Currently utilized clinician-rated symptom scales for tardive dyskinesia (TD) have not kept up with the expanding spectrum of TD phenomenology. The objective of this study was to develop and test the reliability of a new instrument, the CTI.

A movement disorder neurologist devised the outline of the scale. A steering committee (four neurologists and two psychiatrists) provided revisions until consensus was reached. The resulting instrument assesses frequency of abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, limb/trunk, complex movements (e.g., handwringing, self-caressing), and vocalizations. The CTI rates symptoms from 0–3 with 0 = absent, 1 = infrequent/intermittent or only present with activating maneuvers, 2 = frequent intermittent, brief periods without movements, 3 = constant or nearly constant. Functional impairments including activities of daily living (ADL), social impairment, symptom bother, and harm are rated 0–3 with 0 = patient is unaware or unaffected, 1 = symptoms mildly impact patient, 2 = symptoms moderately impact patient, 3 = symptoms severely impact patient. Following institutional review board approval, the CTI underwent inter-rater and test-retest reliability testing. Videos of patient TD examinations were obtained and reviewed by two movement disorder specialists to confirm the diagnosis of TD by consensus and the adequacy to demonstrate a TD-consistent movement. Vignettes were created to include patients’ symptom descriptions and functional, social, or occupational impairments/limitations. Four clinicians rated each video/vignette. Selected videos/vignettes were also subject to an intra-rater retest. Interrater agreement was analyzed via 2-way random-effects interclass correlation (ICC) and test-retest agreement assessment utilizing Kendall’s tau-b.

45 video/vignettes were assessed for interrater reliability, and 16 for test-retest reliability. ICCs for movement frequency were as follows: abnormal eye movement .89; abnormal tongue/mouth movement .91; abnormal jaw movement .89; abnormal limb movement .76; complex movement .87; abnormal vocalization .77; and functional impairments including harm .82; social embarrassment .88; ADLs .83; and symptom bother .92. Retests were conducted on mean (SD) 15 (3) days later with scores ranging from .66–.87.

The CTI is a new instrument with good reliability in assessing TD symptoms and functional impacts. Future validation study is warranted.

Neurocrine Biosciences

Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.

To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.

This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.

The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.

Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.

Personality traits may predict antidepressant discontinuation and response. However, previous studies were rather small, only explored a few personality traits and did not include adverse drug effects nor the interdependency between antidepressant discontinuation patterns and response.

GENDEP included 589 patients with unipolar moderate-severe depression treated with escitalopram or nortriptyline for 12 weeks. Seven personality dimensions were measured using the self-reported 240-item Temperament and Character Inventory-Revised (TCI-R). We applied Cox proportional models to study discontinuation patterns, logistic and linear regression to investigate response and remission after 8 and 12 weeks, and mixed-effects linear models regarding time-varying treatment response and adverse drug reactions.

Low harm avoidance, low cooperativeness, high self-transcendence and high novelty seeking were associated with higher risks for antidepressant discontinuation, independent of depressed mood, adverse drug reactions, drug, sex and age. Regression analyses showed that higher novelty seeking and cooperativeness scores were associated with a greater likelihood of response and remission after 8 and 12 weeks, respectively, but we found no correlations with response in the mixed-effects models. Only high harm avoidance was associated with more self-reported adverse effects.

This study, representing the largest investigation between several personality traits and response to two different antidepressants, suggests that correlations between personality traits and antidepressant treatment response may be confounded by differential rates of discontinuation. Future trials on personality in the treatment of depression need to consider this interdependency and study whether interventions aiming at improving compliance for some personality types may improve response to antidepressants.

Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.

To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.

Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.

Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.

AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.

Polymorphisms in dopamine transporter gene (DAT1) has been associated with ADHD in previous studies. Some data point also to the role of DAT1 gene in cognitive functions, such as attention, affecting ADHD phenotype.

Two hundred five children with diagnosis of ADHD (187 boys, 18 girls; age 10.9±2.7) and 155 healthy controls (80 boys, 75 girls; age 10.3±2.3) were recruited. DAT rs463379 SNP intron polymorphism was genotyped. Both (unmedicated for 48 hours) patients and healthy controls were assessed with modified Stroop Interference Test (SIT).

