Showing papers in "Archives of General Psychiatry in 2003"
TL;DR: The brevity and accuracy of the K6 and K10 scales make them attractive screens for SMI, and routine inclusion of either scale in clinical studies would create an important, and heretofore missing, crosswalk between community and clinical epidemiology.
Abstract: Background Public Law 102-321 established a block grant for adults with "serious mental illness" (SMI) and required the Substance Abuse and Mental Health Services Administration (SAMHSA) to develop a method to estimate the prevalence of SMI. Methods Three SMI screening scales were developed for possible use in the SAMHSA National Household Survey on Drug Abuse: the Composite International Diagnostic Interview Short-Form (CIDI-SF) scale, the K10/K6 nonspecific distress scales, and the World Health Organization Disability Assessment Schedule (WHO-DAS). An enriched convenience sample of 155 respondents was administered all screening scales followed by the 12-month Structured Clinical Interview for DSM-IV and the Global Assessment of Functioning (GAF). We defined SMI as any 12-month DSM-IV disorder, other than a substance use disorder, with a GAF score of less than 60. Results All screening scales were significantly related to SMI. However, neither the CIDI-SF nor the WHO-DAS improved prediction significantly over the K10 or K6 scales. The area under the receiver operating characteristic curve of SMI was 0.854 for K10 and 0.865 for K6. The most efficient screening scale, K6, had a sensitivity (SE) of 0.36 (0.08) and a specificity of 0.96 (0.02) in predicting SMI. Conclusions The brevity and accuracy of the K6 and K10 scales make them attractive screens for SMI. Routine inclusion of either scale in clinical studies would create an important, and heretofore missing, crosswalk between community and clinical epidemiology.
4,170 citations
TL;DR: The risk of having at least 1 psychiatric disorder by age 16 years is much higher than point estimates would suggest and concurrent comorbidity and homotypic and heterotypic continuity are more marked in girls than in boys.
Abstract: Results: Although 3-month prevalence of any disorder averaged 13.3% (95% confidence interval [CI], 11.7%15.0%), during the study period 36.7% of participants (31% of girls and 42% of boys) had at least 1 psychiatric disorder. Some disorders (social anxiety, panic, depression, and substance abuse) increased in prevalence, whereas others, including separation anxiety disorder and attention-deficit/hyperactivity disorder (ADHD), decreased. Lagged analyses showed that children with a history of psychiatric disorder were 3 times more likely than those with no previous disorder to have a diagnosis at any subsequent wave (odds ratio, 3.7; 95% CI, 2.94.9; P.001). Risk from a previous diagnosis was high among both girls and boys, but it was significantly higher among girls. Continuity of the same disorder (homotypic) was significant for all disorders except specific phobias. Continuity from one diagnosis to another (heterotypic) was significant from depression to anxiety and anxiety to depression, from ADHD to oppositional defiant disorder, and from anxiety and conduct disorder to substance abuse. Almost all the heterotypic continuity was seen in girls. Conclusions: The risk of having at least 1 psychiatric disorder by age 16 years is much higher than point estimates would suggest. Concurrent comorbidity and homotypic and heterotypic continuity are more marked in girls than in boys.
3,729 citations
TL;DR: Despite evidence of heterogeneity across studies, meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences.
Abstract: Context There are many published twin studies of schizophrenia. Although these studies have been reviewed previously, to our knowledge, no review has provided quantitative summary estimates of the impact of genes and environment on liability to schizophrenia that also accounted for the different ascertainment strategies used. Objective To calculate meta-analytic estimates of heritability in liability and shared and individual-specific environmental effects from the pooled twin data. Data Sources We used a structured literature search to identify all published twin studies of schizophrenia, including MEDLINE, dissertation, and books-in-print searches. Study Selection Of the 14 identified studies, 12 met the minimal inclusion criteria of systematic ascertainment. Data Synthesis By using a multigroup twin model, we found evidence for substantial additive genetic effects—the point estimate of heritability in liability to schizophrenia was 81% (95% confidence interval, 73%-90%). Notably, there was consistent evidence across these studies for common or shared environmental influences on liability to schizophrenia—joint estimate, 11% (95% confidence interval, 3%-19%). Conclusions Despite evidence of heterogeneity across studies, these meta-analytic results from 12 published twin studies of schizophrenia are consistent with a view of schizophrenia as a complex trait that results from genetic and environmental etiological influences. These results are broadly informative in that they provide no information about the specific identity of these etiological influences, but they do provide a component of a unifying empirical basis supporting the rationality of searches for underlying genetic and common environmental etiological factors.
2,100 citations
TL;DR: Most adult disorders should be reframed as extensions of juvenile disorders, in particular, juvenile conduct disorder is a priority prevention target for reducing psychiatric disorder in the adult population.
Abstract: Background If most adults with mental disorders are found to have a juvenile psychiatric history, this would shift etiologic research and prevention policy to focus more on childhood mental disorders. Method Our prospective longitudinal study followed up a representative birth cohort (N = 1037). We made psychiatric diagnoses according to DSM criteria at 11, 13, 15, 18, 21, and 26 years of age. Adult disorders were defined in the following 3 ways: (1) cases diagnosed using a standardized diagnostic interview, (2) the subset using treatment, and (3) the subset receiving intensive mental health services. Follow-back analyses ascertained the proportion of adult cases who had juvenile diagnoses and the types of juvenile diagnoses they had. Results Among adult cases defined via the Diagnostic Interview Schedule, 73.9% had received a diagnosis before 18 years of age and 50.0% before 15 years of age. Among treatment-using cases, 76.5% received a diagnosis before 18 years of age and 57.5% before 15 years of age. Among cases receiving intensive mental health services, 77.9% received a diagnosis before 18 years of age and 60.3% before 15 years of age. Adult disorders were generally preceded by their juvenile counterparts (eg, adult anxiety was preceded by juvenile anxiety), but also by different disorders. Specifically, adult anxiety and schizophreniform disorders were preceded by a broad array of juvenile disorders. For all adult disorders, 25% to 60% of cases had a history of conduct and/or oppositional defiant disorder. Conclusions Most adult disorders should be reframed as extensions of juvenile disorders. In particular, juvenile conduct disorder is a priority prevention target for reducing psychiatric disorder in the adult population.
