Neurocognitive Profile in Indian Individuals Genetically at Risk of Schizophrenia.

BACKGROUND: Cognitive deficits have been noted in patients of schizophrenia in remission, as well as in first-degree relatives. This study aims to evaluate the neurocognitive performance in unaffected first-degree relatives of patients of schizophrenia in comparison with healthy controls, as well as patients of schizophrenia in remission.
METHODS: It was a 1-year case-control study by purposive sampling. Patients with a diagnosis of schizophrenia, first-degree relatives of patients of schizophrenia, and controls from nongenetic relatives of patients were recruited as per inclusion and exclusion criteria. Samples were matched for age and educational status. The General Health Questionnaire 28 (GHQ-28) screened them and they were checked for remission by Positive and Negative Syndrome Scale (PANSS) and then subjected to various instruments for assessment of neurocognition, standardized for the Indian population. To remove the effect of symptoms as confounding factors, PANSS score of <3 for each individual item was set as the criterion for remission. Intelligence quotient (IQ) was screened in all participants to exclude mental retardation. Statistical analysis used was the analysis of variance (ANOVA) with post hoc Fisher's least significant difference (LSD).
RESULTS: Significant neurocognitive impairments were detected in the patients and first-degree relatives when compared with the control subjects. The most common impairment in the patient group was in speed of processing, and among unaffected first-degree relatives, it was in the working memory.
CONCLUSION: Indian individuals genetically at risk of schizophrenia showed significant neurocognitive impairments in all domains compared with controls. Copyright:

Emil Kraepelin described dementia praecox or a group of schizophrenias as a disease with an early onset, a deteriorating course with hallucinations and delusions, and cognitive changes.[1] Bleuler further explained that delusions and hallucinations were secondary to cognitive changes.[2] Cognition is the sum total of mental processes that enable us to acquire knowledge and keep us aware of our surroundings, thereby enabling us to make appropriate judgments.[3] The Division of Mental Disorders of the National Institute of Mental Health (NIMH), USA initiated and funded workshops known as the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS).[4] The different domains of cognition impaired in schizophrenia, according to the NIMH-MATRICS are the speed of processing, attention or vigilance, working memory, verbal memory, visual memory, reasoning, problem-solving, and social cognition. Studies on cognition show that patients with schizophrenia perform at least one standard deviation (SD) below the normal population in global intellectual abilities, which places them in the lower 15 percentile of global intellectual ability.[5] The importance of cognition extends beyond mental processes. Recently, it was noted that weight gain induced by antipsychotic therapy was affected not only by the body mass index (BMI) but also by cognitive performance.[67]

Cognitive deficits in relatives of patients of schizophrenia

Genetic factors are a determinant in the etiology of schizophrenia.[8] Schizophrenia heavily affects certain families. This tendency of genetic loading indicates a need to study relatives to better understand the genetic underpinning. Cognitive assessments performed as a part of routine assessment of asymptomatic people had shown deficits in people who developed schizophrenia years later.[9] Relatives of patients with schizophrenia have been shown to have an increased reaction time, indicating a decreased speed of processing.[10] In a recent ongoing study, known as the Pittsburgh Risk Evaluation Program (PREP), first- and second-degree relatives were shown to have neurocognitive impairments.[11]

Although not diagnostic of a disease but certain symptoms are frequently found with the disease. They exhibit close inheritance with the candidate gene or the gene region.[12] The study of these symptoms is an alternative experimental strategy and can increase our etiological understanding of the disorder. Evidence supports the fact that the same gene may be responsible for cognitive impairment as well as schizophrenia, while other genes may also affect cognition.[13]

Research question

Most of the current literature focuses on the Caucasian race, with the Asian population being severely under-represented despite accounting for two-thirds of the world population. Substantial research since the beginning of this century has suggested genetic variation as the basis for differences in the phenotype and disease susceptibility across groups.[14] A literature search for Indian studies on neurocognitive deficits of schizophrenic probands revealed only a few studies with highly inconsistent results [Table 1]. Domains of cognitive deficits, as prescribed by MATRICES, have rarely been examined. As mentioned by Solanki et al., the tests used in these studies were not standardized for the Indian population. Moreover, we could not obtain any findings on visual learning and visual memory. The domain of speed of processing also remains unexplored. Although executive function has been explored, the ability to innovate spontaneously has not. A test of design fluency, which has a distinct advantage in estimating executive function, might serve this purpose.[15] The effect of intelligence quotient (IQ) as a confounding factor has also not been investigated.

