Family patterns of psychopathology in psychiatric disorders.

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ScienceDirect Comprehensive Psychiatry xx (2014) xxx – xxx www.elsevier.com/locate/comppsych

Family patterns of psychopathology in psychiatric disorders Osman Özdemir a,⁎, Murat Boysan b , Pınar Güzel Özdemir a , Salih Coşkun c , Halil Özcan d , Ekrem Yılmaz a , Ercan Atilla a a

Department of Psychiatry, Yuzuncu Yil University, Van, Turkey Department of Psychology, Faculty of Art, Yuzuncu Yil University, Van, Turkey c Department of Medical Genetics, Dicle University, Diyarbakır, Turkey d Department of Psychiatry, Atatürk University, Erzurum, Turkey

b

Abstract Objective: Familial loading and crucial outcomes of family history of psychopathology in psychiatric disorders have long been recognized. There has been ample literature providing convincing evidence for the importance of family psychopathology in development of emotional disturbances in children as well as worse outcomes in the course of psychiatric disorders. More often, maternal psychopathology seems to have been an issue of interest rather than paternal psychopathology while effects of second-degree familiality have received almost no attention. In this study, we addressed the relations between affected first- and second-degree relatives of probands and categories of psychiatric disorders. Method: Subjects were 350 hospitalized psychiatric inpatients, consecutively admitted to psychiatry clinics in Van, Turkey. Mean age was 34.16 (SD ± 12) and 51.4% of the sample consisted of male patients. Assessment of psychopathology in psychiatric probands was conducted based on DSM-IV TR. Familial loading of psychiatric disorders amongst first- and second-degree relatives of patients were initially noted primarily relying on patients' retrospective reports, and confirmed by both phone call and following official health records via the Medical Knowledge System. We analyzed the data using latent class analysis approach. Results: We found four patterns of familial psychopathology. Latent homogeneous subsets of patients due to familial characteristics were as paternal kinship psychopathology with schizophrenia, paternal kinship psychopathology with mood disorders, maternal kinship psychopathology and core family psychopathology. Conclusion: Family patterns were critical to exerting variation in psychiatric disorders of probands and affected relatives. Probands with a core family pattern of psychopathology exhibited the most colorful clinical presentations in terms of variation in psychopathology. We observed a specificity of intergenerational transmission of psychiatric disorders when family patterns of psychopathology were taken into consideration, even second-degree relatives of psychiatric probands. © 2014 Elsevier Inc. All rights reserved.

1. Introduction There has been a vast body of evidence that psychiatric disorders in parents are substantially associated with a rise in affect regulation problems in a wide range from mild to severe disturbances in children. Almost half of children of ⁎ Corresponding author at: Yuzuncu Yil University, Faculty of Medicine, Department of Psychiatry, Van 65200, Turkey. E-mail addresses: [email protected] (O. Özdemir), [email protected] (M. Boysan), [email protected] (P.G. Özdemir), [email protected] (S. Coşkun), [email protected] (H. Özcan), [email protected] (E. Yılmaz), [email protected] (E. Atilla). http://dx.doi.org/10.1016/j.comppsych.2014.09.014 0010-440X/© 2014 Elsevier Inc. All rights reserved.

parents suffering from psychiatric disorders develop affective problems that persist into adulthood, particularly bipolar disorders and substance misuse [1]. An extensive parental psychopathology research has generally focused on possible influences of maternal emotional difficulties on child development, whilst paternal psychiatric disorders have been demonstrated to exert crucial direct and indirect adverse influences on child's psychological development, even though data concerning the effects of paternal pathology on the offspring relatively lag behind maternal investigations [2]. In a prospective longitudinal community study of parental major depression as a risk factor of psychopathology in offspring, Lieb et al [3] tied parental psychiatric disorders to an increased risk of affected offspring in which

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O. Özdemir et al. / Comprehensive Psychiatry xx (2014) xxx–xxx

odds ratios were virtually in parallel with Birmaher et al. [4] and differences in estimated risks of maternal and paternal psychopathology for intergenerational transmission to the offspring were not substantial. Children of bipolar parents have a virtually 40% risk of a major depressive episode by the age of 20 [5]. Over 20 years, accumulating evidence from family studies strongly suggested that affective disorders have familial underpinnings and having a proband with either major depressive disorder or bipolar disorder puts offspring to a major risk for affective disorders [6,7]. Adjusting for demographic variables, offspring of parents with bipolar disorder had thirteen-fold increased risk for bipolar spectrum disorders and five-fold greater risk for any mood disorders, as well as two-fold higher risk for anxiety spectrum disorders. More offspring of those whose both parents had bipolar disorder more prevalently endorsed bipolar spectrum disorders and more than 75% of these offspring had a mood episode by the age of 12 years [4]. Familiality in affective disorders was the most potent predictor of mood disorders among risk factors [8]. Anxiety disorders in parents are not rare in population and offspring of these parents with anxiety disorders are at a greater risk for anxiety problems [9]. In comparison of rates of anxiety disorders in the offspring, a meta-analysis concerning intergenerational continuity of parental anxiety disorders demonstrated that offspring of non-affected controls significantly differentiated from affected cases in terms of lower rates of anxiety disorders. Evidence for specificity of transmission is mixed and particularly parental anxiety disorders were likely to confer risk for a scope of disorders in the offspring [10]. Comorbid anxiety or mood disorders in parents put the offspring at an increased risk of anxiety disorders, as was the case for having more than one affected parents with anxiety disorders [11,12]. Transmission of adversity is not unidirectional and intergenerational transmission of psychopathology may probably pursue various pathways through miscellaneous developmental mechanisms. Gene–environment interplay in psychiatric disorders has long been a matter of increasing interest in transmission of psychopathology. Causal relations between genetic susceptibility and environmental effects seem to be reciprocally interrelated rather than linear interaction, whilst scholars have also been put forward several forms of gene–environment interplay [13]. Shanahan and Hofer [14] draw on empirical literature to suggest four models of gene– environment interplay: social context can set in motion some genetic inclinations, the context may serve as a precipitator of the effect of genetic influences, environmental contexts may compensate for a genetic diathesis, and finally, there may be environmental limitations to reduce the role of genetic influence, thereby constraining life opportunities and choices. Bronfenbrenner and Ceci [15] placed a great emphasis on advantageous proximal environments which have direct influences on the individual that would increase the genetic effect. Keeping in mind that consideration of a true clear-cut for the possible influences of genes and environments appears like an oversimplification. Separating genetic components of

