Practitioner’s Corner Neurological Soft Signs Discriminate Schizophrenia from Bipolar Disorder
Background. Although neurological soft signs have been consistently described in patients with schizophrenia, their diagnostic specificity is not well clarified. Methods. To test the hypothesis that neurological soft signs are specifically related to schizophrenia, we examined 305 subjects (patients with schizophrenia-spectrum disorder, n = 167; patients with bipolar I disorder, n = 88; controls, n = 50). Neurological soft signs were assessed using the Neurological Evaluation Scale (NES). Multiple logistic regression analysis was used to compute the diagnostic predictive power of neurological soft signs. Results. Patients in the schizophrenia-spectrum disorder group were found to have significantly greater neurological impairment (NES total score = 23.9, standard deviation [SD] 11.2) than those in the bipolar disorder group (NES total score = 18.2, SD 7.6; p < 0.001). Neurological functioning was closely associated with psychopathology (all p < 0.001). The NES total score reliably distinguished patients with schizophrenia spectrum disorders from those with bipolar disorder in 68.7% of the cases (p < 0.001). Moreover, a particular set of neurological soft signs showed specificity for the schizophrenia-spectrum disorder diagnostic group. Conclusions. Our findings suggest that schizophrenia and bipolar disorder can be distinguished in terms of neurological impairment. Furthermore, we recommend the utility of neurological soft signs as a useful, quantifiable, sensitive, and inexpensive tool for the diagnostic work-up of schizophrenia. (Journal of Psychiatric Practice 2014;20:147–153) KEY WORDS: neurological soft signs, Neurological Evaluation Scale, neurological impairment, schizophrenia, bipolar disorder
Journal of Psychiatric Practice Vol. 20, No. 2
SILVIA RIGUCCI, MD GIORGIA DIMITRI-VALENTE, MD GABRIELE MANDARELLI, MD GIOVANNI MANFREDI, MD ANNA COMPARELLI, MD SERGIO DE FILIPPIS, MD SIMONA GHERARDELLI, MD GIUSEPPE BERSANI, MD PAOLO GIRARDI, MD STEFANO FERRACUTI, MD
The diagnosis of schizophrenia based on clinical phenomenology has frequently been challenged in recent years.1 By its nature, a diagnostic approach based solely on the assessment of clinical symptoms could fail to take into account the biological substrate of this complex disorder. Therefore, researchers have recently focused on identifying possible endophenotypes involving neuropsychological, brain morphometric, soft neurologic, and other biological indices that are reliably associated with this pathological condition. Two decades of research on neurological markers of schizophrenia have provided evidence supporting the conceptualization of neurological soft signs—subtle neurological impairment indicating nonlocalizable neurological abnormalities2—as a trait feature of this disorder (for a review, see Bombin et al. 20053). The overrepresentation of these signs among patients with schizophrenia is well established.4–8 However, neurological soft signs are also apparent in numerous other psychiatric disorders, among which bipolar disorder seems to be the only one to lie on a possible continuum with schizophrenia.9 Although some authors have previously demonstrated the specificity of a parRIGUCCI, DIMITRI-VALENTE, MANDARELLI, MANFREDI, COMPARELLI, DE FILIPPIS, GIRARDI, and FERRACUTI: Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Italy; GHERARDELLI and BERSANI: Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy. Copyright ©2014 Lippincott Williams & Wilkins Inc. Please send correspondence to: Silvia Rigucci, MD, Unit of Psychiatry, Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. [email protected] All authors of this paper have no relevant affiliations or financial involvement to disclose. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The study was not funded. DOI: 10.1097/01.pra.0000445250.20875.0e
March 2014
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Practitioner’s Corner ticular set of neurological soft signs for schizophrenia,10 research comparing neurological soft signs in schizophrenia and mood disorders is needed.11,12 Therefore, the goal of our study was to verify the hypothesis that there is a greater frequency of neurological soft signs in patients with schizophrenia than in those with bipolar disorder. We also hypothesized that a distinct pattern of neurological soft signs might discriminate patients with schizophrenia from those with bipolar disorder.
