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Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors
Schizophrenia Research 200 (2018) 20–25
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Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors Victor Peralta a,b,⁎, Lourdes Fañanás c,d, Migdyrai Martín-Reyes a,b, Manuel J. Cuesta b,e a
Mental Health Department, Servicio Navarro de Salud, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNa), Spain Unitat d' Antropologia, Department of Biology Animal, Facultat de Biologia, Universitat de Barcelona, Spain d Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain e Psychiatry Service, Complejo Hospitalario de Navarra, Spain b c
a r t i c l e
i n f o
Article history: Received 3 July 2017 Received in revised form 8 September 2017 Accepted 12 September 2017 Available online 14 September 2017 Keywords: Catatonia Schizophrenia Psychosis Mood disorders Familiality Heritability
a b s t r a c t Background: This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders. Methods: Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h2) was estimated by linear mixed models using family membership as a random effect, with h2 indicating the portion of phenotypic variance accounted for by family membership. Results: Familiality estimates highly varied for individual catatonia signs (h2 = 0.17–0.65), principal component analysis-derived factors (h2 = 0.29–0.49), number of catatonia signs present (h2 = 0.03–0.43) and severity of the catatonia syndrome (h2 = 0.25–0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h2 = 0.65), presence of ≥5 catatonia signs (h2 = 0.43), a classical catatonia factor (h2 = 0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h2 = 0.59) and the diagnostic construct of psychosis with prominent catatonia features (h2 = 0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h2 = 0.40–0.47). Conclusions: The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial-genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Family-genetic factors have traditionally been regarded as a cornerstone of psychiatric nosology (Robins and Guze, 1970; Craddock et al., 2009), and there is a substantial genetic contribution to the etiology of psychotic and mood disorders (Cardno et al., 1999; Lichtenstein et al., 2009; Wray and Gottesman, 2012); however, authors disagree about the phenotype(s) definition(s) that best correlate with the familialgenetic underpinnings of psychotic disorders. A recent review of the evidence using a range of validating criteria including familial-genetic
Abbreviations: APA, American Psychiatric Association; CASH, Comprehensive Assessment of Symptoms and History schedule; PCA, Principal Component Analysis. ⁎ Corresponding author at: Mental Health Department, Servicio Navarro de Salud, Plaza de la Paz s/n, 31002 Pamplona, Spain. E-mail address: [email protected] (V. Peralta).
http://dx.doi.org/10.1016/j.schres.2017.09.013 0920-9964/© 2017 Elsevier B.V. All rights reserved.
risk factors concluded that there is insufficient evidence of the etiology and pathophysiology to base classification of psychotic disorders on causality (Carpenter et al., 2009). A major research challenge is, therefore, to detect phenotypes that maximize the phenotype-genotype correlation as a first step in unravelling the molecular genetic underpinnings of psychotic disorders. Catatonia is increasingly recognized as one of the major psychopathological domains within psychotic and mood disorders (Peralta and Cuesta, 2001a; Ungvary et al., 2010), although with a disputed nosological status regarding categories of psychiatric disorders (Pfuhlmann and Stöber, 2001; Peralta et al., 2001; Fink et al., 2010). In fact, until DSM-5, catatonia has been mainly viewed as a subtype of schizophrenia, and currently as an unspecific syndrome that may appear in many psychiatric disorders and other medical conditions (APA, 2013; Tandon et al., 2013; Braff et al., 2013). Despite the relevance of catatonia in psychotic disorders, its etiological underpinnings remains poorly researched.
V. Peralta et al. / Schizophrenia Research 200 (2018) 20–25
Regarding familial-genetic factors, several lines of evidence indicate that they are of importance in catatonia. First, catatonic schizophrenia appears to have higher familial loading of psychotic disorders than noncatatonic schizophrenia (Scharfetter and Nüsperli, 1980; Mimica et al., 2001; Stöber, 2004). Second, a catatonia syndrome predicts higher morbidity risk of mood disorders in the first-degree relatives of probands with psychotic disorders (Van Os et al., 1997; Peralta and Cuesta, 2007). Thirdly, the Wernicke-Kleist-Leonhard school of psychiatry (Ungvari, 1993) views catatonia as an heterogeneous syndrome from the familial-genetic perspective, in that systematic catatonia and motility psychosis exhibit low familiality, whereas periodic catatonia is highly familial (Leonhard, 1957; Franzek and Beckmann, 1998) with a morbidity risk of 26.9% and major gene effect and anticipation (Stöber et al., 1995). According to this data, catatonia appears to be a heterogeneous syndrome regarding familial-genetic risk factors, and thus a major research challenge is to detect catatonia phenotypes that maximize the phenotype-genotype correlation as a first step in unravelling their molecular genetic underpinnings. A useful approach to this endeavour is to examine different catatonia phenotypes and compare their predictive validity regarding familial aggregation. The main goal of the present study was to examine the degree of familial aggregation, also known as familiality/transmissibility (Kendler and Neale, 2009) or multifactorial/generalized heritability (Rice, 2008), of the catatonia phenotype in a broad sample of multiplex families with psychotic and mood disorders. More specifically, we examined the familiality of (1) individual catatonia signs, (2) empirically-derived catatonia syndromes, (3) different severity definitions of a catatonia syndrome, and (4) the familiality of catatonia across diagnostic classes of psychotic and mood disorders. With these goals in mind we sought to determine the catatonia phenotype that could maximize the phenotype-genotype correlation. 2. Methods 2.1. Subjects The methodology, including ascertainment procedure and characteristics of the subjects included in this study, has been described in detail elsewhere (Peralta et al., 2016). Briefly, probands were identified through the psychiatric case register of Navarra (Spain) as patients who had attended mental health services from a defined catchment area between 1990 and 2014. Inclusion criteria for the probands included: age N15 years, residing in Navarra, meeting a lifetime DSM-IV diagnosis for a functional psychotic disorder (APA, 1994), having at least one first-degree relative with the same diagnosis and willing to participate, as well as both biological parents being willing and able to participate. The latter criterion was required to delineate the relationships between the affected members of each family (McGrath et al., 2009). The project was approved by the ethics committee of the Regional Health Service of Navarra and written informed consent was obtained from all study participants or their legal representatives. The present study is based on a total of 441 families comprising 2703 individuals, of whom 1094 were affected and 1609 unaffected (Table 1). The average of subjects per family was 6.98 (s.d. = 2.56, range 3–17) and the average of affected subjects per family was 2.80 (s.d. = 1.18; range 2–8). Probands and affected relatives did not significantly differ in their DSM-IV diagnoses excepting for delusional disorder (probands = 2.3%, relatives = 7.4%, p b 0.001); however, differences in that diagnosis, were irrelevant for this study, since, by definition, a diagnosis of catatonia is incompatible with a diagnosis of delusional disorder. 2.2. Assessment All participants underwent face-to-face psychiatric assessments using the Comprehensive Assessment of Symptoms and History (CASH) schedule (Andreasen et al., 1992). The CASH is a semi-structured interview designed to provide a comprehensive information base
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Table 1 Sample description (N = 2703).