familial loading and investigating solely interfamily mechanisms in terms of shared environment presents some difficulties and yet risk estimation from family loading seems to be complicated. Even genetic loading for risk of psychopathology may considerably vary within affected individuals [16]. These effects are not separate, while variations in heritability arise from contextual factors are considerable, as well as the process is bidirectional in nature in a broad range of multifactorial conditions [13]. An important aspect of expanding the elucidation of effects of parental emotional dysfunction is to examine the complex relations between parental symptomatology, child socio-emotional development and family functioning. The developmental process is multifaceted and central to effects of parental psychopathology on children's capacity to both resilience and vulnerability in the face of adversity. Models of familial transmission of psychopathology underscore the role of psychopathology in each parent to be influential in the developmental trajectory through epigenesis, development of maladaptive mechanisms leading to self-dysregulation, and exposure to contextual stressors engendering from parental emotional disturbance as well as marital discord and conflict [2,17]. Mental health problems may interfere with optimal parenting skills and result in risky family environments characterized by conflict and aggression, and by relations that are cold, dismissive and neglectful [18]. Mothers with depressive disorders spent substantially shorter time with their children, were less able to provide daily routines, were more irritated; and were more likely to physically or verbally aggress their children [19]. Depressive parents were also more negative, unsupportive and intrusive with their children [20]. Children living in risky family systems may probably be more apprehended with their family stability, commensurate with exposure to marital conflict that may mediate the linkages between parental psychopathology and child adjustment problems [21]. It is apparent that rates of transmission of parental psychiatric disorders to children are substantial and affected parents pose risk to the offspring probably independent from longevity or severity of parental psychopathology [22]. A more accurate elucidation of the process of intergenerational transmission of psychopathology is important for many reasons but at the outset it will provide a more profound understanding of the pathways to a range of psychological disturbances in children. It appears that an extensive research involving transmission of psychiatric disorders has focused on possible influences of mental problems in first-degree relatives on children and potential pathways in intergenerational transmission of disorder from caregivers or core family members. However, transmission of disorders from second-degree relatives has received almost no attention in the empirical literature. In this study, an advanced method of latent class analysis algorithm was applied to examine the patterns of associations between presence of psychopathology in relatives of case probands and categories of disorders in a relatively representative sample of psychiatric patients.


This investigation of transmission characteristics of psychiatric disorders also involved prevalence and possible influences of psychopathology among second degree relatives of patients which may have important implications in understanding of intergenerational transmission mechanisms.

2. Method 2.1. Procedure This is a clinical cohort study conducted in the Yuzuncu Yil University School of Medicine Department of Psychiatry, Dicle University School of Medicine, Van Education and Research Hospital, and Ipekyolu Public Hospital. The sample was comprised of 350 hospitalized psychiatric inpatients from the centers mentioned above between April 2011 and September 2013. The psychiatric evaluation and diagnosis were made after consensus of two experienced psychiatrist by means of Diagnostic Manuals of Mental Disorders (DSM IV-TR) and Structured Clinical Interview for Axis I Disorder (SCID-I)[23]. All patients underwent a detailed clinical evaluation including physical, neurological and laboratory examination in order to exclude primary medical conditions. Family history of psychiatric disorder was taken from patients and their companions. Most of the relatives with various psychiatric diagnoses were also in our clinical follow-up as patients. Also we reached the other relatives of the primary study group with psychiatric diagnosis by phone and by the Medical Knowledge System of our country databank. The study protocol was approved by Yüzüncü yil University Ethics Committee and each subject gave informed consent. Inclusion criteria were being above the age of 16 and having a psychiatric diagnosis of Axis I disorders including depressive disorders, bipolar disorders, schizophrenia, obsessive–compulsive disorder, panic disorder, generalized anxiety disorder, somatoform disorder, and a psychiatric disorder not otherwise specified. Exclusion criteria were any psychiatric diagnosis due to a primary medical condition, alcoholism and/or drug abuse other than nicotine, pregnancy, intellectual disability and neurological disorders. Our primary aim of this study was to explore familial transmission patterns of psychiatric disorders. Secondary aim was to investigate the relations between kinship and categories of axis I disorders. 2.2. Statistical analysis The latent structure of patterns of family psychopathology among the psychiatric sample of this study was examined by applying latent class analysis (LCA) to the data involving frequency of affected first- and second degree relatives of case probands with axis I disorders along with categories of psychopathology among psychiatric probands. LCA assumes that associations among individual categorical variables are due to an underlying latent structure in which respondents with similar features can be grouped into homogeneous subsets.

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LCA is used to determine subsets of cases predicated in observed patterns of traits. Examination of underlying latent structure is implemented through deriving conditional probabilities that indicate the probability of a manifest variable to place in a given latent subset. The goal of the analysis is to determine the optimal number of latent classes that adequately represents associations among manifest variables, starting with a 2-class model and fitting successive models with increasing number of classes. Goodness of fit statistics of the Akaike Information Criterion (AIC) and Adjusted Bayesian Criterion (ABIC) were used to select the optimal number of classes. We compared successive models by these two criteria, global measures of goodness of fit that weight the fit and parsimony of the model. The lower the goodness of fit statistics, the better is the model [24]. When the number of observed variables is large, the inflation of likelihood statistics violates the theoretical assumption of χ 2 distribution. Therefore, we bootstrapped 1000 times in each step of the analysis and used an α level of p b .05. The statistical software Mplus 4.1 was used for the analyses [25]. In the further analyses, to investigate differences between latent subgroups, we used analysis of variance to compare age, years of education, number of siblings, age-at-onset and duration of disorders across latent classes. We regressed posterior latent class membership probability of each latent class onto sex, presence of a stressor, type of onset (acute vs insidious), presence of family psychopathology, prevalence rates of male and female relatives with a psychiatric disorder to understand relations of these clinical variables with latent homogeneous subsets of psychiatric patients. Furthermore, we also run separate logistic regression of posterior latent class membership probability for each subgroup on individual category of psychiatric disorders reported for case probands and for relatives of case probands to untangle patterns of psychopathology among probands, and first- and seconddegree relatives. 3. Results 3.1. Participants Overall, 350 hospitalized inpatients with axis-I psychiatric disorders participated in the study. As shown in Table 1, the mean age of the sample was 34.16 years (SD ± 12.03) and age ranged between 16 and 77. 51.43% of the participants were male, 61.14% reported acute onset of the disorder, 42.82% had at least one stressor prior to the onset, and 82.57% reported psychopathology in either first-degree family members or second-degree relatives. The average years of education was 8.17 (SD ± 4.46), mean number of siblings was 6.34 (SD ± 3.21), mean age-at-onset of the disorders was 23.83 (SD ± 9.45), and mean duration of the disorders was 10.34 (SD ± 9.49). Virtually one third of the participants (36.57%) had bipolar disorders, 16% had obsessive–compulsive disorder, 14% had schizophrenia, 12.57% had depressive disorders, 8.29% had panic disorders,

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Table 1 Demographic and clinical characteristics of the sample (N = 350). Age Gender Education (yrs) Job status

(Mean, SD) Male (N, %) (Mean, SD) Student (N, %) Employee (N, %) Housewife (N, %) Unemployed (N, %) Retired (N, %) Number of siblings (Mean, SD) Psychiatric diagnosis Depressive Disorders (N, %) of patients Bipolar Disorders (N, %) Schizophrenia (N, %) Obsessive–Compulsive Disorder (N, %) Panic Disorder (N, %) Generalized Anxiety Disorder (N, %) Somatoform Disorder (N, %) Disorders Not Otherwise Specified (N, %) Type of onset (Acute Acute (N, %) vs Insidious) Presence of a stressor (N, %) Presence of family (N, %) psychopathology Age at onset of the (Mean, SD) disorder Duration of the (Mean, SD) disorder

