The Neuropsychological Profile of Psychotic Major Depression and its Relation to Cortisol

The Neuropsychological Profile of Psychotic Major Depression and its Relation to Cortisol Rowena G. Gomez, Shelley H. Fleming, Jennifer Keller, Benjamin Flores, Heather Kenna, Charles DeBattista, Brent Solvason, and Alan F. Schatzberg Background: Our study described the neuropsychological profile of psychotic major depression (PMD) compared to nonpsychotic major depression (NPMD) patients and psychiatrically healthy controls (HC). We predicted that higher cortisol levels would be associated with greater cognitive deficits. Methods: Twenty-nine PMDs, 24 NPMDs, and 26 HCs were recruited at Stanford University Medical Center. Psychiatric ratings, cortisol levels from 1800-0900 hours, and neuropsychological test data were obtained. Results: PMDs had more severe cognitive impairments compared with NPMDs and HCs with the exception of simple verbal attention. PMDs had elevated mean cortisol levels from 1800 to 0100 hours which were significantly correlated with poorer verbal memory and psychomotor speed performance. Cortisol slopes from 1800 to 0100 hours were also significantly correlated with verbal memory and working memory. Conclusions: While PMDs’ ability to attend passively to information appears intact, they have more difficulty processing, manipulating, and encoding new information. Elevated cortisol levels, as seen in PMD patients, are associated with poorer cognitive performance especially related to verbal memory for lists of words and working memory. Key Words: Affective disorders, psychotic major depression, cognition, neuropsychology, cortisol

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ome depressed patients suffer from psychotic symptoms such as hallucinations and delusions. In a European sample, Ohayon and Schatzberg (2002) observed that nearly 19% of subjects with major depression (MDD) had psychotic features, consistent with other estimates of MDD and MDD with psychotic features (Johnson et al 1991). Psychotic symptoms such as nihilistic, guilty, or somatic delusions, and auditory hallucinations by definition are only present during depressive episodes, making psychotic major depression (PMD) distinct from schizoaffective disorder (Schatzberg and Rothschild 1992). In schizoaffective disorders psychotic symptoms must also be present when depression is absent, although they can also occur during depressive episodes. Psychotic major depression has other unique characteristics from nonpsychotic major depression (NPMD) including neuroendocrine and cognitive differences. Hyperactivity of the hypothalamic-pituitary-adrenocorticotical axis (HPA) in PMD patients has been observed in several studies (Anton 1987; Belanoff et al 2001; Coryell 1996; Evans et al 1983; Mendlewicz and Franckson 1982; Nelson and Davis 1997; Schatzberg et al 1983). The HPA axis, which consists of the hypothalamus, pituitary gland, and adrenal gland, is a stress-responsive system that regulates the production of cortisol. Increased levels of cortisol have been related to neurological changes which include cortical atrophy, ventrical enlargement, and smaller hippocampi (Axelson et al 1993; Sapolsky 1986; Sapolsky et al 1985; Stokes 1995;

From the Department of Psychiatry and Behavioral Sciences (RCG, SHF, JK, BF, HKG, CD, BS, AFS), Stanford University School of Medicine, Stanford; and the Palo Alto Veterans Health Care System (SHF), Palo Alto, California. Address reprint requests to Rowena G. Gomez, Ph.D., Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305-5723; E-mail: rggomez@ stanford.edu. Received October 21, 2004; revised May 3, 2005; revised October 4, 2005; accepted November 22, 2005.

