Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Unattended Hospital and Home Sleep Apnea Testing Following Cerebrovascular Events.

BACKGROUND: Home sleep apnea testing (HSAT) is an alternative to polysomnography for the detection of obstructive sleep apnea (OSA). We assessed the feasibility of HSAT as an unattended screening tool for patients with a stroke or transient ischemic attack (TIA). AIMS: The primary outcome was the feasibility of unattended HSAT, as defined by analyzability of the data. Secondary outcomes included determining (1) predictors of obtaining nonanalyzable sleep data and (2) time to OSA detection and continuous positive airway pressure (CPAP) initiation. METHODS: In this single-center prospective observational study, inpatients or outpatients who had sustained a stroke or TIA were screened for OSA using the ApneaLink Plus ambulatory sleep monitor in their home or hospital room. RESULTS: There were 102 patients who completed unattended sleep monitoring. Mean age was 68.7 ± 13.7 years, 55.9% were male, 57.8% were outpatients, and 77.5% had a stroke (22.5% with TIA). Eighty-two (80.4%) patients obtained four or more hours of analyzable sleep data. Functional dependence (defined as a modified Rankin Scale of >2) and elevated body mass index were independently associated with obtaining nonanalyzable data. OSA was detected in 63.4% (52 of 82) of patients and, of those, 34 of 52 (65.4%) initiated CPAP therapy. The mean time from study recruitment to HSAT was 1.7 days (median: 1, interquartile range [IQR]: 2) and CPAP was initiated on average within 62.7 days of recruitment (median: 53, IQR: 30). CONCLUSIONS: Unattended HSAT can be feasibly implemented after stroke or TIA. This method facilitates rapid diagnosis and management of OSA in both the outpatient and inpatient settings.

Movements in brain death: a systematic review.

Brain death is the irreversible lost of function of the brain including the brainstem. The presence of spontaneous or reflex movements constitutes a challenge for the neurological determination of death. We reviewed historical aspects and practical implications of the presence of spontaneous or reflex movements in individuals with brain death and postulated pathophysiological mechanisms. We identified and reviewed 131 articles on movements in individuals with confirmed diagnosis of brain death using Medline from January 1960 until December 2007, using 'brain death' or 'cerebral death' and 'movements' or 'spinal reflex' as search terms. There was no previous systematic review of the literature on this topic. Plantar withdrawal responses, muscle stretch reflexes, abdominal contractions, Lazarus's sign, respiratory-like movements, among others were described. For the most part, these movements have been considered to be spinal reflexes. These movements are present in as many as 40-50% of heart-beating cadavers. Although limited information is available on the determinants and pathophysiological mechanisms of spinal reflexes, clinicians and health care providers should be aware of them and that they do not preclude the diagnosis of brain death or organ transplantation.

Exercise Training Increases Parietal Lobe Cerebral Blood Flow in Chronic Stroke: An Observational Study.

Exercise is increasingly recommended as an essential component of stroke rehabilitation, yet uncertainty remains with respect to its direct effect on the cerebral vasculature. The current study first demonstrated the repeatability of pseudo-continuous arterial spin labeling (ASL) magnetic resonance imaging (MRI) in older adults with stroke, and then investigated the change in cerebrovascular function following a 6-month cardiovascular rehabilitation program. In the repeatability study, 12 participants at least 3 months post-stroke underwent two ASL imaging scans 1 month apart. In the prospective observational study, eight individuals underwent ASL imaging and aerobic fitness testing before and after a 6-month cardiovascular rehabilitation program. Cerebral blood flow (CBF) and the spatial coefficient of variation of CBF (sCoV) were quantified to characterize tissue-level perfusion and large cerebral artery transit time properties, respectively. In repeat scanning, intraclass correlation (ICC) indicated moderate test-retest reliability for global gray matter CBF (ICC = 0.73) and excellent reliability for sCoV (ICC = 0.94). In the observational study, gray matter CBF increased after training (baseline: 40 ± 13 vs. 6-month: 46 ± 12 ml·100 g-1·min-1, P = 0.036). The greatest change occurred in the parietal lobe (+18 ± 12%). Gray matter sCoV, however, did not change following training (P = 0.31). This study provides preliminary evidence that exercise-based rehabilitation in chronic stroke enhances tissue-level perfusion, without changing the relative hemodynamic properties of the large cerebral arteries.

