Objective: Neurological soft signs (NSS) and sleep disorders are quite common in schizophrenia. Both symptom clusters have been proposed as candidate endophenotypes for the disorder. This study aimed to investigate the relationships between NSS, chronotype and sleep quality among patients with schizophrenia. Method: Positive and Negative Syndrome Scale, The Neurological Evaluation Scale (NES), Morningness-Eveningness Questionnaire (MEQ), Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were administered to 50 patients with schizophrenia and 50 age- and gender-matched healthy control participants. Group differences were assessed using multivariate covariance models. We used stepwise multiple regression analysis to evaluate the potential relationships between NSS and clinical characteristics, diurnal preferences, sleep quality, anxiety, and depression in patients with schizophrenia. Results: Patients with schizophrenia were more likely to reveal severe impairments in NSS than healthy control participants even after controlling for demographic characteristics and the MEQ, PSQI, BAI, and BDI scores. In addition, patients were more prone to report evening-type characteristics than healthy individuals. Sleep disturbances were significant correlates of deficits in total NES, motor coordination, and other NSS. PSQI global and poor habitual sleep efficiency were associated with sequencing of complex motor acts. No relationships were found between NSS and chronotype. However, general psychopathology significantly contributed to NSS. Conclusion: The data showed that evening-type diurnal preferences and sleep quality as well as NSS seem to have complex implications in schizophrenia.
1. Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry 1988; 145:11-18.
2. Tucker GJ, Silberfarb PM. Neurologic dysfunction in schizophrenia: significance for diagnostic practice: In Akiskal H, Webb W, editors. Psychiatric Diagnosis: Exploration of Biological Predictors. New York: Spektrum, 1978, 453-462.
3. Boks MP, Russo S, Knegtering R, van den Bosch RJ. The specificity of neurological signs in schizophrenia: a review. Schizophr Res 2000; 43:109-116.
4. Bachmann S, Schröder J. Neurological Soft Signs in Schizophrenia: An Update on the State- versus Trait-Perspective. Front Psychiatry 2018; 8:272.
5. Chan RC, Xu T, Heinrichs RW, Yu Y, Wang Y. Neurological soft signs in schizophrenia: a meta-analysis. Schizophr Bull 2010; 36:1089-1104.
6. Woods BT, Kinney DK, Yurgelun-Todd D. Neurologic abnormalities in schizophrenic patients and their families. I. Comparison of schizophrenic, bipolar, and substance abuse patients and normal controls. Arch Gen Psychiatry 1986; 43:657- 663.
7. Xu T, Wang Y, Li Z, Huang J, Lui SS, Tan SP, et al. Heritability and familiality of neurological soft signs: evidence from healthy twins, patients with schizophrenia and non-psychotic firstdegree relatives. Psychol Med 2016; 46:117-123.
8. Caldani S, Amado I, Bendjemaa N, Vialatte F, Mam-Lam-Fook C, Gaillard R, et al. Oculomotricity and Neurological Soft Signs: Can we refine the endophenotype? A study in subjects belonging to the spectrum of schizophrenia. Psychiatry Res 2017; 256:490- 497.
9. Peralta V, de Jalón EG, Campos MS, Basterra V, Sanchez-Torres A, Cuesta MJ. Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders. Psychol Med 2011; 41:1279- 1289.
10. Kolakowska T, Williams AO, Jambor K, Ardern M. Schizophrenia with good and poor outcome. III: Neurological ‘soft’ signs, cognitive impairment and their clinical significance. Br J Psychiatry 1985; 146:348-357.
11. Feng Y, Wang Z, Lin G, Qian H, Gao Z, Wang X, et al. Neurological soft signs and neurocognitive deficits in remitted patients with schizophrenia, their first-degree unaffected relatives, and healthy controls. Eur Arch Psychiatry Clin Neurosci 2020; 270:383-391.
