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Antipsychotics Do Not Influence Neurological Soft Signs in Children and Adolescents at Ultra-High Risk for Psychosis

A Pilot Study


Journal of Psychiatric Practice®: May 2019 - Volume 25 - Issue 3 - p 186–191
doi: 10.1097/PRA.0000000000000387

Objective: Ultra-high risk for psychosis (UHR) is considered as the condition that temporally precedes the onset of psychotic symptoms. In addition to the core symptoms, patients with schizophrenia show motor abnormalities, also known as neurological soft signs (NSS), that are considered an endophenotype for psychotic disorders and particularly for schizophrenia. Antipsychotic medications do not appear to influence NSS in individuals with schizophrenia. However, NSS in UHR subjects have been poorly studied and, to date, we do not know what effects antipsychotics have in early treated UHR subjects. Therefore, we evaluated NSS in treated UHR subjects in comparison with drug-naive UHR subjects and a group of healthy control subjects and the effect of pharmacological treatment on early treated UHR children and adolescents.

Patients and Methods: Fifteen UHR subjects receiving pharmacological treatment, 15 drug-naive UHR subjects, and 25 healthy control subjects were evaluated for NSS to analyze any differences between clinical subjects and healthy controls and to evaluate the effect of antipsychotic medications in early treated UHR subjects.

Results: Both clinical groups showed a greater number of NSS compared with the healthy control subjects. However, no significant differences in NSS were found between treated and drug-naive UHR subjects.

Conclusions: Consistent with what has been observed in the population of patients with a first psychotic episode and/or with schizophrenia, our results support the conclusion that antipsychotic medications do not influence NSS in children and adolescents who are at high risk for psychosis.

PITZIANTI, PASINI: Department of Systems Medicine, Unit of Child Neurology and Psychiatry, “Tor Vergata” University of Rome, and USL Umbria 2, Terni, Italy

CASARELLI: Department of Systems Medicine, Unit of Child Neurology and Psychiatry, “Tor Vergata” University of Rome, Italy

PONTILLO, VICARI, ARMANDO: Department of Neuroscience, Unit of Child Neuropsychiatry, Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy

The authors declare no conflicts of interest.

Please send correspondence to: Augusto Pasini, MD, PhD Department of Systems Medicine, Unit of Child Neurology and Psychiatry, “Tor Vergata” University of Rome, Viale Oxford 81, Rome 00133, Italy (e-mail:

Early-onset schizophrenia, which represents 15% of all forms of psychosis, occurs in individuals under 18 years of age and has a more severe prognosis compared with adult-onset schizophrenia. Several studies have shown that lack of early treatment in psychosis results in a longer duration of symptoms during the first episode and is an independent predictive factor for a worse prognosis.1–5 Over the past 2 decades, clinicians have shown greater interest in early diagnosis and treatment of psychosis to improve patient outcomes. For the same reason, the international scientific community proposed including a high-risk mental state for psychosis, characterized by attenuated psychotic symptoms, also known as attenuated psychotic syndrome, in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The high-risk mental state for psychosis, also known as ultra-high risk for psychosis (UHR), was described by Yung and McGorry in 1996.6,7 On the basis of Yung and McGorry’s description, UHR can be considered as the time interval between the first behavioral manifestations and the onset of psychotic symptoms, based on the presence of signs and symptoms with high predictive sensitivity and representing a risk of nonquantifiable magnitude for onset of psychosis. Moreover, UHR is characterized by a wide range of phenomena, including attenuated psychotic symptoms, neurotic and mood-related symptoms, and behavioral changes. These symptoms are often disabling and some, such as suicidal thoughts, are potentially life-threatening.6,7 In addition to the core symptoms of psychosis, the majority of patients with schizophrenia exhibit motor abnormalities, also known as neurological soft signs (NSS).8 Moreover, scientific evidence has shown that, compared with healthy controls, drug-naive patients in a first psychotic episode as well as nonpsychotic subjects who are at high risk of psychosis with at least 2 first-and/or second-degree relatives with schizophrenia show neurological dysfunctions, including NSS.9 NSS are classically described as minor motor abnormalities detected during a neurological examination in individuals without other signs of transient or constant neurological disorders.10 In particular, NSS refer to subtle neurological abnormalities in motor coordination, sensory integration, and sequencing of complex motor acts11 that cannot be related to impairment of a specific brain region and result in considerable sociopsychological dysfunction.12 NSS are commonly observed in children with typical development, reflecting the immaturity of the central nervous system. However, the persistence of NSS into later childhood and adolescence suggests motor dysfunction and could be a marker of atypical neurodevelopment.13 NSS are mainly represented by overflow movements and dysrhythmia. Overflow movements are defined as co-movements of body parts not specifically needed to efficiently complete a motor task.14 Dysrhythmia is defined as an improper timing and/or rhythm of movement.13 NSS are classically described as a group of nonlocalizable neurological abnormalities that are considered to reflect diffuse brain structural changes. However, recent magnetic resonance imaging studies have identified alterations in specific cerebral areas associated with NSS, including dorsolateral and medial prefrontal cortices, lateral temporal, occipital, and superior parietal cortices, and medial parieto-occipital cortices.15,16 A recent meta-analysis of structural and functional magnetic resonance imaging studies reported that NSS are associated with atrophy of the precentral gyrus, the cerebellum, the inferior frontal gyrus, and the thalamus and with altered brain activation in the inferior frontal gyrus, bilateral putamen, the cerebellum, and the superior temporal gyrus.17 On the basis of this scientific evidence, in 2012 Mayoral et al18 suggested that NSS represent an endophenotype for psychotic disorders and particularly for schizophrenia. Therefore, the evaluation of NSS is essential for our understanding of the biological bases of neurodevelopmental disorders, including psychotic disorders and schizophrenia.19–22 Epidemiological data show that NSS have been found to be prevalent in patients with schizophrenia,8 and a reduction in NSS has been observed in the remission phase of psychotic symptoms in adolescents and adults with schizophrenia, although their prevalence remains higher than in the normal population.23 To our knowledge, only 2 studies have focused on the evaluation of NSS in UHR subjects. These studies indicated that patients in a first psychotic episode and UHR individuals did not differ in number of NSS,24 and that UHR individuals showed a greater expression of NSS compared with healthy controls.25 On the basis of our systematic review of the scientific literature, it emerged that antipsychotic medications do not appear to influence NSS in patients with schizophrenia.26 To date, this issue has not been studied in UHR children and adolescents treated early with antipsychotics. Thus, the objective of our study was to evaluate NSS in a group of UHR subjects who were being pharmacologically treated in comparison with a group of UHR drug-naive subjects and a group of healthy controls to evaluate the possible effect of pharmacological treatment on UHR children and adolescents receiving early treatment with antipsychotics.

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The study included 55 subjects divided into 2 clinical groups and a control group: 15 subjects at UHR for psychosis treated pharmacologically with risperidone at a dose of 1 mg/d (10 males and 5 females), 15 drug-naive subjects at UHR for psychosis (10 males and 5 females), and 25 healthy controls (16 males and 9 females) aged 7 to 18 years with IQs ≥80. All subjects in the 2 clinical groups were consecutively enrolled at the Unit of Child Neuropsychiatry of Children’s Hospital Bambino Gesù, Rome, Italy. The diagnosis of UHR was based on prodromal assessment with the Structured Interview for Prodromal Syndromes (SIPS) and the Scale of Prodromal Symptoms (SOPS),27 which was carried out by an experienced child psychiatrist. Interviews using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL)27 were used to exclude other psychiatric comorbidities in the 2 clinical groups. The healthy children were recruited in schools and selected from a pool of subjects who participated voluntarily in the study. None of them had a history of a neurological or psychiatric disease or a learning disability. The interview with the K-SADS-PL28 was also used to exclude children with psychiatric disorders from the control group. Cognitive evaluation of all subjects included in this study was done using the Wechsler Intelligence Scale for Children-III (WISC-III).29 The evaluation of NSS was carried out when the treated UHR subjects had been taking risperidone 1 mg/d for  6 months; this group had not previously taken any other antipsychotics or other psychotropic drugs, The drug-naive UHR subjects and the control subjects had not previously taken any antipsychotics or other psychotropic drugs. Before the testing, the parents or legal guardians of all of the subjects included in the study signed written informed consents provided by Children’s Hospital Bambino Gesù, IRCCS, Rome, Italy.