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation.

A mother's cortisol secretion is importantly associated with her own mental health and her infant's cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother's history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion.

A birth-season/DRD4 gene interaction predicts weight gain and obesity in women with seasonal affective disorder: A seasonal thrifty phenotype hypothesis.

We have recently described an association between the hypofunctional 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), weight gain, and obesity in women with seasonal affective disorder (SAD). In the current study, we examined whether season-of-birth might interact with the 7R allele to influence body weight regulation in SAD. In 182 female probands with SAD, we performed an analysis of covariance predicting maximum lifetime body mass index (BMI) with both the exon-3 variable number of tandem repeat polymorphism of DRD4 and season-of-birth as independent variables, and age as the covariate. The overall model was highly significant (F = 4.42, df = 8, 173, p < 0.0001) with season-of-birth predicting maximal lifetime BMI both on its own and in its interaction with the 7R allele. The latter finding was attributable to 7-repeat carriers born in the spring (N = 17), who had a mean maximal lifetime BMI of 33.7 kg/m2 (SD 8.6), compared to 26.7 kg/m2 (SD 5.4) for all other probands combined (N = 165) (F = 20.01, df = 1, 179, p < 0.0001). The lifetime rate of obesity (maximal BMI > 30 kg/m2) was also significantly higher in the 7R/spring birth group (9/17=52.9% vs 32/165=19.4%; chi2 = 9.94, df = 1, p = 0.002; odds ratio = 4.68, 95% CI = 1.67-13.07). These data may reflect a novel gene-environment interaction, during early brain development, which establishes an increased risk for obesity in women with SAD. Although the mechanism for season-of-birth effects in psychiatric disorders is unknown, a characteristic pattern of melatonin exposure during the second and third trimesters may be of particular relevance in this study population. We speculate that these data may reflect the vestigial expression of a seasonal thrifty phenotype that contributed to the positive selection of the 7R allele over the past 40,000 years.

Identifying obstructive sleep apnea after stroke/TIA: evaluating four simple screening tools.

OBJECTIVE: Despite its high prevalence and unfavorable clinical consequences, obstructive sleep apnea (OSA) often remains underappreciated after cerebrovascular events. The purpose of our study was to evaluate the clinical utility of four simple paper-based screening tools for excluding OSA after stroke or transient ischemic attack (TIA). PATIENTS/METHODS: Sixty-nine inpatients and outpatients with stroke or TIA during the past 180 days completed the 4-Variable screening tool (4V), STOP-BAG questionnaire (ie, STOP-BANG questionnaire without the neck circumference measurement), Berlin questionnaire, and the Sleep Obstructive apnea score optimized for Stroke (SOS). They subsequently underwent objective testing using a portable sleep monitoring device. Cutoffs were selected to maximize sensitivity and exclude OSA (AHI ≥ 10) in ≥10% of the cohort. RESULTS: The mean age was 68.3 ± 14.2 years and 47.8% were male. Thirty-two patients (46.4%) were found to have OSA. Male sex, body mass index (BMI), and atrial fibrillation were independent predictors of OSA. Among the screening tools, the 4V had the greatest area under the curve (AUC) of 0.688 (p = 0.007); the sensitivity was 96.9% for a cutoff of <6. The STOP-BAG also significantly detected OSA with an AUC of 0.677 (p = 0.012); the sensitivity was 93.8% for a cutoff of <2. Scores on the 4V and STOP-BAG were significantly correlated with the AHI. CONCLUSIONS: The 4V and STOP-BAG questionnaire may aid clinicians with ruling out OSA within 180 days of stroke/TIA. Due to the atypical presentation of poststroke/TIA OSA, these tools are only moderately predictive; objective testing should still be used for OSA diagnosis in this population.

