Clinical Decision Path for Identifying Recurrent Falls in Late Middle-Aged and Older Patients With Chronic Schizophrenia.

BACKGROUND: Falls are a major hazard for elderly patients with schizophrenia. As patients with schizophrenia may experience a more-accelerated rate of physical aging than the overall elderly population, the risk of falls may emerge during the late middle-age period in this population. Furthermore, the risk of falls is affected by multiple, interrelated risk factors. PURPOSE: This study was undertaken to capture the complexity of the risk of falls in patients with schizophrenia. A cross-sectional approach was used to apply classification and regression tree (CART) analysis to generate a clinical decision path to identify the risk factors of recurrent falls in late middle-aged and older patients with schizophrenia. METHODS: Two hundred ninety-one patients aged 55 years or older were recruited from psychiatric halfway houses for assessment. Frailty, physical functional performance, depressive severity, cognitive function, and level of fatigue were measured, respectively, using the Study of Osteoporotic Fractures Frailty Index, Short Physical Performance Battery (SPPB), Center for Epidemiological Studies Depression Scale, Short Portable Mental Status Questionnaire (SPMSQ), and Chinese version of the Fatigue Severity Scale. The variables revealed by descriptive statistics to be statistically significant were further analyzed using CART analysis. RESULTS: The overall proportion of recurrent fallers in this study was 19.2%. CART analysis revealed eight end groups and identified four predictors: frailty, physical functional performance, cognitive function, and sex. The most prominent condition for recurrent fallers was frailty, present in 57.1% of the frail participants. In the nonfrail group (both prefrail and robust), participants with an SPPB score of less than 10 had a 29.7% chance of being a recurrent faller versus 13.6% for those with an SPPB score of 10 or more. Furthermore, an SPMSQ score of 7 was the next-best split among participants without frailty, with an SPPB score of 10 or more. Finally, among participants without frailty and with an SPPB score of 10 or more and an SPMSQ score of more than 7, the proportion of recurrent fallers was higher in women than men. CONCLUSIONS: The results of this study indicate that assessing frailty status may be an effective, first-step approach to identifying schizophrenic patients at an increased risk of recurrent falls. Among patients with prefrailty or robust status, an SPPB score cutoff of 10, an SPMSQ score cutoff of 7, and being female may be used sequentially to identify individuals at a heightened risk of recurrent falls.

An exploration of the sleep quality and potential violence among patients with schizophrenia in community.

PURPOSE: Sleep quality in patients with schizophrenia is correlated with potential violence. However, few studies have conducted in-depth discussions on community patients with schizophrenia. The purpose of this study was to explore the influences of demographic characteristics, psychiatric symptom severity, and sleep quality in community patients with schizophrenia on the risks of potential violence and its subdimensions (ie, physical aggression, verbal aggression, anger, and hostility). DESIGN AND METHODS: This study adopted a cross-sectional research design. Using convenience sampling, 78 community patients with schizophrenia were recruited from psychiatric outpatient clinics, day wards, and those who received home-care services. FINDINGS: This study discovered that sleep quality is a crucial factor that influences the risks of potential violence. Analysis on the subdimensions revealed that having a violence history during the preceding month and sleep quality are crucial factors that influence physical aggression. In addition, sleep quality is a crucial factor that influences the occurrence of anger. Age and sleep quality substantially influence hostility. However, this study did not identify any crucial factors that influenced verbal aggression. PRACTICE IMPLICATIONS: In the future, community nursing professionals should collect data on the patients' age, whether the patients exhibited violence behavior during the preceding month, and their sleep quality to prevent risks of potential violence, physical aggression, anger, or hostility.

Effects of GADL1 overexpression on cell migration and the associated morphological changes.

Lithium has been used for maintenance treatment of bipolar disorder, but drug response varies among patients. Single-nucleotide polymorphisms in glutamate decarboxylase-like protein 1 (GADL1) are found to be associated with lithium response in Han Chinese bipolar patients. In this study, we assessed GADL1 function using a neuroblastoma cell line that stably overexpressed GADL1. Genes encoding factors involved in cell migration, such as FN1, ITGA2, ITGAV and CCL2, were downregulated in GADL1-overexpressing cells. GADL1 overexpression indeed suppressed cell migration. Cell migration speed and perimeter length exhibited similar trends, both of which were decreased under GADL1 overexpression or lithium treatment but increased upon stimulation with CCL2. Secreted GADL1 or its enzyme product, taurine, in the conditioned medium might exert only mild effects on the observed changes. Compared with SH-SY5Y cells, GADL1-overexpressing cells were much more sensitive to CCL2 treatment but less sensitive to lithium, indicating that the level of GADL1 expression can affect cell sensitivity to lithium or  CCL2 treatment. Together, these results suggest that cell migration and related morphological changes might provide good indicators of the sensitivity toward lithium treatment, and the GADL1 stable overexpression cell line might serve as a useful platform to screen novel therapeutics for bipolar disorder.