Age, mean (s.d.), years Gender, male, n (%) Education, mean (s.d.), years No. of family members affected, mean (s.d.) No. of family members affected included in the study, mean (s.d.) Age at illness onset, mean (s.d.), years Time from onset, mean (SD), years Global assessment of functioning DM-IV diagnosis, n (%) Schizophrenia Nonschizophrenic nonaffective psychoses Bipolar disorder Major depressive disorder
Affected (n = 1094)
Unaffected (n = 1609)
44.1 (15.2) 552 (50.5) 9.7 (3.5) 2.95 (1.31) 2.80 (1.18)
46.8 (17.3) 829 (51.5) 10.1 (3.1) – –
27.6 (11.5) 16.5 (12.2) 63.2 (21.1)
– – –
395 (36.1) 294 (26.9) 239 (21.8) 166 (15.2)
– – – –
concerning clinical features of psychotic and mood disorders. Because the information base is broad, the schedule is not wedded to a specific diagnostic system thus permitting clinicians and researchers to make diagnoses using a wide range of systems, including the DSM-IV classification. Interviews were conducted by experienced psychiatrists or clinical psychologists with established reliability (N0.80) for CASH global symptom ratings and diagnoses (Peralta et al., 2013). Full blind assessment within families was not possible, since not all family members could be assessed by different raters. Information for rating symptoms and diagnoses was derived from all available sources of information, including direct diagnostic interviews, family history reports, medical records and information provided by close relatives or significant others. Two senior researchers (VP, MJC) through a best estimate procedure using all the available records arrived at independent diagnoses, reached a consensus and determined the final diagnoses. Final diagnoses were blind performed to subject identity and group status (proband, relative) in about 75% of the pedigrees. 2.3. Definition of the catatonia phenotype Catatonia signs were assessed by means of the catatonia module from the CASH, which includes 6 motor signs: stupor, rigidity, waxy flexibility, excitement, posturing and mannerisms, the last two items being collapsed into a single rating, and a global severity rating of catatonia. In order to achieve both a more comprehensive assessment of the catatonia syndrome and a DSM-IV diagnosis of catatonia, CASH motor signs were supplemented with 2 motor behavior items from other CASH modules (ritualistic/stereotyped behavior and motor retardation) and 3 additional catatonia items necessary to make a DSM-IV diagnosis of catatonia (negativism, mutism and echo-phenomena), which were rated according to the Modified Rogers Scale (Lund et al., 1991). A total of 10 catatonia signs were rated as their worst on a lifetime basis following the general CASH symptom scoring that combines frequency and severity and ranges between 0 (absent) and 5 (severe). A motor sign was considered to be present if it was rated at the level of mild or higher (score ≥ 2), and the total number of catatonia signs present was also recorded. A diagnosis of catatonia was made according to the DSM-IV criteria, which was also rated according to the following severity criteria: 0 = absent catatonia signs, 1 = subclinical catatonia (catatonia signs present but not fulfilling the criteria for a catatonia diagnosis), 2 = catatonia present with mild intensity, 3 = catatonia present with moderate intensity, and 4 = catatonia present with severe intensity. A high convergent validity between the CASH and DSM-IV catatonia severity ratings has been shown (r = 0.89) (Peralta et al., 2010). We defined also a catatonia phenotype on the basis of the factor structure of the catatonia signs (see below). Lastly, and in order to achieve a phenotype definition of catatonia that takes into account the lifetime severity of the whole clinical
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Table 2 Factor structure of catatonia signs.
Psychomotor retardation Excitement Ritualistic/stereotyped behavior Mutism Waxy flexibility Rigidity Stupor Negativism Mannerisms/posturing Echo-phenomena Explained variance (%)
Factor I
Factor II
Factor III
0.19 −0.18 −0.13 0.87 0.74 0.77 0.74 0.81 0.19 0.38 40.5
−0.15 0.16 0.93 −0.04 −0.04 0.12 −0.13 −0.02 0.77 0.38 13.7
0.73 0.87 0.02 −0.08 −0.05 −0.01 0.12 −0.01 −0.02 0.04 11.3
Factor loadings ≥0.5 are in bold. Factor I: classical catatonia; Factor II: bizarre motility; Factor III: abnormal motor activity.
picture of the subjects, we created a “psychosis with prominent catatonia features” diagnostic construct, which was defined as a global severity rating of catatonia equal or higher than those of the other major domains of psychopathology including hallucinations, delusions, formal thought disorder, negative symptoms, mania and depression, all as scored with the CASH. 2.4. Procedure
Familiality of the catatonia phenotypes was examined by means of generalized linear mixed models (Tenesa and Haley, 2013) using mixed-effects binary logistic regression. All models included age and gender as fixed effects, and family membership as a random effect. A robust sandwich estimator was used to account for the non-normality of the data. Two models were run for each variable: a null model incorporating only the fixed effects (h2 = 0), and a general model with the addition of family membership as a random effect. Log likelihoods for each model were compared using the Wald chi-squared statistic with 1 df. For clustered data, the mixed-effects model assumes that data within clusters (i.e., families) are dependent, and the degree of dependence is jointly estimated along with the regression coefficients of the fixed effects (Heck et al., 2012). The degree of dependence attributable to families is characterized by the between-families variance, which is estimated in the mixed model, indicating the portion of phenotypic variance accounted for by family membership (h2). This estimated variance represents the population variance of family effects, and therefore our results pertain to the population of families of which this sample is representative. As variance components are nonnegative by definition, a one-tailed p-value was applied as is typical for this test (Snijders and Bosker, 2012), and adjusted Wald confidence intervals were calculated (Agresti, 2011). Statistical analyses were performed using IBM SPSS Statistics 20. 3. Results
We examined the familiality of the following catatonia phenotypes: individual catatonia signs, catatonia syndromes defined by Principal Component Analysis (PCA) of the catatonia signs, number of catatonia signs endorsed, a DSM-IV diagnosis of catatonia and its severity, the diagnosis of psychosis with prominent catatonic features, and the familiality of a diagnosis of catatonia across diagnostic categories of psychotic and affective disorders. Due to the low prevalence rate of specific DSM-IV diagnoses other than schizophrenia and affective psychoses, they were merged into a single group of nonschizophrenic nonaffective psychoses (NSNAP). 2.5. Statistical methods The factor structure of catatonia signs was examined by means of PCA. The eigenvalue N1 criterion was used to determine the number of factors to retain, and given that catatonia items were assumed to be correlated, we used the promax rotation procedure. Factor scores were extracted using the regression method and the presence of a categorically defined factor syndrome was determined according to the upper tertile of each factor score.
PCA resulted in 3 catatonia factors explaining the 65.1% of the total variance (Table 2). The first factor (classical catatonia) was made of stupor, mutism, rigidity, waxy flexibility and negativism; the second factor (bizarre motility) was made of ritualistic/stereotyped behavior and mannerisms/posturing; and the third factor (abnormal motor activity) was made of psychomotor retardation and excitement. Echo-phenomena did load modestly on the first two factors. The distribution of catatonia features across diagnoses is presented in Table 3. Most of the affected subjects (85.6%) had at least 1 catatonic sign, with psychomotor retardation being the most frequent sign (49.8%) and echo-phenomena the less frequent one (7.5%). The percent of subjects with a DSM-IV diagnosis of catatonia at the levels of mild or higher, moderate or higher and severe was 33.2%, 24% and 15.4%, respectively. A diagnosis of psychosis with prominent catatonic features (n = 106) was observed in 9.7% of the subjects. Number of catatonia signs and severity of DSM-IV catatonia were strongly associated (r = 0.78, p b 0.001). Familiality estimates (h2) of catatonia signs showed significant evidence of familial aggregation, although their magnitude varied considerably (Table 4). High familial aggregation was observed for rigidity
Table 3 Catatonia phenotypes across diagnoses of psychotic and mood disorders.
Psychomotor retardation, n (%) Excitement, n (%) Ritualistic/stereotyped behavior, n (%) Mutism, n (%) Waxy flexibility, n (%) Rigidity, n (%) Stupor, n (%) Echophenomena, n (%) Negativism, n (%) Mannerisms/posturing, n (%) DSM-IV catatonia syndrome, n (%) Psychosis with prominent catatonic features, n (%) No. of catatonia signs, mean (s.d.) Severity of catatonia, mean (s.d.) Factor 1: classical catatonia (s.d.) Factor 2: bizarre motility (s.d.) Factor 3: abnormal motor activity (s.d.)
