Spectroscopic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using proton magnetic resonance spectroscopy: a controlled study.

BACKGROUND: The main aim of the present study is to determine the role of metabolites observed using proton magnetic resonance spectroscopy (1H-MRS) in obsessive-compulsive disorder (OCD). As the literature describing biochemical changes in OCD yields conflicting results, we focused on accurate metabolite quantification of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline-containing compounds (tCh), and myo-inositol (mI) in the anterior cingulate cortex (ACC) to capture the small metabolic changes between OCD patients and controls and between OCD patients with and without medication. METHODS: In total 46 patients with OCD and 46 healthy controls (HC) matched for age and sex were included in the study. The severity of symptoms in the OCD was evaluated on the day of magnetic resonance imaging (MRI) using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Subjects underwent 1H-MRS from the pregenual ACC (pgACC) region to calculate concentrations of tNAA, tCr, tCho, and mI. Twenty-eight OCD and 28 HC subjects were included in the statistical analysis. We compared differences between groups for all selected metabolites and in OCD patients we analyzed the relationship between metabolite levels and symptom severity, medication status, age, and the duration of illness. RESULTS: Significant decreases in tCr (U = 253.00, p = 0.022) and mI (U = 197.00, p = 0.001) in the pgACC were observed in the OCD group. No statistically significant differences were found in tNAA and tCho levels; however, tCho revealed a trend towards lower concentrations in OCD patients (U = 278.00, p = 0.062). Metabolic concentrations showed no significant correlations with the age and duration of illness. The correlation statistics found a significant negative correlation between tCr levels and YBOCS compulsions subscale (cor = -0.380, p = 0.046). tCho and YBOCS compulsions subscale showed a trend towards a negative correlation (cor = -0.351, p = 0.067). Analysis of subgroups with or without medication showed no differences. CONCLUSIONS: Patients with OCD present metabolic disruption in the pgACC. The decrease in tCr shows an important relationship with OCD symptomatology. tCr as a marker of cerebral bioenergetics may also be considered as a biomarker of the severity of compulsions. The study failed to prove that metabolic changes correlate with the medication status or the duration of illness. It seems that a disruption in the balance between these metabolites and their transmission may play a role in the pathophysiology of OCD.

Investigating the phenotypic and genetic associations between personality traits and suicidal behavior across major mental health diagnoses.

Personality traits influence risk for suicidal behavior. We examined phenotype- and genotype-level associations between the Big Five personality traits and suicidal ideation and attempt in major depressive, bipolar and schizoaffective disorder, and schizophrenia patients (N = 3012) using fixed- and random-effects inverse variance-weighted meta-analyses. Suicidal ideations were more likely to be reported by patients with higher neuroticism and lower extraversion phenotypic scores, but showed no significant association with polygenic load for these personality traits. Our findings provide new insights into the association between personality and suicidal behavior across mental illnesses and suggest that the genetic component of personality traits is unlikely to have strong causal effects on suicidal behavior.

Associated factors of REM sleep without atonia in younger (≤ 50 years) hospitalized psychiatric patients.

BACKGROUND: Isolated REM sleep without atonia (RSWA) as a main polysomnograhic feature of REM sleep behaviour disorder (RBD) is thought to be a prodromal or subclinical state of the disease. RSWA/RBD occurence in psychiatric population is much more frequent than in general population but its associated factors are still not known. METHODS: We invited 88 psychiatry in-patients to undervent video-polysomnography. The visual scoring was focused on RSWA in submentales and flexores digitales superficiales muscles. This parametr was subsequently correlated mainly with age/gender, their medication and mental status. RESULTS: The RWSA was mostly still in normal range despite the fact, that selected psychiatry patients (≤ 50 years) were taking several classes of psychoactive medication. 3,6% had convincingly RBD, although 35.7% reported rare lifetime occurence of dream-enacting behaviour and 62.8% sporadic nightmares. We found correlation between RSWA and SNRI medication class (p = 0.015), specifically venlafaxine (p = 0.029) as well as quetiapine (p = 0.030). Another significant associated factors were current anxiety (p < 0.001) and depressive symptoms (p = 0.05), but we found no relation between RSWA and given diagnosis. CONLUCIONS: Isolated RSWA in younger psychiatry patients might be a result of multiple factors, including medication and current mental status but these factors are in most cases not sufficient to manifest RBD.