1,911 citations
TL;DR: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar.
Abstract: Background: Patterns of comorbidity suggest that the common psychiatric and substance use syndromes may be divisible into 2 broad groups of internalizing and externalizing disorders. We do not know how genetic and environmental risk factors contribute to this pattern of comorbidity or whether the etiologic structure of these groups differ in men and women. Methods: Lifetime diagnoses for 10 psychiatric syndromes were obtained at a personal interview in more than 5600 members of male-male and female-female twin pairs ascertained from a population-based registry. Multivariate twin modeling was performed using the program Mx. Results: We first fit models to the following 7 syndromes: major depression, generalized anxiety disorder, phobia, alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder. The full model, which could be constrained to equality in male and female subjects, identified 2 genetic factors. The first had strongest loadings on alcohol dependence, drug abuse/dependence, adult antisocial behavior, and conduct disorder; the second, on major depression, generalized anxiety disorder, and phobia. Alcohol dependence and drug abuse/dependence had substantial disorder-specific genetic risk factors. Shared environmental factors were most pronounced for conduct disorder and adult antisocial behavior. No clear internalizing/externalizing structure was seen for the unique environmental common factors. We then fit models to 5 internalizing syndromes. The full model, which could also be constrained to equality in men and women, revealed one genetic factor loading most heavily on major depression and generalized anxiety disorder and another loading most strongly on animal and situational phobia. Conclusions: The underlying structure of the genetic and environmental risk factors for the common psychiatric and drug abuse disorders in men and women is very similar. Genetic risk factors predispose to 2 broad groups of internalizing and externalizing disorders. Within the internalizing disorders, 2 genetic factors are seen that predispose to disorders dominated by anxious-misery and fear. Substance use disorders have disorder-specific genetic risks. The externalizing disorders of conduct disorder and adult antisocial behavior are significantly influenced by the shared environment. The pattern of lifetime comorbidity of common psychiatric and substance use disorders results largely from the effects of genetic risk factors. Arch Gen Psychiatry. 2003;60:929-937
1,711 citations
TL;DR: It is suggested that clozapine therapy significantly reduces suicidal behavior in patients with schizophrenia and schizoaffective disorder at high risk for suicide, and use of clozAPine in this population should lead to a significant reduction in suicidal behavior.
Abstract: Background Approximately 50% of patients with schizophrenia or schizoaffective disorder attempt suicide, and approximately 10% die of suicide. Study results suggest that clozapine therapy significantly reduces suicidal behavior in these patients. Methods A multicenter, randomized, international, 2-year study comparing the risk for suicidal behavior in patients treated with clozapine vs olanzapine was conducted in 980 patients with schizophrenia or schizoaffective disorder, 26.8% of whom were refractory to previous treatment, who were considered at high risk for suicide because of previous suicide attempts or current suicidal ideation. To equalize clinical contact across treatments, all patients were seen weekly for 6 months and then biweekly for 18 months. Subsequent to randomization, unmasked clinicians at each site could make any interventions necessary to prevent the occurrence of suicide attempts. Suicidal behavior was assessed at each visit. Primary end points included suicide attempts (including those that led to death), hospitalizations to prevent suicide, and a rating of "much worsening of suicidality" from baseline. Masked raters, including an independent suicide monitoring board, determined when end point criteria were achieved. Results Suicidal behavior was significantly less in patients treated with clozapine vs olanzapine (hazard ratio, 0.76; 95% confidence interval, 0.58-0.97; P = .03). Fewer clozapine-treated patients attempted suicide (34 vs 55; P = .03), required hospitalizations (82 vs 107; P =.05) or rescue interventions (118 vs 155; P = .01) to prevent suicide, or required concomitant treatment with antidepressants (221 vs 258; P = .01) or anxiolytics or soporifics (301 vs 331; P =.03). Overall, few of these high-risk patients died of suicide during the study (5 clozapine vs 3 olanzapine-treated patients; P = .73). Conclusions Clozapine therapy demonstrated superiority to olanzapine therapy in preventing suicide attempts in patients with schizophrenia and schizoaffective disorder at high risk for suicide. Use of clozapine in this population should lead to a significant reduction in suicidal behavior.
1,175 citations
TL;DR: The data indicate that the social deficits characteristic of autism spectrum disorders are common, and it may be arbitrary where cutoffs are made between research designations of being "affected" vs "unaffected" with a pervasive developmental disorder.
Abstract: Background Recent research has indicated that autism is not a discrete disorder and that family members of autistic probands have an increased likelihood of exhibiting autistic symptoms with a wide range of severity, often below the threshold for a diagnosis of an autism spectrum disorder. Objective To examine the distribution and genetic structure of autistic traits in the general population using a newly established quantitative measure of autistic traits, the Social Responsiveness Scale (formerly known as the Social Reciprocity Scale). Methods The sample consisted of 788 pairs of twins aged 7 to 15 years, randomly selected from the pool of participants in a large epidemiologic study (the Missouri Twin Study). One parent of each pair of twins completed the Social Responsiveness Scale on each child. The data were subjected to structural equation modeling. Results Autistic traits as measured by the Social Responsiveness Scale were continuously distributed and moderately to highly heritable. Levels of severity of autistic traits at or above the previously published mean for patients with pervasive developmental disorder not otherwise specified were found in 1.4% of boys and 0.3% of girls. Structural equation modeling revealed no evidence for the existence of sex-specific genetic influences, and suggested specific mechanisms by which females may be relatively protected from vulnerability to autistic traits. Conclusions These data indicate that the social deficits characteristic of autism spectrum disorders are common. Given the continuous distribution of these traits, it may be arbitrary where cutoffs are made between research designations of being "affected" vs "unaffected" with a pervasive developmental disorder. The genes influencing autistic traits appear to be the same for boys and girls. Lower prevalence (and severity) of autistic traits in girls may be the result of increased sensitivity to early environmental influences that operate to promote social competency.