A Cys 23-Ser 23 substitution in the 5-HT(2C) receptor gene influences body weight regulation in females with seasonal affective disorder: an Austrian-Canadian collaborative study.

Most females with seasonal affective disorder (SAD) exhibit atypical vegetative symptoms such as overeating, and weight gain when depressed. The serotonin 2C receptor (5-HT(2C)) plays a key role in control of appetite and satiety. A 5-HT(2C) Cys 23 Ser substitution, coded for by a single nucleotide polymorphism (Cys 23 Ser) within the 5-HT(2C) gene, has been shown to influence 5-HT(2C) function. We hypothesized that Cys 23 Ser influences weight regulation in females with SAD. Two independent samples from Austria (162 females with SAD, 119 controls), and Canada (90 females with SAD, 42 controls) were genotyped for Cys 23 Ser. Influence on weight regulation was analyzed within patients with atypical features. In Austrians, genotype distribution differed between patients and controls (p=0.044) and Cys 23 Ser was associated with weight (p=0.039), body mass index (BMI; p=0.038), and seasonal appetite change (p=0.031). All values were highest in Cys/Cys, intermediate in Cys/Ser, and lowest in Ser/Ser carriers. In Canadian patients, Cys 23 Ser was associated with minimum lifetime BMI (p=0.046), with lowest values in Ser/Ser carriers. Our data provide evidence that Cys 23 Ser mediates severity of weight regulation disturbances in females with SAD, and the gene-dose effect-like differences suggest a direct functional role of Cys 23 Ser in the behavioral regulation of body weight.

DRD2 and SLC6A3 moderate impact of maternal depressive symptoms on infant cortisol.

Both maternal depressive symptoms and infants' dopamine-related genetic characteristics have been linked to infants' hypothalamic-pituitary-adrenal (HPA) functioning. This study investigated the interactive influence of maternal depressive symptoms and infant DRD2 and SLC6A3 genotypes on infant cortisol reactivity; whether this interaction reflects diathesis-stress or differential susceptibility; and whether this interaction influences the flexibility of the infant cortisol response across challenges known to exert differential effects on infant cortisol reactivity. A community sample of 314 mother-infant dyads participated in toy frustration (age 16 months) and maternal separation (age 17 months) challenges, and salivary cortisol was collected at baseline, +20, and +40min. Maternal depressive symptoms were assessed with the Beck Depression Inventory-II at infant age 16 months. Infant buccal cells were collected at both time points for genotyping. DRD2 and SLC6A3 genotypes moderated the relation between maternal depressive symptomatology and infant cortisol reactivity in a diathesis-stress manner in the context of toy frustration, and in a differential susceptibility manner in the context of maternal separation. Higher levels of maternal depressive symptoms predicted reduced cortisol flexibility across challenges for infants with at least one A1 allele of DRD2 and infants with the 10/10 genotype of SLC6A3. Results suggest that maternal depressive symptomatology is related to infants' cortisol reactivity and to the flexibility of that reactivity across psychosocial challenges, but this relation is dependent on the infant's genetic characteristics.

Cortisol concentrations in 12- to 18-month-old infants: stability over time, location, and stressor.

