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A twin study of generalized anxiety disorder and major depression
Abstract
SYNOPSIS
Previous analyses with a sample of female twins sampled from the general population in Virginia have suggested that generalized anxiety disorder (GAD) and major depression (MD) share their genetic determinants but have partly different environmental determinants. The goal of this report is to examine whether these findings apply to samples that include male as well as female twins and contain high proportions of subjects who had been hospitalized for MD.
The subjects were ascertained through two different sources: ( i ) index probands were ascertained through the Swedish Psychiatric Twin Registry for a diagnosis of unipolar or bipolar affective illness; ( ii ) control twin probands were ascertained through the Swedish Twin Registry. Subjects were sent questionnaires for the assessment of lifetime history of GAD and MD. Positing multinormal distribution of the liability for GAD and MD, we fitted bivariate models to examine the sources of comorbidity.
The full model included additive genetic effects, shared environment and individual-specific environment, as well as scalar and non-scalar sex limitations and different thresholds across genders. The best-fitting model included: ( i ) a genetic correlation of unity; ( ii ) no common environment; ( iii ) an individual-specific environmental correlation of 0·28; ( iv ) different thresholds across genders, but neither scalar nor non-scalar sex-limitations. A model that included additive and dominant genetic effects and individual-specific environment, with correlation of unity for both additive and dominant genetic effects, provided an equivalent fit.
These analyses confirm that GAD and MD share the same genetic factors but that their environmental determinants are mostly distinct. Moreover, the present report supports the feasibility of combining clinically ascertained and general-population samples into a single bivariate analysis.
... . They also share much of their underlying genetic influences (twin r g : $1.00 (Kendler et al., 1992;Purves et al., 2020;Roy, Neale, Pedersen, Mathé, & Kendler, 1995), SNP-based r g : $0.8 (Kendler et al., 1992;Purves et al., 2020;Roy et al., 1995). Decades of work have demonstrated that liability to anxiety and depression is influenced by numerous individual genetic variants, each associated with a very small effect. ...
... . They also share much of their underlying genetic influences (twin r g : $1.00 (Kendler et al., 1992;Purves et al., 2020;Roy, Neale, Pedersen, Mathé, & Kendler, 1995), SNP-based r g : $0.8 (Kendler et al., 1992;Purves et al., 2020;Roy et al., 1995). Decades of work have demonstrated that liability to anxiety and depression is influenced by numerous individual genetic variants, each associated with a very small effect. ...
The requirement for large sample sizes for psychiatric genetic analyses necessitates novel approaches to derive cases. Anxiety and depression show substantial genetic overlap and share pharmacological treatments. Data on prescribed medication could be effective for inferring case status when other indicators of mental health are unavailable. We investigated self-reported current medication use in UK Biobank participants of European ancestry. Medication Status cases reported using antidepressant or anxiolytic medication (n = 22,218), controls did not report psychotropic medication use (n = 168,959). A subset, “Medication Only,” additionally did not meet criteria for any other mental health indicator (case n = 2,643, control n = 107,029). We assessed genetic overlap between these phenotypes and two published genetic association studies of anxiety and depression, and an internalizing disorder trait derived from symptom-based questionnaires in UK Biobank. Genetic correlations between Medication Status and the three anxiety and depression phenotypes were significant (rg = 0.60–0.73). In the Medication Only subset, the genetic correlation with depression was significant (rg = 0.51). The three polygenic scores explained 0.33% – 0.80% of the variance in Medication Status and 0.07% – 0.19% of the variance in Medication Only. This study provides evidence that self-reported current medication use offers an alternate or supplementary anxiety or depression phenotype in genetic studies where diagnostic information is sparse or unavailable.
... We will also examine the estimated genetic correlations among these four disorders. While we anticipate from multiple prior studies a high genetic correlation between MD and AD (Kendler et al., 1992;Roy et al., 1995), the genetic correlation between FM and IBS would be particularly informative about the degree to which two FSDs, which present with quite different symptom patterns, substantially share the same etiologic factors, including genetic vulnerabilities, as has been previously proposed (Wessely, Nimnuan, & Sharpe, 1999). ...
