INTRODUCTION

 

Psychotic major depression is a discrete disorder and separate from non-psychotic major depression^1,2. They differ in presenting features, biological measures, familial transmission, course and outcome, and response to treatment^3-5. Mood disorders may be associated with a distinct pattern of cognitive impairment^6-8. About 50% to 75% of all depressed patients have a cognitive impairment, sometimes referred to as depressive pseudo-dementia^9-11. Persons who are depressed may have (reversible) cognitive deficits as a consequence of motivational and attention problems^12,13. Cognitive impairment is also likely to be a key factor affecting the subject's ability to function occupationally and, hence, the timing of his or her return to work^14-17. It has been proposed that raised cortisol levels during depression might be associated with cognitive impairments^18-20.  Changes in hippocampal activity may be also involved in steroid-related cognitive changes^21,22. It was hypothesized that corticosteroids act to suppress the ability of the hippocampus to filter out behaviorally irrelevant stimuli.^23,24,26-29.

 

The aim of this work is to find out the different cognitive deficits in major depressed patients psychotic and non-psychotic and the relation of these deficits to the levels of cortisol.

 

PATIENTS AND METHODS

 

Patients

This comparative cross-sectional study was conducted on 80 patients selected from the psychiatric outpatient clinic of Kasr Al-Aini Hospital. They were divided into two groups: Group one: Consisted of 40 patients diagnosed as major depressive disorder with psychotic features. Group two: Consisted of 40 patients diagnosed as major depressive disorder without psychotic features. They were diagnosed according to the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), Axis I disorders³⁰, by the residents and were reassessed by a senior psychiatrist to confirm diagnosis. Inclusion criteria:  Age ranged between 20 and 50 years, both sexes were included and patients should be un-medicated or with a washout period of antipsychotics and/or antidepressants for at least 2 weeks. Exclusion criteria: Patients with major medical illnesses particularly endocrinopathies, patients taking hormonal therapy, patients with history of neurological disorders or of substance dependence or abuse within 6 months, history of head injury with loss of consciousness, and other medical disorders that may affect brain functions, or recent/current ECT or treatment with anticonvulsants or benzodiazepines. This was to avoid any factors that might affect cognitive functions or hormonal profile of our patients.

 

Methods

Informed consent and a full clinical psychiatric sheet were taken for each patient. All patients were subjected to the following:

 

Laboratory Investigations

Estimation of cortisol level at 8.00 am and at 8.00 pm in the same day for each individual using Radioimmune Assay. A large number of cortisol immunoassays have been developed using different types of antibodies, processing schemes, labels, and measurement principles including beta and gamma counting, photometry, fluorometry, and chemiluminescence³¹. Cortisol is quantitatively displaced from endogenous binding proteins by protein-binding agents such as 8-anilino-1-naphthalene-sulfonic acid (ANS) or salicylate, by low pH, or by heat treatment³².

 

Hamilton Rating Scale for Depression (HRSD)

This scale contains 24 items to assess the severity of an illness, scored 0 to 4 or 0 to 2 with a total score of 0 to 76. The original recommendation for this scale was that it is not to be used as a checklist, but with the clinical judgment of a skilled rater using all sources of information³³.

 

Wechsler Adult Intelligence Scale-Revised (WAIS-R)

It is the best standardized and most widely used intelligence test in clinical practice today. The WAIS comprises 11 subtests made up of six verbal subtests (Information, Comprehension, Arithmetic, Similarities, Digit span and Vocabulary) and five performance subtests (Picture completion, Block design, Picture arrangement, Object assembly and Digit symbol), which yield a verbal IQ, a performance IQ, and a full-scale IQ. Variability in functioning is revealed through discrepancies between verbal and performance IQs and by the scatter pattern between subtests³⁴.

 

Wisconsin Card Sorting Test (WCST)

It assesses abstract reasoning and flexibility in problem solving. Stimulus cards of different color, form, and number are presented to patients for sorting into groups according to a principle established by the examiner but unknown to the patient. Successful performance on the WCST requires a complex set of cognitive functions, including the ability to think abstractly, selectively attend to a particular perceptual dimension, and shift cognitive set³⁵.