0006-3223/06/$32.00 doi:10.1016/j.biopsych.2005.11.010

Wolfe et al 2002). Similar neuroimaging abnormalities have been found in PMD patients (Salokangas et al 2002; Gewirtz et al 1994; Rothschild et al 1989; Simpson et al 1999). In other studies of depression, these hormonal and neurological abnormalities have also been associated with cognitive deficits. For instance, higher cortisol levels have been significantly correlated with greater cognitive impairments in depressed patients (O’Brien et al 1996; Van Londen et al 1998). As of yet, relationships between cortisol and cognition in PMD have not been reported. Indeed, relatively few studies have investigated neuropsychological functioning in PMDs compared with NPMDs. These published studies have been limited due to various reasons, such as small sample size or restricted neuropsychological battery. The largest study of depressed patients to date was conducted by Basso and Bornstein (1999) who found significant deficits in attention, working memory, language, visuospatial ability, verbal memory and executive functioning between PMD patients compared with NPMDs. Schatzberg and colleagues (2000) also found deficits in attention, response inhibition, and verbal memory in a relatively small sample of drug-free PMDs. In a recent review and meta-analysis by our group that included five available neuropsychological studies of PMDs (Fleming et al 2004), the greatest cognitive deficits of PMDs compared with NPMDs were verbal memory, executive functioning, and psychomotor speed. These conclusions were largely supported by a subsequent, recent report by (Hill et al 2004) in first episode PMD patients. Finding a relationship between cognition and cortisol in psychotic major depression may have important clinical implications because evidence suggests that manipulation of cortisol levels significantly affects cognition. For instance, (Lupien et al 1999) found significant detriments in working memory in healthy young men who were administered a high dose of hydrocortisone. In a study of older adults, Lupien and colleagues (2002) improved or worsened verbal memory performance by increasing or decreasing cortisol levels. In relation to the present study, we ultimately wanted to know if normalizing cortisol levels in PMDs would lead to improved cognition. In order to examine this question, we needed to first establish a relationship between these two variables in the PMD population. Specifically, we wanted to determine if higher levels of cortisol lead to worse cognitive performance. While cortisol and cognition have been BIOL PSYCHIATRY 2006;60:472– 478 © 2006 Society of Biological Psychiatry

BIOL PSYCHIATRY 2006;60:472– 478 473

R.G. Gomez et al examined separately in PMDs (Belanoff et al 2001), there is no study to date that has analyzed the relationship between cortisol and cognition in these patients. The important distinctions of this present study, compared to previous studies in this area, are three fold: (1) that there are two, not just one, comparison groups: healthy controls and nonpsychotic depressed patients, (2) we employed the most comprehensive neuropsychological battery to date, and (3) we examined the relationship between measures of cortisol activity and neuropsychological measures among PMDs and NPMDs to assess their relationship to each other. The present study is part of a larger study of psychotic major depression conducted in the Depression Research Clinic at Stanford University. The goals of this study were to thoroughly describe the neuropsychological profile of psychotic major depression and compare it to the profiles of NPMD patients and psychiatrically healthy participants and evaluate the relationship between cortisol and cognition. Based on our previous PMD study on cognition (Schatzberg et al 2000), we wanted to replicate our findings that PMDs would have more severe cognitive impairments in the domains of attention, executive functioning, response inhibition and verbal memory as compared with NPMDs and healthy controls, and that NPMDs would have more severe cognitive impairments compared to healthy controls on executive functioning tasks and memory tasks. Furthermore, we hypothesized that higher levels of cortisol would be associated with greater cognitive deficits, especially in regards to memory and executive functioning.

positive symptom subscale of the Brief Psychotic Rating Scale BPRS; Overall and Gorham 1961), which consists of four items: conceptual disorganization, suspiciousness, hallucinations, and unusual thought content. The healthy controls must have a score of less than 6 on the HDRS and no psychotic symptoms as measured by the BPRS positive symptom subscale. The healthy controls must also not have a history of psychiatric disorders as determined by the Structured Clinical Interview for DSM-IV-TR Axis I Disorders - Patient Edition (First et al 1997). Participants were allowed to remain on psychiatric medications, if the dose had not been adjusted for at least one week. Participants who had electroconvulsive therapy or substance abuse in the last six months were excluded from the study. Neuropsychological Measures by Cognitive Domains Premorbid Intelligence. Wechsler Test of Adult Reading (Wechsler 2001) is one of the most up-to-date and commonly used measures of premorbid intelligence. The task requires the participant to pronounce various words varying in difficulty. Based on their performance (total number correct) and their demographic variables (e.g., years of education, gender), an estimate of premorbid intelligence is determined based on United States norms. Attention. Digit span forward from the Wechsler Adult Intelligence Scale-III (Wechsler 1997) provides a verbal measure of simple attention. In this task, the participant must repeat a list of digits in the order that was orally presented. Sequences of increasing length are administered. Trail Making Test, Part A provides a nonverbal measure of attention and psychomotor speed. In this timed task, the participant must connect numbered dots in sequence as fast as possible without making any mistakes. Performance is measured by the time it takes the participant to correctly complete the task. Working Memory. Digit backward from the WAIS-III is the second part of the Digit Span subtest. In this task the participants must repeat a list of digits in reverse order. Sequences of increasing length are administered. Letter-number sequencing from the WAIS-III consists of combinations of numbers and letters in which the participant must reorganize them in to digits in numerical order then letters in alphabetical order. Each item consists of three trials of similar lengths. The combination of numbers and letters increase in length until the participant incorrectly responses to at least two of the three trials, and then the task is terminated. These measures of working memory assess the participants’ capacity to correctly manipulate a number of units of information. Semantic Fluency. Animal naming measures one’s ability to access and utilize semantic memory or memory for meanings of words by asking participants to name as many different animals as possible in one minute.