MATERIALS AND METHODS Participants Between October 2010 and November 2011, 167 patients with schizophrenia spectrum disorder and 88 patients with bipolar I disorder were recruited for the study by purposive sampling of those who attended the outpatient services at Sapienza, the University of Rome (Sant’Andrea Hospital and Umberto I Hospital). Inclusion criteria were a diagnosis of schizophrenia, schizoaffective disorder, brief psychotic disorder, or bipolar I disorder according to the criteria in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition Text-Revision (DSM-IVTR)13 and age between 18 and 65 years. The diagnosis made by the treatment staff was confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).14 Exclusion criteria were previous or current substance abuse, dementia, mental retardation, epilepsy, Parkinson’s disease, or other chronic neurological illnesses. During the assessment, all patients were in clinical remission and were receiving psychiatric medications (35 were receiving conventional antipsychotics and 188 were receiving atypical antipsychotics, Table 1). Prior to being enrolled in the study, each patient was informed about the goals of the study and the study procedures; written informed consent was obtained from all participants. The study protocol and consent procedures were reviewed and approved by the Ethics Committee of the Hospital “S. Andrea” at Sapienza University of Rome. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Fifty healthy subjects in the same age group as the patients were recruited by word of mouth. These participants were interviewed by a trainee to exclude both current or past neuropsychiatric disorders and a history of psychotic disorders in first-degree relatives.
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Procedure Severity of psychiatric symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS)15 by two trainees and a senior psychiatrist (GD, SR, and GM) who had established good interrater reliability (intraclass correlation coefficient [ICC] for the PANSS positive symptom subscale was 0.87, for the negative symptom subscale ICC was 0.83, for the general psychopathology subscale ICC was 0.85, and for the total score ICC was 0.84). For statistical analyses, we used a PANSS pentagonal model as described by Emsley et al.16 Neurological soft signs were assessed using the Italian version of the Neurological Evaluation Scale (NES),2 as described in a previous report.17 The NES is the most widely used instrument for assessing neurological deficits in schizophrenia. It consists of 26 items presented in a fixed order. The items are scored with reference to provided descriptive anchors on a 3point Likert scale (no abnormality = 0, mild but definite impairment = 1, marked impairment = 2), with the exception of “suck” and “snout” reflexes, which are scored 0 or 2. The scale comprises the following conceptually derived subscales: sensory integration, motor coordination, and sequencing of complex motor task. After initial training, two residents (GD, SR) performed the neurological assessments; interrater reliability between raters for the total score was assessed in 30 subjects and was very good (ICC = 0.95). Patients received routine outpatient care; no special interventions (psychological treatments, intensive case management) were provided. Statistical Analysis Statistical analyses were conducted using the Statistical Software for Social Sciences (SPSS) v 18.0. Independent sample t tests were used to compare continuous variables between groups. Chi squared (with 2 x 2 continuity correction) of Fisher’s Exact test was used to compare categorical variables, as appropriate. Results were tested with Bonferroni correction for multiple comparisons. Bivariate correlations were calculated with Pearson’s correlation coefficient; partial correlation adjusted for age was then considered. Multiple logistic regression was used to verify the predictive power of the NES for group membership (i.e., schizophrenia spectrum or bipolar disorder). Statistical analyses were two-
Journal of Psychiatric Practice Vol. 20, No. 2
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Practitioner’s Corner tailed. The alpha significance value was set at 0.05.