Cerebral blood flow autoregulation is impaired in schizophrenia: A pilot study.

Patients with schizophrenia have a higher risk of cardiovascular diseases and higher mortality from them than does the general population; however, the underlying mechanism remains unclear. Impaired cerebral autoregulation is associated with cerebrovascular diseases and their mortality. Increased or decreased cerebral blood flow in different brain regions has been reported in patients with schizophrenia, which implies impaired cerebral autoregulation. This study investigated the cerebral autoregulation in 21 patients with schizophrenia and 23 age- and sex-matched healthy controls. None of the participants had a history of cardiovascular diseases, hypertension, or diabetes. All participants underwent 10-min blood pressure and cerebral blood flow recording through finger plethysmography and Doppler ultrasonography, respectively. Cerebral autoregulation was assessed by analyzing two autoregulation indices: the mean blood pressure and cerebral blood flow correlation coefficient (Mx), and the phase shift between the waveforms of blood pressure and cerebral blood flow determined using transfer function analysis. Compared with the controls, the patients had a significantly higher Mx (0.257 vs. 0.399, p=0.036) and lower phase shift (44.3° vs. 38.7° in the 0.07-0.20Hz frequency band, p=0.019), which indicated impaired maintenance of constant cerebral blood flow and a delayed cerebrovascular autoregulatory response. Impaired cerebral autoregulation may be caused by schizophrenia and may not be an artifact of coexisting medical conditions. The mechanism underlying impaired cerebral autoregulation in schizophrenia and its probable role in the development of cerebrovascular diseases require further investigation.

Depression as the Primary Cause of Insomnia and Excessive Daytime Sleepiness in a Family with Multiple Cases of Spinocerebellar Ataxia.

ABSTRACT: Spinocerebellar ataxia (SCA) is a hereditary disease characterized by central nervous system-related motor dysfunctions. Sleep disorders and frequent non-motor manifestations are commonly comorbid with SCA. To elucidate this relationship, we present three cases in a family that included multiple SCA type 2 patients with various sleep disorders. Complete physical examination, and genetic and imaging studies were performed. Anti-parkinsonism medications were prescribed after neurological examination. Clonazepam and/or quetiapine were administered for sleep disorders but failed to resolve insomnia and excessive daytime sleepiness (EDS). Based on DSM-5 criteria, all cases were diagnosed with depression. After treatment with serotonin-norepinephrine reuptake inhibitors and noradrenergic and specific serotonergic antidepressants, symptoms of insomnia and EDS, which are strongly associated with depression in SCA type 2 patients, improved significantly. It is crucial to recognize insomnia and EDS in neurodegenerative diseases, not only for earlier diagnosis, but also to improve quality of life.

Effect of valproic acid on dementia onset in patients with bipolar disorder.

BACKGROUND: Valproic acid (VPA) is widely used for treating patients with bipolar disorder; however, it has adverse effects on cognitive function. This study investigated the effect of VPA on the risk of dementia in patients with bipolar disorder. METHODS: We analyzed data from Taiwan's Longitudinal Health Insurance Database 2010. Patients with bipolar disorder who were prescribed VPA for 28 days or at least once per month for 3 consecutive months after the index date were classified as the VPA-treated group, whereas those who did not receive VPA were classified as the VPA-untreated group. Both groups were tracked until the end of 2013 or until loss to follow-up to identify new-onset dementia events. Multivariable Cox proportional hazards models were used to estimate the hazard ratio (HR) of subsequent dementia associated with VPA treatment after adjustment for confounding variables. RESULTS: The study comprised 5158 patients with bipolar disorder. The multivariable-adjusted HR for newly diagnosed dementia was 1.73 (95% confidence interval [CI], 1.24-2.41, P=0.001) for the VPA-treated group compared with the VPA-untreated group after adjustment for potential confounders. The VPA-treated group had a higher risk than did the VPA-untreated group after propensity score adjustment (HR=1.95, 95% CI=1.42-2.67, P<0.001). LIMITATION: Certain variables that may affect the incidence of dementia were unavailable in the claims database and thus could not be considered. CONCLUSION: Treating bipolar disorder with VPA increases the risk of dementia by 73-95%.