34.16 180 8.21 41 118 126 57 8 6.34 44 128 49 56

12.03 51.43 4.46 11.71 33.71 36.00 16.29 2.29 3.21 12.57 36.57 14.00 16.00

29 21 2 21

8.29 6.00 0.57 6.00

214

61.14

150 289

42.86 82.57

23.83

9.45

10.34

9.49

6% had generalized anxiety disorder, 6% had some type of psychiatric disorders not otherwise specified, and 0.57% had somatoform disorder. 3.2. Latent class analysis The LCA models were fit to a data matrix including nosological classification of axis-I affected probands and endorsement of psychiatric disorders among first- and second-degree relatives of these probands. Model fit criteria, described in the methods section, indicated that a 4-class model was superior to either a 3-class or a 2-model as well as a 5-class model. Table 2 presents the goodness of fit indexes for 2- to 5-class models. 3.3. Conditional probabilities for family patterns of psychopathology The proportions and conditional probabilities of relatives of patients with a psychiatric diagnosis, interpreted as the probability of a trait to take place in a latent homogeneous subset and significance of P values for the conditional probabilities are presented in Table 3. Probands subsumed under latent class 1 (LC1; 40.3% of the sample) exhibited a paternal characteristic of psychopathology. We observed statistically significant conditional probabilities for psychiatric disorders among fathers, paternal uncle, paternal aunts, paternal uncles' children as well as sisters and cousins of those patients classified in this group. Patients allocated in latent class 2 (LC2; 15.7% of the sample) also exhibited a

paternal pattern of psychopathology that frequency of psychiatric disorders was greater among fathers, brothers, paternal uncles' children and cousins but sisters. Of four family patterns of psychiatric transmission had the patients in either LC1 or LC2 no maternal psychopathology. Psychiatric patients in latent class 3 (LC3; 21.7% of the sample) reported severe emotional disturbances among their mothers, brothers, maternal uncles, maternal aunts, maternal uncles' children and maternal aunts' children. Psychiatric probands classified in latent class 4 (LC4; 22.3% of the sample) exhibited a family pattern of core family psychopathology in which pervasiveness of psychopathology was significantly greater among first-degree relatives such as mothers, fathers, sisters, and brothers of these patients with the exception of paternal uncles, a second-degree relative. 3.4. Logistic regressions of posterior membership probability of each latent class on psychiatric diagnoses of probands and relatives As described in the Methods section, categories of psychiatric diagnoses were put as an unordered categorical variable into the latent class models that the LCA did not generate the conditional probabilities for the probands' diagnostic categories. Therefore, posterior conditional probability of each latent class in turn regressed on axis I psychiatric disorders from which the participants were suffering. Table 4 reports proportions of psychiatric diagnoses of probands by latent classes, and ODDS ratios with 95% confidence intervals. Posterior latent class membership probabilities of psychiatric probands in the LC1 exhibited significant linkage to diagnosis of schizophrenia (ODDS = 2.11, 95% CI = 1.05–4.25) and to psychiatric disorders not otherwise specified (ODDS = 15.06, 95% CI = 3.85–58.91). Psychiatric patients in LC2 were more likely to have depressive disorders and bipolar disorders (respectively, ODDS = 3.07, 95% CI = 1.41–6.67 for depressive disorders, and ODDS = 1.77, 95% CI = 1.04–3.33 for bipolar disorders); on the contrary, patients who were in LC2 were less likely to have obsessive–compulsive disorder and panic disorder (ODDS = 0.27, 95% CI = 0.08–0.95 for obsessive–compulsive disorders, and ODDS = 0.87, 95% CI = 0.27–2.82 for panic disorders). Psychiatric probands in LC3 who had a maternal pattern intergenerational transmission of psychiatric disorders had a preponderance of generalized anxiety disorder (ODDS = 12.50, 95% CI = 4.21–37.13) over other categories of psychiatric diagnoses, while psychiatric patients with maternal pattern of family psychopathology were less prone to have depressive disorders (ODDS = 0.36, 95% CI = 0.13–0.94) and panic disorder (ODDS = 0.15, 95% CI = 0.03–0.75) as compared to other latent classes. Of note were the probands in LC4 at higher risk of anxiety disorders, particularly panic disorder (ODDS = 2.37, 95% CI = 1.18–4.76) and generalized anxiety disorder (ODDS = 2.55, 95% CI = 1.04– 6.23); whereas the patients were at a significantly lower risk for bipolar disorders (ODDS = 0.39, 95% CI = 0.20–0.75). As can be seen in Table 5, we explored the associations between posterior probabilities of latent class membership of


each latent class and categories of psychiatric diagnoses in the first- and second degree relatives of psychiatric patients by running separate logistic regression models for each latent class. In total, we ran thirty-three logistic regressions. Logistic risk analyses showed that depressive disorders and generalized anxiety disorder were less likely to be observed among relatives of patients in LC1 (ODDS = 0.41, 95% CI = 0.06– 0.35 for depressive disorders, and ODDS = 0.12, 95% CI = 0.02–0.75 for generalized anxiety disorder). Nevertheless, first- and second-degree relatives of these probands were more pervasively suffering from schizophrenia (ODDS = 1.95, 95% CI = 01.06–3.60). Depressive disorders and bipolar disorders were prevalent and significantly associated with posterior group membership probabilities among relatives of patients in LC2 (ODDS = 4.77, 95% CI = 2.38–9.58 for depressive disorders, and ODDS = 2.16, 95% CI = 1.11– 4.20 for bipolar disorders). None of the axis I psychiatric disorders could be specified in terms of associations with posterior membership probabilities derived from the LCA for LC3. Relatives of psychiatric patients classified in LC4 exhibited a variation in psychiatric diagnoses that depressive disorders (ODDS = 2.05, 95% CI = 1.02–4.14), obsessive compulsive disorders (ODDS = 4.29, 95% CI = 2.15–8.57), panic disorder (ODDS = 4.24, 95% CI = 1.69–10.65), generalized anxiety disorder (ODDS = 3.14, 95% CI = 1.01– 9.82), and psychiatric disorders not otherwise specified (ODDS = 2.55, 95% CI = 1.03–6.98) were considerable in the relatives of these probands, but schizophrenia was less likely to be reported (ODDS = 0.33, 95% CI = 0.13–0.84).

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the clinical variables. Logistic regressions of posterior latent class membership probabilities on dependent variables demonstrated that four latent profiles of family psychopathology did not differentiate in terms of presence of a stressor at the time of onset and type of onset of the disorder. Patients subsumed under LC1 were less likely to have a psychiatric disorder among first- or second degree relatives (ODDS = 0.15, 95% CI = 0.08–0.31) and reported much less cases of psychopathology among their female relatives (ODDS = 0.15, 95% CI = 0.09–0.26). On the contrary, all psychiatric probands in LC2 in which participants exhibited a paternal kinship predominance had at least a relative suffering from some type of a psychiatric disorder and at least a male relative with severe emotional disturbance. Being in LC2 was negatively associated with having a female relative suffering from psychopathology. Maternal kinship psychopathology subset of psychiatric patients (LC3) had greater prevalence of emotional disorders among their female relatives (ODDS = 1.98, 95% CI = 1.14–3.43); contrarily, male relatives with psychopathology were less likely to be reported (ODDS = 0.49, 95% CI = 0.28–0.84). All patients with a pattern of core family psychopathology (LC4) had at least one relative suffering from severe emotional problems and all had at least one female relative with a psychiatric disorder. Most of the probands in LC4 were also females (ODDS = 1.97, 95% CI = 1.10–3.54). Patients of those who were grouped in LC4 had fewer male relatives with a psychiatric disorder than other latent subgroups of probands (ODDS = 0.50, 95% CI = 0.28–0.89) (Table 7).