Table 1. Characteristics of the sample Schizophrenia spectrum Bipolar disorder disorder (N = 167) (N = 88)
RESULTS Sample Characteristics
Age (yrs), mean (SD)a
34.9 (11.2)
42.9 (13.5)
p < 0.02
The study involved 305 subjects: 50 Male/femaleb 131/36 41/47 < 0.001 healthy control subjects, 167 patients Substance abuse, n (%)b 25 (15%) 14 (15.9%) < 0.01 with schizophrenia spectrum disorder (137 patients with schizophrenia, 19 Alcohol abuse, n (%)b 13 (7.8%) 13 (14.8%) NS with schizoaffective disorder, 8 a Years of illness, mean (SD) 12.2 (9.9) 12.5 (11.1) NS patients with brief psychosis, and 3 patients with psychosis not otherwise Conventional antipsychotics (%)b 13.2% 5.7% < 0.05 specified [NOS]), and 88 patients with Atypical antipsychotics (%)b 42.5% 67% < 0.05 bipolar I disorder. Of the patients with b bipolar disorder, 40.6% had had two Mood stabilizers (%) 31.1% 84% < 0.05 episodes and 59.3% had had three or b Antidepressants (%) 9% 16% < 0.05 more episodes, and 47% had a history Olanzapine mEeq, mean (SD) 18.8 (15.1) 12.6 (15.5) < 0.05 of psychotic symptoms. The two groups of patients differed significantPANSS total score, mean (SD)a 82.2 (21.6) 67.8 (15.2) < 0.001 ly in terms of age and gender: patients a PANSS positive score, mean (SD) 18.4 (7.9) 12.7 (4.7) < 0.001 in the schizophrenia spectrum disorder group were significantly younger PANSS negative score, mean (SD)a 22.5 (8.6) 17.3 (5.9) < 0.001 than patients in the bipolar disorder ap values by independent sample Student’s t-test group (p < 0.02) and included more bp values by chi-squared analysis male patients (p < 0.001). In addition, SD: standard deviation; as expected, the patients in the schizPANSS: Positive and Negative Syndrome Scale for Schizophrenia ophrenia spectrum group received conventional antipsychotics more fre0.001), and that the bipolar disorder group had sigquently and in higher doses (p < 0.05), while the nificantly higher NES total scores than the healthy patients in the bipolar disorder group received mood controls (mean difference 12.1, 95% CI 10.3–13.9, p < stabilizers more frequently (Table 1). Current mEq 0.001). olanzapine units in the schizophrenia spectrum disorder group and the bipolar disorder group were 18.8 (SD 15.1) and 12.6 (SD 15.5), respectively. Mean Neurological Soft Signs Across Diagnoses duration of illness was 12.2 (SD 9.9) years in the Patients in the schizophrenia spectrum disorders schizophrenia spectrum disorder group and 12.5 (SD group showed more neurological soft signs (NES 11.1) years in the bipolar disorder group. total score = 23.9 ± 11.2) than those in the bipolar disorder group (NES total score = 18.2 ± 7.6). Neurological Soft Signs in Patients and Patients in the schizophrenia spectrum disorder Controls group had greater motor impairment compared to patients in the bipolar disorder group on all subPatients had more neurological soft signs (NES total scales (p < 0.001 for all subscales). Significant differscore and all subscales) than healthy controls (p < ences between patients in the two groups were found 0.001). Independent sample t-test showed that on 15 of the 26 NES items (Table 2), with patients in patients in the schizophrenia spectrum disorder the schizophrenia spectrum group having worse pergroup had significantly higher NES total scores than formance than those in the bipolar disorder group on patients in the bipolar disorder group (mean differall 15 items except the Romberg test. ence 17.9, 95% confidence interval [CI] 16.1–19.9, p
33
5.30
1
9.56
1.40–65.24
NES total score: < 10
Model: Cox & Snell R2 = 0.23, df = 6, 2 = 35.22, p < 0.001; accuracy in group membership classification (schizophrenia spectrum disorder) = 68.7%. Wald: parametric statistical test used to evaluate association between items; df: degrees of freedom; OR: odds ratio; CI: confidence interval; PANSS: Positive and Negative Syndrome Scale for Schizophrenia; NES: Neurological Evaluation Scale
accepted that neurological soft signs are associated with psychopathology, especially negative symptoms and formal thought disorders,22 while there is little evidence17,23–26 to support an association between neurological soft signs and positive symptoms. Moreover, in half of the studies in which associations with positive symptoms have been reported, there were also significant associations between neurological soft signs and negative symptoms and global psychopathology.27 A possible limitation of our study is the failure to take into account the fact that symptoms may also differentiate within groups of patients (i.e., within groups with schizophrenia spectrum disorder and bipolar disorder). Otherwise, linear regression analyses found that, among psychopathological domains, higher scores for neurological soft signs were only predicted by severity of negative symptoms, suggesting that neurological soft signs may be a function of these symptoms. Diagnostic Utility and Validity of Neurological Soft Signs Patients with schizophrenia spectrum disorder were accurately classified as having such a disorder in 68.7% of the cases (p < 0.001) when NES total score
