidence from randomized, placebo-controlled trials is sparse, and a formal risk/benefit assessment of the use of these agents in a nonpsychotic patient population is not yet possible. As a representative agent from the atypical antipsychotic class with a novel mechanism of action and a relatively low adverse effect burden, aripiprazole represents an interesting potential treatment for depressive and anxiety disorders. In this review, we focus on the rationale for the use of aripiprazole in these disorders. Preclinical data suggests that aripiprazole has a number of possible mechanisms of action that may be important in the treatment of depressive and anxiety disorders. Such mechanisms include aripiprazole action at serotonin (5-HT) receptors as a 5-HT1A partial receptor agonist, a 5-HT2C partial receptor agonist and a 5-HT2A receptor antagonist. Aripiprazole also acts as a dopamine D2 partial receptor agonist, and has a possible action at adrenergic receptors. Furthermore, aripiprazole may have possible neuroprotective effects. Clinical studies demonstrate that aripiprazole may be useful in the treatment of bipolar depression, major depressive disorder, treatment-resistant depression and possibly anxiety disorders. Clinical data also suggest that aripiprazole may have a lower adverse effect burden than the other atypical drugs. Future research may confirm the potential utility of aripiprazole in the treatment of depressive and anxiety disorders.

Objectives. The SLC6A3 40 base variable number of tandem repeats (VNTR) polymorphism has been associated with several clinical phenotypes associated with dysregulation of dopamine transmission. However, there is only little evidence about a possible influence of such genetic variant on the response to antipsychotics. The aim of the present study is to investigate whether SLC6A3 40 base VNTR polymorphism could modulate response to risperidone in a sample of Korean schizophrenia subjects. Methods. One hundred and forty-two schizophrenia inpatients were treated with a flexible dose of risperidone. Efficacy was assessed at baseline and at discharge using the scores of the Clinical Global Impression-severity (CGI-S), Brief Psychiatric Rating Scale (BPRS) and Positive and Negative Symptom Score (PANSS). Multivariate analysis of covariance was used to test possible influences of SLC6A3 VNTR variants on clinical scores. Results. None of the genotypes and of the alleles under investigation was associated with clinical scores at discharge or with changes of clinical scores over time. In addition, we also failed to find any association between genotypes and allele frequency distribution in accordance with treatment response defined as a 20% (or 30%) or more reduction in the total PANSS scores from the baseline to the end of treatment. Conclusion. Our findings do not suggest a possible association between SLC6A3 40 base VNTR polymorphism and response to risperidone. However, because of several limitations including the investigation of a single drug, the flexible design of the present study and the absence of a complete coverage of features which could influence the response, further investigations could be required.

The aim of the present work is to investigate the existence of epistatic interactions possibly influencing psychotropic agents' response between rs6740584 within Cyclic adenosine monophosphate Response Element Binding (CREB) and rs12775799 within cAMP response element-modulator (CREM) variants in bipolar disorder (BD) and major depressive disorder (MDD). All BD and MDD patients were administered with the Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAMD) at baseline and at endpoint, respectively. A multiple regression model was employed to investigate the existence of possible epistatic interactions between the two variants and diverse clinical factors including drug response in affective disorders. No significant epistatic interaction was observed between rs6740584 within CREB and rs12775799 within CREM on both symptom improvement and other clinical factors in affective disorders. Our preliminary results suggest that no epistatic interaction between rs6740584 within CREB and rs12775799 within CREM should exist on clinical improvement and clinical factors in affective disorders.

OBJECTIVE: This study investigated whether selected D-amino acid oxidase activator ( DAOA) gene single nucleotide polymorphisms (SNPs; rs3916966, rs3916967, rs2391191, rs3916968, rs7139958, rs9558571, rs778293) are associated with major depressive disorder (MDD) and bipolar disorder (BD), and whether they can predict clinical outcomes in Korean in-patients treated with antidepressants and mood stabilizers, respectively. METHODS: In total, 145 patients with MDD, 132 patients with BD and 170 psychiatrically healthy controls were genotyped for the DAOA SNPs. Baseline and final clinical assessments included the Montgomery—Asberg Depression Rating Scale and Young Mania Rating Scale for patients with MDD and BD, respectively. RESULTS: There was no association between DAOA SNP genotypes or alleles with diagnosis, clinical improvement, response rates or remission rates for MDD and BD. Haplotype analyses found no association with MDD or BD diagnosis or clinical outcomes. CONCLUSIONS: The findings suggest that the DAOA SNPs investigated may not affect MDD or BD phenotype, clinical symptoms or other clinical factors, and are unlikely to be involved in MDD or BD development and treatment outcomes. Given the study's limitations, further investigation should be carried out.