Background
Functional Somatic Disorders (FSD) and Internalizing Psychiatric Disorders (IPD) are frequently comorbid and likely share familial/genetic risk factors.
Methods
We performed a Common Factor Multivariate Analysis of 2 FSDs, Fibromyalgia (FM) and Irritable Bowel Syndrome (IBS), and two IPDs, Major Depression (MD) and Anxiety Disorders (AD), in five kinds of Swedish female–female relative pairs: monozygotic (n = 8,052) dizygotic (n = 7216), full siblings (n = 712,762), half-siblings reared together (n = 23,623), and half-siblings reared apart (n = 53,873). Model fitting was by full information maximum likelihood using OpenMx.
Results
The best-fit model included genetic, shared environmental, and unique environmental factors. The common factor, ~50% heritable with a small shared environmental effect, loaded more strongly on the two IPDs (~0.80) than the 2 FSDs (0.40). Disorder-specific genetic effects were larger for the 2 FSDs (~0.30) than the 2 IPDs (~0.03). Estimated genetic correlations were high for MD and AD (+0.91), moderate between IBS and IPDs (+0.62), and intermediate between FM and MD (+0.54), FM and AD (+0.28), and FM and IBS (+0.38). Shared environmental influences on all disorders were present but small.
Conclusions
In women, FSDs and IPDs shared a moderate proportion of their genetic risk factors, greater for IBS than for FM. However, the genetic sharing between IBS and FM was less than between MD and AD, suggesting that FSDs do not form a highly genetically coherent group of disorders. The shared environment made a modest contribution to the familial aggregation of FSDs and IPDs.
... There is significant genetic overlap between psychiatric disorders. Family and twin studies first identified positive correlations and patterns of inheritance between psychiatric disorders [17][18][19]. The introduction of methods for estimating heritability and genetic correlations using GWAS summary statistics, such as linkage disequilibrium score regression (LDSC) [20] later identified genetic correlations across numerous psychiatric phenotypes [15,21,22]. ...
Over 90% of drug candidates fail in clinical trials, while it takes 10–15 years and one billion US dollars to develop a single successful drug. Drug development is more challenging for psychiatric disorders, where disease comorbidity and complex symptom profiles obscure the identification of causal mechanisms for therapeutic intervention. One promising approach for determining more suitable drug candidates in clinical trials is integrating human genetic data into the selection process. Genome-wide association studies have identified thousands of replicable risk loci for psychiatric disorders, and sophisticated statistical tools are increasingly effective at using these data to pinpoint likely causal genes. These studies have also uncovered shared or pleiotropic genetic risk factors underlying comorbid psychiatric disorders. In this article, we argue that leveraging pleiotropic effects will provide opportunities to discover novel drug targets and identify more effective treatments for psychiatric disorders by targeting a common mechanism rather than treating each disease separately.
... Individual differences in terms of the biochemical functioning of the brain make some individuals more likely to develop depressive disorders (Haenisch and Bönisch, 2011). Genetic and epigenetic factors play a role in the development of depression (Kendler, 1996;Sullivan et al., 1996;Roy et al. 1995), as well as brain structure and functioning (MacQueen and Frodl, 2011). Depression is also associated with hormonal dysfunction, inflammatory processes, and sleep dysregulation processes (Dobson and Dozois, 2011). ...
This thesis focuses on depression, examining its clinical representations, treatments, and determinants through a sociological lens, while incorporating concepts from psychiatry.
The first part analyses depression prevalence, utilizing data from various global and national sources to highlight its increased diagnosis and explore the term "epidemic." It critically evaluates whether this increase constitutes an actual epidemic, delving into the sociological explanations for the rise in depression, contrasting social change theories with diagnostic practice explanations. It argues that depression's depiction as a widespread issue is influenced by social, historical, and cultural contexts.
The second part presents an empirical investigation into depression as a sociological object, using qualitative methods like semi-structured interviews, participant observation, and document analysis in two healthcare settings in Milan, Italy. The study explores both professional and patient perspectives, examining representations of depression among mental health professionals and the social dynamics involved in depressive and anxiety disorders in patients. It also addresses the diagnostic and treatment practices concerning depression, considering the biopsychosocial model. The thesis contributes to understanding the complexity of depression and its treatment in the context of public healthcare systems.