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was entered as the predictor variable. It is noteworthy that the predictive power of the NES for diagnosis was significant only for higher total scores. Although neurological soft signs have been demonstrated in other neuropsychiatric conditions such as bipolar disorder, unipolar depression, and obsessivecompulsive disorder,3 they seem to be more specific to schizophrenia. The results of our study clearly demonstrate the utility of this marker in classifying and differentiating schizophrenia spectrum disorders from mood disorders. Advantages and Limitations The potential influence of sociodemographic variables on the prevalence of neurological soft signs is an important issue in conceptualizing neurological abnormalities as a trait feature. Gender has consistently been shown not to account for variance in the presence and severity of neurological soft signs. Consistent with this, we did not find correlations between gender and neurological impairment in our study. Most past studies have also not found an association between neurological soft signs and age (for a review, see Whitty et al. 200928). However, like other studies that tended to use older cohorts, we detected a positive correlation between older age and more neurological impairment in our study.29 We also included patients with schizoaffective disorder in the schizophrenia spectrum disorder group in our study, based on the concept of the schizoaffective spectrum and a continuum model of psychotic illness.30 There is evidence that neurological soft signs are not related to medication.7,31 The vast majority of studies have not found associations between antipsychotic dosage and overall severity of neurological impairment. Neurological soft signs also appear to be independent of the type of antipsychotic medication because similar rates are observed among patients treated with atypical and conventional antipsychotics (for a review, see Whitty et al.28). As expected, we did not detect a correlation between treatment and neurological impairment. However, it is interesting that we did find a specific pattern of signs that reliably differentiate schizophrenia from bipolar disorder. Taken together, our findings highlight the role of neurological soft signs as one of the most acknowledged candidate endophenotypes for schizophrenia, suggesting their potential utility in the diagnostic work-up. Thus, we recom-
Journal of Psychiatric Practice Vol. 20, No. 2
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Practitioner’s Corner mend the potential use of subtle neurological abnormalities as a quick, quantifiable, sensitive, inexpensive, and user-friendly bedside early detection and diagnostic tool for clinical practice.
References 1.
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Egan MF, Hyde TM, Bonomo JB, et al. Relative risk of neurological signs in siblings of patients with schizophrenia. Am J Psychiatry 2001;158:1827–34. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): A structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989;27:335–50. Bombin I, Arango C, Buchanan RW. Significance and meaning of neurological signs in schizophrenia: Two decades later. Schizophr Bull 2005;31:962–77. Rossi A, De Cataldo S, Di Michele V, et al. Neurological soft signs in schizophrenia. Br J Psychiatry 1990;157:735–9. Schröder J, Wenz F, Schad LR, et al. Sensorimotor cortex and supplementary motor area changes in schizophrenia. A study with functional magnetic resonance imaging. Br J Psychiatry 1995;167:197–201. Mohr F, Hubmann W, Cohen R, et al. Neurological soft signs in schizophrenia: Assessment and correlates. Europ Arch Psychiatry Clin Neurosci 1996;246:240–8. Chen EY, Kwok CL, Au JW, et al. Progressive deterioration of soft neurological signs in chronic schizophrenic patients. Acta Psychiatr Scand 2000;102:342–9. Bersani G, Clemente R, Gherardelli S, et al. Deficit of executive functions in schizophrenia: Relationship to neurological soft signs and psychopathology. Psychopathology 2004;37:118–23. van Os J, Linscott RJ, Myin-Germeys I, et al. A systematic review and meta-analysis of the psychosis continuum: Evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med 2009;39: 179–95. Boks MP, Liddle PF, Burgerhof JG, et al. Neurological soft signs discriminating mood disorders from first episode schizophrenia. Acta Psychiatr Scand 2004;110:29–35. Krebs MO, Gut-Fayand A, Bourdel M, et al. Validation and factorial structure of a standardized neurological examination assessing neurological soft signs in schizophrenia. Schizophr Res 2000;45:245–60. Keshavan MS, Sanders RD, Sweeney JA, et al. Diagnostic specificity and neuroanatomical validity of neurological abnormalities in first-episode psychoses. Am J Psychiatry 2003;160:1298–304. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition, text revision. Washington, DC: American Psychiatric Association; 2000. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I): Clinician version. Washington, DC: American Psychiatric Press, 1997.