: Due to low number of patients with CC genotype, in analysis we combined CC and GC genotypes. In patients GG compared to CC + GC genotype was associated with lower number of errors in part A ST (2.5±3.3 vs. 4.1±4.7; p=0.01). In part B of SIT, controls and patients with GG performed better (made less errors) than individuals with GC and GG genotypes; respectively (0.4±0.7 vs. 0.5±0.9 vs. 1.3±1.0; p=0.02); (1.0±1.4 vs. 2.0±3.3; p=0.03). Part C of SIT was performed better (less errors and shorter time) in patients with GG genotype vs. patients with other genotypes, respectively (139.9±48.0 vs. 166.2±67.6; p=0.009); (6.8±5.6 vs. 10.1±8.5; p=0.009).

We observed association between polymorphism in intron of DAT1 gene and performance in SIT. GG genotype of rs463379 SNP may be related to better cognitive functioning (better inhibition) in patients with ADHD. This may suggest the role of inhibition as intermediate variable between genotype and clinical picture of ADHD.

In two recent studies the SNP rs2230912 (Gln460Arg) located in exon 13 of P2RX7-gene (chromosome 12q24) provided the strongest evidence of association with bipolar disorder (BP) (Barden et al,2006; McQuillin et al, 2008) and in one study with the unipolar major depression (Mdd-UP) ( Lucae et al, 2006).

In the present study we investigated the involvement of the SNP rs2230912 in BPI in four European samples from Germany, Poland, Romania and Russia and in the combined sample (N=1445) in comparison with a combined sample of 2006 normal controls. Additionally, a Mdd-UP sample (N=640) from Germany was studied.

All patients were diagnosed according to DSM-IV-R. The BPI sample consisted of 802 females (55.5%) and 643 males (44.5%); the mean AO was 26.9 (SD=10.6); the mean age-at-interview was 42.7 (SD=12.5). The control sample had a mean age of 39.74 (SD=11.22) [1113 females (55.5%); 893 males (44.5%)]. Genotyping of all national samples was performed at Bonn University using the Mass ARRAY system on a Sequenom Compact MALDI-TOF-device. The single marker analysis was performed with FAMHAP software.

There was no allelic association between the G-allele of the SNP rs2230912 and either BPI or Mdd-UP both in the national samples and in the combined sample. The genotypic analysis also indicated no significant results. Our samples of patients and controls had genotypic distributions similar to those of the previously published studies and even in these studies there were no significant differences in genotype frequencies between BPI patients and controls.

The catecholamine hypothesis of affective disorders suggests that depression is associated with a functional decrease of catecholamines. There is consistent evidence that COMT gene would be a candidate gene for studies of bipolar disorder.

The study was performed on patients with bipolar disorder n=298 (male n=126, female n=172). Control subjects were blood donors n=336 (male n=130, female n=206), who were not psychiatrically assessed. The subgroup of patients with psychotic features not congruent with mood contained n=88 patients, males n=41, females n=47. The subgroup of patients with psychotic features congruent with mood contained n=89 patients, males n=47, females n=42. The subgroup of patients with melancholic depression contained n=197 patients, males n=76, females n= 121. A polymorphism was analysed by PCR-RFLP method.

There were no differences in the frequency of genotypes, alleles between patients and controls in the whole group (p=0,286 for genotypes, p= 0,652 for alleles). Dividing the patients according to the gender, no differences in the frequency of either genotypes or alleles were found (p=0,298 for genotype males, p=0,456 for genotypes females). We did not find the association in the subgroup of patients with psychotic features congruent (p=0,828 for genotypes, p= 0,866 for alleles), or not congruent with mood (p=0,116 for genotypes, p= 0,673 for alleles) and with the subgroup of patients with depression with melancholic features (p= 0,758 for genotypes, p= 0,849 for alleles).

Results of our study suggest that the polymorphism of COMT gene is not associated with the susceptibility to bipolar disorder.

Working memory and executive functions, connected with the activity of prefrontal cortex play an important role in complex mental processes. Wisconsin Card Sorting Test (WCST) is a main tool used for neuropsychological assessment of prefrontal cortex activity. Molecular genetics studies show the association between the performance on WCST and polymorphism of dopaminergic system genes in schizophrenia and healthy subjects, also with polymorphism of BDNF gene in bipolar disorders.

In this study an association between performance on WCST and polymorphisms of selected candidate genes was assessed.