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Assessment of NSS

The Physical and Neurological Assessment of Subtle Signs (PANESS)30 was used to assess motor function. It was evaluated by a child neurologist trained to reliability criteria using the PANESS. The examiner was blind to the child’s diagnostic status at the time of assessment and during scoring. The PANESS has been found to have adequate test-retest reliability,31 interrater reliability, internal consistency,32 and sensitivity to age-related changes14 in more current and diverse cohorts. The PANESS measures salient components of motor function, including lateral preference, gaits, balance, motor persistence, coordination, overflow, dysrhythmia, and timed movements. Three primary outcome variables were obtained: (1) total overflow movements included the total number of abnormal movements for age observed during stressed gaits (ie, walking on heels, toes, or sides of feet), tandem gaits (walking in tandem forward and backward, touching heels to toes), and timed movements; (2) total dysrhythmia included total number of timed motor examination trials in which the children failed to maintain a steady rhythm throughout the task; and (3) total speed of timed activities of hands/feet included 3 repetitive movements and 3 sequenced movements performed bilaterally: toe tapping, alternating heel-toe tapping, repetitive hand patting, hand pronation/supination, repetitive finger tapping, and finger sequencing.

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Statistical Analysis

The statistical analysis was carried out using the Statistical Package for Social Sciences SPSS software (version 17.0, Chicago, IL). For the statistical analysis, an α level of 0.05 was applied. Comparison of independent samples was performed with Mann-Whitney U tests.

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Table 1 summarizes the demographic and clinical characteristics of the 2 groups of UHR patients and the healthy control subjects enrolled in this study. We found a statistically significant difference in total overflow movements (Z=−4.783; P=0.001), total dysrhythmia (Z=−4.977; P=0.001), and total speed of timed activities (Z=−3.973, P=0.001) between the UHR subjects (both with or without pharmacological treatment) and the healthy controls (Table 2). In contrast, we found no significant differences in total overflow movements (Z=−0.146; P=0.886), total dysrhythmia (Z=−1.30; P=0.208), and total speed of timed activities (Z=−0.229, P=0.822) between the UHR subjects who received pharmacological treatment and the drug-naive UHR subjects (Table 3).







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In agreement with the only 2 previous studies focused on motor abnormalities in UHR subjects,24,25 we found that UHR patients showed a greater number of NSS in term of overflow movements, dysrhythmia, and slowness during motor time tasks compared with healthy controls and a number of NSS similar to that seen in subjects with a first episode of psychosis. It is interesting to note that an important report based on 5-year follow-up showed long-term stability of NSS in the offspring of patients with schizophrenia.33 As a whole, the scientific evidence supports the hypothesis that NSS can be considered as an endophenotype for psychotic disorders, particularly for schizophrenia.18 Therefore, we believe that NSS could be considered as a marker of atypical neurodevelopment and/or an index of vulnerability to psychosis. This hypothesis is also supported by the results of diffusion tensor imaging studies done in UHR subjects with NSS, in which altered development of white matter was observed in the same cerebral circuits altered in schizophrenia, such as cortico-cerebello-thalamo-cortical circuits.25 It is interesting to note that these cerebral circuits are involved in the integration of motor and sensory systems.25 Several studies have shown that there were no differences in NSS between medicated subjects (chronic patients with schizophrenia) and nonmedicated subjects (patients at the first episode of schizophrenia) and there was no correlation between NSS and either the daily dosage of medication or the length of treatment.34 Moreover, in a study of patients with a first episode of psychosis, the rates of NSS did not differ significantly between antipsychotic-naive patients and patients treated with antipsychotics, with 97.1% of antipsychotic-naive subjects with psychosis showing at least 1 neurological sign.35 Therefore, as reviewed by D’Agati et al in 2012,26 there is a general consensus on the independence of NSS from the effects of antipsychotic medications in patients with a first episode of psychosis. Moreover, in a study published in 2005, Bersani et al36 did not find any significant differences in the number of NSS in adults with schizophrenia treated with a conventional antipsychotic (haloperidol) and those treated with an atypical antipsychotic (risperidone, olanzapine, or clozapine). Our data confirmed no significant differences in overflow movements, dysrhythmia, and speed of timed activities between UHR subjects receiving pharmacological treatment and drug-naive UHR subjects. This result is consistent with observations in the population of patients with a first episode of psychosis as well as in patients with schizophrenia who have had multiple psychotic episodes.26,34–36 Conversely, psychostimulant drugs, such as the indirect dopamine agonist methylphenidate, seem to reduce NSS in subjects with attention deficit/hyperactivity disorder.26 Stray et al37 observed marked improvement or complete resolution of motor dysfunctions in patients with attention deficit/hyperactivity disorder following treatment with methylphenidate. Antipsychotics and methylphenidate have different actions on the dopaminergic receptors expressed by oligodendrocytes, which could explain their differing pharmacological effects on NSS. Methylphenidate produces an increase in dopamine signaling through multiple actions, including blockade of the reuptake dopamine transporter and disinhibition of dopamine D2 receptors.38 Scientific evidence suggests that dopamine plays a role in myelinogenesis by regulating the activity of oligodendrocytes.39 According to this theory, dysfunctions of the dopamine system play an important role in oligodendroglial abnormalities.40 Oligodendrocytes express the D2-like receptors for dopamine during their development, while the oligondendrocyte progenitors express D3 receptors. When the precursors of the oligodendrocytes divide and migrate during brain development, dopamine can act on these cells favoring and directing their correct migration.41 It is hypothesized that altered levels of dopamine associated with the psychotic state could activate the D3 receptors in the immature oligodendrocytes, blocking their maturation and altering the correct development of myelin.42 It has been suggested that such a reduction in the number of mature oligodendrocytes may produce white matter abnormalities and alteration of the interhemispheric and intrahemispheric connectivity in patients with schizophrenia.43 It is interesting to note that there is a relationship between the persistence of NSS and the presence of white matter abnormalities and dopamine system dysfunction in the cortico-cortical and cortical-subcortical circuits involved in motor control and cognition in patients with schizophrenia.26,44