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15. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–76. 16. Emsley R, Rabinowitz J, Torreman M, et al. The factor structure for the Positive and Negative Syndrome Scale (PANSS) in recent-onset psychosis. Schizophr Res 2003;61:47–57. 17. Bersani G, Quartini A, Paolemili M, et al. Neurological soft signs and corpus callosum morphology in schizophrenia. Neurosci Lett 2011;499:170–4. 18. Giles LL, DelBello MP, Gilbert DL, et al. Cerebellar ataxia in youths at risk for bipolar disorder. Bipolar Disord 2008;10:733–7. 19. Mills NP, Delbello MP, Adler CM, et al. MRI analysis of cerebellar vermal abnormalities in bipolar disorder. Am J Psychiatry 2005;162:1530–2. 20. Cecil KM, DelBello MP, Sellars MC, et al. Proton magnetic resonance spectroscopy of the frontal lobe and cerebellar vermis in children with a mood disorder and a familial risk for bipolar disorders. J Child Adolesc Psychopharmacol 2003;13:545–55. 21. Chang K, Adleman NE, Dienes K, et al. Anomalous prefrontal-subcortical activation in familial pediatric bipolar disorder: A functional magnetic resonance imaging investigation. Arch Gen Psychiatry 2004;61:781–92. 22. Peralta V, Moreno-Izco L, Sanchez-Torres A, et al. Characterization of the deficit syndrome in drug-naive schizophrenia patients: The role of spontaneous movement disorders and neurological soft signs. Schizophr Bull 2014;40:214–24. 23. Chen EY, Hui CL, Chan RC, et al. A 3-year prospective study of neurological soft signs in first-episode schizophrenia. Schizophr Res 2005;75:45–54. 24. Wong AH, Voruganti LN, Heslegrave RJ, et al. Neurocognitive deficits and neurological signs in schizophrenia. Schizophr Res 1997;23:139–46. 25. Smith RC, Kadewari RP, Rosenberger JR, et al. Nonresponding schizophrenia: Differentiation by neurological soft signs and neuropsychological tests. Schizophr Bull 1999;25:813–25. 26. Yazici AH, Demir B, Yazici KM, et al. Neurological soft signs in schizophrenic patients and their nonpsychotic siblings. Schizophr Res 2002;58:241–6. 27. Scheffer RE. Abnormal neurological signs at the onset of psychosis. Schizophr Res 2004;70:19–26. 28. Whitty PF, Owoeye O, Waddington JL. Neurological signs and involuntary movements in schizophrenia: Intrinsic to and informative on systems pathobiology. Schizophr Bull 2009;35:415–24. 29. Sanders RD, Keshavan MS, Forman SD, et al. Factor structure of neurologic examination abnormalities in unmedicated schizophrenia. Psych Res 2000;95:237–43. 30. Peralta V, Cuesta MJ. Exploring the borders of the schizoaffective spectrum: A categorical and dimensional approach. J Affect Disord 2008;108:71–86. 31. Bersani G, Gherardelli S, Clemente R, et al. Neurologic soft signs in schizophrenic patients treated with conventional and atypical antipsychotics. J Clin Psychopharmacol 2005;25:372–5.
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Background. Although neurological soft signs have been consistently described in patients with schizophrenia, their diagnostic specificity is not well clarified. Methods. To test the hypothesis that neurological soft signs are specifically related to schizophrenia, we examined 305 subjects (patients with schizophrenia-spectrum disorder, n = 167; patients with bipolar I disorder, n = 88; controls, n = 50). Neurological soft signs were assessed using the Neurological Evaluation Scale (NES). Multiple logistic regression analysis was used to compute the diagnostic predictive power of neurological soft signs. Results. Patients in the schizophrenia-spectrum disorder group were found to have significantly greater neurological impairment (NES total score = 23.9, standard deviation [SD] 11.2) than those in the bipolar disorder group (NES total score = 18.2, SD 7.6; p < 0.001). Neurological functioning was closely associated with psychopathology (all p < 0.001). The NES total score reliably distinguished patients with schizophrenia spectrum disorders from those with bipolar disorder in 68.7% of the cases (p < 0.001). Moreover, a particular set of neurological soft signs showed specificity for the schizophrenia-spectrum disorder diagnostic group. Conclusions. Our findings suggest that schizophrenia and bipolar disorder can be distinguished in terms of neurological impairment. Furthermore, we recommend the utility of neurological soft signs as a useful, quantifiable, sensitive, and inexpensive tool for the diagnostic work-up of schizophrenia. (Journal of Psychiatric Practice 2014;20:147–153) KEY WORDS: neurological soft signs, Neurological Evaluation Scale, neurological impairment, schizophrenia, bipolar disorder