12. Chan RC, Wang Y, Wang L, Chen EY, Manschreck TC, Li ZJ, et al. Neurological soft signs and their relationships to neurocognitive functions: a re-visit with the structural equation modeling design. PLoS One 2009; 4:e8469.
13. Cuesta MJ, Moreno-Izco L, Ribeiro M, López-Ilundain JM, Lecumberri P, Cabada T, et al. Motor abnormalities and cognitive impairment in first-episode psychosis patients, their unaffected siblings and healthy controls. Schizophr Res 2018; 200:50-55.
14. Lemmer B. Discoveries of rhythms in human biological functions: a historical review. Chronobiol Int 2009; 26:1019-1068.
15. Reinberg A, Ashkenazi I. Concepts in human biological rhythms. Dialogues Clin Neurosci 2003; 5:327-342.
16. Sahbaz C, Devetzioglou T, Ozcelik AM, Kirpinar I. Circadian preferences are associated with vegetative symptoms and comorbid medical diseases in patients with major depression. Biol Rhythm Research 2019; 50:703-717.
17. Adan A, Lachica J, Caci H, Natale V. Circadian typology and temperament and character personality dimensions. Chronobiol Int 2010; 27:181-193.
18. Emens JS, Yuhas K, Rough J, Kochar N, Peters D, Lewy AJ. Phase angle of entrainment in morning- and evening-types under naturalistic conditions. Chronobiol Int 2009; 26:474-493.
19. Gulec M, Selvi Y, Boysan M, Aydin A, Oral E, Aydin EF. Chronotype effects on general well-being and psychopathology levels in healthy young adults. Biological Rhythm Research 2013; 44:457-468.
20. Taillard J, Philip P, Bioulac B. Morningness/eveningness and the need for sleep. J Sleep Res 1999; 8:291-295.
21. Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci 2008; 10:473-481.
22. Selvi Y, Aydin A, Atli A, Boysan M, Selvi F, Besiroglu L. Chronotype differences in suicidal behavior and impulsivity among suicide attempters. Chronobiol Int 2011; 28:170-175.
23. Nutt D, Wilson S, Paterson L. Sleep disorders as core symptoms of depression. Dialogues Clin Neurosci 2008; 10:329-336.
24. Hasler BP, Allen JJ, Sbarra DA, Bootzin RR, Bernert RA. Morningness-eveningness and depression: preliminary evidence for the role of the behavioral activation system and positive affect. Psychiatry Res 2010; 176:166-173.
25. Yates NJ. Schizophrenia: the role of sleep and circadian rhythms in regulating dopamine and psychosis. Rev Neurosci 2016; 27:669-687.
26. Wulff K, Dijk DJ, Middleton B, Foster RG, Joyce EM. Sleep and circadian rhythm disruption in schizophrenia. Br J Psychiatry 2012; 200:308-316.
27. Lemoine P, Zawieja P, Ohayon MM. Associations between morningness/eveningness and psychopathology: an epidemiological survey in three in-patient psychiatric clinics. J Psychiatr Res 2013; 47:1095-1098.
28. Yu JH, Yun CH, Ahn JH, Suh S, Cho HJ, Lee SK, et al. Evening chronotype is associated with metabolic disorders and body composition in middle-aged adults. J Clin Endocrinol Metab 2015; 100:1494-1502.
29. Torner C, Aguilar-Roblero R. Asynchrony in the diurnal rhythms of dopaminergic D2 receptors in different brain regions of the rat. Biol Rhythm Research 2010; 32:363-388.
30. Dijk DJ, Archer SN. PERIOD3, circadian phenotypes, and sleep homeostasis. Sleep Med Rev 2010; 14:151-160.
31. Hampp G, Ripperger JA, Houben T, Schmutz I, Blex C, PerreauLenz S, et al. Regulation of monoamine oxidase A by circadianclock components implies clock influence on mood. Curr Biol 2008; 18:678-683.
