© 2014 John Wiley & Sons A/S Published by John Wiley & Sons Ltd.
Bipolar Disorders 2014: 16: 633–641
BIPOLAR DISORDERS
Original Article
Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis Akabaliev VH, Sivkov ST, Mantarkov MY. Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis. Bipolar Disord 2014: 16: 633–641. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Minor physical anomalies (MPAs) have been investigated by numerous studies in patients with schizophrenia in support of the neurodevelopmental hypothesis of the disorder, but have rarely been examined in patients with bipolar disorder or in direct comparisons between the two conditions. The main objective of the present study was to compare the prevalence of MPAs in psychiatrically healthy controls, patients with bipolar I disorder, and patients with schizophrenia. Methods: A slightly modified version of the Waldrop Physical Anomaly Scale was used to assess MPAs in psychiatrically healthy controls (n = 103), patients with bipolar I disorder (n = 61), and patients with schizophrenia (n = 128). Results: In five out of six topographic regions (mouth, feet, head, eyes, and ears) there was a pattern of lowest regional MPA scores in controls, intermediate in bipolar I disorder, and highest in schizophrenia. The cephalofacial composite score and the total MPA score showed the same pattern, with all between-group differences being statistically significant. Seven individual MPAs in the discriminant analysis model contributed independently to the prediction of the triple-dependent status of ‘psychiatrically healthy control, bipolar I disorder patient, schizophrenia patient’: high/arched palate, fine electric hair, large gap between first and second toes, third toe ≥ second toe, epicanthus, malformed ears, and furrowed tongue. Conclusions: Our findings support the existence of a continuum of neurodevelopmental adversity within the clinical spectrum of psychosis, with bipolar I disorder occupying an intermediate position between psychiatric health and schizophrenia.
As early as 1899, Emil Kraepelin (1) divided psychotic illness into two diagnostic categories: dementia praecox and manic-depressive insanity. The distinction between the two disorders, now known as schizophrenia and bipolar disorder, has been perpetuated in psychiatric nosology over the last century and is currently maintained by the two contemporary diagnostic systems, ICD-10 (2) and DSM-IV (3). The neurodevelopmental hypothesis of schizophrenia was developed in the second half of the
Valentin Hristov Akabalieva, Stefan Todorov Sivkovb and Mladen Yordanov Mantarkova a Department of Psychiatry and Medical Psychology, bDepartment of Anatomy, Histology and Embryology, Medical University, Plovdiv, Bulgaria
doi: 10.1111/bdi.12211 Key words: bipolar I disorder – minor physical anomalies – neurodevelopmental hypothesis – psychotic continuum – schizophrenia Received 13 November 2011, revised and accepted for publication 26 November 2013 Corresponding author: Dr. Mladen Y. Mantarkov Department of Psychiatry and Medical Psychology Medical University, Plovdiv 15A V. Aprilov Boulevard Plovdiv 4002 Bulgaria Fax: +359-32-641-599 E-mail: [email protected]
20th century (4–6) and was revived for both schizophrenia and affective disorders at the turn of the millennium (7–10). It posits that genetic and environmental factors contribute to structural and functional brain changes in the pre- and perinatal periods that increase the risk of disease in later life. Environmental factors may act on a common genetic vulnerability to psychosis to produce schizophrenia, schizoaffective, or mood disorder outcomes (11–13). An authoritative model of
633