Journal of Psychiatric Practice Vol. 20, No. 2
SILVIA RIGUCCI, MD GIORGIA DIMITRI-VALENTE, MD GABRIELE MANDARELLI, MD GIOVANNI MANFREDI, MD ANNA COMPARELLI, MD SERGIO DE FILIPPIS, MD SIMONA GHERARDELLI, MD GIUSEPPE BERSANI, MD PAOLO GIRARDI, MD STEFANO FERRACUTI, MD
The diagnosis of schizophrenia based on clinical phenomenology has frequently been challenged in recent years.1 By its nature, a diagnostic approach based solely on the assessment of clinical symptoms could fail to take into account the biological substrate of this complex disorder. Therefore, researchers have recently focused on identifying possible endophenotypes involving neuropsychological, brain morphometric, soft neurologic, and other biological indices that are reliably associated with this pathological condition. Two decades of research on neurological markers of schizophrenia have provided evidence supporting the conceptualization of neurological soft signs—subtle neurological impairment indicating nonlocalizable neurological abnormalities2—as a trait feature of this disorder (for a review, see Bombin et al. 20053). The overrepresentation of these signs among patients with schizophrenia is well established.4–8 However, neurological soft signs are also apparent in numerous other psychiatric disorders, among which bipolar disorder seems to be the only one to lie on a possible continuum with schizophrenia.9 Although some authors have previously demonstrated the specificity of a parRIGUCCI, DIMITRI-VALENTE, MANDARELLI, MANFREDI, COMPARELLI, DE FILIPPIS, GIRARDI, and FERRACUTI: Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome, Italy; GHERARDELLI and BERSANI: Faculty of Pharmacy and Medicine, Sapienza University of Rome, Italy. Copyright ©2014 Lippincott Williams & Wilkins Inc. Please send correspondence to: Silvia Rigucci, MD, Unit of Psychiatry, Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. [email protected] All authors of this paper have no relevant affiliations or financial involvement to disclose. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. The study was not funded. DOI: 10.1097/01.pra.0000445250.20875.0e
March 2014
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Practitioner’s Corner ticular set of neurological soft signs for schizophrenia,10 research comparing neurological soft signs in schizophrenia and mood disorders is needed.11,12 Therefore, the goal of our study was to verify the hypothesis that there is a greater frequency of neurological soft signs in patients with schizophrenia than in those with bipolar disorder. We also hypothesized that a distinct pattern of neurological soft signs might discriminate patients with schizophrenia from those with bipolar disorder.
MATERIALS AND METHODS Participants Between October 2010 and November 2011, 167 patients with schizophrenia spectrum disorder and 88 patients with bipolar I disorder were recruited for the study by purposive sampling of those who attended the outpatient services at Sapienza, the University of Rome (Sant’Andrea Hospital and Umberto I Hospital). Inclusion criteria were a diagnosis of schizophrenia, schizoaffective disorder, brief psychotic disorder, or bipolar I disorder according to the criteria in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition Text-Revision (DSM-IVTR)13 and age between 18 and 65 years. The diagnosis made by the treatment staff was confirmed using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I).14 Exclusion criteria were previous or current substance abuse, dementia, mental retardation, epilepsy, Parkinson’s disease, or other chronic neurological illnesses. During the assessment, all patients were in clinical remission and were receiving psychiatric medications (35 were receiving conventional antipsychotics and 188 were receiving atypical antipsychotics, Table 1). Prior to being enrolled in the study, each patient was informed about the goals of the study and the study procedures; written informed consent was obtained from all participants. The study protocol and consent procedures were reviewed and approved by the Ethics Committee of the Hospital “S. Andrea” at Sapienza University of Rome. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Fifty healthy subjects in the same age group as the patients were recruited by word of mouth. These participants were interviewed by a trainee to exclude both current or past neuropsychiatric disorders and a history of psychotic disorders in first-degree relatives.
