Comparative effectiveness of aripiprazole and olanzapine on neurocognitive profile of patients with schizophrenia

Abstract

Background:

Schizophrenia causes significant neurocognitive impairment. Treatment with antipsychotics leads to improvement in psychopathology and neurocognitive functions.

Aim:

To see comparative effectiveness of aripiprazole and olanzapine on neurocognitive profile of patients with schizophrenia.

Materials and Methods:

This was a comparative, prospective, and interventional study. Patients with schizophrenia as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), were assessed on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), and neuropsychological tests at baseline. Patients were randomly assigned to aripiprazole (10–30 mg per day, orally) and olanzapine (5–20 mg per day, orally) groups on the basis of computer-generated random table number. Patients were reassessed at 10 weeks.

Results:

A total of 40 patients completed the study duration of 10 weeks. At baseline, the majority of patients showed significant impairment in one or more domains of neurocognition. Both aripiprazole and olanzapine led to improvement in psychiatric symptoms as well as neurocognitive profile. Aripiprazole treatment leads to significant improvement in mental speed as compared to olanzapine. A highly significant decrease in the value of the Stroop effect indicates improvement (P = 0.000**) with aripiprazole and visual–spatial constructive ability (P < 0.001). The olanzapine group showed highly significant improvement in performance of category fluency (P < 0.01) and verbal fluency (P < 0.01).

Conclusion:

The study concludes that aripiprazole and olanzapine have strong potential to improve specific domains of neurocognitive profile.

INTRODUCTION

Schizophrenia is a major mental disorder and leads to social withdrawal, apathy, and cognitive deterioration, which greatly hampers almost all the domains of life of an individual. According to the World Health Organization report, two of three people with psychosis in the world do not receive specialist mental health care. It has far-reaching effects on personality, global functioning, and cognition (WHO, 2009).[1] As per the latest study, about 98% of the patients experienced problems with cognition. Impairment in attention is found to be one of the initial cognitive symptoms of schizophrenia. Also, reduction in mental speed and memory may be apparent at early stages.[2]

Even Kraepelin and Bleuler held a viewpoint that impairment in cognition remained relatively steady in spite of remission of other symptoms.[3,4] Thus, neurocognitive deficits appear to be core elements of the illness. In the existing literature, impairment in neurocognitive tests has been found in variety of domains such as attention,[5] executive functions, processing speed,[6] working memory,[7] verbal fluency,[8] verbal learning and memory,[9,10] visual learning, and visual–spatial constructive ability in people with schizophrenia.

Neurocognitive deficits in schizophrenia are found to be correlated to the presence of positive and negative symptoms. Patients with predominantly negative symptoms showed poorer performance compared to patients with positive symptoms and normal controls.[11] However, evidences regarding the correlation between the presence of positive symptoms and neurocognitive deficits are inconsistent, where a study records strong correlation while the other proves it is independent.[9,11] As antipsychotic medications prove to be the mainstay for the treatment of patients with schizophrenia, their effect on cognition remains critically important. Although researchers have tried to explain the relationship between antipsychotic use and its correlation with cognitive symptoms, the results remain controversial. With the emergence of “second-generation antipsychotics,” hope was created among the researchers to receive relatively better results in cognitive functioning as compared to their “first-generation” counterparts.[12] Kern et al.[13] in a comparative study of aripiprazole and olanzapine on patients with schizophrenia and schizoaffective disorder reported significant improvement in psychopathology from baseline to the 8^th week and then on the 26^th week of assessment with both drugs.[13] It has been proved that on treatment with antipsychotics, there is significant improvement in cognitive functions but improvement does not match to the level of healthy controls and also the improvement in cognition could not be attributed to the improvement in psychopathology, hence creating a conflict between their relationship.[14]

Considering the importance of neurocognitive functioning in patients with schizophrenia, the availability of scant literature on the Indian population with conflictual findings regarding the correlation of cognitive symptoms with psychopathology, the index study is planned to assess and compare the effect of aripiprazole and olanzapine on neurocognitive profile of patients with schizophrenia.