3.5. ANOVA comparisons of demographics across latent classes To explore the differences in age, years of education, number of siblings, age at onset of the disorder and duration of disorder between latent classes, we made comparisons of these variables by utilizing one-way analysis of variance. There was no statistically significant difference across latent classes with the exception of age of onset of the psychiatric disorder (F(3, 346) = 2.823; p b .05), in that maternal kinship psychopathology group (LC3) reported significantly lower mean age-at-onset relative to patients with paternal kinship psychopathology with schizophrenia in LC1 (p b .05), whilst patients in either LC2 or LC4 did not reveal statistically significant differentiation from both LC1 and LC3. Findings are presented in Table 6. 3.6. Logistic regressions of posterior membership probabilities on clinical characteristics To investigate the associations of latent class membership with sex, presence of a stressor at the time of onset, type of onset whether it is acute or insidious, presence of family psychopathology, frequency of patients with a male relative(s) with a psychiatric disorder, and frequency patients with a female relative(s) with a psychiatric disorder, we regressed posterior latent class membership probabilities derived from LCA for each latent subset onto

4. Discussion Mixture modeling techniques, such as latent class analysis (LCA) are a type of cross-sectional mixture analysis involving both categorical and continuous latent variables which is used to identify unobserved heterogeneity in a population. In latent class models, a latent variable is measured with a number of observed response variables and the characteristics of a latent pattern of relations are put forth in a way that groups the sample of subjects into homogeneous subsets. LCA is becoming more commonly used in behavioral and social science research [26]. In the current study, we identified homogeneous subgroups of psychiatric patients by using latent class algorithm due to the connections between the presence of a psychiatric disorder among first- and second-degree relatives of the patients and the types of psychiatric categories that patients were diagnosed with. The latent class analysis of data including connections between family psychopathology with axis I psychiatric disorders indicated a best fit for a four-class model. According to the latent classification, psychiatric patients in LC1 and LC2 revealed a pattern of paternal kinship transmission of risk for psychiatric disorders. These two latent homogeneous subsets of psychiatric patients had a similar family pattern of psychiatric disorders; whereas these psychiatric probands differentiated in psychiatric diagnoses.

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Patients in LC1 were more likely to have schizophrenia while depressive and bipolar disorders were more prevalent in LC2. Subjects subsumed under LC3 showed a pattern of primarily maternal side psychiatric disorders and maternal pattern of psychopathology was significantly associated with generalized anxiety disorder. LC4 was primarily a core family pathology group and obsessive–compulsive disorder and panic disorders were considerably higher among these patients. Of four family patterns of psychopathology, LC1 was the largest group (n = 141, 40.3%). Paternal psychopathology was prevalent in this homogeneous subset of patients as well as paternal kinship of psychiatric disorders such as paternal uncle, paternal aunt, paternal uncle–child as well as cousins. Prevalence rates of psychopathology among patient's sons were the highest among four latent patterns of familial psychiatric disorders. On the contrary, none of the probands in this group reported maternal psychopathology. Number of affected female relatives was significantly lower relative to patients in either LC3 that exhibited a maternal family pattern or LC4 that exhibited a core family pattern of psychopathology. Schizophrenia and psychiatric disorders not otherwise specified were considerable in this latent subset of probands. Patients in LC1 reported relatively lower levels of family psychopathology versus either LC2 or LC4. However, it seems a specifity of intergenerational transmission of psychopathology that, similar to probands, schizophrenia was substantial among first- and second-degree relatives of these probands. Schizophrenia is a chronic, severe, and debilitating condition affecting around 1% of the population throughout lifetime. The risk for schizophrenia associated with familial aggregation has long been recognizant. In a representative data of gender- and age-matched cases with controls, parents and siblings of all subjects, a broad range of psychiatric disorders in first-degree family members of case probands was found to be posing risk for the disorder [27]. Familial factors not only influence illness susceptibility but also clinical presentation of the disorder [28]. Family history is important in the heterogeneity of clinical presentation of schizophrenia tied to sex differences and age-at-onset of the disorder. A meta-analytic investigation of the relations of familial aggregation with the clinical presentations of the disorder put forth that familial loading was predictive of a younger age-at onset and negative symptoms of the disorder. Sex differences in the prevalence and prognosis of the disorder have been widely addressed, i.e., that males have a higher risk and worse prognosis [29]. A comprehensive review provided compelling evidence that sex differences in clinical presentation disappeared in cases with family history relative to the cases without a family history. Negative symptoms were also considerable for the patients with family history; specifically, the differentiation between familial and non-familial cases was due partially to male predominance in familial group of patients [30]. The crucial role of familial loading in schizophrenia has been tied to transmission of genetic material [31], tentative influence of familiality in

brain abnormalities [32,33], and increased emotional stress by product of hyperresponsiveness of family members to adverse life events and high levels of expressed emotions [34]. Although in our study such data including the potential mechanisms of transmission were lacking, we could not find significant linkages of clinical presentations of the disorder with the exception of being less likely to have a familial psychopathology and to have a female relative with a psychiatric disorder to the family pattern of schizophrenia. Differentiation of maternal and paternal effects for the disorder has received less attention in extensive research of schizophrenia. In an early study of maternal and paternal abnormality in schizophrenic probands with affected relatives, based on the Slater [35] computational model, were found to have a dominance in genetic disposition, but manic–depressive probands [36]. However, this finding could not be replicated in a further study that the distribution of unilateral to bilateral pairs of affected relatives did not deviate significantly from expected polygenic inheritance [37]. The connection between paternal age and onset of disorder has been widely focused on that both advanced paternal age and younger paternal age at the time of birth were suggested to be a risk factor for the offspring [38]. Given the findings of more recent investigations concerning parental-of-origin sex effects for the disorder, in line with our findings, paternal side affected parents seem to exert a more crucial influence versus maternal side affected parents on intergenerational transmission of the disorder [39–41]; nevertheless research on parental-of-origin sex effects has not been conclusive and warrants further systematic investigations [42]. LC2 constituted relatively a small proportion of the sample (n = 55; 15.71%). Family pattern of this subset of patients was virtually isomorphic to LC1 that paternal psychopathology was substantial with a lack of maternal emotional disturbance as well. In this group of psychiatric probands paternal kinship pattern was relatively weak versus LC1 that the participants reported a high frequency of emotional disorders only among paternal uncle children and cousins. Psychiatric diagnoses among brothers of these patients were greater relative to LC1, but sisters while the case was exactly inverse for the LC1. As was the case in LC1, the number of affected female relatives was significantly lower in LC2 relative to patients in either LC3 or LC4. All of these probands reported family history of psychopathology and had at least one male psychiatric case among their first- or second-degree relatives. Depressive disorders and bipolar disorders were more common in this homogenous subset than other latent class groups while obsessive– compulsive disorder and panic disorder were less likely to be observed in this group of patients. In agreement with the case probands, depressive and bipolar disorders were more prevalent among first- or second-degree relatives. Genetic underpinnings of the intergenerational transmission of affective disorders are well documented [7,43], even though vulnerability in genetic architecture is not the mere