The effectiveness of prefrontal theta cordance and early reduction of depressive symptoms in the prediction of antidepressant treatment outcome in patients with resistant depression: analysis of naturalistic data.

Current studies suggest that an early improvement of depressive symptoms and the reduction of prefrontal theta cordance value predict the subsequent response to antidepressants. The aim of our study was (1) to compare the predictive abilities of early clinical improvement defined as ≥ 20 % reduction in Montgomery and Åsberg Depression Rating Scale (MADRS) total score at week 1 and 2, and the decrease of prefrontal theta cordance at week 1 in resistant depressive patients and (2) to assess whether the combination of individual predictors yields more robust predictive power than either predictor alone. Eighty-seven subjects were treated (≥ 4 weeks) with various antidepressants chosen according to the judgment of attending psychiatrists. Areas under curve (AUC) were calculated to compare predictive effect of defined single predictors (≥ 20 % reduction in MADRS total score at week 1 and 2, and the decrease of cordance at week 1) and combined prediction models. AUCs of all three predictors were not statistically different (pair-wise comparison). The model combining all predictors yielded an AUC value 0.91 that was significantly higher than AUCs of each individual predictor. The results indicate that the combined predictor model may be a useful and clinically meaningful tool for the prediction of antidepressant response in patients with resistant depression.

Antidepressant monotherapy compared with combinations of antidepressants in the treatment of resistant depressive patients: a randomized, open-label study.

OBJECTIVE: This randomized, 6-week, open-label study compared efficacy of CAD and antidepressant monotherapies (ADM) that had been chosen according to clinical judgment of the attending psychiatrist. METHODS: A total of 60 inpatients (intent-to-treat analysis) with depressive disorder (≥ 1 unsuccessful antidepressant treatment) were randomly assigned to the interventions. The responders who completed the acute phase of study, were evaluated for relapse within 2 months of follow-up treatment. The primary outcome measure was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) and response was defined as a ≥ 50% reduction of MADRS score. RESULTS: Mean changes in total MADRS score from baseline to week 6 for patients in both treatment modalities were not different (ADM = 13.2 ± 8.6 points; CAD = 14.5 ± 9.5 points; P = 0.58). The analysis of covariance performed for significantly higher value of imipramine equivalent dose in CAD group showed only a non-significant between-group difference for total MADRS change (P = 0.17). There were also no differences between groups in response rate (ADM = 48%; CAD = 58%) and number of drop-outs in acute treatment as well as proportion of responders' relapses in the follow-up. CONCLUSION: Both treatment modalities produced clinically relevant reduction of depressive symptomatology in acute treatment of patients with resistant depression and their effect was comparable.

Glutamatergic abnormalities in the pregenual anterior cingulate cortex in obsessive-compulsive disorder using magnetic resonance spectroscopy: A controlled study.

In this study, we utilized proton magnetic resonance spectroscopy (MRS) to understand the role of glutamate (Glu), glutamine (Gln), and gamma-aminobutyric acid (GABA) of OCD patients in the pregenual anterior cingulate cortex (pgACC). In total, 54 patients with OCD and 54 healthy controls (HC) matched for age and sex were included in the study. They underwent MRS in the pgACC region to calculate the concentrations of Glu, Gln, GABA, and Glu + Gln (Glx). After quality control of the MRS data, 21 OCD and 21 HC were statistically analyzed. The severity of symptoms were evaluated using the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the statistical analysis, we compared differences between groups for the metabolites; in the OCD we analyzed the correlations with symptom severity, medication status, age, and duration of illness. A significant decrease in Glx, in Glu, and in Gln in the pgACC were observed in the OCD compared to HC. The correlation statistics showed a significant positive correlation between Glu levels and the YBOCS compulsions subscale. The results indicate that patients with OCD present a disturbance in glutamatergic metabolism in the pgACC. The results also demonstrate that these changes correlate with the severity of compulsions.