MATERIALS AND METHOD

After approval from the Institutional Research and Ethics Committee and Clinical Trials Registry—India (CTRI) registration, the study was conducted at outpatient and inpatient services of the Department of Psychiatry of a tertiary care teaching hospital in North India. It was a comparative, prospective, and interventional study. By taking expected percent response in the olanzapine and aripiprazole groups as 95% each and the equivalence criteria to be an absolute value of 20%, the sample size was calculated as 20 in each group with a power of 80% and a confidence interval of 90%. On adding 30% dropout rate, a minimum of 46 patients were required for the study. All the patients were screened for the study, of which a total of 47 consecutive patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), criteria for the diagnosis of schizophrenia,[15] had total duration of illness of less than five years, and patients in age-group of 18–55 years were included after taking written informed consent from patient's/nominated representative in native language. Patients with history of treatment-resistant schizophrenia (TRS), past history of treatment with olanzapine and aripiprazole, evidence of neurological disorders—head injury, tumors, movement disorders (except antipsychotic-induced), dementia, organic brain syndromes, epilepsy, electroconvulsive therapy (ECT) in past three months, comorbid substance dependence (except nicotine and caffeine), lactation or pregnant females; cognitive remediation in recent past (six months), any unstable medical (hypothyroidism, diabetes insipidus, kidney disease, myasthenia gravis, chronic heart disease) or surgical disorders, and evidence of subnormal intelligence or actively suicidal patients were excluded from the study.

Procedure

The researcher received training from an expert faculty of clinical psychology to assess the individuals for a neuropsychological profile by administering specific tests, and each profile was supervised by the faculty/coauthor. The participants were approached for the study, and consent was sought. Sociodemographic and clinical details were recorded by the researcher. The participants were recruited as per the inclusion and exclusion criteria. The participants recruited for the study were assessed for severity of psychiatric symptomatology using Brief Psychiatric Rating Scale (BPRS),[16] Positive and Negative Syndrome Scale (PANSS),[17] and neurocognitive symptoms at baseline. The complete neurocognitive assessment was completed within maximum of two sittings in a day. Following this, they were randomized using computerized random number tables, under two groups (A and B) who received aripiprazole and olanzapine, respectively [Figure 1]. Dosages of respective drugs were kept in therapeutic range of 10–30 mg/day and 5–20 mg/day orally for aripiprazole and olanzapine, respectively. For aripiprazole, the initial approved recommendation was 10–15 mg/day and uptitration maximum up to 30 mg/day[18], and for olanzapine, initial 5–10 mg/day, increased by 5 mg/day once a week, and maximum of up to 20 mg/day.[19] It was stipulated to achieve maximum tolerable therapeutic dose range within 2–4 weeks of initiation of treatment. After four weeks, no further dose escalation was permitted and patients were observed on the same dose over a period of further six weeks (adequate duration). However, if the patient was unable to tolerate the higher dose during uptitration, then the dose was reduced to half and gradual escalation was conducted to achieve maximum tolerable therapeutic dose by the end of four weeks. It was planned that patient (s) developing any serious side effects such as dystonia and arrhythmias or who withdrew consent to continue in the study would be dropped out and managed as per the standard treatment protocol. Concomitant medications such as anticholinergic drugs for extrapyramidal symptoms and benzodiazepine for sleep disturbance and agitation were permitted whenever required, and doses were documented in each group. It was ensured that benzodiazepines were withheld at least 48 hours before conducting neurocognitive assessment. All the recruited patients were followed up every two weeks. The assessment for changes in psychiatric symptomatology and side effects was performed during follow-ups until 10 weeks. The neurocognitive assessment was performed at the end of 10 weeks. Also, at all visits, patients were told to bring empty strips of medicines which along with corroboration with family member helped to ensure compliance.

Figure 1.

Flowchart

Neuropsychological tests

Attention and executive functions were measured by administration of trail making test (Trail A and Trail B).[20] Mental speed was assessed using the Digit Symbol and Substitution Test (DSST).[21] For the assessment of immediate and working memory, the Digit Span Test was applied.[22] Verbal fluency tests included Controlled Oral Word Association (COWA), which is a measure of phonemic fluency in which subject generates words based on the phonetic similarity of words. The Animal Naming Test (ANT) was used, which is a form of category fluency and includes the content of words in which subject generates words, belonging to a particular semantic category.[21] Response inhibition was assessed using the Stroop test in which the Stroop effect is calculated as the difference in time taken to perform “word only” and “color only” parts. Verbal learning and memory was measured using Rey's Auditory Verbal Learning Test where two lists (A and B) of 15 words each were read out to the patient, and immediate and delayed recall of the number of words were noted. For the assessment of visual learning, memory, and visual–spatial constructive ability, Rey's Complex Figure Test was used in which scores for copy, immediate, and delayed recall were given as per assigned criteria for each unit.[21]