SZ
NSNAP
BD
MDD
Total
131 (33.2) 132 (33.4) 208 (52.7) 98 (24.8) 43 (10.9) 74 (18.7) 81 (20.5) 39 (9.9) 79 (20.0) 150 (38.8) 163 (41.3) 47 (11.9) 2.50 (2.45) 1.51 (1.71) 0.64 (1.57) 1.24 (1.69) 0.37 (1.03)
126 (42.9) 98 (33.3) 44 (15.0) 34 (11.6) 27 (9.2) 35 (11.9) 77 (26.2) 28 (9.5) 47 (16.0) 50 (17.0) 94 (32.0) 32 (12.2) 1.91 (2.43) 1.24 (1.74) 0.47 (1.50) 0.23 (1.23) 0.73 (1.20)
159 (66.5) 90 (37.7) 25 (10.5) 25 (10.5) 14 (5.9) 23 (9.6) 44 (18.4) 13 (5.4) 37 (15.5) 26 (10.9) 70 (29.3) 15 (6.3) 1.99 (2.01) 1.17 (1.59) 0.28 (1.26) 0.05 (0.95) 1.72 (0.83)
129 (77.7) 26 (15.7) 11 (6.6) 21 (12.7) 7 (4.2) 17 (10.2) 35 (21.1) 2 (1.2) 25 (15.1) 11 (6.6) 36 (21.7) 12 (7.2) 2.12 (1.87) 0.86 (1.47) 0.28 (1.24) 0.20 (0.74) 0.89 (0.78)
545 (49.8) 346 (31.6) 288 (26.3) 178 (16.3) 91 (8.3) 149 (13.6) 237 (21.7) 82 (7.5) 188 (17.2) 237 (11.7) 363 (33.2) 106 (9.7) 2.17 (2.29) 1.27 (1.66) 0.46 (1.45) 0.49 (1.43) 0.84 (1.12)
SZ: schizophrenia; NSNAP: nonschizophrenic nonaffective psychosis; BD: bipolar disorder; MDD: major depressive disorder.
V. Peralta et al. / Schizophrenia Research 200 (2018) 20–25 Table 4 Familiality estimates for catatonia signs and syndromes.
Catatonia signs Psychomotor retardation Excitement Ritualistic/stereotyped behavior Mutism Waxy flexibility Rigidity Stupor Echophenomena Negativism Mannerisms/posturing Catatonia syndromes Factor 1: classical catatonia Factor 2: bizarre motility Factor 3: abnormal motor activity
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Table 6 Familiality estimates for catatonia syndromes across diagnostic classes.
h2
95% CI
s.e.
Z
p
Catatonia syndromes
Diagnostic classes
h2
95% CI
s.e.
Z
p
0.17 0.24 0.31 0.65 0.29 0.65 0.47 0.26 0.40 0.44
0.13–0.22 0.19–0.30 0.25–0.40 0.56–0.77 0.22–0.36 0.55–0.78 0.39–0.57 0.20–0.32 0.31–0.51 0.36–0.54
0.06 0.08 0.11 0.15 0.22 0.17 0.13 0.22 0.15 0.13
2.53 2.83 2.87 4.25 3.38 3.78 3.51 3.24 2.73 3.35
0.011 0.005 0.004 b0.001 0.006 b0.001 b0.001 0.008 0.006 0.001
DSM-IV catatonia diagnosis
0.49 0.38 0.29
0.40–0.58 0.30–0.47 0.23–0.37
0.13 0.13 0.11
3.72 3.01 2.75
b0.001 0.003 0.006
SZ NSNAP BD MDD SZ NSNAP BD MDD SZ NSNAP BD MDD SZ NSNAP BD MDD
0.40 0.44 0.47 0.45 0.54 0.57 0.61 0.58 0.27 0.37 0.39 0.38 0.14 0.22 0.22 0.18
0.34–0.48 0.37–0.52 0.40–0.55 0.39–0.53 0.45–0.63 0.48–0.67 0.52–0.71 0.49–0.68 0.20–0.35 0.29–0.47 0.31–0.48 0.30–0.47 0.10–0.19 0.17–0.27 0.17–0.27 0.13–0.23
0.10 0.11 0.11 0.11 0.13 0.14 0.14 0.14 0.12 0.14 0.13 0.13 0.07 0.08 0.08 0.08
4.00 4.00 4.26 4.22 4.04 4.03 4.26 4.02 2.27 2.65 3.05 3.02 1.97 2.76 2.94 2.30
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 0.026 0.008 b0.001 0.003 0.048 0.006 0.003 0.022
and mutism (both h2 = 0.65); substantial familial aggregation (h2 between 0.40 and 0.60) was observed for stupor, negativism and mannerism/posturing, and the other signs showed a fair level familial aggregation (h2 between 0.17 and 0.31). The classical catatonia factor had the highest familiality (h2 = 0.49) of the catatonia factors, which was due to the fact that most of their constituting items had substantial familiality. Number of catatonia signs showed increasing familial aggregation up to 5 signs (h2 = 0.43), and severity of catatonia syndrome showed increasing familial aggregation up to moderate or higher severity degree (h2 = 0.59) (Table 5). The diagnostic construct of psychosis with prominent catatonia features also exhibited substantial familiality (h2 = 0.56). Lastly, we also examined the familiality of a DSM-IV diagnosis of catatonia and the PCA-derived syndromes across diagnostic categories by controlling for specific diagnoses in the linear mixed models. Familiality estimates were fairly similar across the diagnostic categories with no statistically significant differences between diagnoses as showed by non-overlapping confidence intervals (Table 6). 4. Discussion 4.1. Main findings This study examined for the first time the familial aggregation of alternative catatonia phenotypes in a broad sample of multiple affected families with psychotic and mood disorders. Multiplex families represent a powerful tool for examining the familial-genetic underpinnings of complex diseases and are the starting point for both the heritability and linkage studies that underlie much of our knowledge of complex
Table 5 Familiality estimates for number of catatonia signs present, severity levels of a DSM-IV catatonia diagnosis and psychosis with prominent catatonic features.
No. of catatonia signs ≥1 ≥2 ≥3 ≥4 ≥5 ≥6 ≥7 Severity of a DSM-IV catatonia diagnosis Sub-umbral catatonia or higher Mild catatonia or higher Moderate catatonia or higher Severe catatonia Psychosis with prominent catatonia features
h2
95% CI
s.e.
Z
p
0.03 0.05 0.14 0.33 0.43 0.33 0.30
0.00–0.06 0.03–0.09 0.10–0.19 0.27–0.41 0.36–0.52 0.25–0.44 0.22–0.39
0.04 0.05 0.08 0.10 0.12 0.14 0.16
0.92 1.09 2.03 3.40 3.60 2.36 2.51
0.428 0.275 0.043 0.001 b0.001 0.018 0.022
0.25 0.33 0.59 0.49 0.56
0.20–0.31 0.27–0.40 0.50–0.68 0.39–0.62 0.44–0.71
0.08 0.10 0.13 0.17 0.20
3.24 3.32 3.37 2.92 2.86
0.001 0.001 b0.001 0.004 0.003
Classical catatonia syndrome
Bizarre motility syndrome
Abnormal motor activity syndrome
SZ: schizophrenia; NSNAP: nonschizophrenic nonaffective psychosis; BD: bipolar disorder; MDD: major depressive disorder.