Akabaliev et al. differences and similarities between the two disorders (14) has theorized that schizophrenia, but not bipolar disorder, may be ‘subject to additional genes or early insults, which impair neurodevelopment’. However, it is likely that environmental factors themselves confer an additional risk of psychosis across the Kraepelinian divide (15–22). Minor physical anomalies (MPAs) are considered to be phenotypic stigmata of developmental abnormality (23). They comprise a range of subtle, clinically, and cosmetically insignificant errors in the development of morphological structures found in the eyes, ears, mouth, head, hands, and feet (24). As the structures that express MPAs have the same embryonic origin as the central nervous system, MPAs may be valuable biological markers of abnormal brain development (25). MPAs include minor malformations and phenogenetic variants. The former result from impacts that occur during organogenesis (before the 14th gestational week) and can be found in less than 4% of the population. Phenogenetic variants arise after the completion of organogenesis and are observed in more than 4% of the population (26, 27). Once formed, MPAs are not altered either by the subsequent illness, its consequences, or treatment (24). In schizophrenia, the excessive prevalence of MPAs seems firmly established (28); however, to date, relatively few studies in affective disorders have been published (29). Direct comparisons of MPAs between patient groups with affective disorders and schizophrenia are limited. Some have found no differences in the rate of MPAs between patients with schizophrenia and affective disorders (30) while others suggest a significantly higher total MPA score in patients with schizophrenia in comparison with patients with bipolar disorder and psychiatrically healthy controls alike (31, 32). All studies suffer from small sample sizes and inclusion of patients with a spectrum of affective disorders that make the results difficult to interpret. With one exception (32), relevant previous research has used total MPA score of the Waldrop Physical Anomaly Scale as the only outcome measure. However, this scale has been shown to have poor internal consistency in schizophrenia (33) as it combines a heterogeneous group of malformations from different body regions with varying degrees of correlation with the development of the brain and makes no distinction between minor malformations and phenogenetic variants (27, 29, 32, 34). The aim of the present study was to examine MPAs in psychiatrically healthy controls, patients with bipolar I disorder, and patients with schizophrenia. In view of the available literature on prenatal environmental insults in schizophrenia and
634
bipolar disorder, we hypothesized that differences in the prevalence of MPAs might be found between these three groups. We also hypothesized that MPAs of the cephalofacial region may be able to discriminate better between the examined groups as they correlate more strongly with the abnormal development of the brain (24, 35, 36).
Methods Participants
The schizophrenia group consisted of 128 patients (66 men, 62 women) consecutively admitted to the Clinic of Psychiatry (Plovdiv, Bulgaria): mean age 32.09 years [standard deviation (SD) = 9.73 years], mean duration of illness 8.02 years (SD = 7.33 years), and mean number of hospitalizations 4.98 (SD = 5.36). The bipolar I disorder group comprised 61 patients (25 men, 36 women) consecutively admitted to the same clinic: mean age 38.15 years (SD = 14.81 years), mean duration of illness 10.57 years (SD = 11.16 years), and mean number of hospitalizations 4.75 (SD = 4.32). The patients satisfied DSM-IV criteria for a diagnosis of schizophrenia and bipolar I disorder, respectively (3) on the basis of case records review, a semi-structured interview based on a checklist of items from DSMIV (performed by one of the study psychiatrists), and information obtained from relatives to enhance the validity of the diagnosis. Potential subjects were excluded if they had any signs of mental retardation, a history of drug or alcohol abuse, an identifiable neurological disorder (seizure disorder, head injury, multiple sclerosis, etc.), or a general medical condition with direct effects on the central nervous system. The psychiatrically healthy comparison group consisted of 103 subjects (49 men, 54 women) with a mean age of 39.65 years (SD = 10.68 years) and socioeconomic background comparable to that of the patients. Psychiatric health was defined as the absence of a major Axis I or Axis II disorder according to DSM-IV criteria (3). The mean age of the control group was greater than that of the two patient groups in order to minimize the cumulative risk of developing future major psychiatric disorder. The controls satisfied exclusion criteria similar to those applied to the patients. In addition, to better separate the controls from the patient groups, potential controls were excluded if they had a firstdegree relative with a history of psychotic disorder, major mood disorder, or suicide. In order to avoid the potential confounding effects of racial and ethnic variation in the