... Twin studies report substantial genetic correlations between ANX and other psychiatric conditions, particularly MDD (26), helping to explain their high comorbidity. In addition, ANX and depression both share genetic risk factors with heritable personality traits such as neuroticism (27,28). Anxiety symptoms often precede suicidal behaviors (29) with possible causal implications (30). ...
The major anxiety disorders (ANX; including generalized anxiety disorder, panic disorder, and phobias) are highly prevalent, often onset early, persist throughout life, and cause substantial global disability. Although distinct in their clinical presentations, they likely represent differential expressions of a dysregulated threat-response system. Here we present a genome-wide association meta-analysis comprising 122,341 European ancestry ANX cases and 729,881 controls. We identified 58 independent genome-wide significant ANX risk variants and 66 genes with robust biological support. In an independent sample of 1,175,012 self-report ANX cases and 1,956,379 controls, 51 of the 58 associated variants were replicated. As predicted by twin studies, we found substantial genetic correlation between ANX and depression, neuroticism, and other internalizing phenotypes. Follow-up analyses demonstrated enrichment in all major brain regions and highlighted GABAergic signaling as one potential mechanism underlying ANX genetic risk. These results advance our understanding of the genetic architecture of ANX and prioritize genes for functional follow-up studies.
... Recently, these findings were partially confirmed by a large-scale genome-wide association study (GWAS) meta-analysis for CUD that found evidence for overlap in genetic liability between CUD and MDD (genetic correlation, r g = 0.32; Johnson et al. 2020). For comparison, while significant, the genetic overlap between MDD and CUD is lower than between depression and anxiety which is estimated at between 0.74 and 1.00 (Roy et al. 1995;Kendler et al. 2007). To determine the direction of the association, Smolkina et al. (2017) applied a model-fitting approach in which various models which differed in the underlying assumptions about the causal pathways between CUD and MDD (i.e., unidirectional causation, reciprocal causation, and three independent disorders) were fit to the twin data. ...
RationaleCannabis use among people with mood disorders increased in recent years. While comorbidity between cannabis use, cannabis use disorder (CUD), and mood disorders is high, the underlying mechanisms remain unclear.Objectives
We aimed to evaluate (1) the epidemiological evidence for an association between cannabis use, CUD, and mood disorders; (2) prospective longitudinal, genetic, and neurocognitive evidence of underlying mechanisms; and (3) prognosis and treatment options for individuals with CUD and mood disorders.Methods
Narrative review of existing literature is identified through PubMed searches, reviews, and meta-analyses. Evidence was reviewed separately for depression, bipolar disorder, and suicide.ResultsCurrent evidence is limited and mixed but suggestive of a bidirectional relationship between cannabis use, CUD, and the onset of depression. The evidence more consistently points to cannabis use preceding onset of bipolar disorder. Shared neurocognitive mechanisms and underlying genetic and environmental risk factors appear to explain part of the association. However, cannabis use itself may also influence the development of mood disorders, while others may initiate cannabis use to self-medicate symptoms. Comorbid cannabis use and CUD are associated with worse prognosis for depression and bipolar disorder including increased suicidal behaviors. Evidence for targeted treatments is limited.Conclusions
The current evidence base is limited by the lack of well-controlled prospective longitudinal studies and clinical studies including comorbid individuals. Future studies in humans examining the causal pathways and potential mechanisms of the association between cannabis use, CUD, and mood disorder comorbidity are crucial for optimizing harm reduction and treatment strategies.
... The generic alteration of the left VLPFC and the left DLPFC in MDD, GAD and CMG might be relevant to the fact that MDD and GAD share indistinguishable Table 1 Demographic and clinical characteristics of healthy controls and patients with major depressive Disorder, generalized anxiety disorder and their comorbidity. genetic background (Kendler et al., 1992;Roy et al., 1995). The shared dysfunction of these regions might also be associated with the common symptoms of MDD and GAD, like irritability, agitation, concentration difficulties, insomnia, and fatigue (Moffitt et al., 2007;Watson, 2005). ...
Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are frequently comorbid with each other, and both associated with substantial cognitive impairments; however, it is still unclear whether their impairments are neurobiologically similar or distinct. This study aims to investigate the cognitive functions of the prefrontal cortex (PFC) in patients with MDD and GAD during the verbal fluency task (VFT) using functional near-infrared spectroscopy (fNIRS). Fifty-two patients with MDD, fifty-one patients with GAD, fifty-two patients with the comorbidity of MDD and GAD (CMG), and forty-seven healthy controls (HC) participated in the study. Significant hypoactivation in the left ventrolateral and the left dorsolateral PFC was common in all patient groups when compared to HCs, suggesting a shared etiology. Furthermore, MDD patients showed significant hypoactivation at the right frontal pole cortex (FPoC) when compared to HCs and significant hypoactivation at the middle FPoC when compared to the CMG patients. Our work is the first fNIRS study to reveal the shared and unique neurobiological profiles of MDD, GAD and their comorbidity under the same standard experimentation condition, suggesting fNIRS holds promise as an adjutant to assist clinical diagnosis.
In this article, we examine evidence supporting the role of reproductive steroids in the regulation of mood and behavior in women and the nature of that role. In the first half of the article, we review evidence for the following: (i) the reproductive system is designed to regulate behavior; (ii) from the subcellular to cellular to circuit to behavior, reproductive steroids are powerful neuroregulators; (iii) affective disorders are disorders of behavioral state; and (iv) reproductive steroids affect virtually every system implicated in the pathophysiology of depression. In the second half of the article, we discuss the diagnosis of the three reproductive endocrine‐related mood disorders (premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression) and present evidence supporting the relevance of reproductive steroids to these conditions. Existing evidence suggests that changes in reproductive steroid levels during specific reproductive states (i.e., the premenstrual phase of the menstrual cycle, pregnancy, parturition, and the menopause transition) trigger affective dysregulation in susceptible women, thus suggesting the etiopathogenic relevance of these hormonal changes in reproductive mood disorders. Understanding the source of individual susceptibility is critical to both preventing the onset of illness and developing novel, individualized treatments for reproductive‐related affective dysregulation. © 2016 American Physiological Society. Compr Physiol 6:1135‐1160, 2016e.
Introduction
Emotional disorders are highly prevalent among adolescents, with a high rate of comorbidity. Convenient and effective treatment options are needed to reduce costs and improve effectiveness. The unified protocol for transdiagnostic treatment of emotional disorders in adolescents (UP-A) is an evidence-based transdiagnostic approach aimed at ameliorate emotional symptoms. The objective of this study is to assess the efficacy of the UP-A in Chinese adolescents with emotional disorders using multidimensional evaluations.
Methods and analysis
This study is a two-armed, randomised controlled trial on the efficacy of 12 week UP-A on adolescents with emotional disorders along with their parents. Forty-eight participants will be randomly assigned to either the treatment as usual (TAU) group or the TAU combined with UP-A (UP-A+TAU) group. We will evaluate the efficacy of the UP-A, through the following primary and secondary outcomes: emotional disorder severity, emotional symptoms, emotion regulation, cognitive patterns, executive function, resilience, quality of life, social and family functioning. Participants will be assessed at baseline (T1), week 4 (T2), week 8 (T3), post-treatment (T4) and 3 month follow-up (T5).
Discussion
This protocol outlines the first randomised controlled trial investigating the efficacy of the UP-A among Chinese adolescents with emotional disorders. The findings may contribute to providing an effective and feasible transdiagnostic intervention in Chinese clinical settings.
Ethics and dissemination
This trial has been approved by the Ethics and Clinical Research Committees of Peking University Sixth Hospital and will be performed under the Declaration of Helsinki with the Medical Research Involving Human Subjects Act (WMO). The results will be disseminated in a peer-reviewed journal and a conference presentation.
Trial registration number
ChiCTR2300069354.