Functional Connectivity Changes in Obsessive-Compulsive Disorder Correspond to Interference Control and Obsessions Severity.

Introduction: Deficits in neurocognitive mechanisms such as inhibition control and cognitive flexibility have been suggested to mediate the symptoms in obsessive-compulsive disorder (OCD). These mechanisms are proposedly controlled by the "affective" and "executive" orbitofronto-striato-thalamo-cortical (CSTC) circuits with well-documented morphological and functional alterations in OCD that are associated with OCD symptoms. The precuneus region has been suggested in OCD as another key structure associated with the mechanism of "thought-action fusion." Our study aimed to elucidate the association of the altered functional coupling of the CSTC nodes (and precuneus), the OCD symptoms, and interference control/cognitive flexibility. Methods: In a group of 36 (17 medicated and 19 drug-free) OCD patients and matched healthy volunteers, we tested functional connectivity (FC) within the constituents of the dorsolateral prefrontal cortex "executive" CSTC, the orbitofrontal cortex/anterior cingulate "affective" CSTC, and precuneus. The functional connections showing the strongest effects were subsequently entered as explanatory variables to multiple regression analyses to identify possible associations between observed alterations of functional coupling and cognitive (Stroop test) and clinical measures (obsessions, compulsions, and anxiety level). Results: We observed increased FC (FWE p < 0.05 corr.) between CSTC seeds and regions of the parieto-occipital cortex, and between the precuneus and the angular gyrus and dorsolateral prefrontal cortex. Decreased FC was observed within the CSTC loop (caudate nucleus and thalamus) and between the anterior cingulate cortex and the limbic lobe. Linear regression identified a relationship between the altered functional coupling of thalamus with the right somatomotor parietal cortex and the Stroop color-word score. Similar association of thalamus FC has been identified also for obsessions severity. No association was observed for compulsions and anxiety. Conclusions: Our findings demonstrate altered FC in OCD patients with a prevailing increase in FC originating in CSTC regions toward other cortical areas, and a decrease in FC within the constituents of CSTC loops. Moreover, our results support the role of precuneus in OCD. The association of the cognitive and clinical symptoms with the FC between the thalamus and somatomotor cortex indicates that cognitive flexibility and inhibitory control are strongly linked and both mechanisms might contribute to the symptomatology of OCD.

Analysis of a promoter polymorphism in the SMDF neuregulin 1 isoform in Schizophrenia.

BACKGROUND/AIMS: Neuregulin 1 (NRG1) is a positional candidate gene in schizophrenia (SZ). Two major susceptibility loci in the NRG1 gene approximately one million nucleotides apart have been identified in genetic studies. Several candidate functional allelic variants have been described that might be involved in disease susceptibility. However, the findings are still preliminary. We recently mapped active promoters and other regulatory domains in several SZ and bipolar disorder (BD) candidate genes using ChIP-chip (chromatin immunoprecipitation hybridized to microarrays). One was the promoter for the NRG1 isoform, SMDF, which maps to the 3' end of the gene complex. Analysis of the SNP database revealed several polymorphisms within the approximate borders of the region immunoprecipitated in our ChIP-chip experiments, one of which is rs7825588. METHODS: This SNP was analyzed in patients with SZ and BD and its effect on promoter function was assessed by electromobility gel shift assays and luciferase reporter constructs. RESULTS: A significant increase in homozygosity for the minor allele was found in patients with SZ (genotype distribution chi(2) = 7.32, p = 0.03) but not in BD (genotype distribution chi(2) = 0.52, p = 0.77). Molecular studies demonstrated modest, but statistically significant allele-specific differences in protein binding and promoter function. CONCLUSION: The findings suggest that homozygosity for rs725588 could be a risk genotype for SZ.

Is combined treatment more effective than switching to monotherapy in patients with resistant depression? A retrospective study.

