Neurological Soft Signs As an Endophenotype in Siblings of Deficit Versus Nondeficit Schizophrenic Patients Rasha E

Original article 85

Neurological soft signs as an endophenotype in siblings of deficit versus nondeficit schizophrenic patients Rasha E. Bassima, Sohier H. El Ghoniemya and Mohamed Al Dardiryb aDepartment of Neuropsychiatry, Institute of Background Psychiatry, Ain Shams University, Cairo, Egypt and bAL Maamoura Hospital, Ministry of Health, Deficit schizophrenia affects 25–30% of chronic schizophrenic patients. Alexandria, Egypt Endophenotypes are quantifiable biological variations that are types of stable trait

Correspondence to Rasha E. Bassim, MD, PhD, markers of presumed inherited vulnerability to a disease. Neurological soft signs (NSS) Department of Psychiatry, Institute of Psychiatry, are important endophenotypes of schizophrenia that are more prevalent in patients Al Shaab Al Bahary, AL Thahaby ST. block 8, Building 13, 18, Kuwait than in their unaffected relatives and in the general population. Tel: + 965 50 254 433; Objectives e-mail: [email protected], [email protected] This study was conducted to assess and compare the NSS in siblings of deficit and nondeficit schizophrenic patients (S-DSZ and S-NDSZ) and in healthy controls (HCs). Received 25 September 2011 Accepted 14 December 2011 Subjects and methods Forty siblings of each of 40 deficit and 40 nondeficit schizophrenic patients were Middle East Current Psychiatry 2012, 19:85–97 enrolled into the study, along with 40 HCs. The patients’ diagnoses were confirmed with Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Axis-I Disorders and then classified by the Schedule for the Deficit Syndrome. Siblings and HCs were examined with the help of a General Health Questionnaire – Arabic version and with the Neurological Evaluation Scale. Results Prevalence of NSS was higher in S-DSZ than in S-NDSZ. S-DSZ scored higher in each of the three main domains of the Neurological Evaluation Scale, followed by S-NDSZ and HCs. Their sociodemographic profile reflected the impact of possibly inherited negative traits. Conclusion NSS as an endophenotype is a heritable trait marker that is more prevalent in S-DSZ than in S-NDSZ and in HCs. Thus, siblings are high-risk individuals who should be followed up as a part of future preventive strategies, after taking decisions about early intervention, with implications of our results on the choice of medications; besides, the low-risk individuals in the general population should also be followed up for primary prevention.

Keywords: deficit schizophrenia, endophenotypes, neurological soft signs, siblings of deficit schizophrenic patients

Middle East Curr Psychiatry 19:85–97 & 2012 Okasha Institute of Psychiatry, Ain Shams University 2090-5408

than those with nondeficit schizophrenia (NDSZ). In ad- Introduction dition, they have a more frequently insidious onset, as well as The heterogeneity of schizophrenia, together with its dif- more resistance to antipsychotic treatment, and show a worse ferent underlying causes and pathophysiologies, has led long-term outcome [4]. to the proposal of a number of putative subtypes for this disorder. Hence, the concept of the deficit syndrome Although schizophrenia is a complex genetic disorder run- was introduced to reflect a distinct subtype within the ning in families, many questions arise when results show syndrome of schizophrenia [1,2]. It identifies a relatively that most of the affected individuals with schizophrenia homogenous subgroup of patients having three primary (or lack a family history of the disease [5,6]. However, the idiopathic) negative symptoms, with combinations of two or human genes and their phenotypes remain constant until more manifesting in the 12 months preceding the diagnosis disequilibrium occurs resulting in disorders, which are then and present constantly during periods of clinical stability [3]. propagated through further changes [6]. Genetic disequilibrium includes mutations, selection, migration, and other The prevalence of deficit schizophrenia (DSZ) has been consequences of individual mating choices. Schizophrenia reported to be about 15% among patients with first-episode is an example of such a disequilibrium affecting multiple schizophrenia and 25–30% among those with chronic loci and has been related to population drift; hence, it schizophrenia [1]. Patients with DSZ show poorer pre- can persist in the population as a relatively prevalent morbid adjustment and greater genetic load for schizophrenia disorder [7]. These multiple loci pool in certain individuals

2090-5408 & 2012 Okasha Institute of Psychiatry, Ain Shams University DOI: 10.1097/01.XME.0000412906.79378.cb

Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited. 86 Middle East Current Psychiatry who are likely to be more affected by the clinical phenotypes; thus, it becomes common for healthy individuals in Subjects and methods the general population to possess one or a few schizo- Study design phrenia-associated endophenotypes, although actual pre- The study was designed as a cross-sectional comparative valence rates are poorly documented [8,9]. study conducted between May 2010 and March 2011. The sample was a convenient one and included a total of Although several laboratory tests have been conducted 80 individuals recruited from siblings of schizophrenic and biological markers related to the central etiopathol- patients regularly attending the outpatient department ogy of the illness have been identified [10], focusing on of the Kuwait Psychological Medicine Hospital, as well as the endophenotypes has led to a marked difference in the 40 HCs who were recruited from employees and nurses way the disease is perceived. Endophenotypes are consid- at the same hospital after matching for age and sex. ered as quantifiable biological variations or deficits that The Psychological Medicine Hospital is located in the are types of stable trait markers or indicators of presumed Sabah Medical area; it is the only government center inherited vulnerability to a disease [11]. They are for psychiatric services in the State of Kuwait, with sometimes called ‘intermediate phenotype’, ‘biological inpatients, outpatients, and rehabilitation departments marker’, ‘subclinical trait’, or ‘vulnerability marker’ [12]. and facilities. They are associated with the illness in a state-indepen- dent manner and are stable over time. Characteristically, Ethical consideration they are heritable (variance in the endophenotype is asso- Ethical approval for the research protocol was obtained ciated with genetic variance), cosegregate within families, from the Ethical and Research Committee of the Minis- and are found in some unaffected relatives of individuals try of Health in Kuwait. The research team described the with the disorder (because they represent vulnerability study to the patients or their guardians and to the for the disorder, not the disorder itself) at a higher prev- patients’ siblings, ensured confidentiality of information, alence than in the general population [11,12]. and obtained their informed consent for participation. While studying schizophrenia, endophenotype strategies They were informed that their participation was volun- are being used increasingly by researchers because, unlike tary and that they had the freedom to withdraw from the the disorder, endophenotypes are presumed to have more study at any time. straightforward inheritance patterns. They are not visible to the naked eye and are only assessed by experimental Tools and procedures or laboratory-based methods rather than by clinical Structured Clinical Interview for Diagnostic and Statistical observation [6]. Manual of Mental Disorders Axis-I Diagnosis – clinical One of the important endophenotypes of schizophrenia is version [19] neurological soft signs (NSS) [12,13], which are non- The Arabic version [20] of the Structured Clinical Inter- localizing neurological abnormalities that are observed view for Diagnostic and Statistical Manual of Mental Disorders when an individual performs certain simple tasks and are Axis-I Disorders (SCID-I) was used to confirm the diag- established to be an area of abnormality in schizophrenia nosis of chronic schizophrenia in the selected out- and related disorders, suggesting evidence of brain dys- patients. Out of the 80 patients selected initially, only function [14,15]. They are presumed to have genetic 76 fulfilled the desired diagnostic criteria and four more origins because they are more frequently present in were added after confirming their diagnosis. schizophrenic patients than in other psychiatric patients and nonpsychiatric comparison individuals and, interest- The schedule for the deficit syndrome (Appendix II) [21] ingly enough, in relatives of schizophrenic patients who This instrument was used to separate the patients into are intermediate between patients and normal compar- two subtypes: the deficit and nondeficit schizophrenic ison individuals [16,17]. groups. It provides specific criteria for assessing the presence of negative symptoms, the duration of symptoms, and whether the symptoms are primary or secondary. It is a semistructured interview, and to meet the criteria for Hypothesis and objective of the study the deficit syndrome all four of the criteria listed below NSS, as a candidate endophenotype of schizophrenia, are must be satisfied. Criterion 1 includes a list of six neg- more prevalent in patients than in their unaffected ative symptoms, and at least two of the six negative relatives or when compared with the general popula- symptoms must be present in the patient. According to tion [8,13,18]. However, to our knowledge, none of the criterion 2 a combination of two or more of the negative studies have compared the prevalence of such an symptoms listed in criterion 1 should be present for 12 endophenotype in the siblings of different subtypes of months preceding the diagnosis and should be constantly schizophrenic patients (DSZ and NDSZ) and in controls. present during periods of clinical stability (including Accordingly, in this study, we will assess and compare the chronic psychotic states). Criterion 3 requires that the NSS as one of the endophenotypes of schizophrenia in negative symptoms above be primary or idiopathic. siblings of deficit schizophrenic patients (S-DSZ), siblings Criterion 4 mandates that the patient meet Diagnostic of nondeficit schizophrenic patients (S-NDSZ), and in and Statistical Manual of Mental Disorders (DSM) criteria for healthy controls (HCs). schizophrenia.

The General Health Questionnaire – Arabic version [22] They were recruited from the employees and nurses This questionnaire was used to rule out psychiatric working at the same hospital who gave their informed morbidity in both of the sibling groups and in the control consent to participate after being given a detailed des- group. cription of the study. HCs comprised group C.

The Neurological Evaluation Scale (Appendix I) [23] Phase 3: examination of the three groups It is a structured scale that presents scores in four The three groups were examined by means of the subscales: (a) sensory integration, (b) motor coordination, Neurological Evaluation Scale (NES; Appendix I) [23]. (c) sequencing of complex motor acts, and (d) others. Through 26 items it captures a wide range of neurological Statistical analysis signs. Each item is rated on a scale of 0–2 (0 = relatively Data were analyzed using the SPSS software version 10 normal, 1 = some disruption, 2 = major disruption) ac- (SPSS Inc., Chicago, Illinois, USA). The tests used were: cording to standardized criteria. Higher scores indicate (i) descriptive statistics, consisting of arithmetic mean greater neurological impairment. To measure the severity and SD; (ii) nonparametric tests, consisting of the of neurological impairment, the total score and scores for Wilcoxon Mann–Whitney rank-sum test; (iii) comparison each of the four subscales were used. of means, consisting of the w2-test for cross-tabulations; (iv) the correlation matrix; and (v) multivariate regres- The study passes through three phases sion. Level of significance was set at 0.01. Phase 1: recruitment of patients Eighty patients who fulfilled the criteria of chronic schizophrenia according to the DSM IV, SCID-I, had living siblings, and agreed to participate in the study were Results recruited from those attending the outpatient clinic of Sociodemographic characteristics the Kuwait psychological Medicine Hospital. They were The studied sample was divided into three groups: group then examined further by Schedule for the Deficit A comprising S-DSZ, group B comprising S-NDSZ, and Syndrome [21] and classified into two groups (DSZ and group C comprising HCs. The demographic character- NDSZ) with 40 patients in each group. However, at first, istics of the studied sample are presented in Table 1. we had 52 NDSZ and 28 DSZ patients, after which we A significant statistical difference was found between recruited another 25 patients, 16 of whom were found to groups in terms of marital status; 45% of S-DSZ were be DSZ patients and the remaining nine were NDSZ married, although this was the smallest percentage in the patients. Thus, we had a total of 61 NDSZ and 44 DSZ three groups; at the same time the highest percentage patients. of single individuals was also found in the same group. A significant statistical difference was observed in relation At that point, 12 of the NDSZ patients withdrew from to education as well; it was noticed that the majority of the study. Out of the remaining 49 NDSZ patients, we S-DSZ were illiterate and had received only primary randomly excluded nine patients, along with four from education in comparison with the other groups in which the DSZ group, so that we had 80 patients, 40 from each the majority of S-NDSZ had received preparatory group (40 DSZ and 40 NDSZ patients), all with their education. diagnosis confirmed as mentioned before. Neurological soft signs Phase 2: recruitment of patients’ siblings In an attempt to detect soft neurological signs in the The participants (groups A, B, and C) were the siblings of studied group, the NES was applied on all recruited each patient of each group, as well as HCs. Siblings whose participants. It revealed that the percentage of those who ages ranged from 18 to 60 years, belonging to both sexes, scored positively in all aspects of the NES was higher in who agreed to participate in the study were provided a group A than in groups B and C, with mean% of written informed consent form after being given a com- 47.59 ± 32.947 vs. 43.50 ± 29.492 and 21.36 ± 22.676 in plete description of the study. In contrast, those who had groups B and C, respectively, as shown in Table 2. a history of mental retardation, head trauma, alcoholism, drug abuse or dependence, a known neurological disorder, In addition, the mean of the total scores of group A was or a known Axis-I psychiatric disorder were excluded and higher than those of groups B and C in sensory and replaced with another sibling who fulfilled the terms sequencing tests, as shown in Table 3. mentioned above. Thereafter, the recruited siblings were The following results were observed when the scores interviewed using the General Health Questionnaire – of the three groups in the NES were compared. The Arabic version [22] to rule out unrevealed potential psy- number of participants who had high scores in all aspects chiatric morbidity. Thus, we had two groups of siblings, of the NES was higher in group A than in groups B and S-DSZ (group A) and S-NDSZ (group B), each consisting C. Table 4 shows a comparison between the results of the of 40 participants. scores of the NES among the three groups by score inter- These two groups (A and B) were matched for age and vals. In the motor subtests, a larger number of HCs (35) sex with 40 HCs (as revealed by their examination using obtained low scores (0–3) compared with S-NDSZ (31), the General Health Questionnaire). Family history of psy- whereas the number of S-DSZ to obtain low scores was chiatric morbidity was ruled out by verbal history taking. the smallest (20). However, a larger number of S-DSZ (5)