The present study explores whether some single nucleotide polymorphisms (SNPs) within CREB1 (rs2709377 and rs6740584), CREBBP (rs2239317, rs2239316, rs3025702, rs130021, rs130005, rs129974 and rs9392) and CREM (rs1148247, rs4934735, rs12775799, rs6481941 and rs16935888) could be associated with schizophrenia (SKZ) and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. Two-hundred twenty one in-patients suffering from SKZ and 170 psychiatrically healthy controls were genotyped for 10 SNPs within CREB1, CREBBP and CREM. All patients were assessed for the severity of illness at baseline and at discharge by means of the Positive and Negative Symptoms Scale (PANSS). Our findings suggest the lack of influence of SNPs under investigation in the present study on the susceptibility to SKZ and on the response to antipsychotics. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antipsychotics. One hundred forty five patients with MD, 221 in-patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. No significant association was found with the diagnosis of schizophrenia. We observed an association between rs3813296 genotype and improvement on PANSS negative scores. Our findings provide no evidence for an association between SNPs within GRIA1, GRIA2 and GRIA4 under investigation and schizophrenia susceptibility, although rs3813296 (GRIA2) could be associated with improvement on PANSS negative scores. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

OBJECTIVE: The present study aimed to investigate whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with bipolar disorder (BD) and they could predict clinical outcomes in in-patients with BD treated with mood stabilizers. METHODS: One hundred and thirty-two (132) patients with BD and 170 healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures including Young Mania Rating Scale for patients with BD were recorded. Statistical significance was set at the 0.005 level in order to reduce the likelihood of false positive results. RESULTS: We failed to show an evidence for a possible association of GRIA1, GRIA2 and GRIA4 with BD patients, in terms of influences on diagnosis and treatment outcomes, although this was the first study to explore the influence of such genes for bipolar disorder. CONCLUSION: Our results suggest that 17 SNPs within GRIA1, GRIA2 and GRIA4 may not be associated with the development and treatment outcomes in BD. However, taking into account that the several limitations of our study including the moderately small sample size of our study, our findings should be considered with caution and further research is needed to draw more definitive conclusions.

The present study is aimed to exploring whether some single nucleotide polymorphisms (SNPs) within GRIA1, GRIA2 and GRIA4 could be associated with major depressive disorder (MDD) and whether they could predict clinical outcomes in Korean in-patients, respectively, treated with antidepressants. One hundred forty-five (145) patients with MDD and 170 healthy controls were genotyped for 17 SNPs within GRIA1, GRIA2 and GRIA4. Baseline and final clinical measures, including the Montgomery-Asberg Depression Rating Scale (MADRS) for patients with MDD, were recorded. No association was observed between alleles, genotypes and haplotypes under investigation and clinical and demographical variables. As a secondary finding, a marginal association was observed between rs4302506 and rs4403097 alleles within GRIA2 and age of onset in patients with MDD. Our findings provide evidence for a possible association between rs4302506 and rs4403097 SNPs and age of onset in patients with MDD. However, taking into account that the several limitations of our study including the moderately small sample size of our study, our findings should be considered with caution and further research is needed to draw more definitive conclusions.

The aim of this study is to investigate possible associations between a set of single-nucleotide polymorphisms (SNPs) within 10 genes with Schizophrenia (SCZ) and response to antipsychotics in Korean in-patients treated with antipsychotics. Two hundred and twenty-one SCZ in-patients and 170 psychiatrically healthy controls were genotyped for 42 SNPs within ABCB1, ABCB4, TAP2, CLOCK, CPLX1, CPLX2, SYN2, NRG1, 5HTR1A and GPRIN2. Baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), were recorded. Rs10042486 within 5HTR1A was associated with both SCZ and clinical improvement on PANSS total scores as well as on PANSS positive and PANSS negative scores. The haplotype analyses focusing on the four, three and two blocks' haplotypes within 5HTR1A confirmed such findings as well. We did not observe any significant association between the remaining genetic variants under investigation in this study and clinical outcomes. Our preliminary findings suggest that rs10042486 within 5HTR1A promoter region could be associated with SCZ and with clinical improvement on PANSS total, positive and negative scores in Korean patients with SCZ. However, taking into account the several limitations of our study, further research is needed to draw more definitive conclusions.

The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens-Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo-controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders.