The main limitation of our study was the small number of enrolled subjects, which could limit the generalizability of our findings. Therefore, it would be useful to carry out additional larger studies to better understand the relationship between NSS and the effect of different types of pharmacological therapy.

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1. Karson C, Duffy RA, Eramo A, et al. Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review. Neuropsychiatr Dis Treat. 2016;6:57–67.
2. Penttilä M, Jääskeläinen E, Hirvonen N, et al. Duration of untreated psychosis as predictor of long-term outcome in schizophrenia: systematic review and meta-analysis. Br J Psychiatry. 2014;205:88–94.
3. Malla AK, Norman RMG, Manchanda R, et al. One year outcome in first episode psychosis: influence of DUP and other predictors. Schizophr Res. 2002;54:231–242.
4. McGlashan TH. Early detection and intervention in schizophrenia: research. Schizophr Bull. 1996;22:327–345.
5. McGorry PD, Edwards J, Mihailopoulos C, et al. EPPIC: an evolving system of early detection and optimal management. Schizophr Bull. 1996;22:305–326.
6. Yung A, McGorry PD. The initial prodrome in psychosis: descriptive and qualitative aspects. Aust N Z J Psychiatry. 1996;30:587–599.
7. Yung A, McGorry PD. The prodromal phase of first-episode psychosis: past and current conceptualizations. Schizophr Bull. 1996;22:353–370.
8. Chan RC, Xu T, Heinrichs RW, et al. Neurological soft signs in schizophrenia: a meta-analysis. Schizophr Bull. 2009;36:1089–1104.
9. D’Agati E, Pitzianti MB, Curatolo P, et al. Scientific evidence for the evaluation of neurological soft signs as atypical neurodevelopment markers in childhood neuropsychiatric disorders. J Psychiatr Pract. 2018;24:230–238.
10. Fellick JM, Thomson AP, Sills J, et al. Neurological soft signs in mainstream pupils. Arch Dis Child. 2001;85:371–374.
11. Heinrichs DW, Buchanan RW. Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry. 1988;145:11–18.
12. Shafer SQ, Shaffer D, O’Connor PA, et al. Hard thoughts on neurological soft signs. Dev Neuropsychiatry. 1983:133–143.
13. Cole WR, Mostofsky SH, Larson JC, et al. Age-related changes in motor subtle signs among girls and boys with ADHD. Neurology. 2008;71:1514–1520.
14. Larson JC, Mostofsky SH, Goldberg MC, et al. Effects of gender and age on motor exam in typically developing children. Dev Neuropsychol. 2007;32:543–562.
15. Gay O, Plaze M, Oppenheim C, et al. Cortex morphology in first-episode psychosis patients with neurological soft signs. Schizophr Bull. 2013;39:820–829.
16. Kong L, Bachmann S, Thomann PA, et al. Neurological soft signs and grey matter changes: a longitudinal analysis in first-episode schizophrenia. Schizophr Res. 2012;134:27–32.
17. Zhao Q, Li Z, Huang J, et al. Neurological soft signs are not “soft” in brain structure and functional network: evidence from ALE meta-analysis. Schizophr Bull. 2014;40:626–641.
18. Mayoral M, Bombín I, Castro-Fornieles J, et al. Longitudinal study of neurological soft signs in first episode early-onset psychosis. J Child Psychol Psychiatry. 2012;53:323–331.
19. Guz H, Aygun D. Neurological soft signs in obsessive-compulsive disorder. Neurol India. 2004;52:72–75.
20. Hadders-Algra M. Early brain damage and the development of motor behavior in children: clues for therapeutic intervention? Neural Plast. 2001;8:31–49.
21. Kroes M, Kessels AG, Kalff AC, et al. Quality of movement as predictor of ADHD: results from a prospective population study in 5- and 6-year-old children. Dev Med Child Neurol. 2002;44:753–760.
22. Mostofsky SH, Newschaffer CJ, Denckla MB. Overflow movements predict impaired response inhibition in children with ADHD. Percept Mot Skills. 2003;97:1315–1331.