Table 1

Indian studies on neurocognition in schizophrenia

Study	Tests Used	Domains Accessed	Groups Compared	Conclusion
Garg et al. Cognition in unaffected biological siblings of schizophrenia[17]	WCST, CPT, and SWMT	Planning (executive), performance, and concentration	Siblings (n=36) and controls (n=36).	Global impairment in the cognition of siblings
Nehra et al.: Cognitive deficits in the unaffected sibling of patients with schizophrenia[18]	WCST, Brief Visuospatial Memory Test-Revised, HVLT-R, and WAIS DST	Planning (executive), memory, verbal learning performance, and concentration	Patients, siblings, and controls Each group (n=20)	Siblings had verbal learning impairment
Bhatia et al.; Executive functions and cognitive deficits in schizophrenia: Comparisons between probands, parents, and controls in India[19]	TMT	Perceptual-motor and set-shifting	Patients (n=172) and parents (n=196)	Siblings showed significant impairments
Solanki et al.: An Indian experience of neurocognitive endophenotypic markers in unaffected FDR[20]	DST, visuospatial working memory matrix, and TMT	Verbal retention, executive functioning, andworking memory	Siblings (n=40) and controls (n=40).	Verbal, working memory and executive function deficits in siblings.
Harave et al.: Schizophrenia risk and neurocognition[21]	TMT, DST, and WMSspatial span	Attention and executive function	High-risk patients, siblings (n=17), and controls (n=30)	Executive function task performance, attention, and working memory deficits in first-degree relatives.

WCST – Wisconsin Card Sorting Test, CPT – Continuous performance test, SWMT – Spatial working memory test, HVLT-R – Hopkins Verbal Learning Test-Revised, WAIS DST – Wechsler Adult Intelligence Scale Digit Symbol Test, TMT – Trail-making test, PALT – Paired associate learning test, WMS – Wechsler memory scale

We, therefore, decided to screen IQ before the cognitive assessment and exclude subjects with subnormal intelligence. Remission was ascertained for the participating patients. The tests used were standardized for the Indian population, and all domains of neurocognition, as mentioned by NIMH- MATRICES, were assessed using tests different from those already used, thus, enhancing reliability.

SUBJECTS AND METHODS

The study was conducted at a tertiary care center in India for a period of 1 year from January 1, 2011 to December 31, 2011. The institutional ethical committee provided ethical clearance. All patients of schizophrenia in remission (stable) attending the psychiatry outpatient department (OPD) and patients admitted in the psychiatry ward of the hospital were included in the study (Group 1). Eligible first-degree relatives of patients of schizophrenia attending the psychiatry OPD and patients admitted in the psychiatry ward of the hospital were identified (Group 2). The controls were nongenetic relatives of patients, who were neither suffering from a mental illness, attending psychiatry OPD nor admitted in the psychiatry ward of the hospital (Group 3). A cross-sectional analysis was carried out in this case-control study by purposive sampling.

The inclusion criteria were an age between 18 and 50 years, an English education up to at least the tenth grade, and consent to participate in the study. The exclusion criteria were having co-morbid conditions, such as drug abuse (except nicotine dependence); affective disorders; dementia; mental retardation; a history of head injury; or a seizure within 1 year. Subjects showing extrapyramidal symptoms were excluded. Mood symptoms were assessed and their presence was a criterion for exclusion.