1,165 citations
TL;DR: There are substantial genetic and nonshared environmental correlations between mania and depression, but most of the genetic variance in liability to mania is specific to the manic syndrome.
Abstract: Background: Twin studies of bipolar affective disorder (BPD) have either been small or have not used explicit diagnostic criteria. There has been little use of genetic model fitting and no analyses to explore the etiological overlap with unipolar depression (UPD). Methods: Sixty-seven twin pairs, 30 monozygotic and 37 dizygotic, in which the proband had BPD were ascertained, and lifetime diagnoses were made using DSM-IV criteria. Univariate models were applied to estimate the contribution of additive genetic and environmental effects. Bipolar data were then combined with those from 68monozygoticand109dizygoticpairsinwhichtheproband had UPD. Two models were explored: a classic 2-threshold approach, in which BPD and UPD occupy thesamecontinuumofliabilitybutdifferinseverity,and a correlated liability model of mania and depression. Results:Heritability of BPD was estimated at 85% (95% confidence interval [CI], 0.73-0.93) using narrow concordance and 89% (95% CI, 0.61-1.0) using broad concordance, with no shared environmental effects detected. A 2-threshold model was an unsatisfactory fit. Fitting a correlated liability model revealed a genetic correlation of 0.65 (95% CI, 0.58-0.75) between mania and depression and a correlation of 0.59 (95% CI, 0.150.84) for nonfamilial environment. Approximately 71% of the genetic variance for mania was not shared with depression.
1,134 citations
TL;DR: The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms, involving primarily symptoms of minor and subsyndromal severity.
Abstract: Background This is the first prospective longitudinal study, to our knowledge, of the natural history of the weekly symptomatic status of bipolar II disorder (BP-II). Methods Weekly affective symptom status ratings for 86 patients with BP-II were based on interviews conducted at 6- or 12-month intervals during a mean of 13.4 years of prospective follow-up. Percentage of weeks at each symptom severity level and the number of shifts in symptom status and polarity were examined. Predictors of chronicity for BP-II were evaluated using new chronicity measures. Chronicity was also analyzed in relation to the percentage of follow-up weeks with different types of somatic treatment. Results Patients with BP-II were symptomatic 53.9% of all follow-up weeks: depressive symptoms (50.3% of weeks) dominated the course over hypomanic (1.3% of weeks) and cycling/mixed (2.3% of weeks) symptoms. Subsyndromal, minor depressive, and hypomanic symptoms combined were 3 times more common than major depressive symptoms. Longer intake episodes, a family history of affective disorders, and poor previous social functioning predicted greater chronicity. Prescribed somatic treatment did not correlate significantly with symptom chronicity. Patients with BP-II of brief (2-6 days) vs longer (≥7 days) hypomanias were not significantly different on any measure. Conclusions The longitudinal symptomatic course of BP-II is chronic and is dominated by depressive rather than hypomanic or cycling/mixed symptoms. Symptom severity fluctuates frequently within the same patient over time, involving primarily symptoms of minor and subsyndromal severity. Longitudinally, BP-II is expressed as a dimensional illness involving the full severity range of depressive and hypomanic symptoms. Hypomania of long or short duration in BP-II seems to be part of the same disease process.
1,069 citations
TL;DR: Some SGAs are more efficacious than FGAs, and, therefore,SGAs are not a homogeneous group, as suggested by consensus panel recommendations.
Abstract: Background: Consensus panel recommendations regarding choice of an antipsychotic agent for schizophrenia differ markedly, but most consider secondgeneration antipsychotics (SGAs) as a homogeneous group. It has been suggested that SGAs seem falsely more efficacious than first-generation antipsychotics (FGAs) as a result of reduced efficacy due to use of a high-dose comparator, haloperidol. We performed (1) a metaanalysis of randomized efficacy trials comparing SGAs and FGAs, (2) comparisons between SGAs, (3) a doseresponse analysis of FGAs and SGAs, and (4) an analysis of the effect on efficacy of an overly high dose of an FGA comparator. Methods: Literature search of clinical trials between January 1953 and May 2002 of patients with schizophrenia from electronic databases, reference lists, posters, the Food and Drug Administration, and other unpublished data. We included 124 randomized controlled trials with efficacy data on 10 SGAs vs FGAs and 18 studies of comparisons between SGAs. Two of us independently extracted the sample sizes, means, and standard deviation of the efficacy data. Results: Using the Hedges-Olkin algorithm, the effect sizes of clozapine, amisulpride, risperidone, and olanzapine were 0.49, 0.29, 0.25, and 0.21 greater than those of FGAs, with P values of 210 �8 ,3 10 �7 ,2 10 �12 , and 310 �9 , respectively. The remaining 6 SGAs were not significantly different from FGAs, although zotepine was marginally different. No efficacy difference was detected among amisulpride, risperidone, and olanzapine. We found no evidence that the haloperidol dose (or all FGA comparators converted to haloperidol-equivalent doses) affected these results when we examined its effect by drug or in a 2-way analysis of variance model in which SGA effectiveness is entered as a second factor. Conclusion: Some SGAs are more efficacious than FGAs, and, therefore, SGAs are not a homogeneous group. Arch Gen Psychiatry. 2003;60:553-564
882 citations
TL;DR: Patients with chronic schizophrenia showed widespread cortical thinning that particularly affected the prefrontal and temporal cortices, which might reflect underlying neuropathological abnormalities in cortical structure.