OBJECTIVE: The aim of this retrospective study was to compare the efficacy of combination therapy (combinations of antidepressants and various augmentations) and antidepressant monotherapy in the treatment of patients, who failed to respond at least to one previous antidepressant trial in the routine clinical practice. METHODS: We reviewed chart documents of patients hospitalized at Prague Psychiatric Center for depressive disorder from June 2005 to June 2007 and finished at least 4 weeks of new treatment. Depressive symptoms and overall clinical status were assessed using Montgomery and Asberg Depression Rating Scale, Clinical Global Impression and Beck Depression Inventory - Short Form at the baseline and in the end of treatment. RESULTS: We identified 49 inpatients (24-combined treatment, 25-monotherapy), who were suitable for analyses. Both groups were equal in baseline characteristics and in the duration of index episode treatment. The combined treatment was superior to the monotherapy switch in the MADRS median score reduction (16 vs. 9 points, p=0.01). The combined group achieved higher response rate compared to monotherapy group (67% vs. 36%, p=0.05). Number need to treat for response was 3.3 (95% CI, 1.85-37.3). CONCLUSION: The findings of this study suggest that combined treatment is more efficacious than switch to monotherapy in the treatment of resistant depression.

Transcranial Direct-Current Stimulation (tDCS) Versus Venlafaxine ER In The Treatment Of Depression: A Randomized, Double-Blind, Single-Center Study With Open-Label, Follow-Up.

OBJECTIVE: Transcranial direct-current stimulation (tDCS), a relatively new neuromodulation approach, provides some evidence of an antidepressant effect. This randomized, 4-week, double-blind study with 8-week, open-label, follow-up compared the efficacy and tolerability of left anodal tDCS with venlafaxine ER (VNF) in the treatment of depression and prevention of early relapse. METHODS: Subjects (n = 57) received tDCS (2 mA, 20 sessions, 30 mins) plus placebo (n = 29) or VNF plus sham tDCS (n = 28). Responders to both interventions entered the open-label follow-up. The primary outcome was score change in the Montgomery-Åsberg Depression Rating Scale (MADRS) at week 4 of the study. Secondary outcomes were response, remission, dropout rates and relapse rates within the follow-up.The mean change in the MADRS score from baseline to week for patients treated with tDCS was 7.69 (95% CI, 5.09-10.29) points and 9.64 (95% CI, 6.20-13.09) points for patients from the VNF group, a nonsignificant difference (1.95, 95% CI -2.25-6.16; t (55) = 0.93, p= 0.36, Cohen´s d = 0.24). There were no significant between-group differences in the MADRS scores from baseline to endpoint (intention-to-treat analysis). The response/remission rate for tDCS (24%/17%) and VNF (43%/32%) as well as the dropout rate (tDCS/VNF; 6/6) did not differ significantly between groups. In the follow-up, relapse (tDCS/VNF; 1/2) and dropout (tDCS/VNF; 2/3) rates were low and comparable. LIMITATIONS: A relatively small sample size and short duration of the antidepressant treatment; no placebo arm. CONCLUSION: Overall, this study found a similar efficacy of tDCS and VNF in the acute treatment of depression and prevention of early relapse. The real clinical usefulness of tDCS and its optimal parameters in the treatment of depression should be further validated.

ADHD: a hidden comorbidity in adult psychiatric patients.

Adult attention-deficit/hyperactivity disorder (aADHD) has recently been better recognized and treated in many European countries. In spite of this development, aADHD still features as a "hidden" comorbidity, often not diagnosed even in patients under psychiatric treatment for other psychiatric disorders. The aim of this study was to establish the prevalence rates of unrecognized aADHD in academic centers providing regular psychiatric services in the Czech Republic and Hungary. In a population of psychiatric in-and outpatients, Adult ADHD Self-Report Scale was administered. All positively and about half of the negatively screened subjects were clinically interviewed and the DSM diagnosis of ADHD was determined based on the symptom list and Conners' Adult ADHD Rating Scale. The estimated point prevalence rate of unrecognized comorbid aADHD among psychiatric in-and out patients was 6.99% (95% lower CI: 5.11, 95% upper CI 8.86) according to the DSM-IV-TR criteria and 9.27% (95% lower CI: 7.13, 95% upper CI 11.40) according to the DSM-5 criteria. Current suicide risk was significantly associated with the presence of undiagnosed aADHD; however, life time suicide attempts, depression, dysthymia, alcohol and substance dependence, anxiety and stress related disorders were not. Further educational efforts are needed to improve the recognition and treatment of aADHD in adults.