 

Statistical Methods

The mean scores on variable x are symbolized by x (read “X bar”) and is computed with the formula: X= Σxi / N Which instructs one to add all the scores (i.e., Σxi) and divide by N, which is the number of scores in the distribution. The standard deviation (symbolized by S), is defined to be the positive square root of the variance: S= √Σ (Xi ─ X) ∕ N-1⁽³⁶⁾. There are two versions of t- test. The paired-samples t-test (also known as the matched pair’s t-test, the related t-test, and the correlated t-test) compares the means of two paired sets of data.⁽³⁷⁾. Values of the Spearman Correlation Coefficient range from -1 to +1.³⁶

 

RESULTS

 

The two groups showed no differences regarding age, years of formal education and marital status. They significantly differed regarding sex distribution (Table 1).

There was non significant difference between the two groups’ mean on the HRSD nor Total IQ. However they differed significantly regarding the obtained means on verbal, performance and deterioration index (Table 2).

The two study groups differed significantly regarding several domains of the WCST, where the psychotic group was performing more poorly than the non-psychotic group in this test, table 3.

Regarding cortisol level, the psychotic group obtained a significantly higher morning level and a significantly lower evening level. Also the psychotic group obtained a significantly higher percentage of change over the day (Table 4).

There was significant negative and positive correlations between Hamilton symptoms and cortisol levels and percent change of cortisol in psychotic group and non-psychotic group (Table 5).

There was significant negative and positive correlation correlations between cortisol levels and WAIS-R subtests, IQ, deterioration index and WCST in psychotic and non-psychotic group (Table 6).

There was significant correlation between WAIS-R subtests & Hamilton symptoms in psychotic and non- psychotic groups (Tables 7 and 8).

By using Factor Analysis of the Covariance Matrix we found: the loading plot showed that arithmetic and  picture completion are the most two important and orthogonal (independent)  variables that interpret variations in psychotic group, and that comprehension and block design are the most two important and orthogonal (independent)  variables that interpret variations in non-psychotic group.

Table 1. Demographic data of patients in psychotic and non- psychotic groups.

 

		Psychotic	Non-psychotic	P-value	t-value  (X2)
Age		35.85±9.76	33.7±9.47	0.35	0.98
Sex	Male	34 (85%)	18 (45%)	0.008*	7.03
	Female	6 (15%)	22 (55%)
Years of formal education		5.95±5.72	6.65±6.03	0.107	1.03
Marital status	Single	18 (45%)	8 (20%)	0.32	1.01
	Married	20 (50%)	28 (70%)
	Divorced	2 (5%)	4 (10%)
Occupation	Not working	20 (50%)	8 (20%)	0.025*
	Students	2 (5%)	6 (15%)	0.16
	Semiskilled	12 (30%)	0 (0%)	-
	Skilled	0 (0%)	4 (10%)	-
	Professional	0 (0%)	4 (10%)	-
	Housewife	6 (15%)	18 (45%)	0.001*

 

Table 2. Comparison between the two studied groups regarding the mean scores of Hamilton Rating Scale for Depression (HRSD), Wechsler Adult Intelligence Scale-Revised (WAIS-R).

 

		Psychotic Mean±SD	Non-psychotic Mean±SD	P-value	t-value
HRSD		32.6±5.58	31.2±3.86	0.62	0.45
WAIS-R	Verbal IQ	85.35±15.87	92.15±9.34	0.05*	1.85
	Performance IQ	86.2±12.51	93.25±8.36	0.03*	1.99
	Total IQ	85.2±13.34	90.4±8.51	0.07	1.48
	Deterioration Index	7.4±9.70	0.55±10.99	0.028*	1.98

 

Table 3. Comparison between the two studied groups regarding WCST.

 

	Psychotic Mean±SD	Non Psychotic Mean±SD	P-value
No of Trials	128±0	118 ±17.3	0.014*
No of Categories Completed	1.5±1.47	3.55± 2.01	0**
Total correct	54.05±16.36	65.55 ± 16.27	0.016*
Total errors	73.95±16.36	53.2±25.38	0.002**
% of errors	0.58±0.13	0.43±0.18	0.002**
Perseverative response	66.9±26.09	40.55±29.54	0.002**
% of perseverative responses	0.52±0.2	0.33±0.22	0.003**
Perseverative errors	52.7±22.27	30.6±24.1	0.002**
% of perseverative errors	0.41±0.17	0.25±0.18	0.003**
Non perseverative errors	21.05±8.79	22.6±9.29	0.295
% of Non-perseverative errors	0.17±0.07	0.19 ± 0.06	0.13
Conceptual level of response	33.35±19.1	51±20.71	0.004**
% of conceptual level of response	0.24±0.14	0.45±0.22	0**
Trials to complete first category	71.95±44.32	32.15±36.24	0.002**
Failure to maintain set	1.5±.57	0.95±1.36	0.122

 

Table 4. Comparison between the two studied groups regarding the Cortisol Levels.