Methods and Materials Sample Twenty-nine PMD patients, 24 NPMD patients, and 26 normal controls were recruited at Stanford University Medical Center for a study of hypothalamus-pituitary-adrenal (HPA) activity in depression from 2000 to 2004. Psychiatric participants were recruited through inpatient and outpatients facilities at Stanford University or self-referred from online and print study advertisements. Control participants were recruited from the latter two recruitment methods. As shown in Table 1, no significant differences were found between the three clinical groups on age, education, and premorbid estimate of intelligence (see Keller et al, in press, for more details on the patient groups). PMD and NPMD participants were required to meet the following inclusion criteria: a baseline total score of 21 or higher on the 21-item Hamilton Depression Rating Scale HDRS; Hamilton 1960) and a score of at least 7 on the Core Endogenomorphic Scale (Thase et al 1983), which uses seven items included in the 21-item HDRS. These latter two criteria were designed to ensure inclusion of participants with similar minimum levels of endogenous-type symptoms. PMDs had to score a minimum of 5 on the Table 1. Demographic Variables for PMDs, NPMDs, and Healthy Controls PMDs

Age Education Premorbid Intelligence Gender Male Female

NPMDs

Controls

n

M

(SD)

n

M

(SD)

n

M

(SD)

df

F

29 28 17

38.00 15.21 110.18

(12.95) (3.11) (14.97)

24 24 20

38.63 14.92 107.15

(12.00) (2.19) (13.57)

25 25 21

35.12 15.40 113.67

(14.33) (1.96) (12.46)

(2,75) (2,74) (2,55)

.51 .23 .32

13 16

7 17

13 12

PMD, psychotic major depression; NPMD, nonpsychotic major depression.

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Executive Functioning. The Stroop Color and Word Test (Golden 1978) requires the participant to name the printed color of a contradictory color words e.g., the word “yellow” printed in purple ink. This task measures the person’s ability to inhibit the natural behavior of reading words and instead name the color of the print. Performance is recorded as the total number of correct responses in 45 seconds. Trail Making Test Part B is another executive functioning task involving psychomotor speed where the participant must sequentially connect labeled circles containing numbers and letters in a particular sequence. This type of executive functioning measures the persons’ ability to switch sets between numbers and alphabetical letters. Performance is measured by the time it takes the participant to correctly complete the task. Controlled-Word Association Test (letter or phonemic fluency; Thurstone and Thurstone 1949) is a task that requires the participant to names as many words in one minute that begin with a particular letter. This type of executive functioning task measures phonemic fluency, the ability to come up with words that begin with a similar sound. Verbal Memory. Two verbal memory tasks were given to measure both recall and recognition of verbal information. California Verbal Learning Test II CVLT-II; Delis et al 2001) is a list-learning task with a short delay free and cued recall and a 20-minute delay recall condition. Logical Memory from the Wechsler Memory Scale-III WMS-III; Wechsler 1997b) requires the participants to listen to two stories and then immediately after hearing each story, retell it from memory and then again after a 30-minute delay. They are also given a recognition task of answering yes or no questions regarding both stories.