Cultural adaptation and validation of the Chinese version of the Fatigue Severity Scale in patients with major depressive disorder and nondepressive people.

PURPOSE: The aims of the study were to adapt the Fatigue Severity Scale to Chinese conditions and assess the psychometric properties of the Chinese version in patients with major depressive disorder (MDD) and nondepressive people. METHODS: A total of 101 patients with MDD and 94 nondepressive persons were included in this study. A forward and backward translation procedure was performed for developing a culturally acceptable Chinese version of the Fatigue Severity Scale (CFSS). Validity was assessed according to construct validity, internal consistency, concurrent validity, divergent validity, and contrasted-group validity. RESULTS: The CFSS exhibited a one-factor structure in patients with MDD and the nondepressive participants. A 7-item version of CFSS and an 8-item version of the CFSS demonstrated better model fit than the original 9-item version in the patients with MDD and the nondepressive participants, respectively. In both participant groups, internal consistency values were within acceptable ranges. In addition, concurrent validity and divergent validity were confirmed in both groups. The average CFSS score of patients with MDD was significantly higher than that of the nondepressive participants. CONCLUSION: The 9-item CFSS is a valid instrument for assessing fatigue-related impairment in Chinese-speaking patients with MDD. However, the two reduced-item CFSS versions showed better psychometric properties than the original version in the patients with MDD and the nondepressive participants.

A Systemic Review and Experts' Consensus for Long-acting Injectable Antipsychotics in Bipolar Disorder.

Bipolar disorder (BD) is a major psychiatric disorder that is easily misdiagnosed. Patient adherence to a treatment regimen is of utmost importance for successful outcomes in BD. Several trials of antipsychotics suggested that depot antipsychotics, including long-acting first- and second-generation agents, are effective in preventing non-adherence, partial adherence, and in reducing relapse in BD. Various long-acting injectable (LAI) antipsychotics are available, including fluphenazine decanoate, haloperidol decanoate, olanzapine pamoate, risperidone microspheres, paliperidone palmitate, and aripiprazole monohydrate. Due to the increasing number of BD patients receiving LAI antipsychotics, treatment guidelines have been developed. However, the clinical applicability of LAI antipsychotics remains a global cause for concern, particularly in Asian countries. Expert physicians from Taiwan participated in a consensus meeting, which was held to review key areas based on both current literature and clinical practice. The purpose of this meeting was to generate a practical and implementable set of recommendations for LAI antipsychotic use to treat BD; target patient groups, dosage, administration, and adverse effects were considered. Experts recommended using LAI antipsychotics in patients with schizophrenia, rapid cycling BD, BD I, and bipolar-type schizoaffective disorder. LAI antipsychotic use was recommended in BD patients with the following characteristics: multiple episodes and low adherence; seldom yet serious episodes; low adherence potential per a physician's clinical judgment; preference for injectable agents over oral agents; and multiple oral agent users still experiencing residual symptoms.

Mean arterial pressure is better at predicting future metabolic syndrome in the normotensive elderly: a prospective cohort study in Taiwan.

OBJECTIVE: To compare four different blood pressure (BP) measurements-systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP)-in predicting future metabolic syndrome (MetS) among the normotensive elderly population, and to estimate the optimal cutoff value of the best single measurement for clinical practice. METHODS: A total of 2782 non-medicated participants aged ≥ 60 years were enrolled in a standard health examination program in Taiwan from January 2004 to December 2013. Two thirds of the participants were randomly designated as the training group (n=1855) and the other one third as the validation group (n=927). The mean follow-up time was 3.60 years for both the training and validation groups. MAP and PP were calculated from SBP and DBP. RESULTS: SBP, DBP, and MAP were associated with future MetS, whereas PP was not. MAP had the largest hazard ratio in Cox regression (men 1.342 [95% CI 1.158-1.555] and women 1.348 [95% CI 1.185-1.534] in the training group; men 1.640 [95% CI 1.317-2.041] and women 1.485 [95% CI 1.230-1.794] in the validation group) and the largest area under the receiver operating characteristic curve (men 0.598 ± 0.021 and women 0.602 ± 0.021 in the training group). Multivariable Cox regression further indicated that a higher MAP level was independently associated with the future occurrence of MetS. Participants with MAP above the cutoff value (84.0mm Hg for men, 83.3mm Hg for women) had a higher cumulative incidence of MetS than did their counterparts after four years' follow-up in both the training and validation groups. The results derived from the training data could be replicated in the validation data, indicating that the results were generalizable across distinct samples. CONCLUSIONS: MAP is more accurate than SBP, DBP, and PP in predicting future MetS among the normotensive geriatric population. Calculation of MAP is recommended when dealing with normotensive patients aged ≥ 60 years in clinical practice.