Table 1 Sociodemographic characteristics of the studied group N =40

Group A Group B Group C S-DSZ S-NDSZ HC Test used P-value

Age Mean ± SD 38.2 ± 3.4 34.7 ± 4.9 31.4 ± 5.1 F = 1.712 40.1 insignificant Sex M/F 29 (11) 28 (12) 24 (16) Marital status Single 11 (27.5%) 9 (22.5%) 6 (15%) w2 = 11.81 o0.001 significant Married 18 (45%) 21 (52.5%) 29 (72.5%) Divorced 9 (22.5%) 10 (25%) 5 (12.5%) Widowed 2 (5%) 0 (0%) 0 (0%) Educational level Illiterate 15 (37.5%) 10 (25%) 7 (17.5%) w2 = 9.18 o0.01 significant Primary 17 (42.5%) 6 (15%) 9 (22.5%) Preparatory 8 (20%) 21 (52.5%) 15 (37.5%) Secondary 0 (0%) 3 (7.5%) 3 (7.5%) University 0 (0%) 0 (0%) 6 (15%) Occupational status Unemployed 11 (27.5%) 8 (20%) 4 (10%) w2 = 0.71 40.1 insignificant Manual 1 (2.5%) 1 (2.5%) 0 (0%) Clerical 28 (70%) 29 (72.5%) 31 (77.5%) Professional 0 (0%) 2 (5%) 5 (12.5%)

Table 2 Mean scores obtained by the participants and the percentage of those who obtained positive results in the Neurological Evaluation Scale scores N =40

Group A Group B Group C S-DSZ S-NDSZ HC

Mean ± SD 47.59± 32.947 43.50 ± 29.492 21.36 ± 22.676 F-value 10.64 P-value 0.0001(highly significant) Motor Right Left Right Left Right Left Finger to nose 36 36 32 34 12 6 Rapid alternating movements 8 16 6 16 4 6 Finger thumb opposition 18 24 12 18 8 8 Tandem walk 24 20 6 Sensory Audiovisual integration 98 74 22 Stereognosis 90 86 52 76 0 2 Graphesthesia 84 86 50 70 12 14 Extinction 42 30 4 Right–left confusion 84 90 48 Motor coordination Right Left Right Left Right Left Fist ring test 94 96 64 94 18 12 Fist edge Palm test 92 88 68 92 26 16 Ozeretski test 100 78 26 Rhythm tapping (B) 40 44 18 Others Right Left Right Left Right Left Romberg test 8 10 2 Adventitious overflow R 30 30 34 32 8 8 Tremors R 26 24 22 26 10 10 Handedness 90 96 90 Footedness 86 94 86 Eyedness 86 94 86 Memory 5 66 70 24 Memory 10 58 64 30 Rhythm tapping (A) 76 74 38 Mirror movements 34 42 32 40 34 40 Synkinesis 32 28 30 30 46 46 Convergence 20 20 24 24 12 14 Gaze impersistence 14 14 18 18 10 12 Glabellar reflex 46 42 48 Snout reflex 0 0 0 Grasp 6 6 6 6 2 0 Suck reflex 10 8 8 HC, healthy control; S-DSZ, siblings of deficit schizophrenic patients; S-NDSZ, siblings of nondeficit schizophrenic patients. obtained high scores (6–9) compared with none of the Similar results were found for the other three sub- S-NDSZ and one HC. The results of the motor subtests tests. However, the sensory subtest comparison was were significant (Po0.01). insignificant.

Table 3 Mean of the total scores of the Neurological Evaluation Scale tests for the study groups Mean ± SD

Group A Group B Group C S-DSZ S-NDSZ HC F-value P-value

Motor 1.94 ± 0.23 1.96 ± 0.12 1.46 ± 0.7 11.624 o0.01 significant Sensory 9.30 ± 3.10 2.95 ± 2.3 5.96 ± 101 Sequencing 8.06 ± 0.87 1.98 ± 0.14 6.44 ± 0.8 Others 8.48 ± 0.91 4.14 ± 0.37 7.84 ± 0.89 HC, healthy control; S-DSZ, siblings of deficit schizophrenic patients; S-NDSZ, siblings of nondeficit schizophrenic patients.