The confidentiality of the information obtained was maintained, and the principles enunciated in the Declaration of Helsinki[23] were complied with the Indian Council of Medical Research's (ICMR) ethical guidelines for biomedical research on human subjects were adhered to.[24]

Statistical analysis

Data were coded and analyzed using the Statistical Package for the Social Sciences software (IBM Corp., Armonk, version 26.0). For ordinal variables, unpaired t-test, mean, and standard deviation were applied. For categorical variables, Chi-square test and frequency tabulation were performed. Where the data were heterogeneous, appropriate nonparametric tests were applied. Repeated measures analysis of variance (ANOVA) tests were applied to analyze repeated intragroup measurements. The measure of significance is indicated by P < 0.05 and highly significant by P < 0.001. Spearman's product-moment correlation was applied to see correlates.

RESULTS

A total of 47 patients were enrolled in the study. Seven patients were lost to follow-up and hence dropped out of the study. Of these seven, four were from the aripiprazole group and three were from the olanzapine group. Three patients from the aripiprazole group and one from the olanzapine group were lost to follow-up before 2^nd week of assessment. One patient from the aripiprazole group withdrew the consent to continue the study due to no perceived improvement at four weeks. The rest of the two patients from the olanzapine group were lost to follow-up after assessment at the end of four weeks. None of the patients from either of the groups developed any serious side effects.

Finally, 40 patients (20 in each group) completed the study and were analyzed.

Both groups are comparable on sociodemographic and clinical variables as depicted in Table 1. The mean age of the study group was 26.57 years (SD = 3.36). No significant difference emerged on positive symptoms, negative symptoms, general psychopathology symptoms, and PANSS total scores between the two groups at baseline. BPRS scores were also comparable in both groups (P > 0.05).

Table 1.

Comparison of sociodemographic characteristics and clinical profile of patients enrolled in the study (N=40)

Variable	Aripiprazole (n=20)	Olanzapine (n=20)	Significance
Age in years (mean, SD)	26.80 (2.98)	26.35 (3.74)	0.677
Variable	Frequency (%)
Sex
Male	9 (45.0%)	11 (55.0%)	0.527
Female	11 (55.0%)	9 (45.0%)
Education
School-educated	9 (45.0%)	7 (35.0%)	0.519
College-educated	11 (55.0%)	13 (65.0%)
Occupation
Working	11 (55.0%)	9 (45.0%)	0.791
Not working	7 (35.0%)	8 (40.0%)
Student	2 (10.0%)	3 (15.0%)
Marital status
Single	8 (40.0%)	8 (40.0%)	0.588
Married	9 (45.0%)	11 (55.0%)
Divorced	1 (5.0%)	0 (0.0%)
Separated	2 (10.0%)	1 (5.05)
Income (INR)
<5000	7 (35.0%)	8 (40.0%)	0.788
5001-10000	6 (30.0%)	7 (35.0%)
>10000	7 (35.0%)	5 (25%)
Locality
Urban	14 (70.0%)	14 (70.0%)	1.00
Rural	6 (30.0%)	6 (30.0%)
Total duration of illness Mean in years (SD)	2.92 (0.87)	2.50 (1.07)	0.179
Variables	Mean (SD)		Significance
Positive symptoms	25.00 (4.86)	25.45 (4.91)	0.773
Negative symptoms	18.55 (3.59)	17.60 (5.76)	0.535
General psychopathology symptoms	36.90 (6.27)	37.90 (7.58)	0.625
PANSS total	80.45 (10.00)	81.50 (14.56)	0.792
BPRS	42.75 (9.07)	42.10 (5.57)	0.097

SD: Standard deviation; PANSS: Positive and Negative Syndrome Scale; BPRS: Brief Psychiatric Rating Scale

Table 2 depicts the mean values of different parameters used to assess neurocognitive profile of patients in both groups. No statistically significant difference in baseline neurocognitive profile was found between the groups.