Risk factors of depression after prolonged low-dose rate environmental radiation exposure.

PURPOSE: More than 10,000 Taiwanese people were exposed to excessive protracted low-dose rate radiation from contaminated reinforcement bars, which were installed in buildings before 1992. This study was conducted to assess the prevalence of depression amongst the exposed and identify related determinants now that more than two decades have passed since this population was informed of their exposure to radiation. MATERIALS AND METHODS: We used the Beck depression inventory (BDI)-1A questionnaire to survey 2143 eligible people during their annual physical examinations between March 2009 and December 2009. In total, 1621 people participated in the survey. We employed multivariate logistic regression models with generalized estimating equations method to identify the determinants of depression. RESULTS: The prevalence of depression (BDI-IA score ≥ 12) was 18.7%. Those who exhibited higher cumulative exposure [adjusted odds ratio (OR): 1.46, 95% confidence interval (CI): 1.02-2.07] and a previous history of depression (adjusted OR: 2.49, 95% CI: 1.36-4.58) were significantly associated with the risk of depression, whereas education level was inversely related to depression (adjusted OR: 0.71, 95% CI: 0.50-0.99). CONCLUSION: Long-term, low-dose rate radiation exposure early in life might cause subsequent psychological stress and an increased risk of depression decades later.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Incidence of first onset alcohol use disorder: a 16-year follow-up in the Taiwanese aborigines.

PURPOSE: To investigate the incidence and cumulative risk of first onset alcohol use disorder (AUD) in a 16-year follow-up among Taiwanese aboriginal populations. METHODS: Participants included in this study were cohort subjects free from any AUD at phase 1 survey (n = 428 for DSM-3-R and 451 for DSM-4) of the Taiwan aboriginal study project conducted in 1986-1988. They were reassessed approximately 16 years later, with a response rate of 98.8 %. A Chinese version of the WHO schedules for clinical assessment in neuropsychiatry was employed to assess the lifetime drinking history and AUD. RESULTS: Age-standardized annual incidence rates of AUD in all groups were 2.26 and 1.75 % according to DSM-3-R and DSM-4, respectively. The overall incidence rates of AUD were comparable to most of other studies in Caucasian populations, but the sex ratios of women to men were higher in this study (1:2-3) than in the latter (1:6). The incidence of AUD was higher with DSM-3-R than with DSM-4 criteria in this study, attributable to the exclusion of physical/psychological harm in DSM-4 alcohol abuse. The cumulative risks of DSM-4 AUD in this study were very high, being 72.2 ± 19.8 for men and 48.7 ± 8.2 for women up to the age of 65 years. CONCLUSIONS: High incidence rates and cumulative risks of AUD in Taiwanese aborigines demand effective prevention strategy.

Effects of paliperidone extended release on the symptoms and functioning of schizophrenia.