MPAs in schizophrenia and bipolar I disorder rate items because of the high prevalence of the former and only occasional occurrence of the latter. As a result of this distinction, our modification of the scale consisted of 19 items (Table 1). Furrowed tongue was graded by scoring 1 for randomly furrowed tongue (a normal variant) and a score of 2 for transversely furrowed tongue (frequently observed in pathological conditions). In the original scale, both types are scored as a value = 1. To determine the variable ‘low-seated ears’, we verified the ear canal position by the level of the ear canal on the head in relation to the midface, with the head of the subject placed in the Frankfurt horizontal line. Intercanthal distance abnormality was also determined in cases of hypotelorism. The intercanthal distance as well as the head circumference were scored as 1 if they differed from the same-sex mean for psychiatrically healthy controls by 1.5–2.0 SDs and 2 if they differed by more than two SDs in both directions. All examinations were performed by the same assessor (the study anatomist), who had had no formal psychiatric training. Additionally, in order to minimize potential scorer bias, the assessor was not granted access to case-report forms and performed all assessments after the patients had
expression of MPAs, all patients and controls were of Bulgarian ethnicity; individuals were excluded if their parental or grandparental ethnic group was other than Bulgarian. The study was approved by the local Ethics Committee and all subjects gave written informed consent to participate. Assessment of MPAs
The subjects were examined with a slightly modified version of the Waldrop Physical Anomaly Scale (37). The original scale includes 18 morphological abnormalities from six body regions: head, eyes, ears, mouth, hands, and feet. Most of the abnormalities are scored qualitatively as present (given a value = 1) or absent (given a value = 0). The variables (fine electric hair, head circumference, epicanthus, intercanthal distance, low-seated ears, high/arched palate, and third toe ≥ second) are scored in a graded manner (i.e., a value of 1 or 2, according to severity). For the present study, we introduced the following modifications: the categories ‘adherent ear lobes’ and ‘lower edges of the ears that extend backward/upward’ (two grades of a single item in the original scale) were defined as sepa-
Table 1. Three-group discriminant analysis between controls, patients with bipolar I disorder, and patients with schizophrenia
Predictor variables Included in the model High/arched palate Fine electric hair Big gap between first and second toes Third toe ≥ second toe Epicanthus Malformed ears Furrowed tongue Excluded from the model Lower edges of the ears that extend back/upward Abnormal head circumference Single transverse palmar crease Hair whorls ≥ 2 Tongue with smooth/rough spots Adherent ear lobes Abnormal intercanthal distance Partial syndactyly of second and third toe Low-seated ears Soft and pliable ears Curved fifth finger Asymmetrical ears
Canonical discriminant coefficient (standardized)
Correlation function-variablea
Wilks’ lambda
F function 1
F function 2
F function 1
F function 2
Value
df
F
p-value
0.26 0.39 0.19 0.29 0.30 0.28 0.71
0.64 0.42 0.37 0.24 0.27 0.21 0.20
0.34 0.26 0.18 0.36 0.34 0.25 0.71
0.84 0.78 0.74 0.71 0.69 0.67 0.65
2/287 4/572 6/570 8/568 10/566 12/564 14/562
27.93 18.82 15.47 13.30 11.60 10.47 9.64
0.000 0.000 0.000 0.000 0.000 0.000 0.000
0.096 0.146 0.040 0.019 0.047 0.029 0.050 0.079 0.019 0.115 0.046 0.120
0.08 0.08 0.01 0.00 0.03 0.00 0.02 0.03 0.04 0.07 0.03 0.10
0.64 0.64 0.64 0.64 0.64 0.65 0.64 0.65 0.65 0.65 0.65 0.65
0.67 0.44 0.43 0.30 0.29 0.28 0.12
3.37 2.59 2.46 1.98 1.78 1.17 1.56 1.36 0.97 0.49 0.48 0.34
a
Indicates the highest absolute correlation between variable and canonical function.
