István Bitter

Common variants conferring risk of schizophrenia

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the ‘genomic disorders’, have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis

BACKGROUND In spite of the growing literature about adult attention-deficit hyperactivity disorder (ADHD), relatively little is known about the prevalence and correlates of this disorder. AIMS To estimate the prevalence of adult ADHD and to identify its demographic correlates using meta-regression analysis. METHOD We used the MEDLINE, PsycLit and EMBASE databases as well as hand-searching to find relevant publications. RESULTS The pooled prevalence of adult ADHD was 2.5% (95% CI 2.1-3.1). Gender and mean age, interacting with each other, were significantly related to prevalence of ADHD. Meta-regression analysis indicated that the proportion of participants with ADHD decreased with age when men and women were equally represented in the sample. CONCLUSIONS Prevalence of ADHD in adults declines with age in the general population. We think, however, that the unclear validity of DSM-IV diagnostic criteria for this condition can lead to reduced prevalence rates by underestimation of the prevalence of adult ADHD.

Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial

BACKGROUND Duloxetine is a balanced and potent dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE) that has previously been shown to be effective in the acute treatment of major depressive disorder (MDD). This placebo-controlled study assesses the safety and efficacy of duloxetine (80 or 120 mg/day) and paroxetine (20 mg QD) during an initial 8-week acute phase and subsequent 6-month continuation phase treatment of MDD. METHOD In this randomized, double-blind, placebo-controlled trial, adult outpatients (age >or= 18 years) meeting DSM-IV criteria for MDD received placebo (n = 93), duloxetine 80 mg/day (40 mg BID; n = 95), duloxetine 120 mg/day (60 mg BID; n = 93), or paroxetine (20 mg QD; n = 86) for 8 weeks. Patients who had a >or= 30% reduction from baseline in HAMD(17) total score during the acute phase were allowed to continue on the same (blinded) treatment for a 6-month continuation phase. Efficacy measures included the 17-item Hamilton Rating Scale for Depression (HAMD(17)) total score, HAMD(17) subscales, the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAMA), Visual Analog Scales (VAS) for pain, the Clinical Global Impression of Severity (CGI-S) and Patient Global Impression of Improvement (PGI-I) scales, the 28-item Somatic Symptom Inventory (SSI), and the Sheehan Disability Scale (SDS). Safety and tolerability were assessed using treatment-emergent adverse events, discontinuations due to adverse events, vital signs, ECGs, laboratory tests, and the Arizona Sexual Experiences Scale (ASEX). RESULTS During the acute phase, patients receiving duloxetine 80 mg/day, duloxetine 120 mg/day, or paroxetine 20 mg QD had significantly greater reductions in HAMD(17) total score compared with placebo. Both duloxetine (80 and 120 mg/day) and paroxetine treatment groups had significantly greater improvement, compared with placebo, in MADRS, HAMA, CGI-S, and PGI-I scales. Estimated probabilities of remission at week 8 for patients receiving duloxetine 80 mg/day (51%), duloxetine 120 mg/day (58%), and paroxetine (47%) were significantly greater compared with those receiving placebo (30%). The rate of discontinuation due to adverse events among duloxetine-treated patients (80 and 120 mg/day) did not differ significantly from the rate in the placebo group. Treatment-emergent adverse events reported significantly more frequently by duloxetine-treated patients than by patients receiving placebo were constipation (80 and 120 mg/day), increased sweating (120 mg/day), and somnolence (120 mg/day). The incidence of acute treatment-emergent sexual dysfunction in duloxetine- and paroxetine-treated patients was 46.5% and 62.8%, respectively. During the 6-month continuation phase, duloxetine (80 and 120 mg/day) and paroxetine treatment groups demonstrated significant improvement in HAMD(17) total score. Treatment-emergent adverse events occurring most frequently in each active treatment group during the continuation phase were viral infection (duloxetine 80 mg/day), diarrhea (duloxetine 120 mg/day), and headache (paroxetine 20 mg QD). CONCLUSION These data support previous findings that duloxetine is safe, efficacious, and well tolerated in the acute treatment of MDD. Furthermore, these data provide the first demonstration under double-blind, placebo-controlled conditions that the efficacy and tolerability of duloxetine are maintained during chronic treatment.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders, Part III: Maintenance Treatment

Summary As with the two preceding guidelines of this series, these practice guidelines for the pharmacological maintenance treatment of bipolar disorder were developed by an international task force of the World Federation of Societies of Biological Psychiatry (WFSBP). Their purpose is to supply a systematic overview of all scientific evidence relating to maintenance treatment. The data used for these guidelines were extracted from a MEDLINE and EMBASE search, from recent proceedings from key conferences and various national and international treatment guidelines. The scientific justification of support for particular treatments was categorised into four levels of evidence (A-D). As these guidelines are intended for clinical use, the scientific evidence was not only graded, but also reviewed by the experts of the task force to ensure practicality.