Abstract: Background: Schizophrenia is characterized by small reductions in cortical gray matter volume, particularly in the temporal and prefrontal cortices. The question of whether cortical thickness is reduced in schizophrenia has not been addressed using magnetic resonance imaging(MRI)techniques.Ourobjectivesweretotestthehypothesis that cortical thinning in patients with schizophrenia(relativetocontrolsubjects)isgreaterintemporal and prefrontal regions of interest (ROIs) than in control ROIs (superior parietal, calcarine, postcentral, central, and precentral cortices), and to obtain an unbiased estimate of the distribution of cortical thinning in patients (relative to controls) by constructing mean and statistical cortical thickness difference maps. Methods: Participants included 33 right-handed outpatients receiving medication and meeting DSM-IV criteriaforschizophreniaand32healthyvolunteers,matched on age and parental socioeconomic status. After highresolution MRI scans, models of the gray-white and pial surfaces were generated for each individual’s cortex, and the distance between these 2 surfaces was used to compute cortical thickness. A surface-based averaging technique that aligned the main cortical folds across individualsallowedbetween-groupcomparisonsofthickness within ROIs, and at multiple, uniformly sampled loci across the cortical ribbon. Results:Relativetocontrols,patientsshowedgreatercortical thinning in temporal-prefrontal ROIs than in control ROIs, as revealed by a significant (P.009) interaction between group and region type. Cortical thickness difference maps revealed significant (at P.05, corrected) thinning within the orbitofrontal cortices bilaterally; the inferior frontal, inferior temporal, and occipitotemporal cortices on the left; and within the medial temporal and medial frontal cortices on the right. Superior parietal and primary somatosensory and motor cortices were relatively spared, even at subthreshold significance levels. Conclusions: Patients with chronic schizophrenia showedwidespreadcorticalthinningthatparticularlyaffected the prefrontal and temporal cortices. This thinning might reflect underlying neuropathological abnormalities in cortical structure. Arch Gen Psychiatry. 2003;60:878-888
TL;DR: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine isMore effective than olanZapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.
Abstract: Background Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression. Objective To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Design Double-blind, 8-week, randomized controlled trial. Setting Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86). Main Outcome Measure Changes in MADRS total scores using mixed-effects model repeated-measures analyses. Results During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group ( P Conclusions Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.
TL;DR: Findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
Abstract: Background Suicide is a major public health concern. Although authors of many studies have examined the neurobiological aspects of suicide, the molecular mechanisms associated with suicidal behavior remain unclear. Brain-derived neurotrophic factor (BDNF), one of the most important neurotrophins, after binding with and activating receptor tyrosine kinase B (trk B), is directly involved in many physiological functions in the brain, including cell survival and synaptic plasticity. The present study was performed to examine whether the expression of BDNF and/or trk B isoforms was altered in postmortem brain in subjects who commit suicide (hereafter referred to as suicide subjects) and whether these alterations were associated with specific psychopathologic conditions. Methods These studies were performed in prefrontal cortex in Brodmann area 9 and hippocampus obtained in 27 suicide subjects and 21 nonpsychiatric control subjects. Levels of messenger RNA and protein levels of BDNF and trk B were determined with competitive reverse transcriptase–polymerase chain reaction and Western blot technique, respectively. The level of neuron-specific enolase messenger RNA as a neuronal marker was also determined in these brain areas. Results Messenger RNA levels of BDNF and trk B were significantly reduced, independently and as a ratio to neuron-specific enolase, in both prefrontal cortex and hippocampus in suicide subjects, as compared with those in control subjects. These reductions were associated with significant decreases in the protein levels of BDNF and of full-length trk B but not trk B's truncated isoform. These changes were present in all suicide subjects regardless of psychiatric diagnosis and were unrelated to postmortem interval, age, sex, or pH of the brain. Conclusions Given the importance of BDNF in mediating physiological functions, including cell survival and synaptic plasticity, our findings of reduced expression of BDNF and trk B in postmortem brain in suicide subjects suggest that these molecules may play an important role in the pathophysiological aspects of suicidal behavior.
TL;DR: H humiliating events that directly devalue an individual in a core role were strongly linked to risk for depressive episodes, and event dimensions and categories that predispose to pure MD vs pure GAS episodes can be distinguished with moderate specificity.
Abstract: Background Although substantial evidence suggests that stressful life events predispose to the onset of episodes of depression and anxiety, the essential features of these events that are depressogenic and anxiogenic remain uncertain. Methods High contextual threat stressful life events, assessed in 98 592 person-months from 7322 male and female adult twins ascertained from a population-based registry, were blindly rated on the dimensions of humiliation, entrapment, loss, and danger and their categories. Onsets of pure major depression (MD), pure generalized anxiety syndrome (GAS) (defined as generalized anxiety disorder with a 2-week minimum duration), and mixed MD-GAS episodes were examined using logistic regression. Results Onsets of pure MD and mixed MD-GAS were predicted by higher ratings of loss and humiliation. Onsets of pure GAS were predicted by higher ratings of loss and danger. High ratings of entrapment predicted only onsets of mixed episodes. The loss categories of death and respondent-initiated separation predicted pure MD but not pure GAS episodes. Events with a combination of humiliation (especially other-initiated separation) and loss were more depressogenic than pure loss events, including death. No sex differences were seen in the prediction of episodes of illness by event categories. Conclusions In addition to loss, humiliating events that directly devalue an individual in a core role were strongly linked to risk for depressive episodes. Event dimensions and categories that predispose to pure MD vs pure GAS episodes can be distinguished with moderate specificity. The event dimensions that preceded mixed MD-GAS episodes were largely the sum of those that preceded pure MD and pure GAS episodes.