Procedure After subjects signed informed consent, they were admitted to the Stanford University Hospital General Clinical Research Center (GCRC). All participants underwent structural and functional MRI (these findings will be reported elsewhere), neuropsychological testing, psychological interviews, and blood sampling over a period of two days (see Keller et al, in press, for cortisol findings). The entire protocol for this study was approved by the Stanford University Institutional Review Board. On the first day of testing, subjects had an intravenous line placed in their arm at 1600 hours to collect blood for determining cortisol and adrenocorticotropin (ACTH) levels. These blood samples were collected hourly from 1800 to 0900 hours the next morning. Patients stayed in the hospital overnight. Overnight samples were collected because previous studies indicated that this was the time of day when the groups differed the most on cortisol measures (Posener et al 2000; Sachar et al 1973). Statistical Analyses Statistical analyses conducted in this study included analyses of variance (ANOVA) with post-hoc Bonferroni method and bivariate Pearson correlations using SPSS 13.0 (SPSS Inc., Chicago, Illinois). ANOVAs were used to detect differences in neuropsychological performance and cortisol levels between the three clinical groups. Bivariate correlations were used to determine relationships between cortisol levels and neuropsychological performance. Since the cortisol measures (means and slopes from 1800 hours to 0100 hours and from 0100 hours to 0900 hours) were found to be normally distributed, Pearson’s correlation analyses were conducted.

Table 2. Cognitive Performance at Time 1 between PMDs (P), NPMDs (NP), and Healthy Controls (HC) PMDs

Attention Digit Span Forwards Trail Making Test A Working Memory Digit Backwards Letter-Number Seq. Executive Function Stroop (Color-Word) Trail Making Test B COWA Semantic Fluency Verbal Memory CVLT Short delay free Short delay cued Long delay free Long delay cued Recognition Logical Memory Immediate recall Delayed recall Recognition

NPMDs

Controls

n

M

(SD)

n

M

(SD)

n

M

(SD)

df

F

Bonferroni Comparisons

28 28

10.5 36.9

(3.3) (15.5)

20 22

10.3 28.09

(2.7) (10.3)

21 25

11.8 26.5

(2.2) (9.4)

(2, 66) (2, 72)

1.8 5.5a

P ⫽ NP ⫽ HC P ⬍ (NP ⫽ HC)

28 27

6.6 9.1

(2.4) (3.2)

20 23

7.3 11.1

(1.9) (2.2)

21 25

8.5 12.4

(2.5) (3.0)

(2, 66) (2, 72)

4.2a 9.1c

NP ⫽ (P & HC), P ⬍ HC P ⬍ (NP ⫽ HC)

27 28 26 25

33.1 86.2 37.0 16.6

(7.7) (35.5) (10.7) (4.5)

23 22 23 23

42.9 64.0 39.8 19.8

(10.2) (16.2) (11.0) (4.8)

25 22 25 24

45.5 57.2 45.4 22.7

(13.3) (20.9) (13.0) (4.8)

(2, 72) (2, 71) (2, 71) (2, 69)

9.8c 7.9b 3.4a 10.5c

P ⬍ (NP ⫽ HC) P ⬍ (NP ⫽ HC) NP ⫽ (P & HC), P ⬍ HC NP ⫽ (P & HC), P ⬍ HC

28 28 28 28 28

7.1 8.8 7.8 8.7 13.6

(3.8) (3.6) (4.0) (3.3) (3.2)

23 23 23 23 23

11.3 12.1 11.6 12.2 14.7

(2.8) (2.3) (2.8) (2.5) (2.1)

24 24 24 24 24

10.8 12.0 11.5 12.2 14.7

(2.7) (2.4) (2.9) (2.5) (1.0)

(2, 72) (2, 72) (2, 72) (2, 72) (2, 72)

9.6c 11.8c 11.1c 13.7c 1.6

P ⬍ (NP ⫽ HC) P ⬍ (NP ⫽ HC) P ⬍ (NP ⫽ HC) P ⬍ (NP ⫽ HC) PMD ⫽ NPMD ⫽ HC

27 27 27

20.5 18.2 23.6

(7.2) (7.8) (2.7)

23 23 23

23.2 24.0 25.7

(8.6) (9.0) (2.5)

24 24 24

30.5 33.0 27.4

(7.7) (6.0) (2.1)

(2, 71) (2, 71) (2, 71)

10.9c 23.7c 15.7c

(P ⫽ NP) ⬍ HC P ⬍ NP ⬍ HC P ⬍ NP ⬍ HC

PMD, psychotic major depression; NPMD, nonpsychotic major depression; COWA, controlled word association test; CVLT, California Verbal Learning Test. p ⬍ .05. b p ⬍ .01. c p ⬍ .001. a