Table 4 Comparison between results of the scores of the with the number of S-DSZ to obtain low scores being the Neurological Evaluation Scale among the three groups of the smallest (2). However, a larger number of S-DSZ (1) study, grouped by score intervals obtained high scores (18–24) compared with S-NDSZ (1) Group A Group B Group C and HCs (0). The results of the other subtests were S-DSZ S-NDSZ HC Total w2 P significant. Motor 0 20 31 35 86 9.967 o0.01 Significant 3159428 Discussion 6–9 5 0 1 6 Total 40 40 40 120 Schizophrenia is a serious mental illness that causes major Sensory disability and psychosocial impairment. Patients with the 0 0 2 34 36 0.24 0.31 insignificant deficit syndrome/subtype have poorer quality of life and 3617528 a more severe form of the illness [24], more cognitive 6 5 14 1 20 impairment, and more frequent side effects, especially 9207027 12–14 9 0 0 9 tardive dyskinesia [25,26]. Early intervention, as sug- Total 40 40 40 120 gested by some, in individuals who appear to have very Sequencing early symptoms of schizophrenia but who have not yet 0 0 1 30 31 7.921 o0.01 significant met DSM-IV criteria for the disorder is recommended [27], 3 3 10 10 23 with recent advances in neurosciences prompting con- 62123044 siderations of schizophrenia from a preventive perspective 9–12 16 6 0 22 Total 40 40 40 120 through either elucidation of potential causal risk factors Others and/or research on risk markers [13]. 0 2 4 17 23 14.847 o0.001 significant As stated by Robert and Yourell [27], there are physical 3791127 vulnerabilities for schizophrenia, such as genetic risks, as 6159832 987318 well as environmental factors that trigger those vulner- 12 6 7 1 14 abilities. Endophenotypes, or ‘intermediate phenotypes’, 15 1 3 0 4 are best considered as quantifiable biological variations or 18–24 1 1 0 2 Total 40 40 40 120 deficits that are types of stable trait markers or indicators of presumed inherited vulnerability or liability to a HC, healthy control; S-DSZ, siblings of deficit schizophrenic patients; S-NDSZ, siblings of nondeficit schizophrenic patients. disease. They are ‘intermediate’ between a clinical entity and the associated disease vulnerability genes. Although new mutations, deletions, or copy number variants may be the reason in some cases [28], other affected In the sensory subtests, a larger number of HCs (34) individuals are believed to have acquired their liability obtained low scores (0–3) compared with S-NDSZ (2), for the disorder through inheritance of several common and the number of S-DSZ to obtain low scores was single-nucleotide polymorphism-based variants, likely acting the smallest. However, a larger number of S-DSZ (9) multiplicatively [29]. At a genetic level, collections of obtained high scores (12–14) compared with S-NDSZ (0) smaller numbers of single-nucleotide polymorphisms may and HCs (0). The results of the sensory subtests were manifest as endophenotypic abnormalities [30]. insignificant (P = 0.34). Several studies have discussed and compared neurological In the motor sequencing subtests, a larger number of impairment in patients with schizophrenia and in their HCs (30) obtained low scores (0–3) compared with S- siblings/first-degree relatives, whether soft signs or hard NDSZ (1), and number of S-DSZ to obtain low scores signs, primitive reflexes, integrative sensory functions, was the smallest (0). However, a larger number of S-DSZ or motor functions [31]. These studies include those (16) obtained high scores (9–12) compared with S-NDSZ comparing deficit with nondeficit patients [4,32,33] or (6) and HCs (0). The results of the motor sequencing comparing patients with schizophrenia with their siblings/ subtests were significant (P 0.01). o first-degree relatives [13]. Other studies have compared In the other subtests a larger number of HCs (17) schizophrenic patients with their siblings/first-degree re- obtained low scores (0–3) compared with S-NDSZ (4), latives and HCs [31]. Accordingly, this study was designed

Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited. 90 Middle East Current Psychiatry to assess and compare the NSS as a candidate endopheno- results of other studies [31], suggesting a similar wide- type of schizophrenia in S-DSZ, S-NDSZ, and HCs. We spread area of subtle brain abnormality that is character- chose the NSS as a candidate endophenotype because of istic of schizophrenia [34]. Whereas the motor sequencing it being a quantifiable potential endophenotype, having a impairment was inversely proportional to the total and crucial role in the ‘target features’ encompassing the idea regional gray matter volume, cerebellar atrophy was that genetic and nongenetic processes lead to neurointe- particularly related to the NSS of rhythmic drumming grative defects that later manifest in the neurocognitive and forefinger–right thumb opposition and forefinger–left system [4,6,11,32,33]. thumb opposition tasks [35]; further, cerebellar neurological signs have smaller total cerebellar tissue volume [36]. Sociodemographic variables The sociodemographic analysis of our subjects’ data Meanwhile, we cannot disregard the controls involved in showed that the S-DSZ suffer more from the impact of our study. Those with positive scores in the NES denoting the possibly inherited traits of negative symptoms on the presence of NSS and without a known family history their social and marital life, as reflected by the highest of schizophrenia have the genetic characteristics of the percentage of single individuals (27.5%) and lowest pathological process of the disorder. They are liable to percentage of married ones (45%), in comparison with develop the disorder and follow the same prognostic steps, the S-NDSZ and matched HCs. They also showed lower or produce offspring with greater numbers of abnormal achievements in educational levels, reflecting the impact endophenotypes, thus increasing the risk of their devel- of the possible heritability of negative symptoms, as well oping schizophrenia. as ‘possible’ affected executive functions similar to those of the patients themselves [15,24]. These high-risk groups have to be given prominence by policy makers when taking important decisions about With regard to occupational status, we could not arrive at ethical issues involving medicating or not medicating a definite conclusion on the basis of our results because of individuals who do not fulfill all the criteria of the disorder, the nature of the Kuwaiti government’s social care system or those in prodromas. and employment policy, offering jobs with fair incomes for most of the citizens, regardless of their qualifications, as Conclusion a part of the national social support strategies. DSZ is a subtype of schizophrenia with a relatively high The results of the current study agree with previous prevalence among those patients, inflicting considerable reports indicating the role of NSS as a trait marker in the burden on the psychiatric resources as a whole. It is siblings of schizophrenic patients [4,32,33]. First of all, significantly associated with the identifiable and measur- the percentage of siblings with positive scores in the NES able trait marker/endophenotype NSS that is also highly was higher in both groups of siblings than in the HC prevalent in their nonaffected siblings, more than in the group (C). Moreover, comparison between the three nonaffected S-NDSZ, and in turn is higher than in HCs. groups involved in the study showed more prevalence of Studies should start considering schizophrenia from NSS among S-DSZ than in the other two groups, being preventive perspectives, with strategies targeting high- intermediate in S-NDSZ and lowest in HCs, as reported risk and low-risk groups in the population, consequently by Merchi et al. [33]. influencing policy makers’ decisions regarding ethical treatment strategies. In fact, S-DSZ scored remarkably higher in the three main domains of the NES, namely, motor coordination Recommendations tests, tests of sequencing of complex motor acts, and In view of our study results, we would recommend integrative sensory function tests. These results match carrying out similar studies, on larger scales, to elicit more those of Merchi et al. [33], clarifying the genetic role of informative data for better and more specific results. NSS as a target feature and a measurable marker [11,32]. Endophenotypes hold much promise in preventive research because they can be used to identify individuals Although the results of the integrative sensory functions who are at high risk for developing psychiatric disorders, as tests were statistically insignificant, S-DSZ scored higher well as the low-risk ones. They can also identify those with than the other two groups in those tests. Their higher single or few endophenotypic abnormalities who may be scores indicated more impairment in stereognosis, extinc- more likely to produce offspring with greater number of tion, and audiovisual integration, whereas the S-NDSZ scored a little higher in the right–left confusion only, abnormal endophenotypes, thus increasing the prevalence of the disorder. Further, ethical issues such as whether or which did not affect the total scores of the integrative not to follow-up these population groups and when to start sensory function tests when summed at the end. S-DSZ medications have to be settled by our policy makers. Our also showed greater impairment (with statistical signifi- research in schizophrenia should be redirected toward cance) in sequencing tests and motor coordination tests, primary prevention by developing more tools that would which is consistent with the results of Ismail et al. [31]. help us to achieve this objective, such as the NSS However, our study could not localize specific areas that examination, which is a simple low-cost tool that can be were more affected than others. On the contrary, there used as a screening tool in recommended areas of study as was a dispersion of localization because of the variations well as along with other tools in premarital assessment for in the recorded NSS. These variations paralleled the couples contemplating marriage with a partner at risk for

Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited. Studying neurological soft signs of siblings Bassim et al.91 schizophrenia in order to avoid potential appearance of 13 Mechri A, Bourdel MC, Slama H, Gourion D, Gaha L, Krebs MO. Neurolo- gical soft signs in patients with schizophrenia and their unaffected siblings: hereditary disorders in their offspring. Hence, ambitious frequency and correlates in two ethnic and socioeconomic distinct popula- studies should be conducted as a part of the general future tions. Eur Arch Psychiatry Clin Neurosci 2009; 259:218–226. preventive strategy, aiming at placing psychiatry beside 14 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 other medical branches in the era of primary prevention. schizophrenia and related disorders, their first-degree biological relatives and non-psychiatric controls. 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Comparative analysis of soft neurological signs in positive and negative of schizophrenia: the concept. Am J Psychiatry 1988; 145:578–583. subtype of schizophrenia. Psychiatr Danub 2009; 21:174–178. 4 Galderisi S, Maj M, Mucci A, Cassano GB, Invernizzi G, Rossi A, et al. 33 Mechri A, Slama H, Bourdel MC, Chebel S, Mandhouj O, Krebs MO, et al. Historical, psychopathological, neurological and neuropsychological aspects Neurological soft signs in schizophrenic patients and their nonaffected sib- of deficit schizophrenia: a multicenter study. Am J Psychiatry 2002; lings. Encephale 2008; 34:483–489. 159:983–990. 34 Frith C. Cognitive neuropsychology. J Ment Health 1996; 5:3–7. 5 Waddington JL, Corvin AP, Donohoe G, O’Tuathaigh CMP, Mitchell KJ, Gill M. Functional genomics and schizophrenia: endophenotypes and mutant 35 Bersani G, Paolemili M, Quartini A, Clemente R, Gherardelli S, Iannitelli A, models. Psychiatr Clin North Am 2007; 30:365–399. et al. Neurological soft signs and cerebral measurements investigated by means of MRI in schizophrenic patients. Neurosci Lett 2007; 413:82–87. 6 Allen AJ, Griss ME, Folley BS, Hawkins KA, Pearlson GD. Endophenotypes in schizophrenia: a selective review. Schizophr Res 2009; 109 (1–3): 24–37. 36 Ho BC, Mola C, Andreasen NC. Cerebellar dysfunction in neuroleptic naive 7 Sullivan PF, Kendler KS, Neale MC. Schizophrenia as a complex trait: evi- schizophrenia patients: clinical, cognitive and neuroanatomic correlates of dence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; cerebellar neurologic signs. Biol Psychiatry 2004; 55:1146–1153. 60:1187–1192. 8 Keller MC, Miller G. Resolving the paradox of common, harmful, heritable mental disorders: which evolutionary genetic models work best? Behav Brain Sci 2006; 29:385–404. Appendix 1. Neurological Evaluation Scale 9 Pearlson GD, Folley BS. Endophenotypes, dimensions, risks: is psychosis analogous to common inherited medical illnesses? Clin EEG Neurosci 1. Tandem walk 2008; 39:73–77. 10 Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth Instructions: Participant to walk, in a straight line, 12 feet, DF, et al. Biomarkers and surrogate endpoints: preferred definitions and heel to toe. conceptual framework. Clin Pharmacol Ther 2001; 69:89–95. 11 Chan RCK, Gottesman II. Neurological soft signs as candidate en- Assessment: 0 = no missteps after the subject has com- dophenotypes for schizophrenia: a shooting star or a Northern star? Neu- pleted the first full step; 1 = one or two missteps after rosci Biobehav Rev 2008; 32:957–971. 12 Gottesman II, Gould TD. The endophenotype concept in psychiatry: ety- the completion of the first full step; 2 = three or more mology and strategic intentions. Am J Psychiatry 2003; 160:636–645. missteps, grabbing, or falling.