BACKGROUND: Sparse information on early development of hypothalamic pituitary adrenal (HPA) axis responsivity in human infants limits our understanding of stress hormone regulation and vulnerability to psychopathology. We considered whether infant cortisol stress response (CSR) is a suitable endocrine phenotype for developmental stress research. METHODS: We assessed stability of key CSR parameters across time, location, and stressor through saliva samples taken before and then 20 and 40 min following exposure to two stressors administered 1 week apart in 27 infants aged 12 to 18 months. Time-matched home samples were collected to control for circadian rhythm and to evaluate baseline stability. RESULTS: Baseline cortisol concentrations, peak percent change, and area under the curve (AUC) were stable across time and stressors. Following both stressors, half the infants exhibited peak cortisol concentrations at 20 min poststress; half peaked at 40 min poststress. For 56% of the infants, peak response time was inconsistent across stressors. CONCLUSIONS: In humans, baseline and CSR are stable by 12 to 18 months. Variation in CSR time course across stressors indicates that infant CSR should be sampled beyond 30 min. Results support using infant CSR, particularly as measured by AUC, as a valid endocrine phenotype for developmental stress research.

The dopamine-4 receptor gene associated with binge eating and weight gain in women with seasonal affective disorder: an evolutionary perspective.

BACKGROUND: We recently described a preliminary association between the hypofunctional seven-repeat allele of the dopamine-4 receptor gene (DRD4) and increased maximal lifetime body mass index in women with seasonal affective disorder (SAD). In this study, we examined whether binge eating behavior mediated this putative association. METHODS: The study sample consisted of 131 women with winter SAD who reported increased intake of high-carbohydrate/high-fat foods during depressive episodes. We compared rates of binge eating behavior in the two genotypic groups defined by the presence or absence of the seven-repeat allele of DRD4. RESULTS: Consistent with our working hypothesis, the proportion of binge eaters was significantly greater in probands with the seven-repeat allele (18 of 46, 39.1%) than in probands without this allele (14 of 85, 16.5%) [chi(2)(1)= 8.32, p = .004; odds ratio = 3.25, 95% confidence interval 1.43, 7.41]. CONCLUSIONS: Pending replication in other samples, these results point to a genetic factor that could help in the early identification and treatment of women at higher risk for seasonal weight gain associated with binge eating behavior. At a theoretic level, the current results suggest a novel link between evolutionary models of seasonal weight gain on the one hand and the DRD4 gene on the other.

A drosophila model for attention deficit hyperactivity disorder (ADHD): No evidence of association with PRKG1 gene.

Attention deficit hyperactivity disorder (ADHD) is a prevalent psychiatric condition in children and follow up studies have indicated that 22-33% of patients continue to suffer from ADHD during late adolescence and adulthood. The action of psychostimulant drugs may be determined by additional mechanisms beyond the dopamine transporter and receptors. We are exploring new methodology for discovering these mechanisms. For example, in Drosophila, such an additional determinant of psychostimulant action could be protein kinase G (PKG) that affects food-search behavior. Here we initiated studies with the human homologue of PKG, the PRKG1 gene. The aim of this study was to investigate for the presence of linkage disequilibrium between the protein kinase G gene (PRKG1) and adult ADHD in a sample of nuclear families. Genotyping data for the C2276T polymorphism were analyzed using the Transmission Disequilibrium Test (TDT). Sixty three nuclear families were informative for the TDT on C2276T polymorphism, which showed no preferential transmission of either allele (chi-square = 0.778, df = 1, p = 0.316). These findings exclude a direct involvement of this genetic marker of the Protein kinase G gene in the pathogenesis of ADHD.

Pharmacogenetics of tardive dyskinesia: combined analysis of 780 patients supports association with dopamine D3 receptor gene Ser9Gly polymorphism.