Table 2.

Comparison of neurocognitive profile between two groups at baseline

Tests	Aripiprazole	Olanzapine	Significance
Attention
Trail A Meantime in sec. (SD)	75.90 (28.10)	69.70 (34.40)	0.536
Trail B Meantime in sec. (SD)	154.60 (63.04)	151.65 (80.16)	0.898
Mental speed
Digit Symbol Substitution Test Meantime in sec. (SD)	258.20 (55.14)	258.75 (60.82)	0.976
Test for response inhibition
Stroop (Stroop effect) Meantime in sec. (SD)	208.65 (32.44)	201.90 (43.92)	0.584
Verbal learning and memory
Rey's Auditory Verbal Learning Test
Immediate recall W (SD)	8.80 (1.47)	8.30 (1.97)	0.370
Delayed recall W (SD)	8.60 (1.50)	8.10 (1.83)	0.351
LTPR W (SD)	78.375 (16.47)	82.04 (12.69)	0.435
Visual learning, memory, and visual–spatial constructive ability
Rey's Complex Figure Test
Copy TS (SD)	29.90 (3.00)	31.05 (4.90)	0.377
Immediate recall TS (SD)	17.57 (5.26)	18.25 (5.60)	0.697
Delayed recall TS (SD)	14.37 (3.90)	14.30 (3.36)	0.949
Category fluency
Animal Naming n (SD)	8.25 (2.46)	9.60 (2.83)	0.117
Phonemic fluency
Controlled Oral Word Association n (SD)	5.99 (1.97)	6.810 (2.21)	0.223
Immediate and working memory
Digit Span Number of patients showing impairment Frequency (%)	11 (55%)	10 (50%)	0.751

SD: Standard deviation; W: Aaverage number of words recalled; TS: Total score; LTPR: Long-term percent retention; n: Average number of words

The final assessment for reduction in psychopathology was conducted at the end of 10 weeks. It was noticed that both olanzapine and aripiprazole were successful in improving psychiatric symptomatology. There was greater reduction in scores on positive symptoms, general psychopathology, and total PANSS scores in the olanzapine group as compared to the aripiprazole group, and difference in scores of positive symptoms (P = 0.001*) was statistically significant [Table 3].

Table 3.

Comparison of psychiatric symptomatology between two groups at 10 weeks

Variable	Aripiprazole (n=20) Mean (SD)		Olanzapine (n=20) Mean (SD)		Significance
	Baseline	10 weeks	Baseline	10 weeks
Positive symptoms	25.00 (4.86)	11.75 (2.09)	25.45 (4.91)	9.50 (1.67)	0.001*
Negative symptoms	18.55 (3.59)	7.70 (1.17)	17.60 (5.76)	8.85 (3.66)	0.189
General psychopathology symptoms	36.90 (6.27)	20.00 (2.75)	37.90 (7.58)	18.60 (2.39)	0.094
PANSS total	80.45 (10.00)	39.35 (3.81)	81.50 (14.56)	37.00 (5.43)	0.123

SD: Standard deviation; PANSS: Positive and Negative Syndrome Scale; *Significant

Both aripiprazole and olanzapine groups showed comparable improvement in attention. The aripiprazole treatment led to significant improvement in mental speed as compared to olanzapine. A highly significant decrease in the value of the Stroop effect indicates improvement (P = 0.000**) with aripiprazole. Improvement was comparable between both groups (P*>0.05) for response inhibition and verbal learning and memory. Patients treated with aripiprazole displayed highly significant improvement (P < 0.001) in visual–spatial constructive ability as indicated by increase in average total score of copy domain of Rey's Complex Figure Test. Also, a statistically significant improvement in immediate recall was seen (P < 0.05). No significant improvement was seen with olanzapine. No improvement in category and phonemic fluency was seen with aripiprazole. The olanzapine group showed highly significant improvement in performance of category fluency (P < 0.01) and verbal fluency (P < 0.01). Seven patients (35%) showed improvement in immediate and working memory on treatment with aripiprazole. The difference from baseline was significant (P = 0.012*), whereas two patients (10%) showed improvement when treated with olanzapine. The difference from baseline was not significant [Table 4].

Table 4.