BACKGROUND: We aimed to explore relations between symptomatic remission and functionality evaluation in schizophrenia patients treated with paliperidone extended-release (ER), as seen in a normal day-to-day practice, using flexible dosing regimens of paliperidone ER. We explored symptomatic remission rate in patients treated with flexibly dosed paliperidone ER by 8 items of Positive and Negative Syndrome Scale (PANSS) and change of Personal and Social Performance (PSP) scale. METHOD: This was a 12-week multicenter, open-label, prospective clinical study conducted in in-patient and out-patient populations. Flexible dosing in the range 3-12 mg/day was used throughout the study. All subjects attended clinic visits on weeks 0, 4, 8, and 12 as usual clinical practice for the 12-week observation period. Data were summarized with respect to demographic and baseline characteristics, efficacy measurement with PANSS scale, PSP, and social functioning score, and safety observations. Descriptive statistics were performed to identify the retention rate at each visit as well as the symptomatic remission rate. Summary statistics of average doses the subjects received were based on all subjects participating in the study. RESULTS: A total of 480 patients were enrolled. Among them, 426 patients (88.8%) had evaluation at week 4 and 350 (72.9%) completed the 12-week evaluation. Patients with at least moderate severity of schizophrenia were evaluated as "mild" or better on PANSS scale by all 8 items after 12 weeks of treatment with paliperidone ER. There was significant improvement in patients' functionality as measured by PSP improvement and score changes. Concerning the other efficacy parameters, PANSS total scale, PSP total scale, and social functioning total scale at the end of study all indicated statistically significant improvement by comparison with baseline. The safety profile also demonstrated that paliperidone ER was well-tolerated without clinically significant changes after treatment administration. CONCLUSIONS: Although the short-term nature of this study may limit the potential for assessing improvements in function, it is noteworthy that in the present short-term study significant improvements in patient personal and social functioning with paliperidone ER treatment were observed, as assessed by PSP scale. TRIAL REGISTRATION: Clinical Trials. PAL-TWN-MA3.

White matter abnormalities of fronto-striato-thalamic circuitry in obsessive-compulsive disorder: A study using diffusion spectrum imaging tractography.

Previous studies have reported white matter abnormalities in patients with obsessive-compulsive disorder (OCD). This study aimed to further explore white matter abnormalities in OCD patients through diffusion spectrum imaging (DSI) and tractography of the two white matter tracts which most probably play an important role in OCD neuropathology: the anterior segment of cingulum bundles (ACB) and the anterior thalamic radiations (ATR). Twelve right-handed, medicated adult patients with OCD and 12 matched controls underwent DSI on a 3 tesla magnetic resonance imaging (MRI) system. Tractography based on DSI data was reconstructed to define the ACB and ATR. Mean generalized fractional anisotropy (GFA) was calculated for each targeted tract and was used to analyze local changes in microstructural integrity along individual tracts. There was a significantly lower mean GFA in both the right ATR and left ACB in OCD subjects compared to controls. OCD subjects also demonstrated decreased left-lateralized asymmetry of the ACB when compared to controls. Furthermore, the mean GFA of the left ACB positively correlated with OCD subjects' obsessive subscores on the Yale-Brown Obsessive-Compulsive scale. This study supports the white matter abnormalities in the ACB and ATR of OCD subjects, which corroborates neurobiological models that posit a defect in fronto-striato-thalamic circuitry in OCD.

The microstructural integrity of the corpus callosum and associated impulsivity in alcohol dependence: a tractography-based segmentation study using diffusion spectrum imaging.

Previous post-mortem and structural magnetic resonance imaging (MRI) studies in patients with alcohol dependence have demonstrated abnormalities of brain white matter. The present study investigated the microstructural integrity in the corpus callosum and the associations of this integrity with neurobehavioral assessments. Twenty-five male cases fulfilling the DSM-IV diagnosis of alcohol dependence and 15 male control subjects were scanned using a 3T MRI system. Callosal fiber tracts were reconstructed by diffusion spectrum imaging tractography and were subdivided into seven functionally distinct segments. The microstructural integrity was quantified in terms of generalized fractional anisotropy (GFA). Compared with normal subjects, men with alcohol dependence showed lower GFA values on all segments of the corpus callosum. The segment interconnecting the bilateral orbitofrontal cortices was the most affected. The score on the Barratt Impulsivity Scale showed an inverse relationship with GFA on the callosal fiber tracts connecting the bilateral orbitofrontal cortices. Furthermore, the duration of regular use was negatively associated with GFA on the callosal fiber tracts connecting the bilateral temporal and parietal cortices. Our findings suggest that a high self-rated impulsivity level was associated with low anisotropy in white matter of corpus callosum sectors extending to the orbitofrontal cortex.

The effects of gender and a co-occurring depressive disorder on neurocognitive functioning in patients with alcohol dependence.