A specially prepared pro forma was used to collect the patients' sociodemographic data, history, and examination findings. The International Classification of Diseases 10 Diagnostic Criteria for Research (ICD-10 DCR) for Psychiatric Illnesses by the World Health Organization (WHO) were used to diagnose each patient.[16] Mental retardation was ruled out by screening all subjects using Raven's Colored Progressive Matrices (CPM), minimizing the effect of IQ as a confounding factor. All subjects were checked for remission using the Positive and Negative Syndrome Scale (PANSS). The accepted reported criterion for remissions was a PANSS score of <3 for each item in the last 6 months.[24] The General Health Questionnaire 28 (GHQ-28) was used to check the presence of any psychiatric comorbidity. Subsequently, cognitive assessment tests were performed to estimate the extent and nature of cognitive dysfunctions. All these tests have been standardized and validated for the Indian population [Table 2].[21] The speed of processing was tested by the Digit symbol substitution test (DSST), where the time taken to perform the task was the score. Verbal working memory was tested by the N-Back test, while Visual N-Back tested visual working memory. Correct identification was scored as a hit, while not identifying and misidentifying were scored as an error. The Verbal Paired Associates Test tested verbal learning, where the number of pairs correctly reproduced forms the score. Visual learning was tested by the PGI-visual recognition test, where a correct identification and naming of the object is given one mark, while a correct identification but wrong naming fetches ½ mark. Attention and concentration were tested by digit forward, digit backward, and serial subtraction test. Animal name and design fluency (DF) tests were used for assessment of executive function, where the number of items generated is the score.

Table 2

Tests used in the assessment of each domain of cognition and description

Domain	Test	Description
Speed of processing	DSST[22]	Sheets with four rows each having 26 randomly arranged digits have to be substituted with symbols mentioned on top in a key
Working memory	Verbal N-Back Test[22]	A subject respond in N back-1 test whenever a consonant is repeated consecutively, and in N back-2 the subject responds when it is repeated after an intervening consonant
	Visual N-Back Test[22]	In Visual N-back 1, the subject is told to report if the positions of two dots coincide. In Visual N-back 2, the subject is told to report if the position of the dot coincides to the last but one card
Learning and memory	Verbal Paired Associates Test[23]	Five pairs of nouns are repeated one after the other. After this, the subject is told the first noun and asked to repeat the other.
	PGI- Visual Recognition[23]	First, a subject is shown a card containing ten pictures and asked to memorize. Next, another card containing pictures from the first card, as well as other pictures, is shown, and the subject is asked to identify the pictures.
Attention and vigilance	Digit Forward[24] and Digit Backward[24]Serial Subtraction[22]	Digits are read at 1 digit per second and a gradually increasing number of digits are presented. In digit forward, the subject has to reproduce in the same order while backward it is to be reproduced in the reverse order. The subject has to subtract a number from another repeatedly and report the result.
Executive function	Animal Name Test[22]DF[22]	The subject is asked to generate from memory as many animal names as possible excluding birds, snakes, and fish.The subject has to draw novel designs.

DSST – Digit symbol substitution test, DF – Design fluency

Data

Data obtained were tabulated and the means, SDs, and percentages were calculated. Chi-square was used for testing the association (comparing the proportions) and analysis of variance (ANOVA) for comparison of means. Post hoc Fisher's least significant difference (LSD) was used to compare the significance of the group differences. Statistical significance was set at P < 0.05. The null hypothesis was that there is no significant difference between the groups. As multiple tests were applied to the same population, Bonferroni's correction was applied. To keep familywise error rates to a minimum, the critical P value derived was 0.003. Microsoft Excel and the Statistical Package for the Social Sciences (SPSS) software, version 16, were used for analysis.

RESULTS

Sociodemographic details

The three groups—patients (Group 1, n = 34); unaffected first-degree relatives (Group 2, n = 37); and controls (Group 3, n = 47)—were matched in age (P = 0.5) and educational status (P = 0.76) but not on sex distribution (P = 0.01) [Table 3]. The mean (± SD) duration of disease was 3.7 years among patients.