Brain Age in Early Stages of Bipolar Disorders or Schizophrenia.

Background: The greater presence of neurodevelopmental antecedants may differentiate schizophrenia from bipolar disorders (BD). Machine learning/pattern recognition allows us to estimate the biological age of the brain from structural magnetic resonance imaging scans (MRI). The discrepancy between brain and chronological age could contribute to early detection and differentiation of BD and schizophrenia. Methods: We estimated brain age in 2 studies focusing on early stages of schizophrenia or BD. In the first study, we recruited 43 participants with first episode of schizophrenia-spectrum disorders (FES) and 43 controls. In the second study, we included 96 offspring of bipolar parents (48 unaffected, 48 affected) and 60 controls. We used relevance vector regression trained on an independent sample of 504 controls to estimate the brain age of study participants from structural MRI. We calculated the brain-age gap estimate (BrainAGE) score by subtracting the chronological age from the brain age. Results: Participants with FES had higher BrainAGE scores than controls (F(1, 83) = 8.79, corrected P = .008, Cohen's d = 0.64). Their brain age was on average 2.64 ± 4.15 years greater than their chronological age (matched t(42) = 4.36, P < .001). In contrast, participants at risk or in the early stages of BD showed comparable BrainAGE scores to controls (F(2,149) = 1.04, corrected P = .70, η2 = 0.01) and comparable brain and chronological age. Conclusions: Early stages of schizophrenia, but not early stages of BD, were associated with advanced BrainAGE scores. Participants with FES showed neurostructural alterations, which made their brains appear 2.64 years older than their chronological age. BrainAGE scores could aid in early differential diagnosis between BD and schizophrenia.

Analysis of protocadherin alpha gene enhancer polymorphism in bipolar disorder and schizophrenia.

Cadherins and protocadherins are cell adhesion proteins that play an important role in neuronal migration, differentiation and synaptogenesis, properties that make them targets to consider in schizophrenia (SZ) and bipolar disorder (BD) pathogenesis. Consequently, allelic variation occurring in protocadherin and cadherin encoding genes that map to regions of the genome targeted in SZ and BD linkage studies are particularly strong candidates to consider. One such set of candidate genes is the 5q31-linked PCDH family, which consists of more than 50 exons encoding three related, though distinct family members--alpha, beta, and gamma--which can generate thousands of different protocadherin proteins through alternative promoter usage and cis-alternative splicing. In this study, we focused on a SNP, rs31745, which is located in a putative PCDHalpha enhancer mapped by ChIP-chip using antibodies to covalently modified histone H3. A striking increase in homozygotes for the minor allele at this locus was detected in patients with BD. Molecular analysis revealed that the SNP causes allele-specific changes in binding to a brain protein. The findings suggest that the 5q31-linked PCDH locus should be more thoroughly considered as a disease-susceptibility locus in psychiatric disorders.

Early reduction in prefrontal theta QEEG cordance value predicts response to venlafaxine treatment in patients with resistant depressive disorder.

INTRODUCTION: Previous studies of patients with unipolar depression have shown that early decrease of prefrontal EEG cordance in theta band can predict clinical response to various antidepressants. We have now examined whether decrease of prefrontal quantitative EEG (QEEG) cordance value after 1 week of venlafaxine treatment predicts clinical response to venlafaxine in resistant patients. METHOD: We analyzed 25 inpatients who finished 4-week venlafaxine treatment. EEG data were monitored at baseline and after 1 week of treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. Depressive symptoms and clinical status were assessed using Montgomery-Asberg Depression Rating Scale (MADRS), Beck Depression Inventory-Short Form (BDI-S) and Clinical Global Impression (CGI). RESULTS: Eleven of 12 responders (reduction of MADRS >or=50%) and only 5 of 13 non-responders had decreased prefrontal QEEG cordance value after the first week of treatment (p=0.01). The decrease of prefrontal cordance after week 1 in responders was significant (p=0.03) and there was no significant change in non-responders. Positive and negative predictive values of cordance reduction for response were 0.7 and 0.9, respectively. CONCLUSION: The reduction of prefrontal theta QEEG cordance value after first week of treatment might be helpful in the prediction of response to venlafaxine.