TL;DR: Support for the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome is supported.
Abstract: Numerous lines of inquiry implicate connectivity as a central abnormality in schizophrenia. Myelination and factors that affect myelination, such as the function of oligodendroglia, are critical processes that could profoundly affect neuronal connectivity, especially given the diffuse distribution of oligodendrocytes and the widespread distribution of brain regions that have been implicated in schizophrenia. Multiple lines of evidence now converge to implicate oligodendroglia and myelin in schizophrenia. Imaging and neurocytochemical evidence, similarities with demyelinating diseases, age-related changes in white matter, myelin-related gene abnormalities, and morphologic abnormalities in the oligodendroglia demonstrated in schizophrenic brains are all examined in light of the hypothesis that oligodendroglial dysfunction and even death, with subsequent abnormalities in myelin maintenance and repair, contribute to the schizophrenic syndrome.
TL;DR: This meta-analysis provides evidence for a sex difference in the risk of developing schizophrenia, as reported in the published literature from the last 2 decades.
Abstract: Background Sex differences in the risk of a particular disorder can yield important clues regarding its pathogenesis. The evidence for a sex difference in the risk of schizophrenia is inconclusive. The purpose of this study was to integrate results from the published literature and to provide a quantitative index of the male-female ratio for the incidence of schizophrenia. Methods The MEDLINE and PsychLIT databases were searched for English-language publications on "incidence and schizophrenia" that appeared during the period between January 1980 and September 2001. Population-based incidence studies using standard clinical diagnostic criteria were included if they reported sex-specific incidence rates. Sex-specific incidence figures were extracted directly from each study. Categorical analyses were conducted on a subset of studies that met specific methodological criteria (to minimize criterion bias, hospital bias, and age bias). Study categorization and data extraction were performed independently by 2 of us (A. A. and J.-P.S.). Results Log risk ratio meta-analysis was conducted using a random-effects model. The incidence risk ratios for men to develop schizophrenia relative to women were 1.42 (95% confidence interval [CI], 1.30-1.56) when all studies were included in the analysis (49 effect sizes), 1.31 (95% CI, 1.13-1.51) when studies that minimized selection biases were analyzed separately (23 effect sizes), and 1.39 (95% CI, 1.15-1.68) when only high-quality studies were included(11 effect sizes). The sex difference was significantly smaller in studies with sample years before 1980 than those with sample years after 1980. No significant sex differences were reported in studies from developing countries. A final analysis, limited to studies with an age cutoff of 64 years or older(16 effect sizes), yielded a mean risk ratio of 1.32 (95% CI, 1.13-1.55). Conclusion This meta-analysis provides evidence for a sex difference in the risk of developing schizophrenia, as reported in the published literature from the last 2 decades.
TL;DR: Group psychoeducation is an efficacious intervention to prevent recurrence in pharmacologically treated patients with bipolar I and II disorder.
Abstract: Background Studies on individual psychotherapy indicate that some interventions may reduce the number of recurrences in bipolar patients. However, there has been a lack of structured, well-designed, blinded, controlled studies demonstrating the efficacy of group psychoeducation to prevent recurrences in patients with bipolar I and II disorder. Methods One hundred twenty bipolar I and II outpatients in remission (Young Mania Rating Scale score Results Group psychoeducation significantly reduced the number of relapsed patients and the number of recurrences per patient, and increased the time to depressive, manic, hypomanic, and mixed recurrences. The number and length of hospitalizations per patient were also lower in patients who received psychoeducation. Conclusion Group psychoeducation is an efficacious intervention to prevent recurrence in pharmacologically treated patients with bipolar I and II disorder.
TL;DR: Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode.
Abstract: Background Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials. This double-blind, placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder. Methods After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued, patients were randomized to lamotrigine (100-400 mg daily), lithium (0.8-1.1 mEq/L), or placebo as double-blind maintenance treatment for as long as 18 months. Results Of 349 patients who met screening criteria and entered the open-label phase, 175 met stabilization criteria and were randomized to double-blind maintenance treatment (lamotrigine, 59 patients; lithium, 46 patients; and placebo, 70 patients). Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode (lamotrigine vs placebo, P = .02; lithium vs placebo, P = .006). Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02). Lithium was superior to placebo at prolonging the time to a manic, hypomanic, or mixed episode( P =.006). The most common adverse event reported for lamotrigine was headache. Conclusions Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode. The results indicate that lamotrigine is an effective, well-tolerated maintenance treatment for bipolar disorder, particularly for prophylaxis of depression.
TL;DR: The findings provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.
Abstract: Background Cognitive dysfunction in the working memory domain seems to be under genetic control and is a candidate intermediate phenotype in schizophrenia. Genes that affect working memory processing may contribute to risk for schizophrenia. Methods Working memory and attentional processing were assessed in a large and unselected sample of schizophrenic patients, their healthy siblings, and controls(N = 250). We used the n-back task because it allows parametric analysis over increasing loads and delays and parsing of subcomponents of executive cognition and working memory, including temporal indexing and updating. Participants were genotyped for catechol- O -methyltransferase ( COMT ) at the Val158Met locus, which has been shown to affect executive cognition and frontal lobe function, likely because of genetically determined variation in prefrontal dopamine signaling. Results A significant COMT genotype effect was found: Val/Val individuals had the lowest n-back performance, and Met/Met individuals had the highest performance. Effects were similar in the 1- and 2-back conditions and across all groups, whereas no effect on the Continuous Performance Test was seen, suggesting that genotype was not affecting working memory subprocesses related to attention, load, or delay. Siblings also performed significantly worse than controls on the 1- and 2-back conditions. Conclusions A prefrontal cognitive mechanism common to the 1- and 2-back conditions, probably executive processes involved in information updating and temporal indexing, is sensitive to the COMT genotype. Considering that the 3 participant groups were affected more or less linearly by the COMT genotype, an additive genetic model in which the effect of allele load is similar in its effects on prefrontally based working memory irrespective of the genetic or environmental background in which it is expressed is suggested. The findings also provide convergent evidence that an intermediate phenotype related to prefrontal cortical function represents a viable approach to understanding neuropsychiatric disorders with complex genetic etiologies and individual differences in cognition.