2. Romberg test to close his/her eyes during the tapping. Three practice trials are performed first to ensure that the subject Instructions: Participant to stand with his/her feet together, understands the directions. eyes closed, his/her arms held parallel to the floor, and fingers spread apart. The participant is to maintain this Assessment: 0 = no error; 1 = one error; 2 = two or more errors. position for 1 min. 7. Stereognosis Assessment: 0 = relatively stable, minimal swaying; 1 = Instructions: The participant, with eyes closed, is asked to marked swaying; 2 = participant steps to maintain identify an object placed in his/her hand. The participant balance or falls. is instructed to feel the object with one hand and to take 3. Adventitious overflow as much time as needed. If the participant cannot name the object, he/she is asked to describe for what purpose Instructions: Same as the Romberg test. the object is used. The participant starts with the Assessment: 0 = absence of movement of the fingers, hands, dominant hand, on the basis of the previous evaluation of or arms; 1 = irregular fluttering movement of the fingers handedness, or the hand with which he/she writes, if only; 2 = irregular fluttering movement extended to the there is mixed hand dominance. The instructions are hands and/ or the arms. repeated at the beginning of the second trial. 4. Tremor Assessment: 0 = no errors; 1 = one error; 2 = more than one error. Instructions: Same as the Romberg test. 8. Graphesthesia Assessment: 0 = no tremor; 1 = mild, fine tremor; 2 = marked, fine,orcoarsetremor. Instructions: The participant, with eyes closed, is asked to identify the number written on the tip of his/her 5. Cerebral dominance forefinger. The order of hands is determined as in the case of stereognosis. a. Handedness Assessment: 0 = no errors; 1 = one error; 2 = more than one Instructions: Ask participant to demonstrate how he/she error. would write, throw a ball, use a tennis racket, strike a match, use scissors, thread a needle, use a broom, use a 9. Fist–ring test shovel, deal cards, use a hammer, brush teeth, and Instructions: The participant is asked to alternate placing unscrew the lid of a jar. his/her hand on the table, in the position of a fist, with Assessment: R–participant writes with the right hand and the thumb placed either over the knuckles or over the performs at least seven other activities with the right middle phalanges and placing his/her hand, on the table, hand; M–participant writes with the right/left hand but in the position of a ring, with the tips of the thumb and performs less than seven other activities with the right/ the forefinger touching and the remaining three fingers left hand; L–participant writes with the left hand and extended. The participant is to bring his/her arm to the performs at least seven other activities with the left hand. upright position between each change in hand position. If the participant does not perform the movement accu- b. Footedness rately or in a manner that can be appropriately assessed, Instructions: Ask the participant to demonstrate how he/ he/she is to be stopped, to be reinstructed, and to start she would kick a ball. the test again. The participant is to repeat each set of hand position changes 15 times. Assessment: R–participant kicks the ball with the right foot; Assessment:0= no major disruption of motion after the L–participant kicks the ball with the left foot. first repetition; errors limited to incomplete extension of c. Eyedness the fingers in the ring position and no more than two hesitancies in the transition from the fist to the ring or Instructions: Ask the participant to look, with both eyes vice versa and no more than one fist/ring confusion; open, at a distant object through a hole in the center of a 1 = no major disruption of motion after first repetition or 3 Â 5-inch index card that is held with both hands complete breakdown of motion; more than two hesitancies 18 inches in front of the participant. The participant is to in the transition from fist to ring, difficulty in developing close one eye at a time and tell the examiner with which and maintaining a smooth, steady flow of movement, three eye closed did he/she lose sight of the object. to four fist/ring confusions, or any total of three but not Assessment: R–participant loses sight of object with the more than four errors. 2 = major disruption of movement or right eye closed; L–participant loses sight of object with complete breakdown of motion, or more than four fist to the left eye closed. ring hesitations or confusions. 6. Audio–visual integration 10. Fist–edge–palm test Instructions: The participant is asked to match a set of Instructions: Ask the participant, using a smooth and tapping sounds with one of three sets of dots presented steady rhythmic pattern, to touch the table with the side on a 5 Â 7-inch index card. The participant is instructed of his/her fist, the edge of his/her hand, and the palm of

Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited. Studying neurological soft signs of siblings Bassim et al.93 his/her hand. The participant is to break contact with the The participant may have his/her eyes open while surface of the table between each change in hand position, reproducing the series of taps. but not to bring the arm back in full flexion. The participant Assessment: 0 = no errors; 1 = one error of either non- is to repeat this sequence of position changes 15 times. discrimination between soft and hard sounds, rhythm, or Assessment: 0 = no major disruption of motion after the error in number of taps; 2 = more than one error. first repetition; errors limited to no more than two Part B hesitancies in the transition from one position to the next and no more than one mistake in hand position. 1 = no Instructions: Ask the participant to produce a series of taps major disruption of motion after first repetition or as instructed. complete breakdown of motion; more than two hesitan- Assessment: 0 = no errors; 1 = one error; 2 = more than one cies in the transition from one position to another, error. difficulty in developing and maintaining a smooth, steady flow of movement, three to four position confusions, or 14. Rapid alternating movements any total of three or four errors. 2 = major disruption of movement or complete breakdown of motion, or more Instructions: Ask the participant to place his/her hands than four hesitations or position confusions. palm down on legs. The participant is to start with his/her dominant hand and is to slap his/her leg distinctly with 11. Ozeretski test the palm and the back of his/her hand in an alternating Instructions: The participant is to place both hands on the motion. The determination of dominance is as described table, one hand palm down and the other hand in the above (see item 8). The participant is to perform the task shape of a fist. The participant is then asked to alternate 20 times with both hands, one hand at a time. the position of his/her hands simultaneously in a smooth Assessment: 0 = no major disruption of motion, hesitation, and steady motion. The participant is asked to repeat this or mistake in hand placement; 1 = no major disruption of motion 15 times. motion or one to two hesitations or mistakes in hand Assessment: 0 = no major disruption of motion after the placement; 2 = major disruption of motion or three or first repetition; errors limited to no more than two more hesitations or mistakes in hand placement. hesitancies in the transition from one position to the next 15. Finger–thumb opposition and no more than one mistake in hand position. 1 = no major disruption of motion after first repetition or Instructions: Ask the participant to place both hands palm complete breakdown of motion; more than two hesitan- up with fingers fully extended on his/her legs. The cies in the transition from one position to another, participant is to start with his/her dominant hand and is difficulty in developing and maintaining a smooth, steady to touch the tip of his/her fingers with the tip of his/her flow of movement, three to four position confusions, or thumb, from the forefinger to the pinky, returning to the any total of three, but no more than four errors. 2 = major forefinger, for a total of 10 repetitions. disruption of movement or complete breakdown of motion, Assessment: 0 = no major disruption of motion and no more or more than four hesitations or position confusions. than one mistake; 1 = no major disruption of motion or 12. Memory two to three mistakes; 2 = major disruption of motion or four or more mistakes. Instructions: The participant is told four words and is asked to repeat them immediately after they are all presented. 16. Mirror movements If the participant is unable to repeat the four words Instructions: The participant’s hand, which is not perform- correctly, they are presented again. If the participant still ing the finger–thumb opposition test, is observed for cannot repeat the four words after a total of three parallel movements of the fingers and thumb. presentations of the words, the test is terminated and the participant is given a score of 2 for both parts of the item. Assessment: 0 = no observable movements of the fingers; If the participant is able to repeat the four words after the 1 = minor, inconsistent, or repetitive movements of the initial or two subsequent presentations, he/she is then fingers; 2 = consistent, distinctive movements of the asked to remember the words as well as possible and told fingers. that he/she will be asked to repeat the words twice later 17. Extinction (face–hand test) on during the interview. The participant is then asked to recall the four words at 5 and 10 min. Instructions: The participant is seated, with hands resting palm down, on his/her knees and with eyes closed. The Assessment: 0 = participant remembers all the words; participant is told that he/she will be touched on either 1 = participant remembers three words; 2 = participant the cheek, hand, or both and is to say where he/she has remembers fewer than three words. been touched. If the participant names just one touch, 13. Rhythm tapping test he/she is asked – the first time this occurs only – if he/she felt a touch anywhere else. The simultaneous touching is Part A done in the following order: right cheek–left hand, left Instructions: Ask the participant to reproduce exactly the cheek–right hand, right cheek–right hand, left cheek–left series of taps heard when he/she has his/her eyes closed. hand, both hands, and both cheeks.