Variability among individuals in their therapeutic response to psychotropic drugs and in susceptibility to adverse effects is considerable. Pharmacogenetics addresses the contribution of genetic factors to this variability. An important focus of interest in pharmacogenetics has been on candidate genes that play a role in susceptibility to the antipsychotic drug-induced adverse effect, tardive dyskinesia (TD). Four published studies have reported an association between a serine (ser) to glycine (gly) polymorphism in exon 1 of the dopamine D3 receptor gene (DRD3) and TD; three failed to replicate this finding and one found an insignificant trend. We examined the association in a pooled sample of 780 patients (317 with TD and 463 without TD) drawn from 6 research centers, who were divided into 8 groups based on their population origin. The analysis employed stepwise logistic regression so as to allow confounding effects of group, age, and gender to be taken into account. TD was significantly associated with DRD3 gly allele carrier status (x(2)=4.46, df 1, p =.04) and with DRD3 genotype (x(2)=6.62, df 2, p =.04) over and above the effect of group. Similar positive effects were observed when controlling for age and gender (x(2)=5.02, df 1, p =.02 for gly allele carrier status; x(2) = 7.51, df 2, p =.002 for genotype). Examining abnormal involuntary movement scores as a continuous variable, we found that patients homozygous for the gly allele had significantly higher scores than ser-gly heterozygotes (p =.006) or ser-ser homozygotes (p <.0001). We also performed a meta-analysis that included, besides the groups in the combined analysis, three other published studies on DRD3 and TD. The Mantel-Haenszel pooled odds ratio for DRD3 gly allele carrier status increasing susceptibility to TD was 1.33 (95% CI 1.04-1.70, p =.02); the cumulative pooled estimate showed an odds ratio of 1.52 (95% CI 1.08-1.68, p <.0001). These findings support a small but significant contribution of the DRD3 ser9gly polymorphism to TD susceptibility that is demonstrable over and above population effects and the effect of age and gender on the phenotype.

No association of the T102C polymorphism of the serotonin 2A receptor gene (HTR2A) with suicidality in schizophrenia.

Additional evidence for a role of serotonin (5-HT) in the pathogenesis of suicidal behavior is provided by a recent report that the 5-HT2A (HTR2A) T102C polymorphism was associated with suicidality in patients with major depression. Three other studies have, however, failed to find an association between this polymorphism and suicidality in major depression. The goal of the present study was to test the association of allele C of T102C HTR2A polymorphism with suicidality in patients with schizophrenia or schizoaffective disorder. Seventy-one patients with DSM-III-R diagnosis of schizophrenia or schizoaffective disorder were included in the study. Patients were genotyped for the T102C HTR2A polymorphism. Information about lifetime suicidality was obtained during the course of SADS interviews. In addition, current suicidality was assessed by the Hamilton Depression Scale in 46 patients. There were no significant differences in allele frequencies and genotype distributions between suicidal and non-suicidal patients using lifetime or current suicidality measures. The results of this study did not demonstrate a robust association of the allele C of the T102C HTR2A polymorphism with lifetime or current suicidality in patients with schizophrenia. However, the mean Hamilton Depression Scale item for current suicidality was significantly higher in patient with genotype T/C compared to those with genotype C/C (p = 0.01) and marginally higher than for the patients with genotype T/T (p=0.06). The relatively small sample size suggests a study with a larger sample and greater power would be of interest.

Psychiatric pharmacogenetics: personalizing psychostimulant therapy in attention-deficit/hyperactivity disorder.

There is a substantial amount of variation in response and adverse drug reactions to psychostimulant therapy in attention-deficit/hyperactivity disorder (ADHD). Psychiatric pharmacogenetics is a rapidly developing field, which can be applied to identify genetic predictors of this variability in outcome to psychostimulant medications. This article will briefly review ADHD and its pharmacotherapy. This will be followed by an overview of the pharmacokinetics and pharmacodynamics of methylphenidate, the most commonly used psychostimulant in the US. Then the field of psychiatric pharmacogenetics will be introduced and its methodology will be described. This will be followed by a discussion about how pharmacogenetics can be applied to children afflicted with ADHD. The future of psychiatric pharmacogenetics will then be presented with an emphasis being placed on developing prospects that will ensure the continued advancement of this field.

Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?