 

		Psychotic Mean±SD	Non-psychotic Mean±SD	P-value	t-value
Cortisol	AM	15.01±4.29	11.675±4.91	0.011*	2.85
	PM	5.66±1.44	6.71±2.89	0.035*	2.7
	Percentage of change	58.5%±17.4	35.5%±32	0.002*

 

Table 6. Correlation between cortisol levels and WAIS-R subtests, IQ, deterioration index and WCST in psychotic and non-psychotic group.

 

p is significant if r > 0.32           p is highly significant if r > 0.60

 

Table 7. Correlation between WAIS-R subtests  & Hamilton symptoms in psychotic group.

 

	Information	Comprehension	Digit span	Arithmetic	Similarities	Vocabulary	Picture arrangement	Picture completion	Block design	Object assembly	Digit symbol
Depressed Mood	0.309	0.050	0.073	0.235	0.069	0.273	0.123	0.358*	0.027	-0.100	0.164
Disturbed work	0.279	0.116	0.192	0.100	0.111	-0.110	0.174	0.108	-0.179	0.175	0.173
Psychomotor retardation	-0.194	-0.010	-0.455*	-0.317	-0.062	-0.125	-0.054	-0.26	0.240	-0.142	0.167
Anxiety & agitation	-0.107	-0.170	-0.411*	-0.164	0.079	-0.263	-0.049	0.284	0.420*	0.337*	0.176
Somatic symptoms	0.392*	0.359*	-0.050	0.297	0.265	0.178	0.085	0.539*	0.136	-0.034	0.416*
Hypochondriasis	-0.061	0.261	-0.232	0.172	0.124	0.212	-0.232	0.071	0.204	-0.152	-0.123
Lack of insight	0.397*	0.522*	0.490*	0.159	0.369*	-0.136	0.499*	0.113	-0.041	0.334*	0.261
Diurnal variation	-0.091	0.264	0.010	-0.031	-0.127	-0.401*	-0.008	0.114	-0.008	-0.294	0.076
Derealization	0.399*	-0.149	0.318	0.280	0.371*	0.438*	0.156	0.108	0.049	0.251	0.145
suspicions	0.165	0.090	0.242	-0.075	-0.077	-0.220	-0.132	-0.064	-0.218	0.346*	-0.162
obsessions	-0.033	-0.230	0.046	-0.162	0.066	0.073	0.025	-0.255	-0.015	-0.052	-0.115
helplessness	0.100	0.074	0.073	-0.125	0.035	-0.363*	0.082	-0.014	-0.095	0.162	0.010
hopelessness	0.000	-0.075	-0.29	-0.094	-0.055	-0.363*	0.010	0.335*	0.036	0.213	0.306
Worthlessness	0.544*	0.325*	0.194	0.296	0.287	-0.024	0.191	0.658*	-0.051	0.003	0.462*
Guilt	-0.008	-0.220	0.034	-0.064	0.145	-0.200	0.039	0.077	0.532*	0.466*	-0.118
Suicide	0.115	0.049	-0.055	0.366*	0.099	0.241	0.157	0.165	-0.149	-0.050	0.306
Insomnia	-0.255	0.189	-0.43	-0.251	-0.164	-0.336*	0.163	0.037	0.076	0.132	0.066
Weight loss	0.269	0.114	0.384*	0.168	0.167	0.011	0.124	0.138	-0.095	-0.047	0.025

p is significant if r ≥ 0.32                        p is highly significant if r ≥ 0.60

 

Table 8. Correlation between WAIS-R subtests & Hamilton symptoms in nonpsychotic group.