Assessment: 0 = no errors; 1 = one error; 2 = more than one 24. Snout reflex error. Instructions: The participant is instructed to relax, and the 18. Right/left confusion examiner presses his finger against the participant’s philtrum. Instructions: The participant is asked to point to his/her right foot, left hand; place his/her right hand to the left Assessment: 0 = no contraction of the orbicularis orris (or shoulder, the left hand to the right ear; point to the puckering of the lips); 2 = any contraction of the examiner’s left knee, right elbow; with the examiner’s orbicularis orris (or puckering of the lips). arms crossed, point to the examiner’s left hand with his/ 25. Grasp reflex her right hand, and with the examiner recrossing arms, point to the examiner’s right hand with his/her left hand. Instructions: The participant is instructed not to grab, and the examiner strokes the inside of the participant’s palm Assessment: 0 = no errors; 1 = one error; 2 = two or more between the index finger and the thumb. This procedure errors. is repeated a second time with the participant being 19. Synkinesis asked to spell the word ‘help’ backwards. Instructions: The participant is instructed to follow the cap Assessment: 0 = no flexion of the participant’s fingers; of a pen with his/her eyes only as it is moved between 1 = mild flexion of the participant’s fingers on the first extremes of horizontal gaze. If the participant moves his/ trial or flexion of any kind on the second trial; 2 = marked her head, the participant is asked to keep his/her head flexion of the participant’s fingers on the first trial. still and follow the cap of a pen with the eyes only. 26. Suck reflex Assessment: 0 = no movement of the head; 1 = movement Instructions: The examiner places the knuckle of a flexed of the head on the first trial but not when specifically told index finger or a tongue depressor between the partici- to keep the head still; 2 = movement of the head even pant’s lips. when told to keep the head still. Assessment: 0 = no movement; 2 = any pursing or sucking 20. Convergence motion of the participant’s lips. Instructions: The participant is instructed to follow the cap of a pen with his/her eyes as it is moved toward his/her nose. Appendix 2. Clinical correlates of deficit Assessment: 0 = both eyes converge on the object; 1 = one schizophrenia or both eyes are unable to converge completely, but can To meet the criteria for the deficit syndrome, all four of converge more than halfway; 2 = one or both eyes fail to the criteria listed below must be satisfied. converge more than halfway. I. Criterion 1 21. Gaze impersistence Instructions: The participant is instructed to fix his/her (1) At least two of the following six negative symptoms gaze on the cap of a pen at a 451 angle in the horizontal must be present: plane of the right and left visual fields for 30 s. (a) Restricted affect. (b) Diminished emotional range. Assessment: 0 = no deviation from fixation; 1 = deviation from (c) Poverty of speech. fixation after 20 s; 2 = deviation from fixation before 20 s. (d) Curbing of interests. 22. Finger to nose test (e) Diminished sense of purpose. (f) Diminished social drive. Instructions: The participant is instructed to close eyes and touch the tip of his/her nose with the tip of his/her index Criterion 1 relates to negative symptoms, which should finger. be distinguished from deficit features. The latter are nega- Assessment: 0 = no intention tremor or passpointing; tive symptoms that are primary, enduring, and present 1 = mild intention tremor or passpointing; 2 = marked during periods of clinical stability or baseline. For instance, intention tremor or passpointing. demoralization resulting from repeated failure may lead to a high score on the negative symptom items in criterion 1, but 23. Glabellar reflex wouldleadtoaratingof‘false’onitem3,asthesenegative Instructions: The participant is instructed to fix his/her symptoms would be considered secondary, and hence not gaze on a point across the room. The participant is deficit features. approached from above the forehead outside of the visual For each of the six symptoms listed in criterion 1, the field and the examiner taps the glabellar region 10 times rater assesses the patients on a 0–4 scale. A score of 0 with the index finger. implies that the patient is normal relative to the item. A Assessment: 0 = three or fewer blinks; 1 = four or five full score of 1 implies that the patient is possibly but not blinks or more than six partial or full blinks; 2 = six or definitely abnormal relative to the feature, or is slightly more full blinks. unusual relative to the feature but is within the range of