635
Akabaliev et al. received adequate psychopharmacological treatment. Reliability studies were conducted using a second assessor, who was not otherwise involved in the study and was blinded to diagnosis under the same conditions. The second assessor separately examined 30 patients with schizophrenia (15 men, 15 women) and 20 psychiatrically healthy controls (ten men, ten women) from the current study groups. With the exception of one item, Cohen’s j for concordance between categorical/ordinal scores were all > 0.75 and intra-class correlation coefficients for continuous measures were > 0.78. As an acceptable level of reliability was not reached for ‘curved fifth finger’ owing to the lack of clear definitions of its first and second grades (j < 0.60), we introduced another modification to the scale. This item was scored only as present (value = 1) or absent (value = 0), while in the original scale its presence was weighted with a score of 1 or 2. Statistical analyses
Summary scores were calculated for each topographic region, for the two composite regions [the cephalofacial complex (MPA-CF) and the periphery (MPA-P)], and for the total scale (MPA-T). MPA distribution indices (MPA-CF–MPA-P)/ MPA-T were also calculated. We analyzed the data with SPSS 15.0 (Chicago, IL, USA) using descriptive statistics, graphical analysis, analysis of variance with Tukey’s honestly significant difference test (HSD) for multiple comparisons, and three-group discriminant analysis (forward stepwise selection) to test the predictive value of MPAs in the triple-dependent status ‘psychiatrically healthy control, bipolar I disorder
patient, schizophrenia patient’. In the discriminant analysis, the criterion minimization of Wilks’ lambda was used for entering the model. The significance of a change in Wilks’ lambda for entering or exiting the model was based on F-statistics. In the analysis, the 19 MPA items of the scale were the set of independent predictor variables, and the status ‘psychiatrically healthy control, bipolar I disorder patient, schizophrenia patient’ was the tripledependent variable. One subject from the bipolar I disorder group was excluded from the analysis as we could not ascertain all the variables from the scale for that particular subject. The level of statistical significance was set at p < 0.05. Results Comparison of MPA scores between controls, patients with bipolar I disorder, and patients with schizophrenia
In five out of six topographic regions (mouth, feet, head, eyes, and ears), there was a marked pattern of lowest mean regional MPA scores in controls, intermediate in bipolar disorder, and highest in schizophrenia, although not all between-group comparisons showed statistically significant differences (Table 2, Fig. 1). Psychiatrically healthy controls scored significantly lower than patients with schizophrenia in all five regions and lower than patients with bipolar disorder in the mouth and feet regions (p < 0.05). Patients with bipolar disorder scored significantly lower than patients with schizophrenia only in the eyes region (p < 0.05). The hands region was the only exception to the above-mentioned pattern. The hands region was most abnormal in patients with bipolar I disorder, followed by controls and patients with
Table 2. Comparison of regional and total minor physical anomalies (MPA) scores between controls, patients with bipolar I disorder, and patients with schizophrenia CON (n = 103)
BD-I (n = 61)
SCH (n = 128)
Statistical significancea
Topographic region
Mean (SD)
Mean (SD)
Mean (SD)
CON versus BD-I
CON versus SCH
Head Eyes Ears Mouth Cephalofacial region Hands Feet Periphery Total MPA Index of distribution
0.50 (0.77) 0.17 (0.47) 0.95 (0.87) 0.51 (0.80) 2.15 (1.59) 0.56 (0.64) 0.36 (0.64) 0.49 (0.85) 3.07 (1.83) 0.36 (0.62)
0.77 (0.90) 0.25 (0.57) 1.07 (0.81) 1.43 (1.27) 3.51 (1.79) 0.62 (0.66) 0.68 (0.79) 1.32 (1.00) 4.85 (1.84) 0.42 (0.46)
0.99 (1.00) 0.47 (0.70) 1.34 (1.01) 1.54 (1.15) 4.33 (1.91) 0.42 (0.56) 0.85 (0.83) 1.27 (0.99) 5.61 (2.19) 0.55 (0.34)
< 0.05 < 0.05
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05
< 0.05 < 0.05 < 0.05
BD-I = bipolar I disorder; CON = controls; SCH = schizophrenia; SD = standard deviation. Analysis of variance with Tukey’s honestly significant difference for multiple comparisons (p < 0.05).