 

	Information	Comprehension	Digit span	Arithmetic	Similarities	Vocabulary	Picture arrangement	Picture completion	Block design	Object assembly	Digit symbol
Depressed Mood	0.042	-0.044	0.284	0.149	0.322*	0.103	0.059	0.299	0.276	0.514*	-0.119
Disturbed work	0.007	0.344*	0.143	0.259	-0.392*	-0.278	-0.031	0.403*	0.536*	-0.100	0.070
Psychomotor retardation	-0.127	-0.240	0.029	-0.387*	0.187	0.000	-0.108	0.000	-0.064	0.290	-0.061
Anxiety & agitation	-0.191	0.462*	0.000	0.324*	-0.224	-0.372*	0.379*	-0.053	0.323*	-0.049	0.171
Somatic symptoms	-0.359*	-0185	-0.188	-0.221	-0.275	-0.285	-0.235	-0.296	-0.330*	-0.093	-0.092
Hypochondriasis	-0.039	-0.453*	-0.318	-0.132	-0.115	0.174	-0.077	-0.128	-0.368*	-0.343*	-0.117
Lack of insight	-0.313	0.450*	0.039	-0.100	-0.331*	-0.207	0.168	-0.360*	-0.022	-0.219	0.199
Diurnal variation	0.558*	0.111	0.046	0.201	0.206	0.433*	0.441*	0.317	0.154	0.055	0.155
Derealization	-0.148	-0.092	0.118	0.080	-0.435*	-0.377*	-0.338*	-0.191	-0.150	-0.265	-0.303
suspicions	-0.154	0.075	0.196	-0.081	-0.090	0.135	-0.225	0.382*	0.155	0.079	0.222
obsessions	-0.229	-0.345*	-0.242	-0.051	-0.336*	-0.285	0.070	-0.378*	-0.282	0.011	-0.075
helplessness	0.556*	0.000	0.144	0.273	0.166	0.473*	0.193	0.542*	0.073	0.274	0.063
hopelessness	0.101	0.447*	0.125	0.382*	-0.218	-0.067	0.164	0.126	0.289	-0.238	0.373*
Worthlessness	0.203	0.021	0.121	0.306	0.150	0.198	0.463*	0.133	0.178	0.364*	-0.032
Guilt	0.054	0.158	0.543*	0.217	0.305	0.218	-0.213	0.350*	0.511*	0.100	0.161
Suicide	0.088	0.531*	0.492*	0.204	0.338*	0.128	0.020	0.491*	0.641*	0.376*	0.207
Insomnia	0.103	0.083	-0.052	0.111	-0.255	-0.257	0.032	-0.121	-0.022	-0.193	-0.249
Weight loss	-0.254	0.600*	0.235	0.000	-0.294	-0.202	-0.129	0.210	0.193	-0.232	0.184

p is significant if r ≥ 0.32                        p is highly significant if r ≥ 0.60

 

 

DISCUSSION

 

In our study there was a statistically significant difference between the two studied groups as regard mean of 8:00 am cortisol, mean of 8:00 pm cortisol and percent change of cortisol level during a day. Although, the values of cortisol level at both am and pm in both groups are in the normal ranges of the reference laboratory (6-16 µg for 8:00 am and 3-11 µg for 8:00 pm), however the psychotic group had a mean value for 8:00 am significantly higher than that of non-psychotic group. Normally, it is expected to have a change in the value of 8:00 pm cortisol level ≤ 50% of the value of 8:00 am cortisol level in a day for a healthy subject³⁸. In the psychotic group the mean change was more than 50% of 8:00 am value, while non-psychotic group were in normal range of the percent of change, which may reflect that, the activity of HPA axis differs in the two groups of the patients. The psychotic group showed more pronounced disturbance in HPA axis activity. These results are consistent with the results of Schatzberg et al.³⁹, who found a statistically significant group differences during three consecutive time points in the late afternoon (3:00 pm, 3:30 pm and 4:00 pm). In a study carried out by O’Brien et al.⁴⁰, there was a statistically significant difference between depressed subjects and healthy comparison subjects as regard mean of 8:00 am cortisol, mean of 8:00 pm cortisol and percent change of cortisol level during a day.

Results of this study showed no statistically significant difference between the two studied groups regarding Hamilton Rating Scale mean scores. These results are consistent with Nelson et al.⁴¹. However our results are inconsistent with Schatzberg et al.³⁹ as they found that, Hamilton Rating Scale scores were significantly higher for psychotic major depression group than for the non-psychotic major depression group. Similar results were reported by Schatzberg et al.⁴ and by Hill et al.². Comparing our results to other studies, it was found that the mean score of HRSD for both groups in our study was higher than the corresponding groups in these studies, which might be explained by different culture and psychosocial stressors.

On WAIS the two groups differed significantly regarding their mean scores on performance, verbal and deterioration index.