The goal of this pilot study was to explore the putative molecular mechanisms underlying the phenotypic discordance of monozygotic (MZ) twins. Thus, patterns of epigenetic DNA modification were investigated in the 5'-regulatory region of the dopamine D2 receptor gene (DRD2) in two pairs of monozygotic twins, one concordant and one discordant for schizophrenia. The bisulfite DNA modification-based approach was used to fine-map methylated cytosines in DRD2 in genomic DNA extracted from lymphocytes. Numerous DNA methylation differences were identified in the analyzed region both within and between the pairs of MZ twins. "Epigenetic distances" between MZ twins were calculated and used for the comparison of twin DRD2 methylation profiles. It was detected that the affected twin from the pair discordant for schizophrenia was epigenetically "closer" to the affected concordant twins than to his unaffected MZ co-twin. Although the epigenetic analysis was conducted for only several hundred base pairs of DRD2, the fact that numerous studies identified nonuniform methylation patterns across the clones of bisulfite-modified DNA from the same individual, as well as nonuniform patterns across different individuals, argues for the universality of intra- and interindividual epigenetic variation. Epigenetic studies should provide insight into the molecular causes of differential susceptibility to a disease in genetically identical organisms that may generalize to singletons.

Ethical and Policy Considerations in the Application of Pharmacogenomic Testing for Tardive Dyskinesia: Case Study of the Dopamine D3 Receptor.

Tardive dyskinesia (TD) is a serious adverse effect often associated with the first generation antipsychotic medications used in the management of mental health disorders such as schizophrenia. Pharmacogenomics is the study of human genomic variation in relation to individual and population variability in medication response and side effects. Neuropsychiatry is one of the clinical domains in which pharmacogenomic approaches have been extensively studied. In the late 1990s, the Glycine9 (Gly9) allele of the Serine-9-Glycine (Ser9Gly) polymorphism in dopamine D3 receptor gene (DRD3) was found to be associated with both a liability to, and worsened severity of, TD in schizophrenic patients treated with typical antipsychotics. This initial discovery has been subsequently replicated and testing for the Ser9Gly polymorphism has now become commercially available. The question that currently presents itself is whether its use should be encouraged for patients who may be prescribed a typical or atypical antipsychotic medication. However, the translation of this new technology to clinical practice presents multiple social, ethical and policy challenges. Though pharmacogenomic testing holds much promise in this scenario, many important questions remain to be answered before its widespread use can be medically and ethically justified. This article highlights the key advances in our understanding of the role of human genetic variation in the D3 receptor in relation to TD. Then, issues of uncertainty, consent, confidentiality, and access are considered with respect to the use of DRD3 polymorphism testing in risk stratification for susceptibility to tardive dyskinesia. We propose three recommendations that may help bring this technology into the clinic: 1) prospective pharmacogenomic studies of DRD3 polymorphism and TD risk should be conducted; 2) the design of such studies should be influenced by scientists, ethicists and policy makers to protect potentially vulnerable patients; and 3) appropriate knowledge transfer to front-line health care workers must take place.

Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype.

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT(2A)) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT(2A) receptor gene (HTR(2A)) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR(2A) T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR(2A) T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel-Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR(2A) contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

Antipsychotic-induced weight gain: bipolar disorder and leptin.

Novel antipsychotics impart substantial weight gain. Persons with bipolar disorder are frequently treated with these and other agents known to impart substantial weight gain. We sought to describe the influence of adjunctive risperidone and olanzapine on body weight, body mass index (BMI, kg/m2) and serum leptin levels over a prospective observation period of 6 months. Throughout the 6-month investigation, significant increases from baseline to end point in weight were noted with both agents; with significantly greater weight gain with olanzapine (t(10) = 2.761, P = 0.023; t(9) = 4.783, P = 0.001). Leptin levels were highly correlated with increases in weight and were significantly elevated from baseline at 4 months (r = 0.658, P < 0.05). Significant increases in weight and body mass index were apparent at 3 months (P < 0.05). The temporal association between weight increase and leptin changes does not support the notion that leptin is a primary promoter of antipsychotic-induced weight gain; however, a secondary perpetuating role cannot be ruled out.