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Results Analyses of variance indicated significant differences among the three patient groups on most neuropsychological measures (see Table 2). Overall, PMD patients performed significantly worse on most measures of cognitive functioning as compared to both nonpsychotic depressed patients and healthy controls. Specifically as compared to NPMDs, PMDs performed significantly worse on attention [Trails A (p ⬍ .05)]; working memory [Letter-Number Sequencing (p ⬍ .03)]; executive functioning [Trails B (p ⬍ .05), Stroop color-word (p ⬍ .001)]; and verbal memory [CVLT short delay free recall (p ⬍ .001), CVLT short delay cued recall (p ⬍.001), long delay free recall (p ⬍ .001), CVLT long delay cued recall (p ⬍ .001), and Logical Memory Delayed (p ⬍ .02)]. PMDs compared with healthy controls performed significantly worse on all measures with the exception of Digit Span Forwards and CVLT recognition (p s ⬎ .05). The NPMDs performed better than the PMDs but still performed worse than healthy controls on a few of the subtests. Specifically, comparisons between NPMDs and healthy controls indicated significantly poorer performance in NPMDs on measures of verbal memory for narrative information (ie. logical memory immediate recall, delayed recall, and recognition, p s ⬍ .01). Next, we examined the relationship between overnight cortisol levels and neuropsychological performance in the entire study sample. As reported elsewhere (Keller et al, in press), we have explored cortisol means and slopes from 1800 hours to 0100 hours and from 0100 hours to 0900 hours between the three clinical groups and observed that PMD patients demonstrated

elevated mean cortisol levels from 1800 to 0100 hours. As shown in Table 3, the cortisol mean from 1800 hours to 0100 hours correlated consistently significantly and negatively with the verbal memory measure for lists of words (CVLT) and measures of psychomotor speed (Trails A and B) in the overall group. (Notably, Trails B is also a measure of executive functioning— specifically the ability to switch appropriately between sets of numbers and letters in order.) Cortisol mean from 0100 hours to 0900 hours was also significantly correlated with verbal memory for list of words (CVLT). Cortisol slope from1800 hours to 0100 hours was significantly and negatively correlated with measures of working memory (letter-number sequencing) and verbal memory (CVLT and logical memory) in the overall groups such that less negative slope in the evening was associated with poorer performance. Lastly, cortisol slope 0100 hours to 0900 hours was correlated positively with a measure of working memory (letter-number sequencing), such that greater slope was related to better performance. We also conducted the same correlational analyses with only the PMD sample (see Table 4). Because of a small sample size, we had limited power to detect significant correlations between cortisol and cognition and the need for replication with a larger sample is warranted. However, there are some relations worth mentioning. Significant correlations between measures of verbal memory (CVLT measures) and cortisol were found despite the small sample size. In addition, there appears to be a trend for a significant relation between a measure of working memory (letter-number sequencing) and a measure of executive functioning (Trails B) with cortisol

Table 3. Correlations between Cortisol and Neuropsychological Measures at Baseline for all Clinical Groups Cortisol Mean

Neuropsychological Measures Attention Digit Span Forwards Trail Making Test A Working Memory Digit Backwards Letter-Number Seq. Executive Function Stroop (Color-Word) Trail Making Test B COWA Semantic Memory Verbal Memory CVLT Short delay free Short delay cued Long delay free Long delay cued Recognition Logical Memory Immediate recall Delayed recall Recognition