a
636
< 0.05
Bipolar Disorders 2014: 16: 633–641
BIPOLAR DISORDERS
Original Article
Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis Akabaliev VH, Sivkov ST, Mantarkov MY. Minor physical anomalies in schizophrenia and bipolar I disorder and the neurodevelopmental continuum of psychosis. Bipolar Disord 2014: 16: 633–641. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Objectives: Minor physical anomalies (MPAs) have been investigated by numerous studies in patients with schizophrenia in support of the neurodevelopmental hypothesis of the disorder, but have rarely been examined in patients with bipolar disorder or in direct comparisons between the two conditions. The main objective of the present study was to compare the prevalence of MPAs in psychiatrically healthy controls, patients with bipolar I disorder, and patients with schizophrenia. Methods: A slightly modified version of the Waldrop Physical Anomaly Scale was used to assess MPAs in psychiatrically healthy controls (n = 103), patients with bipolar I disorder (n = 61), and patients with schizophrenia (n = 128). Results: In five out of six topographic regions (mouth, feet, head, eyes, and ears) there was a pattern of lowest regional MPA scores in controls, intermediate in bipolar I disorder, and highest in schizophrenia. The cephalofacial composite score and the total MPA score showed the same pattern, with all between-group differences being statistically significant. Seven individual MPAs in the discriminant analysis model contributed independently to the prediction of the triple-dependent status of ‘psychiatrically healthy control, bipolar I disorder patient, schizophrenia patient’: high/arched palate, fine electric hair, large gap between first and second toes, third toe ≥ second toe, epicanthus, malformed ears, and furrowed tongue. Conclusions: Our findings support the existence of a continuum of neurodevelopmental adversity within the clinical spectrum of psychosis, with bipolar I disorder occupying an intermediate position between psychiatric health and schizophrenia.
As early as 1899, Emil Kraepelin (1) divided psychotic illness into two diagnostic categories: dementia praecox and manic-depressive insanity. The distinction between the two disorders, now known as schizophrenia and bipolar disorder, has been perpetuated in psychiatric nosology over the last century and is currently maintained by the two contemporary diagnostic systems, ICD-10 (2) and DSM-IV (3). The neurodevelopmental hypothesis of schizophrenia was developed in the second half of the
Valentin Hristov Akabalieva, Stefan Todorov Sivkovb and Mladen Yordanov Mantarkova a Department of Psychiatry and Medical Psychology, bDepartment of Anatomy, Histology and Embryology, Medical University, Plovdiv, Bulgaria
doi: 10.1111/bdi.12211 Key words: bipolar I disorder – minor physical anomalies – neurodevelopmental hypothesis – psychotic continuum – schizophrenia Received 13 November 2011, revised and accepted for publication 26 November 2013 Corresponding author: Dr. Mladen Y. Mantarkov Department of Psychiatry and Medical Psychology Medical University, Plovdiv 15A V. Aprilov Boulevard Plovdiv 4002 Bulgaria Fax: +359-32-641-599 E-mail: [email protected]
20th century (4–6) and was revived for both schizophrenia and affective disorders at the turn of the millennium (7–10). It posits that genetic and environmental factors contribute to structural and functional brain changes in the pre- and perinatal periods that increase the risk of disease in later life. Environmental factors may act on a common genetic vulnerability to psychosis to produce schizophrenia, schizoaffective, or mood disorder outcomes (11–13). An authoritative model of
633