Table 3

Demographic Variables

Variable	Group 1 Patient (n=34)	Group 2 First-degree Relative (n=37)	Group 3 Control (n=47)	Chi- Square	F	P
Sex (Male)	22 (64%)	22 (59%)	42 (89%)	10.98		0.01
Age (years)	30.88±8.24	31.27±8.87	29.26±7.91		0.70	0.50
Education
School	12 (35.5%)	8 (21.6%)	11 (23.4%)	4.95		0.76
High School	6 (17.6%)	5 (13.5%)	10 (21.3%)
Graduate	7 (20.6%)	9 (24.3%)	10 (21.3%)
Post Grad	2 (5.9%)	2 (5.4%)	5 (10.6%)
Professional	7 (20.6%)	13 (35.1%)	11 (23.4%)
GHQ Score	6.03±1.14	2.00±0.81	1.87±0.74		254	<0.001

GHQ – General Health Questionnaire

Clinical details

Among the patients, most were patients of residual schizophrenia (n = 27). Six patients had undifferentiated schizophrenia and one had paranoid schizophrenia.

Cognitive assessment

Unaffected first-degree relatives showed significant impairments compared with controls in all domains except learning [Table 4]. Based on the norms for the Indian population, the most common impairment in the patients was in the speed of processing, while the most common impairment in the unaffected first-degree relatives was in working memory [Table 5].

Table 4

Performance of the groups in various cognitive assessment tests with post hoc assessment of test of significance of difference among the groups

	Group 1 Patient (n=34)	Group 2 First-Degree Relative (n=37)	Group 3 Control (n=47)	Cumulative		Post hoc (LSD) P
				F	P	Patient vs First-Degree Relative	Patient vs Control	First-Degree Relative vs Control
DSST (sec)	253 (25)	251 (17)	221 (20)	20.06	<0.001	0.08	<0.001	<0.001
N- Back Test
N-Back 1 Hit	6.18 (2.29)	6.65 (1.75)	8.49 (0.8)	22.91	<0.001	0.23	<0.001	<0.001
N- Back 1 Error	7.06 (4.24)	5.49 (3.22)	2.91 (1.77)	18.45	<0.001	0.04	<0.001	0.03
N-Back 2 Hit	4.82 (1.91)	5.05 (1.22)	6.55 (1.19)	17.75	<0.001	0.51	<0.001	<0.001
N-Back 2 Error	7.97 (3.5)	8.92 (3.75)	5.00 (1.85)	19.25	<0.001	0.19	<0.001	<0.001
Visual N Back Test
1 Hit	5.38 (1.39)	5.62 (1.26)	8.04 (0.93)	65.44	<0.001	0.39	<0.001	<0.001
1 Error	8.18 (2.26)	8.00 (2.27)	5.83 (1.85)	16.22	<0.001	0.73	<0.001	<0.001
2 Hit	3.85 (0.99)	3.70 (0.85)	7.23 (1.86)	90.02	<0.001	0.65	<0.001	<0.001
2 Error	13.91 (2.52)	14.41 (2.83)	9.62 (3.61)	30.89	<0.001	0.51	<0.001	<0.001
Verbal Paired Associates Test
Similar Pair	4.24 (0.89)	4.49 (0.80)	4.70 (0.55)	3.92	0.02	0.16	0.01	0.18
Dis-Similar Pair	12.38 (1.78)	12.84 (1.61)	13.36 (1.47)	3.74	0.03	0.23	0.01	0.14
PGI- Visual repetitive Card	8.21 (1.2)	8.43 (0.73)	8.85 (0.83)	5.11	0.01	0.30	0.01	0.04
Digit Forward	5.68 (0.68)	5.49 (0.56)	5.83 (0.76)	2.63	0.08	0.24	0.32	0.02
Digit Backward	4.47 (0.75)	4.46 (0.61)	4.96 (0.51)	9.06	<0.001	0.94	<0.001	<0.001
Serial Subtraction	10.15 (1.3)	9.95 (0.88)	10.79 (1.16)	6.46	<0.001	0.45	0.01	<0.001
Animal Name Test	5.62 (1.58)	5.76 (0.98)	6.57 (0.95)	8.16	<0.001	0.69	0.01	<0.001
DF Free	4.18	4.03	5.15	10.57	<0.01	0.61	<0.001	<0.001
DF Fixed	3.06	3.11	4.55	12.58	<0.01	0.89	<0.001	<0.001