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Procedure Severity of psychiatric symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS)15 by two trainees and a senior psychiatrist (GD, SR, and GM) who had established good interrater reliability (intraclass correlation coefficient [ICC] for the PANSS positive symptom subscale was 0.87, for the negative symptom subscale ICC was 0.83, for the general psychopathology subscale ICC was 0.85, and for the total score ICC was 0.84). For statistical analyses, we used a PANSS pentagonal model as described by Emsley et al.16 Neurological soft signs were assessed using the Italian version of the Neurological Evaluation Scale (NES),2 as described in a previous report.17 The NES is the most widely used instrument for assessing neurological deficits in schizophrenia. It consists of 26 items presented in a fixed order. The items are scored with reference to provided descriptive anchors on a 3point Likert scale (no abnormality = 0, mild but definite impairment = 1, marked impairment = 2), with the exception of “suck” and “snout” reflexes, which are scored 0 or 2. The scale comprises the following conceptually derived subscales: sensory integration, motor coordination, and sequencing of complex motor task. After initial training, two residents (GD, SR) performed the neurological assessments; interrater reliability between raters for the total score was assessed in 30 subjects and was very good (ICC = 0.95). Patients received routine outpatient care; no special interventions (psychological treatments, intensive case management) were provided. Statistical Analysis Statistical analyses were conducted using the Statistical Software for Social Sciences (SPSS) v 18.0. Independent sample t tests were used to compare continuous variables between groups. Chi squared (with 2 x 2 continuity correction) of Fisher’s Exact test was used to compare categorical variables, as appropriate. Results were tested with Bonferroni correction for multiple comparisons. Bivariate correlations were calculated with Pearson’s correlation coefficient; partial correlation adjusted for age was then considered. Multiple logistic regression was used to verify the predictive power of the NES for group membership (i.e., schizophrenia spectrum or bipolar disorder). Statistical analyses were two-
Journal of Psychiatric Practice Vol. 20, No. 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Practitioner’s Corner tailed. The alpha significance value was set at 0.05.
Table 1. Characteristics of the sample Schizophrenia spectrum Bipolar disorder disorder (N = 167) (N = 88)
RESULTS Sample Characteristics
Age (yrs), mean (SD)a
34.9 (11.2)
42.9 (13.5)
p < 0.02
The study involved 305 subjects: 50 Male/femaleb 131/36 41/47 < 0.001 healthy control subjects, 167 patients Substance abuse, n (%)b 25 (15%) 14 (15.9%) < 0.01 with schizophrenia spectrum disorder (137 patients with schizophrenia, 19 Alcohol abuse, n (%)b 13 (7.8%) 13 (14.8%) NS with schizoaffective disorder, 8 a Years of illness, mean (SD) 12.2 (9.9) 12.5 (11.1) NS patients with brief psychosis, and 3 patients with psychosis not otherwise Conventional antipsychotics (%)b 13.2% 5.7% < 0.05 specified [NOS]), and 88 patients with Atypical antipsychotics (%)b 42.5% 67% < 0.05 bipolar I disorder. Of the patients with b bipolar disorder, 40.6% had had two Mood stabilizers (%) 31.1% 84% < 0.05 episodes and 59.3% had had three or b Antidepressants (%) 9% 16% < 0.05 more episodes, and 47% had a history Olanzapine mEeq, mean (SD) 18.8 (15.1) 12.6 (15.5) < 0.05 of psychotic symptoms. The two groups of patients differed significantPANSS total score, mean (SD)a 82.2 (21.6) 67.8 (15.2) < 0.001 ly in terms of age and gender: patients a PANSS positive score, mean (SD) 18.4 (7.9) 12.7 (4.7) < 0.001 in the schizophrenia spectrum disorder group were significantly younger PANSS negative score, mean (SD)a 22.5 (8.6) 17.3 (5.9) < 0.001 than patients in the bipolar disorder ap values by independent sample Student’s t-test group (p < 0.02) and included more bp values by chi-squared analysis male patients (p < 0.001). In addition, SD: standard deviation; as expected, the patients in the schizPANSS: Positive and Negative Syndrome Scale for Schizophrenia ophrenia spectrum group received conventional antipsychotics more fre0.001), and that the bipolar disorder group had sigquently and in higher doses (p < 0.05), while the nificantly higher NES total scores than the healthy patients in the bipolar disorder group received mood controls (mean difference 12.1, 95% CI 10.3–13.9, p < stabilizers more frequently (Table 1). Current mEq 0.001). olanzapine units in the schizophrenia spectrum disorder group and the bipolar disorder group were 18.8 (SD 15.1) and 12.6 (SD 15.5), respectively. Mean Neurological Soft Signs Across Diagnoses duration of illness was 12.2 (SD 9.9) years in the Patients in the schizophrenia spectrum disorders schizophrenia spectrum disorder group and 12.5 (SD group showed more neurological soft signs (NES 11.1) years in the bipolar disorder group. total score = 23.9 ± 11.2) than those in the bipolar disorder group (NES total score = 18.2 ± 7.6). Neurological Soft Signs in Patients and Patients