TL;DR: The presence of CPPCs increases the duration of depressive mood and patients seeking consultation for a CPPC should be systematically evaluated for depression.
Abstract: Background: Pain syndrome is thought to play a role in depression. This study assesses the prevalence of chronic ( 6 months’ duration) painful physical conditions (CPPCs) (joint/articular, limb, or back pain, headaches, or gastrointestinal diseases) and their relationship with major depressive disorder. Methods: We conducted a cross-sectional telephone survey of a random sample of 18980 subjects from 15 to 100 years old representative of the general populations of the United Kingdom, Germany, Italy, Portugal, and Spain. Answers provided during telephone interviews using the Sleep-EVAL system were the main outcome measure. Interviews included questions about mental disorders and medical conditions. Data on painful physical conditions were obtained through questions about medical treatment, consultations, and/or hospitalizations for medical conditions and a list of 42 diseases. Results: Of all subjects interviewed, 17.1% reported having at least 1 CPPC (95% confidence interval [CI], 16.5%-17.6%). At least 1 depressive symptom (sadness, depression, hopelessness, loss of interest, or lack of pleasure) was present in 16.5% of subjects (95% CI, 16.0%-17.1%); 27.6% of these subjects had at least 1 CPPC. Major depressive disorder was diagnosed in 4.0% of subjects; 43.4% of these subjects had at least 1 CPPC, which was 4 times more often than in subjects without major depressive disorder (odds ratio [OR], 4.0; 95% CI, 3.5-4.7). In a logistic regression model, CPPC was strongly associated with major depressive disorder (OR: CPPC alone, 3.6; CPPC+nonpainful medical condition, 5.2); 24-hour presence of pain made an independent contribution to major depressive disorder diagnosis (OR, 1.6). Conclusions: The presence of CPPCs increases the duration of depressive mood. Patients seeking consultation for a CPPC should be systematically evaluated for depression.
TL;DR: The findings do not support the hypothesis that exposure to traumatic events per se increases the risk for substance use disorders, and a modestly elevated risk for nicotine dependence might be an exception.
Abstract: Background We examine whether exposure to traumatic events increases the risk for nicotine dependence or alcohol or other drug use disorders, independent of posttraumatic stress disorder (PTSD). Methods Data come from a longitudinal epidemiologic study of young adults in southeast Michigan. Prospective data covering a 10-year period and retrospective lifetime data gathered at baseline were used to estimate the risk for onset of substance use disorders in persons with PTSD and in persons exposed to trauma without PTSD, compared with persons who have not been exposed to trauma. The National Institute of Mental Health Diagnostic Interview Schedule for DSM-III-R was used. Logistic regression was used to analyze the prospective data, and Cox proportional hazards survival analysis with time-dependent variables was applied to the lifetime data. Results The prospective and retrospective data show an increased risk for the onset of nicotine dependence and drug abuse or dependence in persons with PTSD, but no increased risk or a significantly ( P =.004) lower risk (for nicotine dependence, in the prospective data) in persons exposed to trauma in the absence of PTSD, compared with unexposed persons. Exposure to trauma in either the presence or the absence of PTSD did not predict alcohol abuse or dependence. Conclusions The findings do not support the hypothesis that exposure to traumatic events per se increases the risk for substance use disorders. A modestly elevated risk for nicotine dependence might be an exception. Posttraumatic stress disorder might be a causal risk factor for nicotine and drug use disorders or, alternatively, the co-occurrence of PTSD and these disorders might be influenced by shared risk factors other than traumatic exposure.
TL;DR: In this article, a randomized controlled trial was performed to determine whether combining family-focused therapy (FFT) with pharmacotherapy during a post-episode interval enhances patients' mood stability during maintenance treatment.
Abstract: Background Bipolar patients are at risk for relapses of their illness even when undergoing optimal pharmacotherapy. This study was performed to determine whether combining family-focused therapy (FFT) with pharmacotherapy during a postepisode interval enhances patients' mood stability during maintenance treatment. Methods In a randomized controlled trial, 101 bipolar patients were assigned to FFT and pharmacotherapy or a less intensive crisis management (CM) intervention and pharmacotherapy. Outcome assessments were conducted every 3 to 6 months for 2 years. Participants (mean +/- SD age, 35.6 +/- 10.2 years) were referred from inpatient or outpatient clinics after onset of a manic, mixed, or depressed episode. FFT consisted of 21 sessions of psychoeducation, communication training, and problem-solving skills training. Crisis management consisted of 2 sessions of family education plus crisis intervention sessions as needed. Both protocols lasted 9 months. Patients received pharmacotherapy for 2 study years. Main outcome measures included time to relapse, depressive and manic symptoms, and medication adherence. Results Rates of study completion did not differ across the FFT (22/31, 71%) and CM groups (43/70, 61%). Patients undergoing FFT had fewer relapses (11/31, 35%) and longer survival intervals (mean +/- SD, 73.5 +/- 28.8 weeks) than patients undergoing CM (38/70, 54%; mean +/- SD, 53.2 +/- 39.6 weeks; hazard ratio, 0.38; 95% confidence interval, 0.20-0.75; P =.003; intent to treat). Patients undergoing FFT showed greater reductions in mood disorder symptoms and better medication adherence during the 2 years than patients undergoing CM. Conclusion Combining family psychoeducation with pharmacotherapy enhances the postepisode symptomatic adjustment and drug adherence of bipolar patients.