Akabaliev et al. differences and similarities between the two disorders (14) has theorized that schizophrenia, but not bipolar disorder, may be ‘subject to additional genes or early insults, which impair neurodevelopment’. However, it is likely that environmental factors themselves confer an additional risk of psychosis across the Kraepelinian divide (15–22). Minor physical anomalies (MPAs) are considered to be phenotypic stigmata of developmental abnormality (23). They comprise a range of subtle, clinically, and cosmetically insignificant errors in the development of morphological structures found in the eyes, ears, mouth, head, hands, and feet (24). As the structures that express MPAs have the same embryonic origin as the central nervous system, MPAs may be valuable biological markers of abnormal brain development (25). MPAs include minor malformations and phenogenetic variants. The former result from impacts that occur during organogenesis (before the 14th gestational week) and can be found in less than 4% of the population. Phenogenetic variants arise after the completion of organogenesis and are observed in more than 4% of the population (26, 27). Once formed, MPAs are not altered either by the subsequent illness, its consequences, or treatment (24). In schizophrenia, the excessive prevalence of MPAs seems firmly established (28); however, to date, relatively few studies in affective disorders have been published (29). Direct comparisons of MPAs between patient groups with affective disorders and schizophrenia are limited. Some have found no differences in the rate of MPAs between patients with schizophrenia and affective disorders (30) while others suggest a significantly higher total MPA score in patients with schizophrenia in comparison with patients with bipolar disorder and psychiatrically healthy controls alike (31, 32). All studies suffer from small sample sizes and inclusion of patients with a spectrum of affective disorders that make the results difficult to interpret. With one exception (32), relevant previous research has used total MPA score of the Waldrop Physical Anomaly Scale as the only outcome measure. However, this scale has been shown to have poor internal consistency in schizophrenia (33) as it combines a heterogeneous group of malformations from different body regions with varying degrees of correlation with the development of the brain and makes no distinction between minor malformations and phenogenetic variants (27, 29, 32, 34). The aim of the present study was to examine MPAs in psychiatrically healthy controls, patients with bipolar I disorder, and patients with schizophrenia. In view of the available literature on prenatal environmental insults in schizophrenia and
634
bipolar disorder, we hypothesized that differences in the prevalence of MPAs might be found between these three groups. We also hypothesized that MPAs of the cephalofacial region may be able to discriminate better between the examined groups as they correlate more strongly with the abnormal development of the brain (24, 35, 36).
Methods Participants
The schizophrenia group consisted of 128 patients (66 men, 62 women) consecutively admitted to the Clinic of Psychiatry (Plovdiv, Bulgaria): mean age 32.09 years [standard deviation (SD) = 9.73 years], mean duration of illness 8.02 years (SD = 7.33 years), and mean number of hospitalizations 4.98 (SD = 5.36). The bipolar I disorder group comprised 61 patients (25 men, 36 women) consecutively admitted to the same clinic: mean age 38.15 years (SD = 14.81 years), mean duration of illness 10.57 years (SD = 11.16 years), and mean number of hospitalizations 4.75 (SD = 4.32). The patients satisfied DSM-IV criteria for a diagnosis of schizophrenia and bipolar I disorder, respectively (3) on the basis of case records review, a semi-structured interview based on a checklist of items from DSMIV (performed by one of the study psychiatrists), and information obtained from relatives to enhance the validity of the diagnosis. Potential subjects were excluded if they had any signs of mental retardation, a history of drug or alcohol abuse, an identifiable neurological disorder (seizure disorder, head injury, multiple sclerosis, etc.), or a general medical condition with direct effects on the central nervous system. The psychiatrically healthy comparison group consisted of 103 subjects (49 men, 54 women) with a mean age of 39.65 years (SD = 10.68 years) and socioeconomic background comparable to that of the patients. Psychiatric health was defined as the absence of a major Axis I or Axis II disorder according to DSM-IV criteria (3). The mean age of the control group was greater than that of the two patient groups in order to minimize the cumulative risk of developing future major psychiatric disorder. The controls satisfied exclusion criteria similar to those applied to the patients. In addition, to better separate the controls from the patient groups, potential controls were excluded if they had a firstdegree relative with a history of psychotic disorder, major mood disorder, or suicide. In order to avoid the potential confounding effects of racial and ethnic variation in the