Cortisol Slope

1800 hours to 0100 hours

0100 hours to 0900 hours

1800 hours to 0100 hours

0100 hours to 0900 hours

r ⫽ ⫺.03 r ⫽ .30c

r ⫽ .05 r ⫽ .19

r ⫽ ⫺.02 r ⫽ .02

r ⫽ .18 r ⫽ ⫺.16

r ⫽ .00 r ⫽ ⫺.22a

r ⫽ ⫺.16 r ⫽ ⫺.16

r ⫽ ⫺.18 r ⫽ ⫺.30b

r ⫽ ⫺.13 r ⫽ .30b r ⫽ ⫺.13 r ⫽ ⫺.06

r ⫽ ⫺.10 r ⫽ ⫺.16 r ⫽ ⫺.02 r ⫽ ⫺.09

r ⫽ ⫺.18 r ⫽ .08 r ⫽ ⫺.18 r ⫽ ⫺.17

r ⫽ ⫺.35c r ⫽ ⫺.38c r ⫽ ⫺.29b r ⫽ ⫺.42d r ⫽ ⫺.54d

r ⫽ ⫺.37c r ⫽ ⫺.35c r ⫽ ⫺.34b r ⫽ ⫺.35c r ⫽ ⫺.38c

r ⫽ ⫺.34c r ⫽ ⫺.29b r ⫽ ⫺.27b r ⫽ ⫺.29b r ⫽ ⫺.26b

r ⫽ .19 r ⫽ .19 r ⫽ .14 r ⫽ .21 r ⫽ .22a

r ⫽ ⫺.16 r ⫽ ⫺.18 r ⫽ ⫺.25b

r ⫽ ⫺.20a r ⫽ ⫺.22 r ⫽ ⫺.10

r ⫽ ⫺.26b r ⫽ ⫺.20 r ⫽ ⫺.14

r ⫽ .22a r ⫽ .13 r ⫽ .19

r ⫽ .00 r ⫽ .24b r ⫽ .15 r ⫽ ⫺.20a r ⫽ .06 r ⫽ .07

COWA, controlled word association test; CVLT, California Verbal Learning Test. p ⬍ .10. b p ⬍ .05. c p ⬍ .01. d p ⬍ .001. a

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Table 4. Correlations between Cortisol and Neuropsychological Measures at Baseline for Only PMD Group (n ⫽ 29) Cortisol Mean

Neuropsychological Measures Attention Digit Span Forwards Trail Making Test A Working Memory Digit Backwards Letter-Number Seq. Executive Function Stroop (Color-Word) Trail Making Test B COWA Semantic Fluency Verbal Memory CVLT Short delay free Short delay cued Long delay free Long delay cued Recognition Logical Memory Immediate recall Delayed recall Recognition

Cortisol Slope

1800 hours to 0100 hours

0100 hours to 0900 hours

1800 hours to 0100 hours

0100 hours to 0900 hours

r ⫽ .09 r ⫽ ⫺.08

r ⫽ .11 r ⫽ ⫺.15

r ⫽ ⫺.06 r ⫽ .30

r ⫽ .11 r ⫽ .05

r ⫽ ⫺.09 r ⫽ ⫺.11

r ⫽ ⫺.08 r ⫽ ⫺.16

r ⫽ .09 r ⫽ ⫺.36a

r ⫽ ⫺.11 r ⫽ ⫺.09

r ⫽ ⫺.04 r ⫽ ⫺.03 r ⫽ ⫺.15 r ⫽ ⫺.18

r ⫽ .14 r ⫽ ⫺.26 r ⫽ ⫺.16 r ⫽ .02

r ⫽ ⫺.23 r ⫽ .36a r ⫽ .20 r ⫽ .19

r ⫽ .09 r ⫽ .12 r ⫽ ⫺.03 r ⫽ ⫺.11

r ⫽ ⫺.50c r ⫽ ⫺.32 r ⫽ ⫺.35a r ⫽ ⫺.36a r ⫽ ⫺.40b

r ⫽ .12 r ⫽ .06 r ⫽ ⫺.05 r ⫽ .03 r ⫽ .36a

r ⫽ ⫺.34a r ⫽ ⫺.27 r ⫽ ⫺.20 r ⫽ ⫺.36a r ⫽ ⫺.68c

r ⫽ ⫺.59c r ⫽ ⫺.41b r ⫽ ⫺.45b r ⫽ ⫺.51c r ⫽ ⫺.56c

r ⫽ ⫺.11 r ⫽ ⫺.05 r ⫽ ⫺.02

r ⫽ .30 r ⫽ .14 r ⫽ .33

r ⫽ .14 r ⫽ .19 r ⫽ .01

r ⫽ ⫺.05 r ⫽ ⫺.09 r ⫽ .05

COWA, controlled word association test; PMD, psychotic major depression; CVLT, California Verbal Learning Test. p ⬍ .10. p ⬍ .05. c p ⬍ .01. a

b

slope from 1800 hours to 0100 hours. Notably, these particular cognitive measures and cortisol were significant when including all three sample groups. No differences in means or slopes were found between the three clinical groups in ACTH levels over the same time periods. There were also very few, inconsistent correlations between ACTH and neuropsychological measures.