32. Wulff K, Porcheret K, Cussans E, Foster RG. Sleep and circadian rhythm disturbances: multiple genes and multiple phenotypes. Curr Opin Genet Dev 2009; 19:237-246.
33. Lunsford-Avery JR, Gonçalves BDSB, Brietzke E, Bressan RA, Gadelha A, Auerbach RP, et al. Adolescents at clinical-high risk for psychosis: circadian rhythm disturbances predict worsened prognosis at 1-year follow-up. Schizophr Res 2017; 189:37-42.
34. Bromundt V, Köster M, Georgiev-Kill A, Opwis K, Wirz-Justice A, Stoppe G, et al. Sleep-wake cycles and cognitive functioning in schizophrenia. Br J Psychiatry 2011; 198:269-276.
35. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV Clinical Version (SCID-I/CV). Washington DC: American Psychiatric Press, 1997.
36. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989; 27:335-350.
37. Tapancı Z, Yıldırım A, Boysan M. Neurological soft signs, dissociation and alexithymia in patients with obsessivecompulsive disorder (OCD) and healthy subjects. Psychiatry Res 2018; 260:90-97.
38. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13(2):261-276.
39. Kostakoglu AE, Batur S, Tiryaki AG, Gogus A. Validity and reliability of the Turkish adaptation of the Positive and Negative Syndrome Scale (PANSS). Türk Psikiyatri Derg 1999; 14:23-32.
40. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976; 4:97-110.
41. Agargun MY, Cilli AS, Boysan M, Selvi Y, Gulec M, Kara H. Turkish Version of Morningness Eveningness Questionnaire (MEQ). Sleep and Hypnosis 2007; 9:16-23.
42. Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28:193-213.
43. Agargun MY, Kara H, Anlar O. The validity and reliability of the Pittsburgh Sleep Quality Index. Turk Psikiyatri Derg 1996; 7:107- 111.
44. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4:561-571.
45. Hisli N. Beck A reliability and validity study of Beck Depression Inventory in a university student sample. Journal of Psychology. 1989; 7:3-13.
46. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988; 56:893-897.
47. Ulusoy M, Sahin N, Erkmen H. Turkish version of the Beck Anxiety Inventory: psychometric properties. Journal of Cognitive Psychotherapy 1998; 12:163- 172.
48. Selvi Y, Aydin A, Boysan M, Atli A, Agargun MY, Besiroglu L. Associations between chronotype, sleep quality, suicidality, and depressive symptoms in patients with major depression and healthy controls. Chronobiol Int 2010; 27:1813-1828.
49. Selvi Y, Boysan M, Kandeger A, Uygur OF, Sayin AA, Akbaba N, et al. Heterogeneity of sleep quality in relation to circadian preferences and depressive symptomatology among major depressive patients. J Affect Disord 2015; 235:242-249.
50. Ramsawh HJ, Stein MB, Belik SL, Jacobi F, Sareen J. Relationship of anxiety disorders, sleep quality, and functional impairment in a community sample. J Psychiatr Res 2009; 43:926-933.
51. Antypa N, Vogelzangs N, Meesters Y, Schoevers R, Penninx BW. Chronotype associations with depression and anxiety disorders in a large cohort study. Depress Anxiety 2016; 33:75-83.
52. Whitty P, Clarke M, Browne S, McTigue O, Kamali M, Feeney L, et al. Prospective evaluation of neurological soft signs in first-episode schizophrenia in relation to psychopathology: state versus trait phenomena. Psychol Med 2003; 33:1479-1484.
53. Chan RCK, Geng FL, Lui SSY, Wang Y, Ho KKY, Hung KSY, et al. Course of neurological soft signs in first-episode schizophrenia: Relationship with negative symptoms and cognitive performances. Sci Rep 2015; 5:11053.