Preface. List of Figures. List of Tables. 1. The Scope of Genetic Analyses. 2. Data Summary. 3. Biometrical Genetics. 4. Matrix Algebra. 5. Path Analysis and Structural Equations. 6. LISREL Models and Methods. 7. Model Fitting Functions and Optimization. 8. Univariate Analysis. 9. Power and Sample Size. 10. Social Interaction. 11. Sex Limitation and GE Interaction. 12. Multivariate Analysis. 13. Direction of Causation. 14. Repeated Measures. 15. Longitudinal Mean Trends. 16. Observer Ratings. 17. Assortment and Cultural Transmission. 18. Future Directions. Appendices: A. List of Participants. B. The Greek Alphabet. C. LISREL Scripts for Univariate Models. D. LISREL Script for Power Calculation. E. LISREL Scripts for Multivariate Models. F. LISREL Script for Sibling Interaction Model. G. LISREL Scripts for Sex and GE Interaction. H. LISREL Script for Rater Bias Model. I. LISREL Scripts for Direction of Causation. J. LISREL Script and Data for Simplex Model. K. LISREL Scripts for Assortment Models. Bibliography. Index.
• Bivariate twin analysis can determine the extent to which two disorders share common genetic, familial environmental, or individual-specific environmental risk factors. We applied this method to lifetime diagnoses of major depression and generalized anxiety disorder as assessed at personal interview in a population-based sample of 1033 pairs of female same-sex twins. Three definitions of generalized anxiety disorder were used that varied in minimum duration (1 vs 6 months) and in the presence or absence of a diagnostic hierarchy. For all definitions of generalized anxiety disorder, the best-fitting twin model was the same. Familial environment played no role in the etiology of either condition. Genetic factors were important for both major depression and generalized anxiety disorder and were completely shared between the two disorders. A modest proportion of the nonfamilial environmental risk factors were shared between major depression and generalized anxiety disorder. Within the limits of our statistical power, our findings suggest that in women, the liability to major depression and generalized anxiety disorder is influenced by the same genetic factors, so that whether a vulnerable woman develops major depression or generalized anxiety disorder is a result of her environmental experiences.
• While traditional multivariate statistical methods can describe patterns of psychiatric symptoms, they cannot provide insight into why certain symptoms tend to co-occur in a population. However, this can be achieved using recently developed methods of multivariate genetic analysis. Examining self-report symptoms in a clinically unselected twin sample (3798 pairs), traditional factor analysis indicates that symptoms of depression and anxiety tend to form separate symptom clusters. Multivariate genetic analysis shows that genes act largely in a nonspecific way to influence the overall level of psychiatric symptoms. No evidence could be found for genes that specifically affect symptoms of depression without also strongly influencing symptoms of anxiety. By contrast, the environment seems to have specific effects, ie, certain features of the environment strongly influence symptoms of anxiety while having little impact on symptoms of depression. These results, which are replicated across sexes, suggest that the separable anxiety and depression symptom clusters in the general population are largely the result of environmental factors.
• Patients with panic disorder or depression have abnormal responses to the \g=a\2-adrenergic receptor partial agonist clonidine. Evidence linking anxiety to noradrenergic dysfunction and the presence of anxiety symptoms in both depression and panic suggest that abnormal responses to clonidine in these disorders could be due to the anxiety symptoms. To explore a possible link between "nonspecific" anxiety symptoms and abnormal responses to clonidine, patients with DSM-III\p=m-\defined generalized anxiety disorder were given intravenous infusions of clonidine hydrochloride. Responses of plasma growth hormone, 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, and psychological states were determined in 11 patients with generalized anxiety disorder and 14 healthy subjects. Clonidine produced significantly smaller growth hormone responses in patients than in healthy controls. The two groups did not differ in 3-methoxy-4-hydroxyphenylglycol, heart rate, blood pressure, or psychological responses to clonidine. These results are compared with data from similar studies on patients with panic disorder and depression. The blunting of the growth hormone response to clonidine in all three disorders could be due to the presence of generalized anxiety symptoms. Subsensitivity of postsynaptic \g=a\2-adrenoreceptors may be present in all three disorders; however, there are alternative interpretations of growth hormone blunting in response to clonidine. Blunting was observed in DSM-III\p=m-\defined generalized anxiety disorder, whether or not the DSM-III-R criterion of excessive worry was also present.