Copyright © Middle East Current Psychiatry. Unauthorized reproduction of this article is prohibited. Studying neurological soft signs of siblings Bassim et al.95 normal variation. A score of 2 or above indicates a clinical deliberate withholding of speech, for instance on the basis judgment that the patient is clearly abnormal relative to of persecutory beliefs or a relatively normal reticence the feature, that is, beyond the range of normal variation. with strangers, would not be considered primary poverty A score of 4 implies that the patient is severely impaired. of speech. The rating is based on both the number of Anchors are provided that describe the scoring for each of words used and the amount of information revealed, these items. To meet the requirements for the deficit including that information that is volunteered and is not syndrome (and to meet criterion 1), a patient must have a absolutely required by a question with a literal answer. score of 2 or above on two of the six items in criterion 1. The abnormality, sometimes called poverty of content of speech, is not rated here. Poverty of content of speech is A few suggested questions are given for each of the negative found in the patient who delivers an adequate amount of symptoms, but the most valuable questions are often based speech or number of words, but little information is on the information that the patient provides spontaneously, conveyed because of vagueness or repetitive, stereotyped, and one should often follow the patient’s lead. It is impor- or cliche-ridden speech. tant to keep in mind that patients may provide socially ap- propriate answers with regard to emotional range, interests, D. Curbing of interests sense of purpose, and social drive. However, such answers This item is used to rate the degree to which the person may be contradicted by the patient’s actions or lack of is interested in the world around him or her, both ideas action. Not infrequently, informants provide information and events. The rating for this item should be based on that contradicts the conclusions derived from the patient both the behavior and the thoughts of the patient. Being interview, and this information may be considered more interested in the world around one is different from valid than that obtained from the interview. having a good fund of knowledge. A. Restricted affect The patient may show a diminished range of interest or This item does not require specific probes; it is to be a diminished depth of interest; either impairment may rated on the basis of what is observed in the interview and be considered pathological. However, a great depth of by others who have had long-term contact with the interest in a narrow range of topics (such as is sometimes patient. Restricted affect refers to observed behaviors found among researchers!) will usually not be considered rather than to the patient’s subjective experience. to be a curbing of interests. A pathological preoccupation with psychotic goals may limit curiosity or interest in other Specifically, one rates the following criteria: things, but this is not a curbing of interests as intended here, as the patient is clearly still lively with regard to this (1) A relatively expressionless face or an unchanging area of function. The patient with an intense but ap- facial expression. parently pathological interest in an unrealistic goal, which (2) Reduced expressive gestures. guides both thought and action, does not show a curbing (3) Diminished modulation of the voice, which supple- of interests. ments the spoken content (changes in speed, volume, and inflection of speech). E. Diminished sense of purpose Under this item, one attempts to rate the following It is important to distinguish primary restricted affect from parameters: a guarded speaking style that is caused by suspiciousness or a relatively normal reticence or shyness in an interview. (1) The degree to which the patient posits goals for his/ These secondary features should be differentiated from a her life. truly restricted affect. (2)Theextenttowhichthepatient fails to initiate or sustain B. Diminished emotional range goal-directed activity because of inadequate drive. (3) The amount of time passed in aimless inactivity. Under this item, one rates the intensity and range of a patient’s (subjective) emotional experience. This item Whether or not the goal is realistic is not relevant. The should be distinguished from the capacity to display affect, patient with a superficial commitment to a goal – that is, which is rated under restricted affect rather than here. An who only pays lip service to a socially acceptable goal – inability to experience pleasure or dysphoria of any kind is should be considered to have a diminished sense of rated; both the range and the intensity are of relevance. A purpose. It may be important to distinguish between an patient who seems to experience little pleasure because of activity for which the patient provides the impetus and feeling tortured by auditory hallucinations would not be one for which another person (such as a family member) considered to have a diminished emotional range. provides it. It is important to distinguish a primary decrease in In many instances, it is crucial, although difficult, to emotional range from a normal reticence with strangers, distinguish a diminished sense of purpose from a patient’s including professionals. (1) psychotic disorganization or C. Poverty of speech (2) feeling of being overwhelmed by something that Poverty of speech does not require specific probes but is would, for most people, require a relatively small rated on the basis of behavior during the interview. The amount of effort.

If a patient has an impaired sense of purpose (a negative (5) Symptoms secondary to continuous exposure to an symptom), which is considered secondary to psychosis understimulating environment (and therefore not a deficit feature), he or she would (6) A primary manifestation of schizophrenia receive a score of at least 2 here and a ‘false’ under criterion 3 (the primary/secondary criterion) for this item. This is not an exhaustive list. Two perspectives may F. Diminished social drive be very helpful in determining whether the symptoms This item is used to rate the degree to which the person are primary or secondary: longitudinal observation and seeks or wishes for social interaction. The avoidant empirical manipulation. Specifically: patient, who longs for social contact and fitfully seeks it but is made uncomfortable by it, is not considered to have (1) Does the patient manifest prominent negative symp- diminished social drive. The rating should consider the toms in the absence of demoralization, depression, patient’s internal experience, statements, and behaviors. and hopelessness? (2) Does the patient manifest prominent negative This item is not equivalent to social withdrawal, and symptoms during periods when he/she is off medica- social success is not rated here. Many schizophrenics have tion and when positive symptoms are relatively serious social disabilities, but most socially impaired mild? persons, schizophrenic and otherwise, usually continue to (3) Is there a history of limited drive, limited emotional seek social interaction of some kind. The term does not expression, and other prominent negative symptoms refer to social withdrawal that is present only during before the onset of psychosis and treatment and psychotic episodes or withdrawal that is due to suspi- before any prolonged experience of exposure to an ciousness, an effort to decrease stimuli, or any factor understimulating environment? other than a lack of interest in relationships. (4) Do manifestations such as a wooden expression II. Criterion 2 diminish with the use of antiparkinsonian medication or during drug-free periods? Some combinations of two or more of the negative symptoms listed above have been present for the preceding 12 months and were always present during periods of clinical We score this item as false if the patient stability (including chronic psychotic states). These symptoms may or may not be detectable during transient (1) attributes his/her impairments to a strong sense of episodes of acute psychotic disorganization or decom- demoralization, suspiciousness, anxiety, etc. and/or a pensation. judgment by the clinician that this statement is III. Criterion 3 consistent with the patient’s behavior and other sources of information; The negative symptoms above are primary or idiopathic, (2) would not satisfy criterion 1 when clinically stable (i.e. that is, not secondary to factors other than the disease not relapsed) but drug-free or when psychotic symp- process. Such factors include the following: toms transiently improve; (3) has vegetative signs of depression, or has other sig- (a) Anxiety nificant signs or symptoms of depression, during the (b) Drug effect periods that the negative symptoms are prominent; (c) Suspiciousness (and other psychotic symptoms) (4) is unable to answer interview questions because of (d) Mental retardation persistent thought disorder during relative remission (e) Depression (5) is so chronically disorganized or suspicious that he/ she is unable to pursue any interests; or It is not always an easy task for the clinician to make a (6) is mentally retarded. valid inference about the cause of negative symptoms. In any individual instance, there may be reasonable chance If the sedation is marked or the patient has strong of an invalid judgment, but in the aggregate, clinicians complaints about sedation, we usually rate this item as are likely to have a high degree of accuracy. Prominent false. negative symptoms can result from the following: IV. Criterion 4 (1) An adaptive response (e.g. withdrawal to protect from The patient meets the Diagnostic and Statistical Manual of excessive stimulation) Mental Disorders criteria for schizophrenia. (2) Dysphoric affect such as depression (3) Demoralization The Schedule for Deficit Syndrome does not provide a (4) Adverse side effects of neuroleptic medication protocol for making this diagnosis.