diseases (Wu et al., 2015). In this article, we assume that familiality – phenotypic resemblance among first-degree relatives– is a useful standard that can guide the selection of phenotypes that will be most effective in defining genetically homogeneous forms of disorders (Risch and Teng, 1998). We found that the way in which catatonia is defined has a strong impact on familiality estimates, and four may be considered as the main findings of this study. First, individual catatonia signs exhibited statistically significant familiality although with a broad range of variation; whereas frequent catatonia signs such as psychomotor retardation and excitement showed fair familiality, classical signs such as rigidity and mutism showed high familiality estimates. Second, empirical clustering of catatonic features confirmed the familiality pattern of individual signs, as the classical catatonia factor showed substantial familiality, the abnormal motor activity factor showed fair familiality with the bizarre motor behavior factor falling in-between. Third, number of catatonia signs and severity of catatonia, which were highly correlated, meaningfully influenced familiality estimates, with 5 or more catatonia signs and a moderate or higher severity level of catatonia showing substantial familiality; in a similar vein, the diagnostic construct of psychosis with prominent catatonia features exhibited substantial familiality. Lastly, familiality of catatonia was not meaningfully influenced by diagnostic class, which supports their consideration, from a familial-genetic perspective, as an unspecific syndrome within psychotic and mood disorders. 4.2. Comparison with the literature Given that this is the first study examining levels of familial aggregation of different definitions of the catatonia phenotype, our results are not readily comparable with any in the literature. However, and considering that our familiality estimates measure the maximal effect of genes (Rice, 2008), some aspects of our results merit comments in relation to previous studies reporting heritability estimates. Overall, those catatonia phenotypes maximizing the familiality estimates (i.e., mutism, rigidity, classical catatonia factor, catatonia severity at the level of moderate or higher, presence of at least 5 catatonia signs, psychosis with prominent catatonia features) do have similar h2 figures than those reported in other family studies for the diagnoses of psychotic and major mood disorders (h2 ~ 60%) (Lichtenstein et al., 2009; Wray and Gottesman, 2012) but lower than those reported in twin studies (h2 ~ 80%) (Cardno et al., 1999; McGuffin et al., 2003). The only previous studies that have examined the familial aggregation of different catatonia phenotypes across psychotic disorders are those from the Leonhard's school (Leonhard, 1957; Stöber et al., 1995; Franzek and Beckmann, 1998, 1999) but their results cannot be directly compared with ours mainly
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because of lack of correspondence of catatonia definitions and nosologic backgrounds. More specifically, a heritability estimate of 0.46 has been reported for periodic catatonia (Franzek and Beckmann, 1998), but this highly specific catatonia form is not comparable to any of our catatonia definitions. Lastly, a previous study found that a PCA-derived catatonia syndrome exhibited similar familiality levels in schizophrenia, affective disorders and psychotic disorders (Van Os et al., 1997), which is in agreement with our findings. Overall, catatonia cut-across all categories of psychotic and mood disorders although some differences in the prevalence pattern of specific motor signs and dimensions are evident (for a systematic review of the matter see Peralta and Cuesta (2017)). Thus, data from the present study and the literature do not support the view of catatonia as a subtype of schizophrenia (Kraepelin, 1919) nor the alternative view that catatonia is particularly prevalent in mood disorders (Abrams and Taylor, 1976). Regarding the factor structure of catatonia, our finding of a single abnormal motor activity factor is at odds with those of the literature (see Peralta and Cuesta (2017) for a review), which usually identify separate retarded and excited factors. This discordance may be explained by the lifetime nature of our assessment in contrast to the usual cross-sectional assessment of motor features in other studies, which putatively favours the finding of separate abnormal motor activity factors.
4.3. Implications The substantial familiality of some catatonia phenotypes found in this study suggests that they are adequate candidates for molecular genetic studies, which may shed light no only on the nature of these particular phenotypes but also on that of the underlying disorder. Furthermore, both the high prevalence and substantial familial aggregation of catatonia in psychotic and mood disorders reinforces the consideration of catatonia as a core domain within these disorders. In this regard, our data support both the divorce of catatonia from schizophrenia held by DSM-5 and its consideration as a specifier in psychotic and mood disorders (Heckers et al., 2010). Catatonia is usually diagnosed by the presence of any three signs (APA, 2013; Peralta and Cuesta, 2001b; Peralta et al., 2010), which sharply contrast with our finding that the presence of 5 or more signs achieved the highest familiality. Acknowledging that the validity of a given clinical phenotype may vary depending on the type of validators considered (Kendler, 1990), our study suggests that defining catatonia by the presence of at least 5 signs may be most appropriate for genetic studies, but not necessarily for other purposes. Furthermore, and providing that number of catatonia signs and catatonia severity are highly correlated, establishing a specified severity level for the catatonia syndrome to determine, for example, treatment with electro-convulsive therapy, may converge with the higher genetic validity of the syndrome. Additionally, and given the high familiality of rigidity and mutism, they should be included in any diagnostic criteria of catatonia, since mutism but not rigidity is included in DSM-5 criteria. In the last years, it has been much debated about whether catatonia should be considered as an independent syndrome within the DSM-5 or not (Francis et al., 2010; Fink et al., 2010; Heckers et al., 2010). However, the intermingled relationships of catatonia signs and syndromes with other domains of psychopathology and diagnoses of psychotic disorders (Peralta et al., 2001), together with the transdiagnostic character of catatonia in terms of familial risk factors, do not support their consideration as an independent syndrome, at least within the framework of psychotic and mood disorders; thus reinforcing the position of DSM-5 of considering catatonia as an unspecific syndrome (Tandon et al., 2013). Notwithstanding this, the substantial familiality of the diagnostic construct of psychosis with prominent catatonic features deserves to be further examined for confirmation and additional examination of risk factors and clinical underpinnings.
4.4. Limitations Several limitations need to be considered when interpreting our findings. First, our familiality estimates quantify the strength of familial resemblance and represents the percentage of variance that is due to all familial effects including additive genetic and those of the familial environment, thus we could not distinguish between genetic and environmental contributions to familial aggregation. However, while everything familial is not genetic, variables that are not familial are unlikely to be genetically informative, and most of the familial resemblance of psychotic and mood disorders is due to genetic factors (Cardno et al., 1999; Lichtenstein et al., 2009). Second, our ascertainment strategy may result in cohort effects due to the selection of family members willing to participate, which may have limited recruitment of more severely disturbed or socially isolated patients. Nevertheless, any such effect should be relatively weak because the Mental Health Service of Navarra is public and highly accessible as most people with psychoses have contact with psychiatric services (Mata et al., 2000). Third, the familiality estimates need to be interpreted as pertaining to our population of psychotic subjects from multiplex families, and extrapolation of our results to more general populations of psychotic and mood disorders should be done cautiously; this limitation, however, does not necessarily invalidate our results, since our primary goal was examining these estimates across catatonia phenotypes rather than estimating the familial risk in the general population. Lastly, we included a limited number of catatonia signs, and although these are among the more commonly recognized catatonia manifestations, including a broader range of signs might have led to different results. Funding source This study was funded by the Department of Health of the Government of Navarra (14/2010); Ministerio de Educación y Ciencia (SAF2008-05674-C03-01-02); Comissionat per a Universitats I Recerca del DIUE (2009SGR827) and Instituto de Salud Carlos III (PI/6//02148). Contributors Victor Peralta and Manuel J. Cuesta designed the study and wrote the manuscript. Lourdes Fañanás and Migdyrai Martín-Reyes managed the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of interest None.
Acknowledgement None.