MPAs in schizophrenia and bipolar I disorder rate items because of the high prevalence of the former and only occasional occurrence of the latter. As a result of this distinction, our modification of the scale consisted of 19 items (Table 1). Furrowed tongue was graded by scoring 1 for randomly furrowed tongue (a normal variant) and a score of 2 for transversely furrowed tongue (frequently observed in pathological conditions). In the original scale, both types are scored as a value = 1. To determine the variable ‘low-seated ears’, we verified the ear canal position by the level of the ear canal on the head in relation to the midface, with the head of the subject placed in the Frankfurt horizontal line. Intercanthal distance abnormality was also determined in cases of hypotelorism. The intercanthal distance as well as the head circumference were scored as 1 if they differed from the same-sex mean for psychiatrically healthy controls by 1.5–2.0 SDs and 2 if they differed by more than two SDs in both directions. All examinations were performed by the same assessor (the study anatomist), who had had no formal psychiatric training. Additionally, in order to minimize potential scorer bias, the assessor was not granted access to case-report forms and performed all assessments after the patients had
expression of MPAs, all patients and controls were of Bulgarian ethnicity; individuals were excluded if their parental or grandparental ethnic group was other than Bulgarian. The study was approved by the local Ethics Committee and all subjects gave written informed consent to participate. Assessment of MPAs
The subjects were examined with a slightly modified version of the Waldrop Physical Anomaly Scale (37). The original scale includes 18 morphological abnormalities from six body regions: head, eyes, ears, mouth, hands, and feet. Most of the abnormalities are scored qualitatively as present (given a value = 1) or absent (given a value = 0). The variables (fine electric hair, head circumference, epicanthus, intercanthal distance, low-seated ears, high/arched palate, and third toe ≥ second) are scored in a graded manner (i.e., a value of 1 or 2, according to severity). For the present study, we introduced the following modifications: the categories ‘adherent ear lobes’ and ‘lower edges of the ears that extend backward/upward’ (two grades of a single item in the original scale) were defined as sepa-
Table 1. Three-group discriminant analysis between controls, patients with bipolar I disorder, and patients with schizophrenia
Predictor variables Included in the model High/arched palate Fine electric hair Big gap between first and second toes Third toe ≥ second toe Epicanthus Malformed ears Furrowed tongue Excluded from the model Lower edges of the ears that extend back/upward Abnormal head circumference Single transverse palmar crease Hair whorls ≥ 2 Tongue with smooth/rough spots Adherent ear lobes Abnormal intercanthal distance Partial syndactyly of second and third toe Low-seated ears Soft and pliable ears Curved fifth finger Asymmetrical ears
Canonical discriminant coefficient (standardized)
Correlation function-variablea
Wilks’ lambda
F function 1
F function 2
F function 1
F function 2
Value
df
F
p-value
0.26 0.39 0.19 0.29 0.30 0.28 0.71
0.64 0.42 0.37 0.24 0.27 0.21 0.20
0.34 0.26 0.18 0.36 0.34 0.25 0.71
0.84 0.78 0.74 0.71 0.69 0.67 0.65
2/287 4/572 6/570 8/568 10/566 12/564 14/562
27.93 18.82 15.47 13.30 11.60 10.47 9.64
0.000 0.000 0.000 0.000 0.000 0.000 0.000
0.096 0.146 0.040 0.019 0.047 0.029 0.050 0.079 0.019 0.115 0.046 0.120
0.08 0.08 0.01 0.00 0.03 0.00 0.02 0.03 0.04 0.07 0.03 0.10
0.64 0.64 0.64 0.64 0.64 0.65 0.64 0.65 0.65 0.65 0.65 0.65
0.67 0.44 0.43 0.30 0.29 0.28 0.12
3.37 2.59 2.46 1.98 1.78 1.17 1.56 1.36 0.97 0.49 0.48 0.34
a
Indicates the highest absolute correlation between variable and canonical function.