The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within the tryptophan hydroxylase 2 gene (TPH2) could be associated with major depression (MD), bipolar disorder (BD) and schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antidepressants, mood stabilizers and antipsychotics, respectively. One hundred forty-five patients with MD, 132 patients with BD, 221 patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for six TPH2 SNPs (rs4570625, rs10748185, rs11179027, rs1386498, rs4469933, and rs17110747). Baseline and final clinical measures, including the Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale and Positive and Negative Syndrome Scale, for patients with MD, BD and schizophrenia, respectively were recorded. None of the SNPs under investigation were associated with MD, BD and schizophrenia. However, in patients with MD, the rs4570625-rs10748185 G-A haplotype was significantly associated with higher endpoint MADRS severity, though not with response. Our results suggest that TPH2 variants neither have a major role in MD, BD and schizophrenia nor in response to treatments.

OBJECTIVE: The present study explored whether d-amino acid oxidase activator (DAOA) variants were associated with schizophrenia and whether they could predict the clinical outcomes of patients treated with various antipsychotics. METHODS: Two hundred and twenty-one (221) patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for seven DAOA single-nucleotide polymorphisms (SNPs) (rs3916966, rs3916967, rs2391191, rs3916968, rs7139958, rs9558571 and rs778293). We also administered baseline and final clinical measures, including the Positive and Negative Symptoms Scale (PANSS), to patients with schizophrenia. RESULTS: None of the SNPs under investigation was associated with the development of schizophrenia. However, the rs7139958 AA and rs9558571 TT as well as the rs7139958 A and rs9558571 T genotypes were associated with higher scores on the PANSS positive subscale among patients with schizophrenia, possibly reflecting their greater susceptibility to the development of more severe positive symptoms. No other allele, genotype, or haplotype under investigation was significantly associated with any of the clinical parameters, including clinical improvement, in patients with schizophrenia. CONCLUSION: Our results suggested that rs7139958 and rs9558571 SNPs may be associated with more severe baseline positive symptoms in patients with schizophrenia. However, further research is needed to draw more definitive conclusions given the limitations of our study.

Background: Despite the increasing evidence relating to strategies for switching between different antipsychotics, little evidence is available about predictors of improvement or worsening while switching. In a previous study, we compared different options for switching to aripiprazole and found that patients with schizophrenia switched to aripiprazole with immediate discontinuation of the previous antipsychotic showed an increase in symptom severity after 1 week. Objective: To identify predictors of worsening in the first 4 weeks after the switch to aripiprazole in partial non-responders to previous treatments. Methods: This was a 12-week randomized, controlled, open-label study that was carried out in the Department of Psychiatry of the Catholic University of Korea, Seoul, Korea. The study included 77 patients with schizophrenia whose symptoms were not optimally controlled and/or who did not tolerate their current antipsychotic medications well. Patients were randomly assigned to one of three different strategies for switching to aripiprazole 10 mg, i.e.: (i) simultaneous discontinuation of the current antipsychotic; (ii) tapering off the current antipsychotic over 4 weeks with half the dose after the first 2 weeks; or (iii) tapering off the current antipsychotic over 4 weeks after maintenance of the current dose for 2 weeks. The main outcome measure was the difference in Brief Psychiatric Rating Scale (BPRS) scores from baseline to weeks 1, 2 and 4. Results: Baseline severity of disease, as measured by the Clinical Global Impression-Severity Scale, BPRS and Schedule for the Assessment of Negative Symptoms, significantly predicted worsening at weeks 1, 2 and 4. Specifically, lesser disease severity at baseline significantly predicted worsening after switching to aripiprazole. Conclusion: Patients with relatively mild illness severity might be more susceptible to early worsening of symptoms when switched to aripiprazole. However, the limitations of the present study, including a small sample size, absence of a control group designed to control for nonspecific factors such as regression to the mean, and implementation of a switching strategy that included only aripiprazole, mean the present findings should be considered with caution and further research is needed.

Suggestive associations have been reported between trace amines and heat shock proteins, and a disrupted pathophysiology that enhances the risk of psychosis and that modifies responses to antipsychotic treatments. Our group previously reported genetic studies on TAAR6 and HSP-70 separately in patients with schizophrenia. In the current study, we investigated possible epistasis between the same set of variations in a sample of 281 patients diagnosed with schizophrenia and 288 healthy controls. We applied the generalized multifactor dimensionality reduction (MDR) method and controlled covariates significantly associated with both diagnosis and treatment efficacy. To the best of our knowledge, epistasis between the present set of variations in schizophrenia has not been tested before. We found significant associations with both the risk of disease and response to treatment. However, the insufficiently balanced accuracy of the applied tests suggests that, despite significantly different genetic variations between cases and controls, these factors have a poor predictive value. Explanations for these findings and possible future directions are also discussed.