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Dissecting the catatonia phenotype in psychotic and mood disorders on the basis of familial-genetic factors Victor Peralta a,b,⁎, Lourdes Fañanás c,d, Migdyrai Martín-Reyes a,b, Manuel J. Cuesta b,e a
Mental Health Department, Servicio Navarro de Salud, Spain Instituto de Investigación Sanitaria de Navarra (IdiSNa), Spain Unitat d' Antropologia, Department of Biology Animal, Facultat de Biologia, Universitat de Barcelona, Spain d Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain e Psychiatry Service, Complejo Hospitalario de Navarra, Spain b c
a r t i c l e
i n f o
Article history: Received 3 July 2017 Received in revised form 8 September 2017 Accepted 12 September 2017 Available online 14 September 2017 Keywords: Catatonia Schizophrenia Psychosis Mood disorders Familiality Heritability
a b s t r a c t Background: This study examines the familial aggregation (familiality) of different phenotypic definitions of catatonia in a sample of multiplex families with psychotic and mood disorders. Methods: Participants were probands with a lifetime diagnosis of a DSM-IV functional psychotic disorder, their parents and at least one first-degree relative with a psychotic disorder. The study sample included 441 families comprising 2703 subjects, of whom 1094 were affected and 1609 unaffected. Familiality (h2) was estimated by linear mixed models using family membership as a random effect, with h2 indicating the portion of phenotypic variance accounted for by family membership. Results: Familiality estimates highly varied for individual catatonia signs (h2 = 0.17–0.65), principal component analysis-derived factors (h2 = 0.29–0.49), number of catatonia signs present (h2 = 0.03–0.43) and severity of the catatonia syndrome (h2 = 0.25–0.59). Phenotypes maximizing familiality estimates included individual signs (mutism and rigidity, both h2 = 0.65), presence of ≥5 catatonia signs (h2 = 0.43), a classical catatonia factor (h2 = 0.49), a DSM-IV catatonia syndrome at a severity level of moderate or higher (h2 = 0.59) and the diagnostic construct of psychosis with prominent catatonia features (h2 = 0.56). Familiality estimates of a DSM-IV catatonia syndrome did not significantly differ across the diagnostic categories of psychotic and mood disorders (h2 = 0.40–0.47). Conclusions: The way in which catatonia is defined has a strong impact on familiality estimates with some catatonia phenotypes exhibiting substantial familial aggregation, which may inform about the most adequate phenotypes for molecular studies. From a familial-genetic perspective, the catatonia phenotype in psychotic and mood disorders has a transdiagnostic character. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Family-genetic factors have traditionally been regarded as a cornerstone of psychiatric nosology (Robins and Guze, 1970; Craddock et al., 2009), and there is a substantial genetic contribution to the etiology of psychotic and mood disorders (Cardno et al., 1999; Lichtenstein et al., 2009; Wray and Gottesman, 2012); however, authors disagree about the phenotype(s) definition(s) that best correlate with the familialgenetic underpinnings of psychotic disorders. A recent review of the evidence using a range of validating criteria including familial-genetic
Abbreviations: APA, American Psychiatric Association; CASH, Comprehensive Assessment of Symptoms and History schedule; PCA, Principal Component Analysis. ⁎ Corresponding author at: Mental Health Department, Servicio Navarro de Salud, Plaza de la Paz s/n, 31002 Pamplona, Spain. E-mail address: [email protected] (V. Peralta).
http://dx.doi.org/10.1016/j.schres.2017.09.013 0920-9964/© 2017 Elsevier B.V. All rights reserved.
risk factors concluded that there is insufficient evidence of the etiology and pathophysiology to base classification of psychotic disorders on causality (Carpenter et al., 2009). A major research challenge is, therefore, to detect phenotypes that maximize the phenotype-genotype correlation as a first step in unravelling the molecular genetic underpinnings of psychotic disorders. Catatonia is increasingly recognized as one of the major psychopathological domains within psychotic and mood disorders (Peralta and Cuesta, 2001a; Ungvary et al., 2010), although with a disputed nosological status regarding categories of psychiatric disorders (Pfuhlmann and Stöber, 2001; Peralta et al., 2001; Fink et al., 2010). In fact, until DSM-5, catatonia has been mainly viewed as a subtype of schizophrenia, and currently as an unspecific syndrome that may appear in many psychiatric disorders and other medical conditions (APA, 2013; Tandon et al., 2013; Braff et al., 2013). Despite the relevance of catatonia in psychotic disorders, its etiological underpinnings remains poorly researched.
V. Peralta et al. / Schizophrenia Research 200 (2018) 20–25
Regarding familial-genetic factors, several lines of evidence indicate that they are of importance in catatonia. First, catatonic schizophrenia appears to have higher familial loading of psychotic disorders than noncatatonic schizophrenia (Scharfetter and Nüsperli, 1980; Mimica et al., 2001; Stöber, 2004). Second, a catatonia syndrome predicts higher morbidity risk of mood disorders in the first-degree relatives of probands with psychotic disorders (Van Os et al., 1997; Peralta and Cuesta, 2007). Thirdly, the Wernicke-Kleist-Leonhard school of psychiatry (Ungvari, 1993) views catatonia as an heterogeneous syndrome from the familial-genetic perspective, in that systematic catatonia and motility psychosis exhibit low familiality, whereas periodic catatonia is highly familial (Leonhard, 1957; Franzek and Beckmann, 1998) with a morbidity risk of 26.9% and major gene effect and anticipation (Stöber et al., 1995). According to this data, catatonia appears to be a heterogeneous syndrome regarding familial-genetic risk factors, and thus a major research challenge is to detect catatonia phenotypes that maximize the phenotype-genotype correlation as a first step in unravelling their molecular genetic underpinnings. A useful approach to this endeavour is to examine different catatonia phenotypes and compare their predictive validity regarding familial aggregation. The main goal of the present study was to examine the degree of familial aggregation, also known as familiality/transmissibility (Kendler and Neale, 2009) or multifactorial/generalized heritability (Rice, 2008), of the catatonia phenotype in a broad sample of multiplex families with psychotic and mood disorders. More specifically, we examined the familiality of (1) individual catatonia signs, (2) empirically-derived catatonia syndromes, (3) different severity definitions of a catatonia syndrome, and (4) the familiality of catatonia across diagnostic classes of psychotic and mood disorders. With these goals in mind we sought to determine the catatonia phenotype that could maximize the phenotype-genotype correlation. 2. Methods 2.1. Subjects The methodology, including ascertainment procedure and characteristics of the subjects included in this study, has been described in detail elsewhere (Peralta et al., 2016). Briefly, probands were identified through the psychiatric case register of Navarra (Spain) as patients who had attended mental health services from a defined catchment area between 1990 and 2014. Inclusion criteria for the probands included: age N15 years, residing in Navarra, meeting a lifetime DSM-IV diagnosis for a functional psychotic disorder (APA, 1994), having at least one first-degree relative with the same diagnosis and willing to participate, as well as both biological parents being willing and able to participate. The latter criterion was required to delineate the relationships between the affected members of each family (McGrath et al., 2009). The project was approved by the ethics committee of the Regional Health Service of Navarra and written informed consent was obtained from all study participants or their legal representatives. The present study is based on a total of 441 families comprising 2703 individuals, of whom 1094 were affected and 1609 unaffected (Table 1). The average of subjects per family was 6.98 (s.d. = 2.56, range 3–17) and the average of affected subjects per family was 2.80 (s.d. = 1.18; range 2–8). Probands and affected relatives did not significantly differ in their DSM-IV diagnoses excepting for delusional disorder (probands = 2.3%, relatives = 7.4%, p b 0.001); however, differences in that diagnosis, were irrelevant for this study, since, by definition, a diagnosis of catatonia is incompatible with a diagnosis of delusional disorder. 2.2. Assessment All participants underwent face-to-face psychiatric assessments using the Comprehensive Assessment of Symptoms and History (CASH) schedule (Andreasen et al., 1992). The CASH is a semi-structured interview designed to provide a comprehensive information base
21
Table 1 Sample description (N = 2703).