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Olanzapine versus clozapine in treatment-resistant or treatment-intolerant schizophrenia

Clozapine has been the gold standard for treatment of patients with refractory schizophrenia but is associated with serious safety liabilities. This has prompted the search for therapeutic alternatives for treatment-resistant schizophrenia. The objective of this study was to compare the efficacy and safety of olanzapine versus clozapine in schizophrenic patients who failed to respond adequately to antipsychotic medication or who experienced intolerable adverse effects associated with the medication. This 18-week, randomized, double-blind, parallel study compared treatment with either olanzapine (5-25 mg/day, n=75) or clozapine (100-500 mg/day, n=72) in patients with schizophrenia who were nonresponsive to, or intolerant of, standard acceptable antipsychotic therapy. At the 18-week endpoint, no statistically significant differences were found between olanzapine and clozapine in any efficacy measure used: Positive and Negative Syndrome Scale (PANSS) total, positive, negative, or general psychopathology or Clinical Global Impression severity (CGI-S). Response rates based on the criteria of Kane et al. [Arch. Gen. Psychiatry 45 (1988) 789] were also not significantly different between olanzapine-treated (57.9%) and clozapine-treated patients (60.8%). There were no significant differences in measurements of extrapyramidal symptoms or electrocardiography, and no clinically and statistically significant changes were seen in vital signs or laboratory measures in either group. Both treatments were well tolerated. Olanzapine demonstrated similar efficacy to clozapine in patients who had failed previous treatment because of lack of efficacy (treatment resistance) or intolerable side effects (treatment intolerance). Olanzapine therefore presents a safe alternative in the treatment of refractory schizophrenia.

Predicting suicidal risk in schizophrenic and schizoaffective patients in a prospective two-year trial

BACKGROUND Enhanced ability to reliably identify risk factors for suicidal behavior permits more focused decisions concerning treatment interventions and support services, with potential reduction in lives lost to suicide. METHODS This study followed 980 patients at high risk for suicide in a multicenter prospective study for 2 years after randomization to clozapine or olanzapine. A priori predictors related to diagnosis, treatment resistance, and clinical constructs of disease symptoms were evaluated as possible predictors of subsequent suicide-related events. RESULTS Ten baseline univariate predictors were identified. Historical predictors were diagnosis of schizoaffective disorder, history or current use at baseline of alcohol or substance abuse, cigarette smoking, number of lifetime suicide attempts, and the number of hospitalizations in the previous 36 months to prevent suicide. Predictive clinical features included greater baseline scores on the InterSePT scale for suicidal thinking, the Covi Anxiety Scale, the Calgary Depression Scale (CDS), and severity of Parkinsonism. Subsequent multivariate analysis revealed the number of hospitalizations in the previous 36 months, baseline CDS, severity of Parkinsons, history of substance abuse, and lifetime suicide attempts. Clozapine, in general, was more effective than olanzapine in decreasing the risk of suicidality, regardless of risk factors present. CONCLUSIONS This is the first prospective analysis of predictors of suicide risk in a large schizophrenic and schizoaffective population judged to be at high risk for suicide. Assessment of these risk factors may aid clinicians in evaluating risk for suicidal behaviors so that appropriate interventions can be made.

Attention deficit hyperactivity disorder (ADHD): gender- and age-related differences in neurocognition

BACKGROUND Despite the growing recognition that the clinical symptom characteristics associated with attention deficit hyperactivity disorder (ADHD) persist into adulthood in a high proportion of subjects, little is known about the persistence of neurocognitive deficits in ADHD. The objective was twofold: (1) to conduct a meta-analysis of neuropsychological studies to characterize attentional performance in subjects with adult ADHD by examining differences in ADHD versus normal control subjects; and (2) to investigate whether these differences vary as a function of age and gender. METHOD Twenty-five neuropsychological studies comparing subjects with adult ADHD and healthy controls were evaluated. Statistical effect size was determined to characterize the difference between ADHD and control subjects. Meta-regression analysis was applied to investigate whether the difference between ADHD and control subjects varied as a function of age and gender across studies. RESULTS Tests measuring focused and sustained attention yielded an effect size with medium to large magnitude whereas tests of simple attention resulted in a small to medium effect size in terms of poorer attention functioning of ADHD subjects versus controls. On some of the measures (e.g. Stroop interference), a lower level of attention functioning in the ADHD group versus the controls was associated with male gender. CONCLUSIONS Adult ADHD subjects display significantly poorer functioning versus healthy controls on complex but not on simple tasks of attention, and the degree of impairment varies with gender, with males displaying a higher level of impairment.

Pharmacotherapy of adult attention deficit hyperactivity disorder (ADHD): a meta-analysis

Our objective was to conduct a meta-analysis of therapeutic efficacy of pharmacological treatment of adult ADHD based on data from controlled clinical trials. We used the search engines PubMed and Medline to identify relevant clinical trials. Short-term studies with double-blind parallel-group design were selected for the analysis. Altogether, we identified 11 trials that met the criteria, and investigated a total of 1991 subjects, 694 and 1297 of whom were treated with placebo or active medication, respectively. In order to pool efficacy data from studies with different characteristics, including different number of participants, different trial duration and measures of efficacy, the statistical effect sizes for each study had to be calculated. Our findings showed that the pooled effect size across all treatments was in the medium-to-high range (Cohens d=0.65, p<0.0001 vs. placebo), and the effect size for stimulants (Cohens d=0.67, p<0.0001 vs. placebo) was somewhat higher than for non-stimulant medications (Cohens d=0.59, p<0.0001 vs. placebo). The current database of controlled trials for adult ADHD is relatively small, and does not include data for many of the potentially important agents. In addition, effect-size estimates for different classes of medications (i.e. stimulant and non-stimulant medications) were based on separate studies; head-to-head comparisons of various agents are severely lacking. Nonetheless, results of this meta-analysis across all ADHD medications in adult subjects demonstrated statistically significant and clinically robust improvement in symptom severity compared to placebo treatment.