AIMS: The present study aims to examine neuropsychological impairments by comorbidity and gender among patients with alcohol dependence. METHODS: The study sample is comprised of 123 subjects who fulfilled a Diagnostic and Statistical Manual of Mental Disorders 4th Edition (DSM-IV) diagnosis of alcohol dependence from January 2006 to December 2007. Subjects were asked to complete the following psychological tests: the Barratt Impulsivity Scale (BIS), Wechsler Adult Intelligence Scale, Wechsler Memory Scale and Color Trails Test. We compared the results of neuropsychological assessments based on two types of classifications: people with comorbid depression and people without comorbidity; females and males. RESULTS: The immediate visual memory and the BIS scores in patients with comorbid depression were significantly different from the scores in patients without comorbidity. In addition, females performed significantly poorer on the Working Memory Index than males and had a later age of regular drinking. CONCLUSIONS: Further investigation of the mechanism associated with the gender difference on cognition and exploration of the temporal relationship between alcohol dependence and depressive disorder on the cognitive aspect is needed.

Case-control study of suicide attempts in the elderly.

BACKGROUND: Prior studies have inadequately explored the relationship between late-life suicidal behavior and subclinical/clinical symptoms. This study aimed to assess the risk associated with subclinical symptoms, mild cognitive impairment and clinical factors among late-life suicide attempters. METHOD: Forty-three elderly patients aged 60 years and older who sought emergency services in a university-affiliated general hospital for attempting suicide and 43 comparison subjects participated in this study between March 2005 and December 2006. The comparison group was recruited by advertising in the community around the hospital. DSM-IV based diagnostic interview and screening instruments including the GDS, MMSE, BSRS-5 and APGAR were applied. Adjusted odds ratios were measured in the final multiple logistic regression model. RESULTS: Suicide attempters were more likely to meet a diagnosis of depressive disorder, after adjustments for BSRS-5 score and drinking habit. The adjusted odds of suicide among people with a BSRS-5 score of more than 5 points was 17.8 times higher than those with the BSRS score less than or equal to 5 points. CONCLUSIONS: Our findings support the significant impact on late-life suicidal behavior from the assessment of subclinical symptoms, including anxiety, depression, hostility, sleep condition and interpersonal symptoms. The assessment of subclinical symptoms by the BSRS-5 may help in the future prevention of late-life suicidal behavior in primary care settings.

The application of a random effects model to censored twin data.

The authors propose a random effects model to analyze the latent genetic and environmental effects on determining censored outcomes in twin studies. In this model, six normally distributed random effects are used to describe the correlation within twin pairs. The authors employ a Monte Carlo Expectation-Maximization approach for obtaining maximum likelihood estimates of fixed effects and the variances of random effects. The variances of the random effects are reparameterized to be equivalent to genetic and environmental effects in traditional twin models. The authors illustrate this model using data from the Vietnam Era Twin Registry to explore the magnitude of the genetic influence on twin similarity for the age of onset of alcohol abuse. Our results show genetic factors contribute about one third of twin similarity in the age of onset of alcohol abuse in male twins. The application of this model to twin data is discussed.

Genetic and environmental contributions to age of onset of alcohol dependence symptoms in male twins.

AIMS: To investigate genetic and environmental influences on the development of specific alcohol dependence symptoms. DESIGN AND PARTICIPANTS: A classical twin study of 3372 male-male twin pairs in the Vietnam Era Twin (VET) Registry based on telephone interviews about alcohol use. MEASUREMENTS: The nine diagnostic symptoms according to the Diagnostic and Statistical Manual of Mental Disorder, version III (revised) (DSM-III-R) definition of alcohol dependence. Symptoms were grouped into those based on impaired control, biological effects and social consequences (Beresford's classification) or early versus late symptoms (Nelson's classification). Survival models with random effects were used to examine the age of onset of each symptom. FINDINGS: Approximately 38% of the variation in age of onset of each symptom group based on Beresford's classification is due to additive genetic factors. The age of onset of late symptoms from Nelson's classification appears to be most affected by genetic factors. Estimates of genetic effects for impaired control symptoms are greatly decreased when twins with comorbid psychiatric disorders are excluded. CONCLUSIONS: Our results support the heritability of age of onset of DSM-III-R-defined symptoms for alcohol dependence. However, no symptom group in Beresford's classification could be identified as more heritable than other symptom groups. A strong association between genetic vulnerability and co-occurring diseases for symptoms indicative of impaired control could be found. In addition, our findings show that the late symptom group could be a good candidate for subsequent genetic research.