Age, mean (s.d.), years Gender, male, n (%) Education, mean (s.d.), years No. of family members affected, mean (s.d.) No. of family members affected included in the study, mean (s.d.) Age at illness onset, mean (s.d.), years Time from onset, mean (SD), years Global assessment of functioning DM-IV diagnosis, n (%) Schizophrenia Nonschizophrenic nonaffective psychoses Bipolar disorder Major depressive disorder
Affected (n = 1094)
Unaffected (n = 1609)
44.1 (15.2) 552 (50.5) 9.7 (3.5) 2.95 (1.31) 2.80 (1.18)
46.8 (17.3) 829 (51.5) 10.1 (3.1) – –
27.6 (11.5) 16.5 (12.2) 63.2 (21.1)
– – –
395 (36.1) 294 (26.9) 239 (21.8) 166 (15.2)
– – – –
concerning clinical features of psychotic and mood disorders. Because the information base is broad, the schedule is not wedded to a specific diagnostic system thus permitting clinicians and researchers to make diagnoses using a wide range of systems, including the DSM-IV classification. Interviews were conducted by experienced psychiatrists or clinical psychologists with established reliability (N0.80) for CASH global symptom ratings and diagnoses (Peralta et al., 2013). Full blind assessment within families was not possible, since not all family members could be assessed by different raters. Information for rating symptoms and diagnoses was derived from all available sources of information, including direct diagnostic interviews, family history reports, medical records and information provided by close relatives or significant others. Two senior researchers (VP, MJC) through a best estimate procedure using all the available records arrived at independent diagnoses, reached a consensus and determined the final diagnoses. Final diagnoses were blind performed to subject identity and group status (proband, relative) in about 75% of the pedigrees. 2.3. Definition of the catatonia phenotype Catatonia signs were assessed by means of the catatonia module from the CASH, which includes 6 motor signs: stupor, rigidity, waxy flexibility, excitement, posturing and mannerisms, the last two items being collapsed into a single rating, and a global severity rating of catatonia. In order to achieve both a more comprehensive assessment of the catatonia syndrome and a DSM-IV diagnosis of catatonia, CASH motor signs were supplemented with 2 motor behavior items from other CASH modules (ritualistic/stereotyped behavior and motor retardation) and 3 additional catatonia items necessary to make a DSM-IV diagnosis of catatonia (negativism, mutism and echo-phenomena), which were rated according to the Modified Rogers Scale (Lund et al., 1991). A total of 10 catatonia signs were rated as their worst on a lifetime basis following the general CASH symptom scoring that combines frequency and severity and ranges between 0 (absent) and 5 (severe). A motor sign was considered to be present if it was rated at the level of mild or higher (score ≥ 2), and the total number of catatonia signs present was also recorded. A diagnosis of catatonia was made according to the DSM-IV criteria, which was also rated according to the following severity criteria: 0 = absent catatonia signs, 1 = subclinical catatonia (catatonia signs present but not fulfilling the criteria for a catatonia diagnosis), 2 = catatonia present with mild intensity, 3 = catatonia present with moderate intensity, and 4 = catatonia present with severe intensity. A high convergent validity between the CASH and DSM-IV catatonia severity ratings has been shown (r = 0.89) (Peralta et al., 2010). We defined also a catatonia phenotype on the basis of the factor structure of the catatonia signs (see below). Lastly, and in order to achieve a phenotype definition of catatonia that takes into account the lifetime severity of the whole clinical
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V. Peralta et al. / Schizophrenia Research 200 (2018) 20–25
Table 2 Factor structure of catatonia signs.
Psychomotor retardation Excitement Ritualistic/stereotyped behavior Mutism Waxy flexibility Rigidity Stupor Negativism Mannerisms/posturing Echo-phenomena Explained variance (%)
Factor I
Factor II
Factor III
0.19 −0.18 −0.13 0.87 0.74 0.77 0.74 0.81 0.19 0.38 40.5
−0.15 0.16 0.93 −0.04 −0.04 0.12 −0.13 −0.02 0.77 0.38 13.7
0.73 0.87 0.02 −0.08 −0.05 −0.01 0.12 −0.01 −0.02 0.04 11.3
Factor loadings ≥0.5 are in bold. Factor I: classical catatonia; Factor II: bizarre motility; Factor III: abnormal motor activity.
picture of the subjects, we created a “psychosis with prominent catatonia features” diagnostic construct, which was defined as a global severity rating of catatonia equal or higher than those of the other major domains of psychopathology including hallucinations, delusions, formal thought disorder, negative symptoms, mania and depression, all as scored with the CASH. 2.4. Procedure
Familiality of the catatonia phenotypes was examined by means of generalized linear mixed models (Tenesa and Haley, 2013) using mixed-effects binary logistic regression. All models included age and gender as fixed effects, and family membership as a random effect. A robust sandwich estimator was used to account for the non-normality of the data. Two models were run for each variable: a null model incorporating only the fixed effects (h2 = 0), and a general model with the addition of family membership as a random effect. Log likelihoods for each model were compared using the Wald chi-squared statistic with 1 df. For clustered data, the mixed-effects model assumes that data within clusters (i.e., families) are dependent, and the degree of dependence is jointly estimated along with the regression coefficients of the fixed effects (Heck et al., 2012). The degree of dependence attributable to families is characterized by the between-families variance, which is estimated in the mixed model, indicating the portion of phenotypic variance accounted for by family membership (h2). This estimated variance represents the population variance of family effects, and therefore our results pertain to the population of families of which this sample is representative. As variance components are nonnegative by definition, a one-tailed p-value was applied as is typical for this test (Snijders and Bosker, 2012), and adjusted Wald confidence intervals were calculated (Agresti, 2011). Statistical analyses were performed using IBM SPSS Statistics 20. 3. Results
We examined the familiality of the following catatonia phenotypes: individual catatonia signs, catatonia syndromes defined by Principal Component Analysis (PCA) of the catatonia signs, number of catatonia signs endorsed, a DSM-IV diagnosis of catatonia and its severity, the diagnosis of psychosis with prominent catatonic features, and the familiality of a diagnosis of catatonia across diagnostic categories of psychotic and affective disorders. Due to the low prevalence rate of specific DSM-IV diagnoses other than schizophrenia and affective psychoses, they were merged into a single group of nonschizophrenic nonaffective psychoses (NSNAP). 2.5. Statistical methods The factor structure of catatonia signs was examined by means of PCA. The eigenvalue N1 criterion was used to determine the number of factors to retain, and given that catatonia items were assumed to be correlated, we used the promax rotation procedure. Factor scores were extracted using the regression method and the presence of a categorically defined factor syndrome was determined according to the upper tertile of each factor score.
PCA resulted in 3 catatonia factors explaining the 65.1% of the total variance (Table 2). The first factor (classical catatonia) was made of stupor, mutism, rigidity, waxy flexibility and negativism; the second factor (bizarre motility) was made of ritualistic/stereotyped behavior and mannerisms/posturing; and the third factor (abnormal motor activity) was made of psychomotor retardation and excitement. Echo-phenomena did load modestly on the first two factors. The distribution of catatonia features across diagnoses is presented in Table 3. Most of the affected subjects (85.6%) had at least 1 catatonic sign, with psychomotor retardation being the most frequent sign (49.8%) and echo-phenomena the less frequent one (7.5%). The percent of subjects with a DSM-IV diagnosis of catatonia at the levels of mild or higher, moderate or higher and severe was 33.2%, 24% and 15.4%, respectively. A diagnosis of psychosis with prominent catatonic features (n = 106) was observed in 9.7% of the subjects. Number of catatonia signs and severity of DSM-IV catatonia were strongly associated (r = 0.78, p b 0.001). Familiality estimates (h2) of catatonia signs showed significant evidence of familial aggregation, although their magnitude varied considerably (Table 4). High familial aggregation was observed for rigidity
Table 3 Catatonia phenotypes across diagnoses of psychotic and mood disorders.