• We examine the relationship between parental loss prior to age 17 years and adult psychopathology in 1018 pairs of female twins from a population-based registry. The relationship between loss and adult psychopathology varied as a function of the kind of loss (death vs separation), the parent involved, and the form of psychopathology. Increased risk for major depression and generalized anxiety disorder was associated with parental separation but not parental death and with separation from either mother or father. Panic disorder was associated with parental death and maternal, but not paternal, separation. Increased risk for phobia was associated with parental death and not parental separation. Risk for eating disorder was unrelated to the experience of parental loss. A model that includes parental loss as a form of "specified" family environment shows that, if it is truly an environmental risk factor for adult psychopatholgic conditions, it can account for between 1.5% and 5.1% of the total variance in liability to these disorders and is responsible for between 7.0% and 20.5% of the tendency for these disorders to aggregate in siblings.
• The history, rationale, and development of the Structured Clinical Interview for DSM-III-R (SCID) is described. The SCID is a semistuctured interview for making the major Axis I DSM-III-R diagnoses. It is administered by a clinician and includes an introductory overview followed by nine modules, seven of which represent the major axis I diagnostic classes. Because of its modular construction, it can be adapted for use in studies in which particular diagnoses are not of interest. Using a decision tree approach, the SCID guides the clinician in testing diagnostic hypotheses as the interview is conducted. The output of the SCID is a record of the presence or absence of each of the disorders being considered, for current episode (past month) and for lifetime occurrence.
Objective:
We sought to compare the probandwise concordance rate (PRC) for affective illness (AI) in monozygotic (MZ) and dizygotic (DZ) twins in samples ascertained through psychiatric hospitalization vs samples from the general population.
Methods:
Twins were ascertained through psychiatric hospitalization for AI from the Swedish Psychiatric Twin Registry or as a matched sample from the population-based Swedish Twin Registry. Lifetime diagnoses were based on a mailed questionnaire containing, in self-report format, DSM-III-R criteria for mania and major depression. Returned questionnaires were obtained from 1484 individuals and both members of 486 pairs, of whom 154 were classified as MZ, 326 as DZ, and six of unknown zygosity.
Results:
No evidence was found for violations of the equal environment assumption. Using either a narrow or broad diagnostic approach, the risk for AI in cotwins of proband twins was independent of the gender, polarity (ie, unipolar vs bipolar) and mode of ascertainment of the affected proband (ie, via hospitalization vs from the general population). Combining both subsamples, PRC for total AI using narrow diagnostic criteria was 48.2% in MZ and 23.4% in DZ twins. Using broad diagnostic criteria, the parallel figures were 69.7% and 34.9%. The risk for bipolar illness was substantially increased in the cotwins of probands with bipolar AI.
Conclusions:
Background:
In epidemiologie samples, the assessment of lifetime history (LTH) of major depression (MD) is not highly reliable. In female twins, we previously found that LTH of MD, as assessed at a single personal interview, was moderately heritable (approximately 40%). In that analysis, errors of measurement could not be discriminated from true environmental effects.Methods:
In 1721 female twins from a populationbased register, including both members of 742 pairs, LTH of MD, covering approximately the same time period, was obtained twice, once by self-administered questionnaire and once at personal interview.Results:
Reliability of LTH of MD was modest (×= + .34, tetrachoric r= + .56) and was predicted by the number of depressive symptoms, treatment seeking, number of episodes, and degree of impairment. Deriving an "index of caseness" from these predictors, the estimated heritability of LTH of MD was greater for more restrictive definitions. Incorporating error of measurement into a structural equation model including both occasions of measurement, the estimated heritability of the liability to LTH of MD increased substantially (approximately 70%). More than half of what was considered environmental effects when LTH of MD was analyzed on the basis of one assessment appeared, when two assessments were used, to reflect measurement error.Conclusions:
Major depression, as assessed over the lifetime, may be a rather highly heritable disorder of moderate reliability rather than a moderately heritable disorder of high reliability.
• A double-blind, placebo-controlled comparison at three collaborating university sites included 242 patients diagnosed as having anxiety disorders. A two-week placebo washout period preceded random assignment to eight weeks of imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo treatment. Antianxiety effects of imipramine were superior to those of the other two agents by the second treatment week; these effects became more clearly significant thereafter and were independent of degree of both baseline depression and anxiety. Excluding patients with possible panic-phobic syndromes from the analyses removed most significant antiphobic and antidepressant effects of imipramine but left intact imipramine's significantly superior antianxiety effects.