TL;DR: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/D) were significantly better than placebo on all efficacy measures as mentioned in this paper.
Abstract: Background: Aripiprazole is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. This multicenter trial examined the efficacy, safety, and tolerability of aripiprazole in patients with acute exacerbation of schizophrenia or schizoaffective disorder. Methods: In this 4-week double-blind study, 404 patients were randomized to 20 mg/d (n=101) or 30 mg/d (n=101)ofaripiprazole,placebo(n=103),or6mg/dofrisperidone (n=99). Efficacy assessments included Positive and Negative Syndrome Scale (PANSS) scores and ClinicalGlobalImpressionscores.Safetyandtolerabilityevaluations included extrapyramidal symptoms and effects on weight, prolactin, and corrected QT (QTc) interval. Results: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were significantly better than placebo on all efficacy measures. Separation from placebo occurred at week 1 for PANSS total and positive scores with aripiprazole and risperidone and for PANSS negative scores with aripiprazole. There were no significant differences between aripiprazole and placebo in mean change from baseline in the extrapyramidal symptom rating scales. Meanprolactinlevelsdecreasedwitharipiprazolebutsignificantlyincreased5-foldwithrisperidone.Meanchange in QTc interval did not differ significantly from placebo with any active treatment group. Aripiprazole and risperidone groups showed a similar lowincidence of clinically significant weight gain. Conclusions: Aripiprazole is effective, safe, and well toleratedforthepositiveandnegativesymptomsinschizophreniaandschizoaffectivedisorder.Itisthefirstnon-D2receptorantagonistwithclearantipsychoticeffectsandrepresents a novel treatment development for psychotic disorders. Arch Gen Psychiatry. 2003;60:681-690
TL;DR: Comorbid psychiatric disorders are a major health problem among detained youth and the odds of having comorbid disorders were higher than expected by chance for most demographic subgroups, except when base rates of disorders were already high or when cell sizes were small.
Abstract: Objective To estimate 6-month prevalence of comorbid psychiatric disorders among juvenile detainees by demographic subgroups (sex, race/ethnicity, and age). Design Epidemiologic study of juvenile detainees. Master's level clinical research interviewers administered the Diagnostic Interview Schedule for Children Version 2.3 to randomly selected detainees. Setting A large temporary detention center for juveniles in Cook County, Illinois (which includes Chicago and surrounding suburbs). Participants Randomly selected, stratified sample of 1829 African American, non-Hispanic white, and Hispanic youth (1172 males, 657 females, aged 10-18 years) arrested and newly detained. Main Outcome Measure Diagnostic Interview Schedule for Children. Results Significantly more females (56.5%) than males (45.9%) met criteria for 2 or more of the following disorders: major depressive, dysthymic, manic, psychotic, panic, separation anxiety, overanxious, generalized anxiety, obsessive-compulsive, attention-deficit/hyperactivity, conduct, oppositional defiant, alcohol, marijuana, and other substance; 17.3% of females and 20.4% of males had only one disorder. We also examined types of disorder: affective, anxiety, substance use, and attention-deficit/hyperactivity or behavioral. The odds of having comorbid disorders were higher than expected by chance for most demographic subgroups, except when base rates of disorders were already high or when cell sizes were small. Nearly 14% of females and 11% of males had both a major mental disorder (psychosis, manic episode, or major depressive episode) and a substance use disorder. Compared with participants with no major mental disorder (the residual category), those with a major mental disorder had significantly greater odds(1.8-4.1) of having substance use disorders. Nearly 30% of females and more than 20% of males with substance use disorders had major mental disorders. Rates of some types of comorbidity were higher among non-Hispanic whites and older adolescents. Conclusions Comorbid psychiatric disorders are a major health problem among detained youth. We recommend directions for research and discuss how to improve treatment and reduce health disparities in the juvenile justice and mental health systems.
TL;DR: There are ongoing changes in the brains of schizophrenic patients during the initial years after diagnosis despite ongoing antipsychotic drug treatment, and progressive changes seem to be most evident in the frontal lobes and to correlate with functional impairment.
Abstract: Background Many studies have shown that structural brain abnormalities in schizophrenia are already present by the time of index evaluation of first-episode patients. However, whether these abnormalities progressively worsen during the subsequent course of the disorder remains unresolved. Methods To study the longitudinal progression of structural brain abnormalities, high-resolution multispectral magnetic resonance images obtained on 73 recent-onset schizophrenic patients and 23 controls were analyzed using state-of-the-art, well-validated, and highly reliable neuroimaging tools. The mean duration between initial and follow-up MRIs was 3 years. Repeated-measures analysis of covariance was carried out to determine (1) whether brain volume changes differed between patients and controls and (2) the significance of regional brain changes on functional outcome in schizophrenia. Results We found accelerated enlargement in cortical sulcal cerebrospinal fluid spaces early in the course of schizophrenia. Instead of the usual trajectory of volume enlargement, patients showed progressive reduction in frontal lobe white matter volume. A reciprocal increase in frontal lobe cerebrospinal fluid volume also occurred at a more rapid rate in patients than in controls. In keeping with most of our a priori hypotheses, patients with poor outcome had greater lateral ventricular enlargement over time than patients with good outcome. Progressive decrement in frontal lobe white matter volume and enlargement in frontal lobe cerebrospinal fluid volume were associated with greater negative symptom severity. Reductions in frontal lobe gray and white matter volumes correlated with poorer executive functioning. Conclusions There are ongoing changes in the brains of schizophrenic patients during the initial years after diagnosis despite ongoing antipsychotic drug treatment. These progressive changes seem to be most evident in the frontal lobes and to correlate with functional impairment. Disruptions in neurodevelopment or neural plasticity may act alone or in combination to bring about these progressive brain deficits in schizophrenia.