Discussion Results indicated that patients with psychotic major depression have more severe cognitive impairments as compared with both nonpsychotic depressed patients and healthy controls. Specifically, more severe deficits were observed for PMDs in working memory, psychomotor speed, immediate and delayed verbal memory, language, and executive functioning. Only simple verbal attention appears to be relatively intact in PMDs. These findings suggest that while PMDs’ ability to attend passively to units of information is within normal limits, they have more difficulty processing, manipulating, and encoding new information. Specific deficits, verbal memory and executive functioning are consistent with prior PMD studies (e.g., Basso and Bornstein 1999; Schatzberg et al 2000). Furthermore, these cognitive processes are believed to be mediated by the hippocampus and prefrontal cortex including the anterior cingulate. Interestingly, these particular brain areas have also been associated with impairment seen with administration of exogenous glucocorticoids as well as with increased endogenous HPA activity, a hallmark PMD (Hill et al 2004; Anton 1987; Schatzberg et al 1995). Furthermore significant correlations have been found www.sobp.org/journal

between executive functioning and cortisol and more prominently between verbal memory and cortisol. However, our finding of impairments in attention and working memory in PMDs was not consistent with a prior study that used the same cognitive tasks. Although we found simple verbal attention to be intact (digit span forward) and working memory to be poorer (digit span backwards and letter-number sequencing) in PMDs compared to the comparison groups, Basso and Bornstein (1999) reported the opposite. Simple attention is widely believed to be a basic cognitive process necessary for higher-level cognitive processes (such as working memory) to occur correctly. Thus, it makes greater theoretical sense for simple attention to be intact and working memory to be more impaired in PMDs than NPMDs rather than vice versa. Unfortunately, this study is difficult to compare with other PMD studies since they did not distinguish between simple attention and working memory and combined these cognitive processes into one cognitive domain – attention. Our data suggest a stronger relationship may exist between a PMD diagnosis and neuropsychological measures rather than between PMD diagnosis and cortisol levels, since relatively greater significant differences were found between PMDs and the comparison groups on neuropsychological measures than on cortisol measures. One possible reason for this is that some of the PMD patients were on antipsychotic medications. These medications may have reduced the variability of cortisol that in turn, may have lessened the ability of detecting more significant relationships between cortisol and PMD diagnosis and cortisol and cognitive performance. Notably, 22 of the 29 PMD patients were on antipsychotic medication in our sample (for a full

R.G. Gomez et al description of medications taken by the PMDs and NPMDs, see Table 1 in Keller et al, in press). Our study has a few limitations. First, our sample is relatively small and larger samples would be ideal to confirm our results. Second, in our selection of subjects, we required PMDs and NPMDs to have a minimum score of 7 on the Thase endogenous symptom scale. Thus, our results are limited to those depressed patients with at least a minimal level of endogenous symptoms. Notably, only one potential patient was excluded specifically because of this criterion. Third, as mentioned earlier, there could be a restriction of range problem in cortisol levels in PMDs due to use of antipsychotic medications. Perhaps more significant cortisol relationships with cognition and PMD diagnosis would be found if the PMD sample was not on antipsychotic medications. Lastly, we reported multiple ANOVA analyses regarding differences in cognitive performance between the three participant groups and multiple correlations between cortisol and cognitive measures. These analyses increase the risk of committing a Familywise Type I error. Thus, our findings are in need of replication to obtain confirmation. Our study has important clinical implications. Many mental health professionals do not regularly differentiate between NPMD and PMD patients. Our study provides evidence that psychologists and psychiatrists should consider cognitive functioning when diagnosing patients and the implications of cognitive deficits when providing treatment in PMD patients. If a nonelderly, depressed patient complains of concentration and memory problems, a brief neuropsychological assessment may help clarify cognitive issues, and the mental health professional may be alerted to possible underlying reasons for these cognitive difficulties (i.e., psychotic symptoms). Furthermore, with impaired working memory and verbal memory, using external memory strategies (e.g., writing things down) or asking the patient to repeat instructions or complex concepts, would likely benefit psychotherapy and medication compliance in patients with psychotic major depression.

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