Comparison of improvement in neurocognitive profile between two groups at 10 weeks

Tests	Aripiprazole		Sig.	Olanzapine		Sig.	P*
	At baseline	At 10 weeks		At baseline	At 10 weeks
Attention
Trail A Meantime in sec. (SD)	75.90 (28.10)	53.90 (23.54)	0.000**	69.70 (34.40)	66.45 (32.59)	0.014*	0.171
Trail B Meantime in sec. (SD)	154.60 (63.04)	127.65 (57.50)	0.000**	151.65 (80.16)	145.55 (76.98)	0.002*	0.410
Mental speed
Digit Symbol Substitution Test Meantime in sec. (SD)	258.20 (55.14)	207.40 (35.67)	0.000**	258.75 (60.82)	246.85 (61.63)	0.063	0.018*
Response inhibition
Stroop (Stroop effect) Meantime in sec. (SD)	208.65 (32.44)	179.00 (29.10)	0.000**	201.90 (43.92)	178.15 (53.40)	0.005*	0.950
Verbal learning and memory
Rey's Auditory Verbal Learning Test
Immediate recall n (SD)	8.80 (1.47)	11.50 (3.06)	0.002*	8.30 (1.97)	10.40 (1.46)	0.002*	0.159
Delayed recall n (SD)	8.60 (1.50)	10.75 (3.47)	0.016*	8.10 (1.83)	10.95 (1.90)	0.000**	0.823
LTPR n (SD)	78.375 (16.47)	88.51 (9.80)	0.038*	82.04 (12.69)	90.27 (9.09)	0.037*	0.561
Visual learning, memory, and visual–spatial constructive ability
Rey's Complex Figure Test
Copy TS (SD)	29.90 (3.00)	32.20 (2.68)	0.000**	31.05 (4.90)	31.50 (4.62)	0.475	0.562
Immediate recall TS (SD)	17.57 (5.26)	19.10 (5.69)	0.041*	18.25 (5.60)	19.05 (5.67)	0.090	0.989
Delayed recall TS (SD)	14.37 (3.90)	15.75 (4.62)	0.059	14.30 (3.36)	15.42 (4.42)	0.156	0.821
Category fluency
Animal Naming W (SD)	8.25 (2.46)	8.75 (2.40)	0.405	9.60 (2.83)	12.7 (2.73)	0.000**	0.000**
Phonemic fluency
Controlled Oral Word Association W (SD)	5.99 (1.97)	6.43 (2.04)	0.189	6.810 (2.21)	10.52 (2.21)	0.000**	0.000**
Immediate and working memory
Digit Span Number of patients showing impairment Frequency (%)	11 (55%)	4 (20%)	0.012*	10 (50%)	8 (40%)	0.503	0.017*

n: Average number of words; SD: Standard deviation; *Significant; **Highly significant; W: Average number of words recalled; LTPR: Long-term percent retention; TS: Total score; P*: Value of significance of difference between aripiprazole and olanzapine at 10 weeks

In the aripiprazole group, score on Trail B test is positively correlated with the negative symptom score. At 10 weeks, this correlation is evident to be significant (.558*). An inverse correlation was found between general psychopathology symptoms and immediate recall in Auditory Verbal Learning Test. The correlation was significant at baseline only (-.527*). In the delayed recall domain of Auditory Verbal Learning Test, an inverse correlation was found with general psychopathology symptoms, which was significant only at baseline (-.466*). In test for visual–spatial constructive ability, CFT C, an inverse correlation with positive symptoms and general psychopathology was observed. The correlation between Complex Figure Test “Copy” domain and positive symptoms is evident to be highly significant (-.623**), and an inverse correlation between Complex Figure Test “Copy” and severity of positive symptoms was found to be significant (-.453*). In the olanzapine group, positive correlation between the severity of positive symptoms and Stroop effect was seen. However, the correlation was significant at baseline only (.453*). The severity of negative symptoms is found to be inversely correlated to visual–spatial constructive ability measured by Complex Figure Test “Copy” domain. The inverse correlation was significant only at 10 weeks (-.470*). It is evident from Table 5 that most of the neuropsychological tests do not display significant correlation with psychiatric symptomatology [Table 5].

Table 5.