TL;DR: The findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.
Abstract: Background Despite the use of mood stabilizers, a significant proportion of patients with bipolar affective disorder experience frequent relapses. A pilot study of cognitive therapy (CT) specifically designed to prevent relapses for bipolar affective disorder showed encouraging results when used in conjunction with mood stabilizers. This article reports the outcome of a randomized controlled study of CT to help prevent relapses and promote social functioning. Methods We randomized 103 patients with bipolar 1 disorder according to the DSM-IV , who experienced frequent relapses despite the prescription of commonly used mood stabilizers, into a CT group or control group. Both the control and CT groups received mood stabilizers and regular psychiatric follow-up. In addition, the CT group received an average of 14 sessions of CT during the first 6 months and 2 booster sessions in the second 6 months. Results During the 12-month period, the CT group had significantly fewer bipolar episodes, days in a bipolar episode, and number of admissions for this type of episode. The CT group also had significantly higher social functioning. During these 12 months, the CT group showed less mood symptoms on the monthly mood questionnaires. Furthermore, there was significantly less fluctuation in manic symptoms in the CT group. The CT group also coped better with manic prodromes at 12 months. Conclusion Our findings support the conclusion that CT specifically designed for relapse prevention in bipolar affective disorder is a useful tool in conjunction with mood stabilizers.
TL;DR: Auditory hallucinations were robustly improved with rTMS relative to sham stimulation, and the mechanism of AHs involves activation of the left temporoparietal cortex, which suggests that one-hertz rT MS deserves additional study as a possible treatment for this syndrome.
Abstract: Background Neuroimaging studies suggest that auditory hallucinations (AHs) of speech arise, at least in part, from activation of brain areas underlying speech perception. One-hertz repetitive transcranial magnetic stimulation (rTMS) produces sustained reductions in cortical activation. Recent results of 4-day administration of 1-Hz rTMS to left temporoparietal cortex were superior to those of sham stimulation in reducing AHs. We sought to determine if a more extended trial of rTMS could significantly reduce AHs that were resistant to antipsychotic medication. Methods Twenty-four patients with schizophrenia or schizoaffective disorder and medication-resistant AHs were randomly allocated to receive rTMS or sham stimulation for 9 days at 90% of motor threshold. Patients receiving sham stimulation were subsequently offered an open-label trial of rTMS. Neuropsychological assessments were administered at baseline and during and following each arm of the trial. Results Auditory hallucinations were robustly improved with rTMS relative to sham stimulation. Frequency and attentional salience were the 2 aspects of hallucinatory experience that showed greatest improvement. Duration of putative treatment effects ranged widely, with 52% of patients maintaining improvement for at least 15 weeks. Repetitive transcranial magnetic stimulation was well tolerated, without evidence of neuropsychological impairment. Conclusions These data suggest that the mechanism of AHs involves activation of the left temporoparietal cortex. One-hertz rTMS deserves additional study as a possible treatment for this syndrome.
TL;DR: Reduced caudate nucleus volumes may be a good candidate marker for a trait abnormality in the structure of the basal ganglia in persons with TS and for the persistence of tic symptoms into adulthood.
Abstract: Although Alzheimer s disease is classified as a neurodegenerative dementia, in Alzheimer s dementia there is increasing evidence of an association with vascular risk factors and vascular pathology. These observations are supported by epidemiological and pathological studies. Vascular factors may play a significant role in the pathogenesis of Alzheimer s dementia. Further research is needed to explore this relationship. Modification of vascular risk factors could make a significant impact towards prevention and treatment of Alzheimer s disease, which is a distressing and prevalent condition in the community. This article considers the relationship of these vascular risk factors and potential mechanisms associated with the aetiopathogenesis of Alzheimer s dementia.
TL;DR: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex and the hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.
Abstract: Background Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. Methods Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. Results Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group ( P = .005) and an exaggerated increase in signal on the left side in the depressed group ( P = .02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state ( P Conclusions Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.
TL;DR: Depressive symptoms and DSM-IV depressive disorders in elderly patients are associated with significantly higher health care costs, even after adjustment for chronic medical illness.
Abstract: Background We examined whether older adults with depressive symptoms below the diagnostic threshold and those with DSM-IV major depression and/or dysthymia have higher medical costs than those without depression. Methods We mailed the PRIME-MD 2-item depression screen to the patients of 2 large primary care clinics of a staff-model health maintenance organization in Seattle, Wash. All 11 679 patients 60 years and older with primary care providers at the participating clinics were included, and 8894 (76.2%) were successfully enrolled. An additional 107 patients were referred to the study by their primary care physician. Nonrespondents were slightly younger and had higher inpatient medical costs in the previous 6 months. Patients with positive findings on at least 1 item or referred by their family physician were offered an interview with the Structured Clinical Interview for DSM-IV. The total cost of medical services for the 6 months before the study was obtained from the cost accounting system of the health maintenance organization. Results Total ambulatory costs were 43% to 52% higher and total ambulatory and inpatient costs were 47% to 51% higher in depressed compared with nondepressed elderly patients after adjustment for chronic medical illness. This increase was seen in every component of health care costs, with only a small percentage due to mental health treatment. In mean costs, depressed elderly patients averaged an increase of 763 US dollars to 979 US dollars in ambulatory costs and 1045 US dollars to 1700 US dollars in ambulatory and inpatient costs. No differences in costs were noted between patients with subthreshold depressive syndromes and those with DSM-IV depressive disorders. Conclusion Depressive symptoms and DSM-IV depressive disorders in elderly patients are associated with significantly higher health care costs, even after adjustment for chronic medical illness.