23. Bachmann S, Degen C, Geider FJ, et al. Neurological soft signs in the clinical course of schizophrenia: results of a meta-analysis. Front Psychiatry. 2014;5:185.
24. Tamagni C, Studerus E, Gschwandtner U, et al. Are neurological soft signs pre-existing markers in individuals with an at-risk mental state for psychosis? Psychiatry Res. 2013;210:427–431.
25. Mittal VA, Dean DJ, Bernard JA, et al. Neurological soft signs predict abnormal cerebellar-thalamic tract development and negative symptoms in adolescents at high risk for psychosis: a longitudinal perspective. Schizophr Bull. 2014;40:1204–1215.
26. D’Agati E, Casarelli L, Pitzianti M, et al. Neuroleptic treatments and overflow movements in schizophrenia: are they independent? Psychiatry Res. 2012;200:970–976.
27. Miller TJ, McQlashan TH, Rosen JL, et al. Prodromal assessment with the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003;29:703–715.
28. Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980–988.
29. Wechsler D. Wechsler Intelligence Scale for Children, 3rd ed. San Antonio, TX: The Psychological Corporation; 1991.
30. Denckla MB. Revised neurological examination for subtle signs. Psychopharmacol Bull. 1985;21:773–800.
31. Holden EW, Tarnowski KJ, Prinz RJ. Reliability of neurological soft signs in children: reevaluation of the PANESS. J Abnorm Child Psychol. 1982;10:163–172.
32. Vitiello B, Ricciuti AJ, Stoff DM, et al. Reliability of subtle (soft) neurological signs in children. J Am Acad Child Adolesc Psychiatry. 1989;28:749–753.
33. Marcus J, Hans SL, Lewow E, et al. Neurological findings in high risk children: childhood assessment and 5-year follow up. Schizophr Bull. 1985;11:85–100.
34. Flyckt L, Sydow O, Bjerkenstedt L, et al. Neurological signs and psychomotor performance in patients with schizophrenia, their relatives and healthy controls. Psychiatry Res. 1999;86:113–129.
35. Browne S, Clarke M, Gervin M, et al. Determinants of neurological dysfunction in first episode schizophrenia. Psychol Med. 2000;30:1433–1441.
36. Bersani G, Gherardelli S, Clemente R, et al. Neurologic soft signs in schizophrenic patients treated with conventional and atypical antipsychotics. J Clin Psychopharmacol. 2005;25:372–375.
37. Stray LL, Ellertsen B, Stray T. Motor function and methylphenidate effect in children with attention deficit hyperactivity disorder. Acta Paediatr. 2010;99:1199–1204.
38. Wilens TE. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008;28(suppl 2):S46–S53.
39. Swarzenski BC, Tang L, Oh YJ, et al. Morphogenic potentials of D2, D3, and D4 dopamine receptors revealed in transfected neuronal cell lines. Proc Natl Acad Sci USA. 1994;91:649–653.
40. Sokolov BP. Oligodendroglial abnormalities in schizophrenia, mood disorders and substance abuse. Comorbidity, shared traits, or molecular phenocopies? Int J Neuropsychopharmacol. 2007;10:547–555.
41. Bongarzone ER, Howard SG, Schonmann V, et al. Identification of the dopamine D3 receptor in oligodendrocyte precursors: potential role in regulating differentiation and myelin formation. J Neurosci. 1998;18:5344–5353.
42. Feng Y. Convergence and divergence in the etiology of myelin impairment in psychiatric disorders and drug addiction. Neurochem Res. 2008;33:1940–1949.
43. Bernstein HG, Steiner J, Guest PC, et al. Glial cells as key players in schizophrenia pathology: recent insights and concepts of therapy. Schizophr Res. 2015;161:4–18.
44. Stewart DG, Davis KL. Possible contributions of myelin and oligodendrocyte dysfunction to schizophrenia. Int Rev Neurobiol. 2004;59:381–424.

neurological soft signs (NSS); ultra-high risk for psychosis; psychosis; early-onset schizophrenia; pharmacological treatment; antipsychotics

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