mechanism of transmission that environment–nature interplay and compromise in quality of parenting due to parental emotional disruptions may also result in vulnerability to internalizing problems in children [44–46]. Offspring of depressed parents have approximately three-fold higher risk of an episode of depression throughout lifetime [3,47]. To date, several lines of research investigating effects of parental depression have suggested that depression in both mothers and fathers put children at high disadvantage of emotional problems, even though maternal depression was more strongly tied to adverse outcomes versus paternal depression [48–54]. A relatively small number of studies including effects of maternal and paternal psychopathology have suggested comparable effects of depression in both parental sides through parenting behaviors [55–60]. Depression in fathers in the postnatal period was more likely to predict incremental risk of couple disharmony and temperament difficulties in the infants [61]. Paternal depression was predictive of children's depressive symptomatology when controlling for mother's current depression [52,62], alongside with mother's past depression [63], and was tied to father– child conflict and marital discord [63]. Studies generally supported the moderating role of paternal depression between maternal depression and children's diagnosis of depressive disorder [64,65] as well as children's maladjustment [48]. Turning to bipolar disorders, positive family history is the most potent determinant which has a strong genetic contribution to the disorder [7,66]. Evidence for genetic component of bipolar disorders derives from heritability estimates ranging from 79% to 83% [67,68]. Meta-analyses of the data including first degree relatives of bipolar disorders reported virtually five- to fourteen-fold risk of disorder in first degree relatives of two probands with bipolar disorders [4,8,69,70]. The data concerning the linkages parent-of-origin sex to affected children's sex are inconclusive in mood disorders. Nomura et al. [71] reported strong relations between paternal and daughter depressive disorder, whilst the case was similar for maternal and sons' depressive symptomatology. Strong linkages between paternal bipolar disorder and affected offspring were found in a representative sample of affective disorders [72]. Grigoroiu-Serbanescu et al. [73] submitted a model of transmission to the next generation covering both paternal and maternal sides that paternal and maternal sides differ in terms of transmission mode of the bipolar disorder. It was suggested that Mendelian major gene model in paternal families and multifactorial model in maternal families are present. On the contrary, Currier et al. [74] reported two times greater risk of maternal transmission of mood disorders compared to paternal transmission. Many other studies could not detect a substantial influence of parental-of-origin sex on sex of affected offspring [3,75–77]. Our findings were compatible with the paternal model of transmission of mood disorders that family pattern of paternal side psychopathology was considerable in probands with depressive disorders and bipolar disorders. Even we observed a specifity of the transmission of the mood disorders that

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Table 2 Goodness of fit statistics for latent classes. Number of Latent Classes

Akaike Information Criterion

Adjusted Bayesian Information Criterion

Latent Class 2 Latent Class 3 Latent Class 4 a Latent Class 5

4283.634 4262.990 4236.403 4244.850

4319.969 4317.836 4309.759 4336.717

a

Bold type indicates the selected best fit model.

depressive and bipolar disorders had a more prevalence among first- and second-degree relatives of these cases. At one extreme, irrespective of some prior findings [71–73], differences in sex of the case probands were not substantial; at another extreme was the fact that the proportion of male affected relatives was greater versus other three family patterns of psychopathology. Maternal kinship psychopathology was the most remarkable feature of probands in LC3, on the other hand, there were no paternal psychiatric disorders. 21.7% of the sample were incorporated into this latent homogeneous subgroup in LCA. High prevalence rates of psychiatric disorders among mothers and second-degree relatives from mother side such as, maternal uncle, maternal aunt, maternal uncle's child, maternal aunt's child were meaningful and determinative of this pattern of familiality. Brothers of these case probands were also at high risk of having a severe emotional problem. Most of the probands in LC3 reported having at least one female psychiatric case among their first- or second-degree relatives and membership of LC3 was inversely associated with having a male case of psychopathology among relatives. Patients in this group had earlier age-at-onset of disorders relative to patients in LC1. These patients reported relatively lower levels of history of psychopathology among first- and second degree relatives. Generalized anxiety disorder was substantial among these psychiatric probands, while depressive disorders and panic disorder were inversely associated with individual membership probabilities of the participants subsumed under LC3. Familiality in the LC3 was not prominent in this homogeneous subset and none of the psychiatric categories was crystallized among first- or second degree relatives of these patients. Current findings for the third latent subset of probands almost entirely agreed to literature concerning maternal pathology with anxiety disorders that we detected a family pattern of generalized anxiety disorder characterized by maternal side psychopathology but paternal emotional disorders. There has been an extensive focus in various strands of research on possible outcomes of maternal depression in children's mental health; while maternal anxiety disorders have received little attention. Although genetic susceptibility to anxiety disorders is relatively weak when compared to mood disorders, particularly bipolar disorders, familial aggregation in anxiety disorders has been well-documented [10,78]. Early age-at-onset of a psychiatric disorder is suggested to be a surrogate indicator of familiality

8


Table 3 Four latent patterns of family psychopathology among psychiatric patients with conditional probabilities and frequencies of first- and second-degree relatives with psychopathology (N = 350). Latent Class 1 (N = 141)

Mother Father Sister Sister 2 Brother Brother 2 Paternal Uncle Maternal Uncle Paternal Aunt Maternal Aunt Daughter Son Grand Mothers Grand Fathers Paternal Uncle Child Maternal Uncle Child Paternal Aunt Child Maternal Aunt Child Cousin

Latent Class 2 (N = 55)



N

%

Π

SE

Π/SE

Π

SE

Π/SE

Π

SE

Π/SE

Π

SE

Π/SE

53 30 90 13 85 19 21 23 19 21 10 18 8 3 27 14 5 8 10

15.14 8.57 25.71 3.71 24.29 5.43 6.00 6.57 5.43 6.00 2.86 5.14 2.29 0.86 7.71 4.00 1.43 2.29 2.86

0.000 0.141 0.153 0.000 0.000 0.000 0.124 0.016 0.119 0.000 0.022 0.103 0.016 0.012 0.171 0.000 0.015 0.012 0.037

⁎⁎⁎ 0.031 0.044 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 0.031 0.015 0.029 ⁎⁎⁎ 0.017 0.028 0.013 0.010 0.034 ⁎⁎⁎ 0.010 0.011 0.016

⁎⁎⁎ 4.588 3.478 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 4.018 1.046 4.163 ⁎⁎⁎ 1.314 3.726 1.192 1.184 5.067 ⁎⁎⁎ 1.423 1.055 2.302

0.000 0.102 0.035 0.000 1.000 0.296 0.000 0.000 0.000 0.030 0.057 0.000 0.000 0.000 0.078 0.012 0.039 0.011 0.098

⁎⁎⁎ 0.045 0.033 ⁎⁎⁎ ⁎⁎⁎ 0.068 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 0.026 0.033 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 0.038 0.021 0.028 0.021 0.042

⁎⁎⁎ 2.298 1.055 ⁎⁎⁎ ⁎⁎⁎ 4.378 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 1.138 1.739 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 2.062 0.575 1.420 0.547 2.345