Changes in QEEG prefrontal cordance as a predictor of response to antidepressants in patients with treatment resistant depressive disorder: a pilot study.

INTRODUCTION: Previous studies of patients with unipolar depression have shown that early decreases of EEG cordance (a new quantitative EEG method) can predict clinical response. We examined whether early QEEG decrease represents a phenomenon associated with response to treatment with different antidepressants in patients with treatment resistant depression. METHOD: The subjects were 17 inpatients with treatment resistant depression. EEG data and response to treatment were monitored at baseline and after 1 and 4 weeks on an antidepressant treatment. QEEG cordance was computed at three frontal electrodes in theta frequency band. The prefrontal cordance combines complementary information from absolute and relative power of EEG spectra. Recent studies have shown that cordance correlates with cortical perfusion. Depressive symptoms were assessed using Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: All 17 patients completed the 4-week study. All five responders showed decreases in prefrontal cordance after the first week of treatment. Only 2 of the 12 nonresponders showed early prefrontal cordance decrease. The decrease of prefrontal QEEG cordance after week 1 in responders as well as the increase in nonresponders were both statistically significant (p-value 0.03 and 0.01, respectively) and the changes of prefrontal cordance values were different between both groups (p-value 0.001). CONCLUSION: Our results suggest that decrease in prefrontal cordance may indicate early changes of prefrontal activity in responders to antidepressants. QEEG cordance may become a useful tool in the prediction of response to antidepressants.

Can prefrontal theta cordance differentiate between depression recovery and dissimulation?

We present a case report of a 37-year old woman diagnosed with depressive disorder, first episode, who was admitted into a psychiatric hospital after a failed suicidal attempt. She responded to antidepressant therapy, as evidenced by a >50% reduction in MADRS total score. She was discharged after 4 weeks of treatment, denying any suicidal ideations. The following day the patient committed suicide; she burned herself to death. It is very likely that the patient dissimulated her symptoms and ideations. Subsequently, her quantitative EEG records were retrospectively analyzed. An increase of prefrontal theta cordance value after the first week of mirtazapine therapy was found. Recently three small studies have revealed that decrease of prefrontal theta cordance after 1 week of antidepressant administration can predict clinical response in patients with unipolar depression. In our previous study the absence of a decreased theta prefrontal cordance was associated with lack of treatment response with NPV 1.0 (Bares et al., 2007). Thus, we hypothesize that prefrontal theta cordance could become an objective marker of change of depressive symptoms, independent of patients' compliance and symptom dissimulation, more precise than objective and self-rated depression rating scales.

Association of schizophrenia in African Americans to polymorphism in synapsin III gene.

Linkage studies in families with schizophrenia have pointed to chromosome 22q12-q13 as one of several regions of the genome that may contain a susceptibility gene. The gene coding for synapsin III, an intrinsic synaptic vesicle membrane protein, maps to this target region. Two tightly linked single-nucleotide polymorphisms were recently found in a small subset of patients with SZ - a synonymous variant, L469L (469G>A), and a non-synonymous variant, S470N (470G>A) - which results in the loss of a mitogen-activated protein kinase serine phosphorylation site. We also found a slight increase in 470A in Caucasian patients from the US with schizophrenia. But, the sample size and allele frequency were too small to draw definitive conclusions. However, both single-nucleotide polymorphisms were much more polymorphic in African American controls than in Caucasian controls, thereby providing a better sample cohort to analyze for schizophrenia involvement. For the codon 469 single-nucleotide polymorphisms, a 50-fold increase was observed in the frequency of 469A in African Americans compared with Caucasians. Furthermore, there was an increase in the percentage of African American patients with schizophrenia who were homozygous for the 469A allele compared with controls who were homozygous (11 versus 5%; AA vs. all other genotypes - Fisher statistic=3.08, P=0.04, one-tailed). An increase in 470A heterozygotes was also found, but the results fell short of being statistically significant. The findings support a role for synapsin III in a subset of African American patients with schizophrenia and raises questions about selective pressure in Africa to account for the extraordinary disparity of the 469 and 470 single-nucleotide polymorphisms in different ethnic populations.