The study included 200 healthy volunteers aged 18-60 years. Neuropsychological assessment was performed using WCST and following domains were evaluated: perseverative errors (inability to change the reaction), nonperseverative errors (attentional inability to avoid distraction), number of completed categories (ability to utilize new information), percent of conceptual responses (ability of conceptual thinking) and set to complete 1st category (ability to formulate a logical conception). Genotyping were done for polymorphism of dopaminergic: D1receptor (-48A/G) and catechol-O-methyltransferase (COMT108/158Val/Met), serotoninergic (5-HTTLPR), glutamatergic: FYNkinase (93A/G, IVS10+37T/C, Ex12+894T/G) and neurotrophic: brain-derived neurotrophic factor (BDNF:C-270T,Val66Met) genes.

A/G polymorphism of DRD1 gene was connected with better results on trials to complete 1st category. Better performance on nonperseverative errors was observed in females with Val/Val genotype of COMT. The C/T genotype of C-270T BDNF polymorphism was associated with higher percentage of conceptual responses.

The results obtained suggest a contribution of studied candidate genes to working memory and executive functions efficiency, connected with prefrontal cortex activity, in healthy subjects.

Neuregulin-1 (NRG1) may be an important factor in pathogenesis of schizophrenia due to its role in neurodevelopmental processes: myelination, neurotransmitter receptor expression and synaptic plasticity. NRG1 has been also implied to play role in cognitive impairments, which are considered to be endophenotypes of schizophrenia, i.e. subclinical, heritable and independent of clinical state traits associated with genetic susceptibility. Surprisingly, a recent meta-analysis (Dickinson, 2007) demonstrated that reliable and easy to administer Digit Symbol Coding Task (DSCT) discriminate people with schizophrenia from comparison individuals better than the more widely studied neuropsychological instruments.

The study was carried out to investigate the association of a polymorphisms of the NRG1 gene (rs62510682) and schizophrenia with respect to performance on DSCT.

We included 103 patients diagnosed with schizophrenia according to ICD-10 criteria and 578 controls in our study. The patients were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. DSCT was administered to 80 patients.

The polymorphisms were in HWE both in the cases’ and controls’ groups. In single marker analysis, we did not find an association for the SNP tested. However; we have found that T allel carriers (TT and/or GT genotype) performed worse than G allel carriers (p=0.4) suggesting weaker cognitive processing efficiency.

Our data do not support the role of the NRG1 gene polymorphism (rs62510682) in the predisposition to schizophrenia; however, the studied SNP might be considered to be a risk factor for cognitive impairment in schizophrenia.

For patients with major depressive disorder (MDD) experiencing side-effects or non-response to their first antidepressant, little is known regarding the effect of switching between a tricyclic antidepressant (TCA) and a selective serotonin reuptake inhibitor (SSRI).

To compare the switch between the TCA nortriptyline and the SSRI escitalopram.

Among 811 adults with MDD treated with nortriptyline or escitalopram for up to 12 weeks, 108 individuals switched from nortriptyline to escitalopram or vice versa because of side-effects or non-response (trial registration: EudraCT No.2004-001723-38 (https://eudract.ema.europa.eu/) and ISRCTN No.03693000 (http://www.controlled-trials.com)). Patients were followed for up to 26 weeks after switching and response was measured with the Montgomery–Åsberg Depression Rating scale (MADRS). We performed adjusted mixed-effects linear regression models with full information maximum likelihood estimation reporting β-coefficients with 95% CIs.

Switching antidepressants resulted in a significant decrease in MADRS scores. This was present for switchers from escitalopram to nortriptyline (n = 36, β = −0.38, 95% CI −0.51 to −0.25, P<0.001) and from nortriptyline to escitalopram (n = 72, β = −0.34, 95% CI −0.41 to −0.26, P<0.001). Both switching options resulted in significant improvement among individuals who switched because of non-response or side-effects. The results were supported by analyses on other rating scales and symptom dimensions.

These results suggest that switching from a TCA to an SSRI or vice versa after non-response or side-effects to the first antidepressant may be a viable approach to achieve response among patients with MDD.

K.J.A. holds an Alberta Centennial Addiction and Mental Health Research Chair, funded by the Government of Alberta. K.J.A. has been a member of various advisory boards, received consultancy fees and honoraria, and has received research grants from various companies including Johnson and Johnson Pharmaceuticals Research and Development and Bristol-Myers Squibb Pharmaceuticals Limited. D.S. has served on advisory boards for, and received unrestricted grants from, Lundbeck and AstraZeneca. A.F. and P.M. have received honoraria for participating in expert panels for Lundbeck and GlaxoSmithKline.