Psychotic patients performed more poorly than non-psychotic patients in both verbal, performance IQ and deterioration index, which might be attributed to cognitive changes which are assumed to be more pronounced in psychotic patients whether due to presence of delusions and hallucinations which could affect their concentration and performance or due to changes occurring in frontal area or hippocampus as a part of elevated cortisol level^42,43. In a study done by Schatzberg et al.⁴ patients with psychotic major depression performed more poorly than did non-psychotic and comparison groups on the WAIS-R verbal subtest. In another study done by Schatzberg et al.³⁹, significant differences were not observed among the three groups (psychotic, non-psychotic & comparison) on the WAIS verbal test scores.

On the WCST the performance of psychotic patients was poorer than that of non-psychotic. The results showed a statistically high significant difference between both studied groups regarding number of trials, number of categories completed, total number of correct, total number of errors, percentage of errors, perservative response and percentage of perservative response. Also, it was found that there were a statistically high significant difference between the two groups in perservative errors, percentage of perservative errors, conceptual level of response, percentage of conceptual level of response and the number of trials to complete 1^st category. The greater deficits in the patients with psychotic major depression might be due either to disorder-specific effects on prefrontal cortex function or to general illness severity. Merriam et al.⁴⁴ who were studying the prefrontal cortical dysfunction in depression determined by WCST and found that patients with major depression exhibited significant deficits when performing the WCST. These deficits were less severe than those in patients with schizophrenia (they studied 79 major depressed patients only 5 of them were psychotic and 47 schizophrenic and schizoaffective patients). Their finding of a significant association between depressive symptoms and the magnitude of WCST deficits in major depression suggested that there may be a relationship between cognitive impairments and state-related physiological abnormalities of prefrontal cortex function during episodes of depression.

Correlation Studies: In psychotic group: There were positive correlations between level of cortisol at 8:00 am and performance of the patients in subtests of picture completion, picture arrangement and digit symbol, which means that high levels of cortisol at 8:00 am were required to perform better in these subtests which are part of performance domain of WAIS-R test. (N.B. the mean value of cortisol level am and pm were in normal ranges of our reference laboratory). There were a positive correlation between level of cortisol at 8:00 pm and performance on digit span and negative correlation to vocabulary subtest. Both subtests are part of verbal domain of WAIS-R test. As such, we can suggest that, the performance subtests are related to levels of cortisol at the morning while verbal subtests are related to levels of cortisol at evening in psychotic group of patients. There were positive correlations between a.m. cortisol and symptoms of helplessness, hopelessness, suicide and guilt which mean that these symptoms became more severe when levels of am cortisol was high.

In non-psychotic group: The level of cortisol at a.m. was positively correlated to subtests of verbal domain and to subtests of performance domain, as the level of a.m. cortisol increased, the performance on these subtests improved. Regarding WCST, there were positive and negative  correlation between a.m. cortisol p.m. cortisol and percent of change in cortisol, which mean that the performance of non-psychotic patients on these tests is decreased if the change in cortisol levels between morning and evening was high. These may suggest that, the cognitive decline in these patients might be related to high discrepancies between levels of cortisol in morning and evening rather than its high levels purse. There were positive correlation between a.m. cortisol and symptoms of disturbed work, sense of helplessness and suicide, while p.m. cortisol was negatively correlated to depressed mood and suspicions. Percent change of cortisol was negatively correlated to symptoms of depressed mood, disturbed work, sense of helplessness and suicide as the percent change increases, the symptoms decreases, which may reflect the role of non-suppression of cortisol level as aggravating the symptoms of major depression in both psychotic and non-psychotic patients. Information subtest was negatively correlated to presence and severity of somatic symptoms. Comprehension was negatively correlated to presence of obsessions while it was positively correlated to presence of anxiety. Anxiety itself had positive correlations to arithmetic, picture arrangement, and block design subtests and had a negative correlation to vocabulary subtest. This could be explained by that, moderate levels of anxiety can have an arousing function that serves behavioral performance up to a point, the point of disability coming when the anxiety symptoms become so severe as to overwhelm information-processing resources⁴⁵.

Factor analysis and many of the correlative studies, although of limited clinical relevance, yet it showed that psychotic and non- psychotic depression are different.

 

Conclusion

Both patients with psychotic major depression and non-psychotic major depression had definite cognitive deficits. Cognitive deficits in depressed patients (both psychotic and non-psychotic) are not age related. Elevated cortisol level and percent of change of cortisol levels are related to the severity of depressive symptoms in both psychotic and non-psychotic depressed patients.

 

[Disclosure: Authors report no conflict of interest]

 

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