0.414 0.000 0.000 0.000 0.132 0.011 0.045 0.156 0.000 0.181 0.043 0.043 0.031 0.014 0.000 0.139 0.000 0.061 0.000

0.055 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 0.044 0.011 0.025 0.040 ⁎⁎⁎ 0.042 0.027 0.026 0.020 0.014 ⁎⁎⁎ 0.036 ⁎⁎⁎ 0.027 ⁎⁎⁎

7.539 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 3.018 0.993 1.765 3.863 ⁎⁎⁎ 4.342 1.608 1.664 1.509 1.035 ⁎⁎⁎ 3.865 ⁎⁎⁎ 2.212 ⁎⁎⁎

0.193 0.086 1.000 0.193 0.314 0.042 0.000 0.086 0.044 0.030 0.000 0.000 0.043 0.000 0.000 0.000 0.015 0.000 0.000

0.050 0.037 ⁎⁎⁎ 0.051 0.064 0.026 ⁎⁎⁎ 0.035 0.027 0.021 ⁎⁎⁎ ⁎⁎⁎ 0.025 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 0.015 ⁎⁎⁎ ⁎⁎⁎

3.814 2.341 ⁎⁎⁎ 3.791 4.884 1.597 ⁎⁎⁎ 2.472 1.605 1.418 ⁎⁎⁎ ⁎⁎⁎ 1.698 ⁎⁎⁎ ⁎⁎⁎ ⁎⁎⁎ 1.003 ⁎⁎⁎ ⁎⁎⁎

Π: Conditional probability; SE: standard error based on 1000 bootstrap replications. Statistics of manifest variables with significant P values derived from Π/SE fraction denoting membership of the relevant latent class were demonstrated with bold figures (p b .05). Eight probands (2.3%) had psychopathology in three siblings and 3 probands (0.9%) had psychopathology in four siblings in their family members. Since the proportions were small we excluded these case siblings from the analysis. ⁎⁎⁎ Standard errors were not computed when boundary values (i.e., either 0.0 or 1.0 conditional probability values) occurred.

or genetic vulnerability in schizophrenia [79,80]; at another extreme associations between family loading and age-atonset may significantly vary in anxiety disorders [81]. In our analysis we found that probands in LC3 reported an earlier age-at-onset than probands in LC1 whilst the familiality in both groups was relatively weak as compared to either paternal mood disorders sub-group (LC2) or core family psychopathology sub-group. Anxious parents versus nonanxious parents interact with their children differently in a fashion of being more withdrawn, of disengagement or of less productive engagement in tasks with their children [82]. In a longitudinal investigation of parent–child interaction of anxious mothers, Harvison et al. [83] submitted that maternal affectionless control mediated the child anxiety in the face of anxiety provoking situations. Considering dyadic relationship between mothers and infants, aged 11–14 months in the postnatal period, mothers with high trait anxiety versus low anxious mothers were more likely to show less sensitive responsibility and reduced emotional tone [84]. A tendency to worry/rumination in mothers with generalized anxiety disorder was strongly tied to interference with maternal responsiveness to infant vocalization as compared to healthy controls, even it was the case for mothers with major depressive disorder to a lesser extent [85]. A vast body of research has given credence to premise that maternal anxiety disorders are of monumental importance in children's later onset of emotional disturbances. These relations seem to be mediated by some parental behaviors including inflated control and irresponsiveness in mother–child interaction

rather than the genetic underpinnings of the anxiety disorders [86–88], in which conflictual parental relations persist as maladaptive internally working models into adulthood in the form of anxiety disorders, particularly generalized anxiety disorder [89,90]. The transmission process in anxiety disorders is seemingly not confinable to the interaction between child and mother in terms of parental attitudes rather maladaptive outcomes of maternal anxiety engender as early as prenatal period through neurobiological development to generate deficits in the further emotional regulation systems of the infant. Possible influences of maternal anxiety begin in the prenatal period that maternal anxiety was immensely associated with less optimal neurobiological development of infant and persist into late periods in the infancy period [91] but the associations were no longer substantial with the paternal anxiety in the postnatal period [92]. Patients in LC4 constituted virtually one fourth of the sample (22.3%). Core family system psychopathology was remarkable in this homogeneous subgroup of probands. Parental psychiatric disorders in both mothers and fathers of these probands were substantial as well as probands' sisters and brothers. It is worth noting that familial loading of psychopathology was generally among first-degree relatives of patients with the exception of maternal uncle that all patients in this group reported family history of psychopathology. All of these patients also reported having a female relative with a psychiatric disorder; whereas these probands were less likely to have a male relative as compared to other

1.567(0.703–3.493) 0.385(0.197–0.753) 0.424(0.154–1.170) 2.365(1.175–4.763) 2.545(1.040–6.226) 1.910(0.657–5.553) 5.457(0.258–115.128) 0.432(0.094–1.990) 15.38 25.64 8.97 24.36 14.10 7.69 1.28 2.56 12 20 7 19 11 6 1 2 0.358(0.130–0.984) 1.195(0.688–2.076) 1.151(0.540–2.454) 1.686(0.847–3.353) 0.148(0.029–0.751) 12.497(4.207–37.126) ⁎⁎⁎(0.000–0.000) ⁎⁎⁎(0.000–0.000) 5.26 40.79 13.16 18.42 2.63 19.74 0.00 0.00 Bold type indicates statistical significance at p b .05. ⁎⁎⁎ Standard errors and confidence intervals were not computed when boundary values occurred.

4 31 10 14 2 15 0 0 3.068(1.412–6.669) 1.771(1.042–3.327) 0.507(0.171–1.499) 0.273(0.079–0.950) 0.866(0.266–2.818) ⁎⁎⁎(0.000–0.000) 7.234(0.375–139.604) 0.567(0.118–2.738) 23.64 47.27 9.09 7.27 7.27 0.00 1.82 3.64 13 26 5 4 4 0 1 2 0.575 (0.262–1.265) 1.125(0.674–1.878) 2.109(1.046–4.252) 0.522(0.254–1.070) 1.376(0.570–3.326) ⁎⁎⁎(0.000–0.000) ⁎⁎⁎(0.000–0.000) 15.059(3.849–58.914) 10.64 36.17 19.15 13.48 8.51 0.00 0.00 12.06 15 51 27 19 12 0 0 17 Depressive Disorders Bipolar Disorders Schizophrenia Obsessive–compulsive Disorder Panic Disorder Generalized Anxiety Disorder Somatoform Disorder Disorders not Otherwise Specified

ODDS (95% CI) % ODDS (95% CI)


% N ODDS (95% CI)


% N ODDS (95% CI)


% N

Table 4 Proportions and logistic regression of posterior latent class probabilities on categories of psychiatric disorders among probands by latent classes (N = 350).