54. Emsley R, Chiliza B, Asmal L, Kilian S, Riaan Olivier M, Phahladira L, et al. Neurological soft signs in first-episode schizophrenia: State- and trait-related relationships to psychopathology, cognition and antipsychotic medication effects. Schizophr Res 2017; 188:144-150.
55. Prikryl R, Ceskova E, Kasparek T, Kucerova H. Neurological soft signs, clinical symptoms and treatment reactivity in patients suffering from first episode schizophrenia. J Psychiatr Res 2006; 40:141-146.
56. Schröder J, Silvestri S, Bubeck B, Karr M, Demisch S, Scherrer S, et al. D2 dopamine receptor up-regulation, treatment response, neurological soft signs, and extrapyramidal side effects in schizophrenia: a follow-up study with 123I-iodobenzamide single photon emission computed tomography in the drugnaive state and after neuroleptic treatment. Biol Psychiatry 1998;43:660-665.
57. Whitty P, Clarke M, McTigue O, Browne S, Gervin M, Kamali M, et al. Diagnostic specificity and predictors of neurological soft signs in schizophrenia, bipolar disorder and other psychoses over the first 4 years of illness. Schizophr Res 2006; 86:110-117.
58. Chen EY, Hui CL, Chan RC, Dunn EL, Miao MY, Yeung WS, et al. A 3-year prospective study of neurological soft signs in firstepisode schizophrenia. Schizophr Res 2005; 75:45-54.
59. Mangot AG, Sawant NS. First episode schizophrenia: neurological abnormalities and prognosis. German J Psychiatry 2013; 16:75- 80.
60. Mittal VA, Hasenkamp W, Sanfilipo M, Wieland S, Angrist B, Rotrosen J, et al. Relation of neurological soft signs to psychiatric symptoms in schizophrenia. Schizophr Res 2007; 94:37-44.
61. Herold CJ, Lässer MM, Seidl UW, Hirjak D, Thomann PA, Schröder J. Neurological soft signs and psychopathology in chronic schizophrenia: a cross-sectional study in three age groups. Front Psychiatry 2018; 9:98.
62. Sagheer TA, Assaad S, Haddad G, Hachem D, Haddad C, Hallit S. Neurological soft signs in bipolar and unipolar disorder: A casecontrol study. Psychiatry Res 2018; 261:253-258.
63. Zhao Q, Ma YT, Lui SS, Liu WH, Xu T, Yu X, et al. Neurological soft signs discriminate schizophrenia from major depression but not bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43:72-78.
64. Shaffer D, Schonfeld I, O’Connor PA, Stokman C, Trautman P, Shafer S, et al. Neurological soft signs. Their relationship to psychiatric disorder and intelligence in childhood and adolescence. Arch Gen Psychiatry 1985; 42:342-351.
65. Livianos L, González-Valls PI, García-Blanco AC, Tobella H, Díaz-Alonso I, Alberola N, et al. Hypoesthesia of the malleolus as a soft sign in depression. J Affect Disord 2015; 171:128-131.
66. Zhao H, Guo W, Niu W, Zhong A, Zhou X. Brain area-related neurological soft signs in depressive patients with different types of childhood maltreatment. Asia Pac Psychiatry 2015; 7:286-291.
67. Castro J, Zanini M, Gonçalves Bda S, Coelho FM, Bressan R, Bittencourt L, et al. Circadian rest-activity rhythm in individuals at risk for psychosis and bipolar disorder. Schizophr Res 2015; 168:50-55.
68. Zanini M, Castro J, Coelho FM, Bittencourt L, Bressan RA, Tufik S, et al. Do sleep abnormalities and misaligned sleep/ circadian rhythm patterns represent early clinical characteristics for developing psychosis in high risk populations? Neurosci Biobehav Rev 2013; 37:2631-2637.
69. Cohrs S. Sleep disturbances in patients with schizophrenia: impact and effect of antipsychotics. CNS Drugs 2008; 22:939- 962.