DSST – Digit symbol substitution test, DF – Design fluency, LSD – Fisher’s least significant difference

Table 5

The prevalence of neurocognitive deficits in patients of schizophrenia, first-degree relatives of patients of schizophrenia, and controls

Domains	Patients of Schizophrenia in Remission	First-degree Relatives of Patients of Schizophrenia	Control Subjects
Speed of processing	67.65%	45.95%	12.77%
Learning and memory	48.04%	39.64%	24.82%
Attention and vigilance	29.41%	27.03%	14.89%
Executive function	53.92%	49.55%	19.86%
Working memory	59.19%	56.42%	15.96%

DISCUSSION

We found neurocognitive impairments in unaffected first-degree relatives similar to those in patients of schizophrenia. Patients and first-degree relatives performed significantly worse than the controls in testing for speed of processing, which could be responsible for the slowness in performing various activities exhibited by the patients of schizophrenia.[25] Garg from India reported similar findings.[17] The bilateral parietal and temporal lobes and left middle frontal gyrus are involved in information processing and, probably, are the affected areas.[26]

Working memory includes verbal and visual memory. The patients and first-degree relatives performed significantly worse than the controls in this domain. From India, Harave and Solanki also reported similar findings. Patients also exhibit reduced blood flow in the inferior frontal gyrus, suggesting it as the area affected in working memory disturbance.[27]

Unlike other domains, unaffected first-degree relatives did not show significant impairments in verbal or visual learning.

Executive function deficits are known to be an integral part of schizophrenia. We found significantly higher executive function impairment even in unaffected first-degree relatives, compared with the controls. We used the animal name test and DF test for executive function assessment. The animal name test results showed that the control subjects performed better than patients of stable schizophrenia and unaffected first-degree relatives did. This set of tests assesses the ability to innovate and generate spontaneously, unlike the Trail-making Test (TMT), where the norm is to perform as instructed. In a recent study on the Indian population by Bhatia et al., the findings indicated significant impairments in first-degree relatives. Frontostriatal abnormalities are thought to explain these deficits.[12] In the assessment of attention and vigilance, the patients and first-degree relatives had performed significantly worse than the controls.[28]

A recent longitudinal cohort of more than 1,000 patients reported that patients had intellectual deterioration and poor academic performances much prior to the onset of the illness.[27] In a cross-sectional study, cognitive deficits in first-episode psychosis were similar to those in patients of chronic, long-standing illness.[2829] Cognitive impairments in schizophrenia are stable and persistent, unlike the progressive deficits of dementia. On the other hand, they are not evident at birth as in patients of intellectual disabilities. We showed that there is a statistically significant difference from controls in the domains of neurocognition in unaffected first-degree relatives of patients of schizophrenia. Thus, cognitive deficits are certain inherited vulnerabilities that are present in genetically susceptible individuals.

CONCLUSION

To conclude, our findings suggest that neurocognitive impairments are present not only in patients of stable schizophrenia but also in the unaffected first-degree relatives of patients of schizophrenia. Neurocognitive impairments could also be screening criteria for those at risk. Our findings are in concurrence with studies from the West and suggest that Indian patients of stable schizophrenia and unaffected first-degree relatives of patients of schizophrenia show similar neurocognitive deficits.

Strengths

Tests standardized for the Indian population were applied[20]

We screened out the confounding effect of IQ

Groups were matched with respect to education and age, which affect cognition

Noncomputerized tests were used as many are not well versed in computers

Only patients in remission were assessed

Conservative correction applied as multiple hypothesis testing was done.

Limitations

Our sample size was constrained as we used patients who visited a general hospital during a period of only 1 year. Nicotine dependence was significantly higher in patients, similar to other Indian community studies.[30]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.