Chronic fatigue syndrome (CFS) is characterized by chronic, medically unexplained fatigue associated with effort- and stress-intolerance, widespread pain, and impairment in sleep and concentration. Although this constellation of symptoms is highly prevalent in clinical practice, the pathophysiological mechanisms underlying CFS are poorly understood. Current evidence indicates similarities in symptomatology, and possibly etiology and pathogenesis, between CFS and depression. Additionally, there is significant overlap between CFS and the syndrome of fibromyalgia for which antidepressants have shown consistent efficacy. Data regarding antidepressant treatment of CFS is less copious and less uniformly positive, such that antidepressant use in CFS remains controversial. The current review aims to summarize available data related to antidepressants and other psychotropic agents in CFS to provide a platform for clinicians to make decisions in their treatment of this challenging syndrome. We identified relevant studies through a PubMed literature search with a combination of the following search terms: 'fatigue,' 'depression,' 'antidepressant,' 'etiology' (e.g., 'neurobiology,' 'neurotransmitter,' 'genetic'), 'diagnosis,' and 'treatment' (e.g., 'antidepressant' plus the specific name). In addition, studies were also identified via the reference sections of retrieved articles. The authors thoroughly reviewed major findings from the scanned literatures and eventually synthesized them, providing summary, interpretation, and future directions.

We recently reported an association betweenTAAR6(trace amine associated receptor 6 gene) variations and schizophrenia (SZ). We now report an association of a set ofTAAR6variations and clinical presentation and outcome in a sample of 240 SZ Korean patients. Patients were selected by a Structured Clinical Interview, DSM-IV Axis I disorders – Clinical Version (SCID-CV). Other psychiatric or neurologic disorders, as well as medical diseases, were exclusion criteria. To assess symptom severity, patients were administered the CGI scale and the PANSS at baseline and at the moment of discharge, 1 month later on average.TAAR6variations rs6903874, rs7452939, rs8192625 and rs4305745 were investigated; rs6903874, rs7452939 and rs8192625 entered the statistical investigation after LD analysis. Rs8192625 G/G homozygosis was found to be significantly associated both with a worse clinical presentation at PANSS total and positive scores and with a shorter period of illness before hospitalization. No haplotype significant findings were found. The present study stands for a role of theTAAR6in the clinical presentation of SZ. Moreover, our results show that this genetic effect may be counteracted by a correct treatment. Haplotype analysis was not informative in our sample, probably also because of the incomplete SNPs' coverage of the gene we performed. Further studies in this direction are warranted.

Dysbindin gene (DTNBP1) has been consistently reported to be associated with schizophrenia. However data from East Asian population has been sparse and inconsistent till today. This study tried to replicate the genetic association of DTNBP1 with schizophrenia in a large Korean sample, as well as analyzing the association of DTNBP1 with clinical variables. Nine hundred and eight (908) patients with schizophrenia and 601 controls were investigated. The high-throughput genotyping method using pyrosequencer (Biotage AB, Sweden) was used for genotyping 4 SNPs (rs3213207, rs1011313, rs760761, and rs2619522). Haplotype analyses revealed a significant association with schizophrenia (P < 0.0001) with the haplotypes A-C-C-C and A-C-T-A having an eminent protective effect toward schizophrenia. The major contribution to the difference in the haplotype distribution between patients and the controls was the rs760761 (C/T) and rs2619522 (A/C) haplotypes (P < 0.0001). No association of DTNBP1 with other clinical variables was found. In conclusion, the present study suggests a possible protective effect of rare DTNBP1 variants in schizophrenia, although subsequent studies in different ethnic groups are warranted.

Objective The present study aimed to explore whether 4 single nucleotide polymorphisms (SNPs) within the AHI1 gene could be associated with major depressive disorder (MD) and bipolar disorder (BD), and whether they could predict clinical outcomes in mood disorders. Methods One hundred and eighty-four (184) patients with MD, 170 patients with BD and 170 healthy controls were genotyped for 4 AHI1 SNPs (rs11154801, rs7750586, rs9647635 and rs9321501). Baseline and final clinical measures for MD patients were assessed through the Hamilton Rating Scale for Depression (HAM-D). Allelic and genotypic frequencies in MD and BD subjects were compared with those of each disorder and healthy group using the χ(2) statistics. Repeated measures ANOVA was used to test possible influences of SNPs on treatment efficacy. Results The rs9647635 A/A was more represented in subjects with BD as compared with MD and healthy subjects together. The rs9647635 A/A was also more presented in patients with MD than in healthy subjects. With regard to the allelic analysis, rs9647635 A allele was more represented in subjects with BD compared with healthy subjects, while it was not observed between patients with MD and healthy subjects. Conclusion Our findings provide potential evidence of an association between some variants of AHI1 and mood disorders susceptibility but not with clinical outcomes. However, we will need to do more adequately-powered and advanced association studies to draw any conclusion due to clear limitations.