Psychomotor retardation, n (%) Excitement, n (%) Ritualistic/stereotyped behavior, n (%) Mutism, n (%) Waxy flexibility, n (%) Rigidity, n (%) Stupor, n (%) Echophenomena, n (%) Negativism, n (%) Mannerisms/posturing, n (%) DSM-IV catatonia syndrome, n (%) Psychosis with prominent catatonic features, n (%) No. of catatonia signs, mean (s.d.) Severity of catatonia, mean (s.d.) Factor 1: classical catatonia (s.d.) Factor 2: bizarre motility (s.d.) Factor 3: abnormal motor activity (s.d.)
SZ
NSNAP
BD
MDD
Total
131 (33.2) 132 (33.4) 208 (52.7) 98 (24.8) 43 (10.9) 74 (18.7) 81 (20.5) 39 (9.9) 79 (20.0) 150 (38.8) 163 (41.3) 47 (11.9) 2.50 (2.45) 1.51 (1.71) 0.64 (1.57) 1.24 (1.69) 0.37 (1.03)
126 (42.9) 98 (33.3) 44 (15.0) 34 (11.6) 27 (9.2) 35 (11.9) 77 (26.2) 28 (9.5) 47 (16.0) 50 (17.0) 94 (32.0) 32 (12.2) 1.91 (2.43) 1.24 (1.74) 0.47 (1.50) 0.23 (1.23) 0.73 (1.20)
159 (66.5) 90 (37.7) 25 (10.5) 25 (10.5) 14 (5.9) 23 (9.6) 44 (18.4) 13 (5.4) 37 (15.5) 26 (10.9) 70 (29.3) 15 (6.3) 1.99 (2.01) 1.17 (1.59) 0.28 (1.26) 0.05 (0.95) 1.72 (0.83)
129 (77.7) 26 (15.7) 11 (6.6) 21 (12.7) 7 (4.2) 17 (10.2) 35 (21.1) 2 (1.2) 25 (15.1) 11 (6.6) 36 (21.7) 12 (7.2) 2.12 (1.87) 0.86 (1.47) 0.28 (1.24) 0.20 (0.74) 0.89 (0.78)
545 (49.8) 346 (31.6) 288 (26.3) 178 (16.3) 91 (8.3) 149 (13.6) 237 (21.7) 82 (7.5) 188 (17.2) 237 (11.7) 363 (33.2) 106 (9.7) 2.17 (2.29) 1.27 (1.66) 0.46 (1.45) 0.49 (1.43) 0.84 (1.12)
SZ: schizophrenia; NSNAP: nonschizophrenic nonaffective psychosis; BD: bipolar disorder; MDD: major depressive disorder.
V. Peralta et al. / Schizophrenia Research 200 (2018) 20–25 Table 4 Familiality estimates for catatonia signs and syndromes.
Catatonia signs Psychomotor retardation Excitement Ritualistic/stereotyped behavior Mutism Waxy flexibility Rigidity Stupor Echophenomena Negativism Mannerisms/posturing Catatonia syndromes Factor 1: classical catatonia Factor 2: bizarre motility Factor 3: abnormal motor activity
23
Table 6 Familiality estimates for catatonia syndromes across diagnostic classes.
h2
95% CI
s.e.
Z
p
Catatonia syndromes
Diagnostic classes
h2
95% CI
s.e.
Z
p
0.17 0.24 0.31 0.65 0.29 0.65 0.47 0.26 0.40 0.44
0.13–0.22 0.19–0.30 0.25–0.40 0.56–0.77 0.22–0.36 0.55–0.78 0.39–0.57 0.20–0.32 0.31–0.51 0.36–0.54
0.06 0.08 0.11 0.15 0.22 0.17 0.13 0.22 0.15 0.13
2.53 2.83 2.87 4.25 3.38 3.78 3.51 3.24 2.73 3.35
0.011 0.005 0.004 b0.001 0.006 b0.001 b0.001 0.008 0.006 0.001
DSM-IV catatonia diagnosis
0.49 0.38 0.29
0.40–0.58 0.30–0.47 0.23–0.37
0.13 0.13 0.11
3.72 3.01 2.75
b0.001 0.003 0.006
SZ NSNAP BD MDD SZ NSNAP BD MDD SZ NSNAP BD MDD SZ NSNAP BD MDD
0.40 0.44 0.47 0.45 0.54 0.57 0.61 0.58 0.27 0.37 0.39 0.38 0.14 0.22 0.22 0.18
0.34–0.48 0.37–0.52 0.40–0.55 0.39–0.53 0.45–0.63 0.48–0.67 0.52–0.71 0.49–0.68 0.20–0.35 0.29–0.47 0.31–0.48 0.30–0.47 0.10–0.19 0.17–0.27 0.17–0.27 0.13–0.23
0.10 0.11 0.11 0.11 0.13 0.14 0.14 0.14 0.12 0.14 0.13 0.13 0.07 0.08 0.08 0.08
4.00 4.00 4.26 4.22 4.04 4.03 4.26 4.02 2.27 2.65 3.05 3.02 1.97 2.76 2.94 2.30
b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 0.026 0.008 b0.001 0.003 0.048 0.006 0.003 0.022
and mutism (both h2 = 0.65); substantial familial aggregation (h2 between 0.40 and 0.60) was observed for stupor, negativism and mannerism/posturing, and the other signs showed a fair level familial aggregation (h2 between 0.17 and 0.31). The classical catatonia factor had the highest familiality (h2 = 0.49) of the catatonia factors, which was due to the fact that most of their constituting items had substantial familiality. Number of catatonia signs showed increasing familial aggregation up to 5 signs (h2 = 0.43), and severity of catatonia syndrome showed increasing familial aggregation up to moderate or higher severity degree (h2 = 0.59) (Table 5). The diagnostic construct of psychosis with prominent catatonia features also exhibited substantial familiality (h2 = 0.56). Lastly, we also examined the familiality of a DSM-IV diagnosis of catatonia and the PCA-derived syndromes across diagnostic categories by controlling for specific diagnoses in the linear mixed models. Familiality estimates were fairly similar across the diagnostic categories with no statistically significant differences between diagnoses as showed by non-overlapping confidence intervals (Table 6). 4. Discussion 4.1. Main findings This study examined for the first time the familial aggregation of alternative catatonia phenotypes in a broad sample of multiple affected families with psychotic and mood disorders. Multiplex families represent a powerful tool for examining the familial-genetic underpinnings of complex diseases and are the starting point for both the heritability and linkage studies that underlie much of our knowledge of complex
Table 5 Familiality estimates for number of catatonia signs present, severity levels of a DSM-IV catatonia diagnosis and psychosis with prominent catatonic features.
No. of catatonia signs ≥1 ≥2 ≥3 ≥4 ≥5 ≥6 ≥7 Severity of a DSM-IV catatonia diagnosis Sub-umbral catatonia or higher Mild catatonia or higher Moderate catatonia or higher Severe catatonia Psychosis with prominent catatonia features
h2
95% CI
s.e.