in the schizophrenia spectrum disorder Controls group had greater motor impairment compared to patients in the bipolar disorder group on all subPatients had more neurological soft signs (NES total scales (p < 0.001 for all subscales). Significant differscore and all subscales) than healthy controls (p < ences between patients in the two groups were found 0.001). Independent sample t-test showed that on 15 of the 26 NES items (Table 2), with patients in patients in the schizophrenia spectrum disorder the schizophrenia spectrum group having worse pergroup had significantly higher NES total scores than formance than those in the bipolar disorder group on patients in the bipolar disorder group (mean differall 15 items except the Romberg test. ence 17.9, 95% confidence interval [CI] 16.1–19.9, p
33
5.30
1
9.56
1.40–65.24
NES total score: < 10
Model: Cox & Snell R2 = 0.23, df = 6, 2 = 35.22, p < 0.001; accuracy in group membership classification (schizophrenia spectrum disorder) = 68.7%. Wald: parametric statistical test used to evaluate association between items; df: degrees of freedom; OR: odds ratio; CI: confidence interval; PANSS: Positive and Negative Syndrome Scale for Schizophrenia; NES: Neurological Evaluation Scale
accepted that neurological soft signs are associated with psychopathology, especially negative symptoms and formal thought disorders,22 while there is little evidence17,23–26 to support an association between neurological soft signs and positive symptoms. Moreover, in half of the studies in which associations with positive symptoms have been reported, there were also significant associations between neurological soft signs and negative symptoms and global psychopathology.27 A possible limitation of our study is the failure to take into account the fact that symptoms may also differentiate within groups of patients (i.e., within groups with schizophrenia spectrum disorder and bipolar disorder). Otherwise, linear regression analyses found that, among psychopathological domains, higher scores for neurological soft signs were only predicted by severity of negative symptoms, suggesting that neurological soft signs may be a function of these symptoms. Diagnostic Utility and Validity of Neurological Soft Signs Patients with schizophrenia spectrum disorder were accurately classified as having such a disorder in 68.7% of the cases (p < 0.001) when NES total score
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was entered as the predictor variable. It is noteworthy that the predictive power of the NES for diagnosis was significant only for higher total scores. Although neurological soft signs have been demonstrated in other neuropsychiatric conditions such as bipolar disorder, unipolar depression, and obsessivecompulsive disorder,3 they seem to be more specific to schizophrenia. The results of our study clearly demonstrate the utility of this marker in classifying and differentiating schizophrenia spectrum disorders from mood disorders. Advantages and Limitations The potential influence of sociodemographic variables on the prevalence of neurological soft signs is an important issue in conceptualizing neurological abnormalities as a trait feature. Gender has consistently been shown not to account for variance in the presence and severity of neurological soft signs. Consistent with this, we did not find correlations between gender and neurological impairment in our study. Most past studies have also not found an association between neurological soft signs and age (for a review, see Whitty et al. 200928). However, like other studies that tended to use older cohorts, we detected a positive correlation between older age and more neurological impairment in our study.29 We also included patients with schizoaffective disorder in the schizophrenia spectrum disorder group in our study, based on the concept of the schizoaffective spectrum and a continuum model of psychotic illness.30 There is evidence that neurological soft signs are not related to medication.7,31 The vast majority of studies have not found associations between antipsychotic dosage and overall severity of neurological impairment. Neurological soft signs also appear to be independent of the type of antipsychotic medication because similar rates are observed among patients treated with atypical and conventional antipsychotics (for a review, see Whitty et al.28). As expected, we did not detect a correlation between treatment and neurological impairment. However, it is interesting that we did find a specific pattern of signs that reliably differentiate schizophrenia from bipolar disorder. Taken together, our findings highlight the role of neurological soft signs as one of the most acknowledged candidate endophenotypes for schizophrenia, suggesting their potential utility in the diagnostic work-up. Thus, we recom-
Journal of Psychiatric Practice Vol. 20, No. 2
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Practitioner’s Corner mend the potential use of subtle neurological abnormalities as a quick, quantifiable, sensitive, inexpensive, and user-friendly bedside early detection and diagnostic tool for clinical practice.
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