N



9

three family patterns of psychopathology. Obsessive compulsive disorder and panic disorder were prevalent among probands with core family pattern of pathology. Intriguingly, LCA detected a variation in psychiatric disorders among relatives of these probands. Depressive disorders, obsessive– compulsive disorder, panic disorder, generalized disorder and psychiatric disorders not otherwise specified were observed among first- and second-degree relatives of the probands subsumed in this sub-group. That psychopathology in both mother and father strongly links to internalizing and externalizing problems in children has been well-established. Maternal and paternal depressive symptomology was associated with marital dissatisfaction and conflict, linked to deficits in parenting including less parental warmth and more psychological control, and resulted in children's externalizing and internalizing problems [56]. In the fourth latent group of probands emotional disturbances in first-degree relatives were salient while this group was more likely to reflect a family process dysfunction on the account of the morbidity being widely observed in siblings concomitant to parental psychopathology. Gender of the child may moderate the risk for vulnerability that boys may be more vulnerable in early and middle childhood whilst girls may exhibit more vulnerability in the adolescence [20]. Even though there was a lack of difference across latent subgroups, our case probands in this subgroup consisted of adults with a mean age of 33 and female probands were more likely to be affected from such a core family dysfunction. In the group there was a preponderance of first-degree affected relatives and all of the probands had family history of a psychiatric disorder and at least one affected female relative. As their first degree relatives, adult male probands were much less likely to be affected from the dysfunction that arises in their family system. In short, it seems like females were more sensitive and vulnerable to the disruptions in the functionality of family system in terms of mental ailment in family members. We observed a colorful clinical presentation of psychiatric disorders in first-degree family members that unipolar depressive disorders, obsessive–compulsive disorder, panic disorder, generalized anxiety disorder and psychiatric disorders not otherwise specified were commonly observed. However, given this variation in psychiatric disorders among first-degree family members we observed that only two nosological entities of obsessive–compulsive disorder and panic disorder were prevalent among probands while bipolar disorders were less likely to be seen in core family pattern of psychopathology as compared to the other three homogeneous subsets. The current findings were compatible with the prior studies. Family studies were suggestive of a high heritability of obsessive compulsive symptoms in children ranging from 45% to 67% and relatively lower genetic effects exerting on obsessive compulsive symptoms in adults, ranging from 27% to 47% [93]. Lenane et al. [94] pointed to family dysfunction in OCD that almost half of the fathers and two thirds of the mothers had one or more psychiatric diagnoses

10


Table 5 Proportions and logistic regression of posterior latent class probabilities on categories of psychiatric disorders among relatives of patients by latent classes (N = 350). Latent Class 1 (N = 141) N Depressive Disorders Bipolar Disorders Schizophrenia Obsessive– compulsive Disorder Panic Disorder Generalized Anxiety Disorder Somatoform Disorder Disorders not Otherwise Specified

%

8


ODDS (95% CI)

N

%

ODDS (95% CI)

Latent Class 3 (N = 76) N

%

ODDS (95% CI)

Latent Class 4 (N = 78) N

%

ODDS (95% CI)

5.67 0.141(0.057–0.348) 20 36.36 4.774(2.378–9.583) 12 15.79 0.695(0.323–1.496) 18 23.08 2.054(1.020–4.138)

27 19.15 0.768(0.426–1.383) 19 34.55 2.157(1.107–4.203) 23 30.26 1.126(0.606–2.093) 15 19.23 0.574(0.275–1.202) 34 24.11 1.947(1.055–3.595) 12 21.82 1.011(0.462–2.214) 15 19.74 0.969(0.493–1.907) 8 10.26 0.333(0.132–0.835) 12 8.51 0.400(0.186–0.859) 4 7.27 0.318(0.094–1.072) 14 18.42 1.085(0.518–2.273) 23 29.49 4.287(2.146–8.565)

5 2

0 7

3.55 0.428(0.146–1.251) 5 1.42 0.122(0.020–0.752) 2

.00

⁎⁎⁎(0.000–000)

4.96 0.822(0.291–2.321)

0 4

9.09 1.495(0.500–4.469) 3.64 0.813(0.165–4.003)

.00

⁎⁎⁎(0.000–000)

7.27 1.138(0.329–3.942)

3 6

3.95 0.244(0.055–1.088) 12 15.38 4.244(1.690–10.653) 7.89 1.845(0.575–5.926) 6 7.69 3.144(1.006–9.824)

0

0.00

3

3.95 0.338(0.080–1.434) 8

⁎⁎⁎(0.000–000)

2

2.56

⁎⁎⁎(0.000–000)

10.26 2.549(1.031–6.981)

Bold type indicates statistical significance at p b .05. ⁎⁎⁎ Standard errors were not computed when boundary values occurred.

and morbidity of psychiatric disorders varied in the firstdegree relatives of OCD probands. One third of the probands reported at least one case of OCD in their first degree relatives. Pauls et al. [95] supported and extended these findings that the rates of OCD were significantly greater among first degree relatives of OCD probands relative to comparison subjects. However, familiality in this psychiatric condition seems to be heterogeneous as the symptom structure. High family loading in the disorder was attested by Nestadt et al. [96] who found that familiality was more considerable for obsessions rather than compulsions. Another family study of OCD reported that morbidity risk for OCD was higher than the morbidity risk for mood disorders in the first-degree relatives of the patients [97]. A systematic case–control study of familiality in obsessive compulsive disorder among first-degree relatives of probands suggested high familial loading in child onset obsessive–compulsive disorder with genetically shared vulnerability of tic disorders [98]. The elucidation of underlying etiological mechanisms would require a drastic change dependent on the definition or subtype of the disorder

[99,100]. Also presence of tics disorders was demonstrated to be associated with familial OCD [101]. In this study we made assessments of obsessive compulsive disorder based on DSM-IV TR in psychiatric inpatients but tics disorders and obsessive compulsive disorder are multidimensional and genetically heterogeneous disorders in nature. Therefore, our findings should be interpreted with caution. Prior findings in the research concerning familiality in panic disorder provided evidence in parallel with the family studies of OCD that panic disorder in probands and symptom severity of the disorder were significantly associated with morbidity of panic disorders in patients' relatives as compared to other clinical diseases [102]. High familiality risk and high morbidity of panic disorders in relatives of the patients were reported in a family study of the disorder. Though findings were mixed, relatives of patients were more likely to have panic disorders and unipolar depression [103,104], which was the case for the current sample. Results from the current study suggest that family models and potential mechanisms of tranmission for nosological entities need further elaboration based on family patterns of

Table 6 ANOVA comparisons across latent classes (N = 350).

Age Education (yrs) Number of siblings Age at onset of disorder Duration of the disorder a





Mean

SD

Mean

SD

Mean

SD

Mean

SD

F (3, 346)

P

Partial η 2

Post-hoc a

35.39 8.11 6.34 25.28 10.11

12.62 4.37 2.99 10.50 9.80

34.75 8.53 6.42 24.15 10.60

12.04 4.27 3.49 8.48 9.84

32.79 7.68 5.66 21.50 11.29

11.89 4.63 3.32 8.39 9.98

32.87 8.47 6.94 23.23 9.64

10.97 4.64 3.22 8.68 8.20

1.164 0.544 2.069 2.823 0.435

.323 .652 .104 .039 .728

.010 .005 .018 .024 .004

– – – LC3 N LC1 –

Post-hoc comparisons were conducted by using the Bonferroni multiple comparison test.

1.969(1.096–3.539) 1.491(0.838–2.653) 0.782(0.437–1.400) ⁎⁎⁎(0.000–000) 0.497(0.277–0.891) ⁎⁎⁎(0.000–000) Bold type indicates statistical significance at p b .05. ⁎⁎⁎ Standard errors were not computed when boundary values occurred.