635
Akabaliev et al. received adequate psychopharmacological treatment. Reliability studies were conducted using a second assessor, who was not otherwise involved in the study and was blinded to diagnosis under the same conditions. The second assessor separately examined 30 patients with schizophrenia (15 men, 15 women) and 20 psychiatrically healthy controls (ten men, ten women) from the current study groups. With the exception of one item, Cohen’s j for concordance between categorical/ordinal scores were all > 0.75 and intra-class correlation coefficients for continuous measures were > 0.78. As an acceptable level of reliability was not reached for ‘curved fifth finger’ owing to the lack of clear definitions of its first and second grades (j < 0.60), we introduced another modification to the scale. This item was scored only as present (value = 1) or absent (value = 0), while in the original scale its presence was weighted with a score of 1 or 2. Statistical analyses
Summary scores were calculated for each topographic region, for the two composite regions [the cephalofacial complex (MPA-CF) and the periphery (MPA-P)], and for the total scale (MPA-T). MPA distribution indices (MPA-CF–MPA-P)/ MPA-T were also calculated. We analyzed the data with SPSS 15.0 (Chicago, IL, USA) using descriptive statistics, graphical analysis, analysis of variance with Tukey’s honestly significant difference test (HSD) for multiple comparisons, and three-group discriminant analysis (forward stepwise selection) to test the predictive value of MPAs in the triple-dependent status ‘psychiatrically healthy control, bipolar I disorder
patient, schizophrenia patient’. In the discriminant analysis, the criterion minimization of Wilks’ lambda was used for entering the model. The significance of a change in Wilks’ lambda for entering or exiting the model was based on F-statistics. In the analysis, the 19 MPA items of the scale were the set of independent predictor variables, and the status ‘psychiatrically healthy control, bipolar I disorder patient, schizophrenia patient’ was the tripledependent variable. One subject from the bipolar I disorder group was excluded from the analysis as we could not ascertain all the variables from the scale for that particular subject. The level of statistical significance was set at p < 0.05. Results Comparison of MPA scores between controls, patients with bipolar I disorder, and patients with schizophrenia
In five out of six topographic regions (mouth, feet, head, eyes, and ears), there was a marked pattern of lowest mean regional MPA scores in controls, intermediate in bipolar disorder, and highest in schizophrenia, although not all between-group comparisons showed statistically significant differences (Table 2, Fig. 1). Psychiatrically healthy controls scored significantly lower than patients with schizophrenia in all five regions and lower than patients with bipolar disorder in the mouth and feet regions (p < 0.05). Patients with bipolar disorder scored significantly lower than patients with schizophrenia only in the eyes region (p < 0.05). The hands region was the only exception to the above-mentioned pattern. The hands region was most abnormal in patients with bipolar I disorder, followed by controls and patients with
Table 2. Comparison of regional and total minor physical anomalies (MPA) scores between controls, patients with bipolar I disorder, and patients with schizophrenia CON (n = 103)
BD-I (n = 61)
SCH (n = 128)
Statistical significancea
Topographic region
Mean (SD)
Mean (SD)
Mean (SD)
CON versus BD-I
CON versus SCH
Head Eyes Ears Mouth Cephalofacial region Hands Feet Periphery Total MPA Index of distribution
0.50 (0.77) 0.17 (0.47) 0.95 (0.87) 0.51 (0.80) 2.15 (1.59) 0.56 (0.64) 0.36 (0.64) 0.49 (0.85) 3.07 (1.83) 0.36 (0.62)
0.77 (0.90) 0.25 (0.57) 1.07 (0.81) 1.43 (1.27) 3.51 (1.79) 0.62 (0.66) 0.68 (0.79) 1.32 (1.00) 4.85 (1.84) 0.42 (0.46)
0.99 (1.00) 0.47 (0.70) 1.34 (1.01) 1.54 (1.15) 4.33 (1.91) 0.42 (0.56) 0.85 (0.83) 1.27 (0.99) 5.61 (2.19) 0.55 (0.34)
< 0.05 < 0.05
< 0.05 < 0.05 < 0.05 < 0.05 < 0.05
< 0.05 < 0.05 < 0.05
BD-I = bipolar I disorder; CON = controls; SCH = schizophrenia; SD = standard deviation. Analysis of variance with Tukey’s honestly significant difference for multiple comparisons (p < 0.05).
a
636
< 0.05