Screening of PIP5K2A promoter region for mutations in bipolar disorder and schizophrenia.

OBJECTIVE: To analyze the promoter region of PIP5K2A, a phosphatidylinositol 4-phosphate 5-kinase that maps to 10p in a region linked to both bipolar disorder and schizophrenia. METHODS: The promoter region was screened by single-strand conformation polymorphism analysis and DNA sequencing. Allele frequencies were determined in a case-control study. Functional significance of a promoter variant was determined by electromobility gel shift assays. RESULTS: Homozygosity for a rare putative promoter variant, -1007C-->T, was found in only two patients with schizophrenia and in no controls or bipolar patients. The variant forms a 7/8 base match for the binding site of Oct-1, a member of the POU homeodomain family. Electromobility gel shift assays revealed increased binding of a brain-specific nuclear protein to the -1007T allele compared with -1007C. CONCLUSION: The data suggest that homozygosity for -1007T could be a rare genetic factor in the development of schizophrenia.

QEEG Theta Cordance in the Prediction of Treatment Outcome to Prefrontal Repetitive Transcranial Magnetic Stimulation or Venlafaxine ER in Patients With Major Depressive Disorder.

The aims of this double-blind study were to assess and compare the efficacy of quantitative electroencephalographic (QEEG) prefrontal theta band cordance in the prediction of response to 4-week, right, prefrontal, 1-Hz repetitive transcranial magnetic stimulation (rTMS) or venlafaxine ER in patients with major depressive disorder (MDD). Prefrontal QEEG cordance values of 50 inpatients (25 subjects in each group) completing 4 weeks of the study were obtained at baseline and after 1 week of treatment. Depressive symptoms were assessed using Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline and at week 1 and 4. Treatment response was defined as a ≥50% reduction in baseline MADRS total score. All responders (n = 9) and 6 of 16 nonresponders in the rTMS group had reduced cordance at week 1 (P < .01). Reduction of theta cordance value at week 1 was detected in all responders (n = 10) to venlafaxine ER, but only in 4 of 15 nonresponders (P = .005). The comparison of the areas under the curve of cordance change for prediction of response between rTMS (0.75) and venlafaxine ER (0.89) treated groups yielded no significant difference (P = .27). Our study indicates that prefrontal QEEG cordance is a promising tool not only for predicting the response to certain antidepressants but also to rTMS treatment, with comparable predictive efficacy for both therapeutic interventions.

Identification of PIK3C3 promoter variant associated with bipolar disorder and schizophrenia.

BACKGROUND: Genes involved in phosphoinositide (PI) lipid metabolism are excellent candidates to consider in the pathogenesis of bipolar disorder (BD) and schizophrenia (SZ). One is PIK3C3, a member of the phosphatidylinositide 3-kinase family that maps closely to markers on 18q linked to both BD and SZ in a few studies. METHODS: The promoter region of PIK3C3 was analyzed for mutations by single-strand conformation polymorphism analysis and sequencing. A case-control association study was conducted to determine the distribution of variant alleles in unrelated patients from three cohorts. Electromobility gel shift assays (EMSA) were performed to assess the functional significance of variants. RESULTS: Two polymorphisms in complete linked disequilibrium with each other were identified, -432C- > T and a "C" insert at position -86. The -432T allele occurs within an octamer containing an ATTT motif resembling members of the POU family of transcription factors. In each population analyzed, an increase in -432T was found in patients. EMSAs showed that a -432T containing oligonucleotide binds to brain proteins that do not recognize -432C. CONCLUSIONS: A promoter mutation in a PI regulator affecting the binding of a POU-type transcription factor may be involved in BD and SZ in a subset of patients.