Acute

ODDS (95% CI) %

58.97 48.72 56.41 100.00 37.18 100.00 46 38 44 78 29 78

N ODDS (95% CI)

0.948(0.554–1.621) 0.942(0.547–1.622) 1.124(0.646–1.955) 0.625(0.320–1.221) 0.488(0.283–0.842) 1.977(1.139–3.430) 50.00 43.42 65.79 89.47 47.37 73.68

% N

38 33 50 68 36 56 0.648(0.343–1.223) 0.657(0.342–1.260) 1.599(0.816–3.135) ⁎⁎⁎(0.000–000) ⁎⁎⁎(0.000–000) 0.209(0.101–0.433)

ODDS (95% CI) %

40.00 34.55 69.09 100.00 100.00 21.82 22 19 38 55 55 12

N ODDS (95% CI)

0.833(0.507–1.367) 1.008(0.611–1.661) 0.823(0.496–1.365) 0.152(0.076–0.306) 0.670(0.408–1.102) 0.151(0.087–0.262) 45.39 42.55 58.16 62.41 47.52 24.11

% N

64 60 82 88 67 34 Female

Latent Class 3 (N = 76) Latent Class 2 (N = 55) Latent Class 1 (N = 141)

Table 7 Proportions and logistic regression of posterior latent class probabilities on clinical characteristics of patients by latent classes (N = 350).

Sex (Male vs Female) Presence of a stressor Type of onset (Acute vs Insidious) Presence of family psychopathology Male relatives with a psychiatric disorder Female relatives with a psychiatric disorder



11

vulnerability. One of the most surprising outcomes of this study is that maternal and paternal underpinnings of familiality of mental ailments are distinguishable that such a conceptual distinction refers to a differentiation in transmission mechanisms and variation in the degree of genetic susceptibility for risk of various psychiatric disorders. We provided a preliminary evidence for a distinction between paternal and maternal family patterns of psychopathology that paternal side vulnerability appears to be related to mood disorders and schizophrenia in which paternal group membership with mood disorders had a greater tendency of familial loading relative to paternal schizophrenics. On the contrary, case probands characterized by maternal side vulnerability were more likely to have generalized anxiety disorder. Finally, case probands with first-degree family members of psychopathology had also a tendency to have obsessive–compulsive disorder (even this is a distinct nosological entity in DSM-5) and panic disorders. Our findings were supportive for and extended the previous research that children whose first-degree family members had emotional problems are at a greater risk for a wide range of behavioral and emotional problems [105,106]. Development of emotional regulation capacity can be severely compromised through mothers' greater symptomatology as well as fathers' impaired well-being whereas the relations were bidirectional that physiological regulation can play a buffering role in compensation of adverse consequences of parental psychopathology [107]. Research on family psychology has widely ignored the role of paternal psychopathology. Merikangas and her colleagues have noted that offspring of both parents suffering from psychopathology may have a greater vulnerability effect to develop emotional disruptions as compared to children who have one or no parent with psychopathology [108,109]. In our data we did not assess the severity of symptoms or quality of life among psychiatric patients, so this caveat should be kept in mind while interpreting our results. However, parental psychopathology in both maternal and paternal sides seems to have differential effects and transmission patterns of psychopathology but psychiatric disorders in both parental sides were more likely to culminate in a variation in psychiatric disorders among family members. Given the family patterns derived from our data the other pole of maternal psychopathology was not paternal psychopathology but rather emotional disturbances and mechanisms of transmission through family members are complicated and should be warranted in further studies. Finally, psychiatric symptomatology in second-order relatives may have implications in risk assessment of children. This study has several limitations. First, we did not control for socio-economic status of patients and their families in the analyses. Second, psychiatric patients and their families were not assessed for axis II disorders, particularly for personality disorders as well as physical disabilities or intelligence. Especially, such deficits in first-degree relatives can have implications in posing children at risk for developing

12


psychopathology. Third, we could also have focused on a specific axis I disorder rather we involved patients diagnosed with an axis I psychiatric disorder consecutively admitted to clinics for seeking help. Intergenerational transmission of psychiatric disorders should probably have differentiated across distinct disorders if a specific diagnostic category or categories had been included in the study. Fourth, given the number of axis-I psychiatric disorders investigated in this study, our sample was relatively small. Further research is needed in larger clinical samples. Finally, we did not implement assessments for comorbid psychiatric conditions of either probands or their relatives. Patterns of familial psychopathology might have differentiated if comorbidity would have been included in the current data. Risk assessment on the basis of family history of psychopathology can potentially accomplish a greater reduction in severe psychological disturbance among risky populations. We defined four patterns of familial psychopathology which have overlapping and distinct features in this study. Current distinction should be more profoundly investigated in larger clinical patient groups covering a broad range of psychiatric disorders, particularly personality disorders. References [1] Carlson GA, Bromet EJ, Driessens C, Mojtabai R, Schwartz JE. Age at onset, childhood psychopathology, and 2-year outcome in psychotic bipolar disorder. Am J Psychiatry 2002;159:307-9. [2] Ramchandani P, Psychogiou L. Paternal psychiatric disorders and children’s psychosocial development. Lancet 2009;374:646-53. [3] Lieb R, Isensee B, Hofler M, Pfister H. Parental major depression and the risk of depression and other mental disorders in offspring: a prospective–longitudinal community study. Arch Gen Psychiatry 2002;59:365-74. [4] Birmaher B, Axelson D, Monk K, Kalas C, Goldstein B, Hickey MB, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring Study. Arch Gen Psychiatry 2009;66:287-96. [5] Puckering C. When a parent suffers from an affective disorder: effect on the child. In: Göpfert M, Webster J, & Seeman MV, editors. Parental psychiatric disorder: distressed parents and their families. New York: Cambridge University Press; 2004. p. 172-84. [6] Valdez R, Yoon PW, Qureshi N, Green RF, Khoury MJ. Family history in public health practice: a genomic tool for disease prevention and health promotion. Annu Rev Publ Health 2010;31:69-87. [7] Merikangas KR, Chakravarti A, Moldin SO, Araj H, Blangero J, Burmeister M, et al. Future of genetics of mood disorders research. Biol Psychiatry 2002;52:457-77. [8] Wilde A, Chan HN, Rahman B, Meiser B, Mitchell PB, Schofield PR, et al. A meta-analysis of the risk of major affective disorder in relatives of individuals affected by major depressive disorder or bipolar disorder. J Affect Disord 2014;158:37-47. [9] Biederman J, Petty C, Faraone SV, Henin A, Hirshfeld-Becker D, Pollack MH, et al. Effects of parental anxiety disorders in children at high risk for panic disorder: a controlled study. J Affect Disord 2006;94:191-7. [10] Hirshfeld-Becker DR, Micco JA, Simoes NA, Henin A. High risk studies and developmental antecedents of anxiety disorders. Am J Med Genet C 2008;148C:99-117. [11] Bierderman J, Petty C, Faraone SV, Hirshfeld-Becker DR, Henin A, Pollack MH, et al. Patterns of comorbidity in panic disorder and major

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