Correlation of cognitive functions with psychiatric symptomatology

Variable		Aripiprazole				Olanzapine
		P	N	G	T	P	N	G	T
Tests	Duration	Spearman's coefficient (r)
Trail A	Baseline	-0.112	0.250	0.002	0.019	0.070	0.029	-0.248	-0.213
	10 wks	-0.283	0.484	0.297	-0.196	0.216	-0.052	0.079	0.126
Trail B	Baseline	-0.073	0.051	0.160	0.027	0.033	-0.057	-0.260	-0.226
	10 wks	-0.020	0.558*	0.260	0.030	0.034	-0.002	0.025	0.097
DSST	Baseline	-0.224	-0.126	0.102	-0.137	-0.038	-0.019	-0.111	-0.204
	10 wks	0.133	0.089	-0.019	0.199	-0.358	-0.275	0.011	-0.094
ANT	Baseline	-0.247	-0.010	-0.325	0.269	0.224	0.157	-0.154	0.091
	10 wks	-0.291	-0.041	-0.259	-0.330	-0.201	-0.251	0.038	-0.155
COWA	Baseline	0.213	0.210	-0.017	0.148	0.408	0.108	0.005	0.175
	10 wks	-0.434	-0.137	0.245	-0.232	0.129	0.147	0.258	0.213
STROOP	Baseline	0.216	0.162	-0.116	0.092	0.453*	0.184	0.071	0.191
	10 wks	-0.282	-0.046	0.305	-0.185	0.324	0.251	0.164	0.153
RVLT Imt. R	Baseline	-0.118	-0.387	-0.256	-0.364	0.229	-0.116	0.011	0.067
	10 weeks	0.165	-0.162	-0.527*	-0.185	0.219	0.269	0.211	0.350
Del. R	Baseline	-0.131	-0.005	-0.466*	-0.252	0.162	0.132	-0.048	0.138
	10 weeks	0.117	0.116	-0.086	0.137	0.087	-0.042	0.360	0.302
LTPR	Baseline	-0.064	0.198	0.433	-0.151	-0.141	0.153	0.033	0.048
	10 weeks	-0.040	-0.062	-0.132	-0.107	0.021	-0.102	0.241	0.166
CFT C	Baseline	-0.174	-0.360	-0.054	0.229	0.249	-0.074	0.220	0.197
	10 weeks	-0.623**	0.377	-0.453*	0.203	0.044	-0.470*	0.012	0.273
CFT IR	Baseline	-0.159	-0.152	-0.124	-0.097	-0.087	0.019	0.049	-0.041
	10 weeks	0.395	0.057	0.203	0.292	0.007	0.078	-0.181	0.097
CFT DR	Baseline	0.191	-0.035	-0.100	-0.045	-0.004	-0.119	0.018	0.104
	10 weeks	0.364	0.140	0.068	0.267	-0.132	-0.125	-0.060	0.022

DSST: Digit Symbol Substitution Test; ANT: Animal Naming Test; COWA: Controlled Oral Word Association Test; RVLT Imt. R: Rey's Auditory Learning Test Immediate Recall; Del. R: Delayed recall; LTPR: Long-term percent retention; CFT C: Complex Figure Test Copy; CFT IR: Complex Figure Test Immediate Recall; CFT DR: Complex Figure Test Delayed Recall; *Significant (P<0.05); **Highly significant (P<0.01); P: Positive symptoms; N: Negative symptoms; G: General psychopathology symptoms; T: Total PANSS score

DISCUSSION

The index study was conducted to compare effectiveness of aripiprazole and olanzapine on neurocognitive profile of patients with schizophrenia. Patients in both groups (aripiprazole and olanzapine) matched on the basis of sociodemographic, psychiatric, and neurocognitive profile at baseline. Unlike the characteristics of our study, it was noticed that most of the studies included patients with higher age-groups and longer duration of illness.[25,26]