70. Krysta K, Krzystanek M, Bratek A, Krupka-Matuszczyk I. Sleep and inflammatory markers in different psychiatric disorders. J Neural Transm (Vienna) 2017; 124(Suppl.1):179-186.
71. Wulff K, Gatti S, Wettstein JG, Foster RG. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease. Nat Rev Neurosci 2010; 11:589-599.
72. Benson KL. Sleep in schizophrenia: impairments, correlates, and treatment. Psychiatr Clin North Am 2006; 29:1033-1045.
73. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res 2009; 110:1-23.
74. Waters F, Manoach DS. Sleep dysfunctions in schizophrenia: a practical review. Open Journal of Psychiatry 2012; 2:384-392.
75. Kilicaslan EE, Esen AT, Kasal MI, Ozelci E, Boysan M, Gulec M. Childhood trauma, depression, and sleep quality and their association with psychotic symptoms and suicidality in schizophrenia. Psychiatry Res 2017; 258:557-564.
76. Cosgrave J, Wulff K, Gehrman P. Sleep, circadian rhythms, and schizophrenia: where we are and where we need to go. Curr Opin Psychiatry 2018; 31:176-182.
77. Tamagni C, Studerus E, Gschwandtner U, Aston J, Borgwardt S, Riecher-Rössler A. Are neurological soft signs pre-existing markers in individuals with an at-risk mental state for psychosis? Psychiatry Res 2013; 210:427-431.
78. Gay O, Plaze M, Oppenheim C, Mouchet-Mages S, Gaillard R, Olie JP, et al. Cortex morphology in first-episode psychosis patients with neurological soft signs. Schizophr Bull 2013; 39:820-829.
79. Gourion D, Goldberger C, Olie JP, Lôo H, Krebs MO. Neurological and morphological anomalies and the genetic liability to schizophrenia: a composite phenotype. Schizophr Res 2004; 67:23-31.
80. Compton MT, Bollini AM, McKenzie Mack L, Kryda AD, Rutland J, Weiss PS, et al. Neurological soft signs and minor physical anomalies in patients with schizophrenia and related disorders, their first-degree biological relatives, and nonpsychiatric controls. Schizophr Res 2007; 94:64-73.
81. Dazzan P, Murray RM. Neurological soft signs in first-episode psychosis: a systematic review. Br J Psychiatry Suppl 2002; 43:s50-57.
82. Srinivasan S, Bettella F, Mattingsdal M, Wang Y, Witoelar A, Schork AJ, et al. Genetic Markers of Human Evolution Are Enriched in Schizophrenia. Biol Psychiatry 2016; 80:284-292.
83. Fountoulakis KN, Panagiotidis P, Kimiskidis V, Nimatoudis I, Gonda X. Prevalence and correlates of neurological soft signs in healthy controls without family history of any mental disorder: A neurodevelopmental variation rather than a specific risk factor? Int J Dev Neurosci 2018; 68:59-65.
84. Chen EY, Kwok CL, Au JW, Chen RY, Lau BS. Progressive deterioration of soft neurological signs in chronic schizophrenic patients. Acta Psychiatr Scand 2000; 102:342-349.
85. Alamiri B, Nelson C, Fitzmaurice GM, Murphy JM, Gilman SE. Neurological soft signs and cognitive performance in early childhood. Dev Psychol 2018; 54:2043-2052.
86. Cai L, Zhu X, Yi J, Bai M, Wang M, Wang Y, et al. Neurological soft signs and their relationship with measures of executive function in Chinese adolescents. J Dev Behav Pediatr 2013; 34:197-203.
87. Martins I, Lauterbach M, Slade P, Luís H, DeRouen T, Martin M, et al. A longitudinal study of neurological soft signs from late childhood into early adulthood. Dev Med Child Neurol 2008; 50:602-607.
88. Gupta S, Andreasen NC, Arndt S, Flaum M, Schultz SK, Hubbard WC, et al. Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995; 152:191-196.