Z
p
0.03 0.05 0.14 0.33 0.43 0.33 0.30
0.00–0.06 0.03–0.09 0.10–0.19 0.27–0.41 0.36–0.52 0.25–0.44 0.22–0.39
0.04 0.05 0.08 0.10 0.12 0.14 0.16
0.92 1.09 2.03 3.40 3.60 2.36 2.51
0.428 0.275 0.043 0.001 b0.001 0.018 0.022
0.25 0.33 0.59 0.49 0.56
0.20–0.31 0.27–0.40 0.50–0.68 0.39–0.62 0.44–0.71
0.08 0.10 0.13 0.17 0.20
3.24 3.32 3.37 2.92 2.86
0.001 0.001 b0.001 0.004 0.003
Classical catatonia syndrome
Bizarre motility syndrome
Abnormal motor activity syndrome
SZ: schizophrenia; NSNAP: nonschizophrenic nonaffective psychosis; BD: bipolar disorder; MDD: major depressive disorder.
diseases (Wu et al., 2015). In this article, we assume that familiality – phenotypic resemblance among first-degree relatives– is a useful standard that can guide the selection of phenotypes that will be most effective in defining genetically homogeneous forms of disorders (Risch and Teng, 1998). We found that the way in which catatonia is defined has a strong impact on familiality estimates, and four may be considered as the main findings of this study. First, individual catatonia signs exhibited statistically significant familiality although with a broad range of variation; whereas frequent catatonia signs such as psychomotor retardation and excitement showed fair familiality, classical signs such as rigidity and mutism showed high familiality estimates. Second, empirical clustering of catatonic features confirmed the familiality pattern of individual signs, as the classical catatonia factor showed substantial familiality, the abnormal motor activity factor showed fair familiality with the bizarre motor behavior factor falling in-between. Third, number of catatonia signs and severity of catatonia, which were highly correlated, meaningfully influenced familiality estimates, with 5 or more catatonia signs and a moderate or higher severity level of catatonia showing substantial familiality; in a similar vein, the diagnostic construct of psychosis with prominent catatonia features exhibited substantial familiality. Lastly, familiality of catatonia was not meaningfully influenced by diagnostic class, which supports their consideration, from a familial-genetic perspective, as an unspecific syndrome within psychotic and mood disorders. 4.2. Comparison with the literature Given that this is the first study examining levels of familial aggregation of different definitions of the catatonia phenotype, our results are not readily comparable with any in the literature. However, and considering that our familiality estimates measure the maximal effect of genes (Rice, 2008), some aspects of our results merit comments in relation to previous studies reporting heritability estimates. Overall, those catatonia phenotypes maximizing the familiality estimates (i.e., mutism, rigidity, classical catatonia factor, catatonia severity at the level of moderate or higher, presence of at least 5 catatonia signs, psychosis with prominent catatonia features) do have similar h2 figures than those reported in other family studies for the diagnoses of psychotic and major mood disorders (h2 ~ 60%) (Lichtenstein et al., 2009; Wray and Gottesman, 2012) but lower than those reported in twin studies (h2 ~ 80%) (Cardno et al., 1999; McGuffin et al., 2003). The only previous studies that have examined the familial aggregation of different catatonia phenotypes across psychotic disorders are those from the Leonhard's school (Leonhard, 1957; Stöber et al., 1995; Franzek and Beckmann, 1998, 1999) but their results cannot be directly compared with ours mainly
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because of lack of correspondence of catatonia definitions and nosologic backgrounds. More specifically, a heritability estimate of 0.46 has been reported for periodic catatonia (Franzek and Beckmann, 1998), but this highly specific catatonia form is not comparable to any of our catatonia definitions. Lastly, a previous study found that a PCA-derived catatonia syndrome exhibited similar familiality levels in schizophrenia, affective disorders and psychotic disorders (Van Os et al., 1997), which is in agreement with our findings. Overall, catatonia cut-across all categories of psychotic and mood disorders although some differences in the prevalence pattern of specific motor signs and dimensions are evident (for a systematic review of the matter see Peralta and Cuesta (2017)). Thus, data from the present study and the literature do not support the view of catatonia as a subtype of schizophrenia (Kraepelin, 1919) nor the alternative view that catatonia is particularly prevalent in mood disorders (Abrams and Taylor, 1976). Regarding the factor structure of catatonia, our finding of a single abnormal motor activity factor is at odds with those of the literature (see Peralta and Cuesta (2017) for a review), which usually identify separate retarded and excited factors. This discordance may be explained by the lifetime nature of our assessment in contrast to the usual cross-sectional assessment of motor features in other studies, which putatively favours the finding of separate abnormal motor activity factors.
4.3. Implications The substantial familiality of some catatonia phenotypes found in this study suggests that they are adequate candidates for molecular genetic studies, which may shed light no only on the nature of these particular phenotypes but also on that of the underlying disorder. Furthermore, both the high prevalence and substantial familial aggregation of catatonia in psychotic and mood disorders reinforces the consideration of catatonia as a core domain within these disorders. In this regard, our data support both the divorce of catatonia from schizophrenia held by DSM-5 and its consideration as a specifier in psychotic and mood disorders (Heckers et al., 2010). Catatonia is usually diagnosed by the presence of any three signs (APA, 2013; Peralta and Cuesta, 2001b; Peralta et al., 2010), which sharply contrast with our finding that the presence of 5 or more signs achieved the highest familiality. Acknowledging that the validity of a given clinical phenotype may vary depending on the type of validators considered (Kendler, 1990), our study suggests that defining catatonia by the presence of at least 5 signs may be most appropriate for genetic studies, but not necessarily for other purposes. Furthermore, and providing that number of catatonia signs and catatonia severity are highly correlated, establishing a specified severity level for the catatonia syndrome to determine, for example, treatment with electro-convulsive therapy, may converge with the higher genetic validity of the syndrome. Additionally, and given the high familiality of rigidity and mutism, they should be included in any diagnostic criteria of catatonia, since mutism but not rigidity is included in DSM-5 criteria. In the last years, it has been much debated about whether catatonia should be considered as an independent syndrome within the DSM-5 or not (Francis et al., 2010; Fink et al., 2010; Heckers et al., 2010). However, the intermingled relationships of catatonia signs and syndromes with other domains of psychopathology and diagnoses of psychotic disorders (Peralta et al., 2001), together with the transdiagnostic character of catatonia in terms of familial risk factors, do not support their consideration as an independent syndrome, at least within the framework of psychotic and mood disorders; thus reinforcing the position of DSM-5 of considering catatonia as an unspecific syndrome (Tandon et al., 2013). Notwithstanding this, the substantial familiality of the diagnostic construct of psychosis with prominent catatonic features deserves to be further examined for confirmation and additional examination of risk factors and clinical underpinnings.
4.4. Limitations Several limitations need to be considered when interpreting our findings. First, our familiality estimates quantify the strength of familial resemblance and represents the percentage of variance that is due to all familial effects including additive genetic and those of the familial environment, thus we could not distinguish between genetic and environmental contributions to familial aggregation. However, while everything familial is not genetic, variables that are not familial are unlikely to be genetically informative, and most of the familial resemblance of psychotic and mood disorders is due to genetic factors (Cardno et al., 1999; Lichtenstein et al., 2009). Second, our ascertainment strategy may result in cohort effects due to the selection of family members willing to participate, which may have limited recruitment of more severely disturbed or socially isolated patients. Nevertheless, any such effect should be relatively weak because the Mental Health Service of Navarra is public and highly accessible as most people with psychoses have contact with psychiatric services (Mata et al., 2000). Third, the familiality estimates need to be interpreted as pertaining to our population of psychotic subjects from multiplex families, and extrapolation of our results to more general populations of psychotic and mood disorders should be done cautiously; this limitation, however, does not necessarily invalidate our results, since our primary goal was examining these estimates across catatonia phenotypes rather than estimating the familial risk in the general population. Lastly, we included a limited number of catatonia signs, and although these are among the more commonly recognized catatonia manifestations, including a broader range of signs might have led to different results. Funding source This study was funded by the Department of Health of the Government of Navarra (14/2010); Ministerio de Educación y Ciencia (SAF2008-05674-C03-01-02); Comissionat per a Universitats I Recerca del DIUE (2009SGR827) and Instituto de Salud Carlos III (PI/6//02148). Contributors Victor Peralta and Manuel J. Cuesta designed the study and wrote the manuscript. Lourdes Fañanás and Migdyrai Martín-Reyes managed the statistical analyses. All authors contributed to and have approved the final manuscript. Conflict of interest None.
Acknowledgement None.
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