The neurocognitive functioning in the patients was assessed using standardized assessment tools. Overall, of 40, about 75% of the patients showed impairment in one or more cognitive domains at the start of the study, which is supported by various meta-analyses[5,9] and study by Dickinson et al.[27] For the aripiprazole group, the findings of our study corroborate and extend the findings of other studies that showed improvements in verbal learning, processing speed, and attention among patients with schizophrenia with treatment.[28,29,30] However, contrary to the findings of the index study, another study showed significant improvement in verbal fluency as well.[28] In the olanzapine group, significant improvement in attention, response inhibition (executive functions), verbal memory, and verbal fluency was seen at the end of 10 weeks [Table 4]. This is akin to the findings of the earlier studies,[26,31,32] whereas no improvement in attention and executive functions over 12-week period was reported by Lindenmayer et al.[33] It was also observed that patients treated with olanzapine showed no significant improvement in speed of processing, visual learning and memory, and immediate and working memory [Table 4]. Our study held forth the findings of other studies,[32,34] whereas Baldez et al. have reported certain degree of improvement in working memory on treatment with olanzapine.[26]

In our study, comparing the effect of aripiprazole and olanzapine on cognition, it was found that both aripiprazole and olanzapine showed comparable improvement in domains of attention, executive functions, and verbal learning and memory [Table 4]. In the study by Kern et al.,[13] improvement in attention was observed with aripiprazole and olanzapine; however, greater improvement in verbal memory with aripiprazole was reported as compared to olanzapine. Also, in contrast to the results of our study, neither of the groups showed improvement in executive functions.[13] Verbal fluency improved with olanzapine but not with aripiprazole [Table 4], which is similar to the results of an open-label trial.[28] However, speed of processing, and immediate and working memory significantly improved with aripiprazole only [Table 4]. This is contrary to the findings of the previous study where both groups showed improvement in these domains.[13] No improvement in visual learning and memory with either of the drugs was observed in our study [Table 4], which is supported by the findings of a study on olanzapine by Meltzer et al.[34] None of the drugs showed worsening in any domain.

A very limited number of studies have discussed the correlation of positive and negative symptoms with neurocognitive deficits, and the results have been inconsistent throughout. In our study, in the aripiprazole group, strong negative association was found between positive and general psychopathology symptoms with visual constructive ability score. Also, we found a negative correlation of general psychopathology with verbal memory. In the olanzapine group, a significant negative correlation between executive function and positive symptoms is evident. The negative correlation between negative symptoms and visual–spatial constructive ability is seen at 10 weeks. Thus, although certain associations of visual–spatial constructive ability, verbal memory, and executive functions with psychopathology turned out to be statistically significant, the correlation of cognitive dysfunction with psychiatric symptoms was found to be quite weak, proving their independence from psychiatric symptoms especially over initial five years of schizophrenia [Table 5]. The findings of our study are in concordance with a network meta-analysis[35] and another study by Manglam and Das.[14] In contrast, another study suggested a positive correlation between negative symptoms and impairment in various cognitive domains. This could be due to the longer duration of illness of patients enrolled in the study.[36]

The index study had multiple strengths. The study included the patients with schizophrenia who had illness for less than five years to remove the confounding effects of the chronicity of the disease. Also, we made sure that the patients had not received either of the drugs at any point of time in the past which may have confounded the results. It is the first study on the Indian population with schizophrenia comparing changes in various domains of neurocognitive profile when treated with aripiprazole and olanzapine. Although this study was conducted using robust methodology and stringent inclusion and exclusion criteria, certain limitations need to be considered while interpreting the results. The study had a small sample size. The study included sample of patients with a similar race and cultural background, and smaller duration of follow-up; thus, the generalizability of the results should be made with caution. Patients’ dropouts before the completion of study, that is, 10 weeks, were not included in the final analysis. Certain confounding factors such as B12 status have not been assessed.

CONCLUSION

The study concludes that the use of either of the drugs has strong potential to improve specific domains of neurocognitive profile. Aripiprazole has proven to be efficient in improving the majority of domains such as attention, mental speed, executive functions, verbal learning and memory, and immediate and working memory, whereas with olanzapine, improvement in attention, mental speed, executive functions, verbal learning, and verbal fluency is evident. Overall aripiprazole is a promising agent showing improvement in greater number of domains of neurocognition in schizophrenia. However, when taken into consideration the effectiveness for improvement in psychiatric symptomatology viz positive, negative, and general psychopathology, olanzapine led to greater improvement in domain of positive symptoms. This study further infers that during the initial phase of schizophrenia (<5-year duration), the neurocognitive decline is not correlated with the severity of symptoms, giving a window of intervention for better long-term outcomes, which needs to be corroborated with future research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.