Neuropsychological Correlates of Methylphenidate Treatment in Adult ADHD With and Without Depression

Archives of Clinical Neuropsychology, Vol. 14, No. 2, pp. 217–233, 1999 Copyright © 1999 National Academy of Neuropsychology Printed in the USA. All rights reserved. 0887-6177/99 $–see front matter

PII S0887-6177(98)00015-8

Neuropsychological Correlates of Methylphenidate Treatment in Adult ADHD With and Without Depression Henry J. Riordan Dartmouth Medical School

Laura A. Flashman and Andrew J. Saykin Dartmouth Medical School and New Hampshire Hospital

Sally A. Frutiger Dartmouth Medical School

Kevin E. Carroll Dartmouth Medical School and New Hampshire Hospital

Leighton Huey Dartmouth Medical School

The purpose of this study was to characterize the neuropsychological profiles of adult patients with attention deficit hyperactivity disorder (ADHD) alone and ADHD with active comorbid depression, and to evaluate changes in the neuropsychological profile in these two groups following a trial of methylphenidate. Forty patients with ADHD were classified into two groups based on their affective status resulting in a group of 21 patients with ADHD alone and 19 patients with ADHD and active comorbid symptoms of depression (ADHD-D). All subjects received a comprehensive neuropsychological evaluation including measures of cognitive, motor and affective functioning before and after treatment. Fifteen normal controls were also assessed at a yoked time interval. At baseline, both patient groups showed impairment in verbal memory, motor and processing speed, visual scanning, and auditory and visual distractibility. Following treatment, both patient groups showed improvement across all neuropsychological measures while controls remained relatively stable over time. Improvement in neuropsychological test performance was not related to gender, affective status or referral source. Patients with active comorbid symptoms of depression show a similar neuropsychological profile and appear equally likely to benefit from me-

The authors acknowledge the following people for their assistance with this project: Suzanne R. Eaton, Sterling C. Johnson, Jessica Lilly, Judy O’Jile, and Cynthia A. Smith. Address correspondence to Laura A. Flashman, Department of Psychiatry, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756-0001; E-mail: [email protected].

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H. J. Riordan et al. thylphenidate intervention as patients with ADHD alone. © 1999 National Academy of Neuropsychopharmacology. Published by Elsevier Science Ltd

The purpose of the present study is to characterize the neuropsychological profiles of patients with attention deficit hyperactivity disorder (ADHD) alone and ADHD with comorbid depression, and to evaluate changes in the neuropsychological profile in these two groups following a trial of methylphenidate. Preliminary studies have suggested that adult ADHD patients differ from controls in verbal list learning (Downey, Stelson, Pomerleau, & Giordani, 1997; Holdnack, Moberg, Arnold, Gur, & Gur, 1995; Mungas, 1983), sustained attention (Arcia & Gualtieri, 1994), slowed cognitive processing (Holdnack et al., 1995), and behavioral symptoms such as impulsivity (Arcia & Gualtieri, 1994). For example, Arcia and Gualtieri (1994) reported that the performance of ADHD subjects was characterized by greater impulsivity and an inability to regulate their actions and responses, problems with sustained attention and relatively poorer performance on measures of memory and learning. Although some researchers have proposed that continuous performance tests (CPT) are helpful in the diagnostic process, questions have been raised concerning their diagnostic utility. The research on CPT has been equivocal in adult patients with ADHD, with some researchers reporting deficits (Gualtieri, Ondrusek, & Finley, 1985; Klee, Garfinkle, & Beauchesne, 1986), whereas others have not (Holdnack et al., 1995; Zametkin et al., 1990). Additionally, studies have also suggested that patients with ADHD and comorbid disorders may differ from patients with ADHD alone. Downey et al. (1997) compared a group of “pure” ADHD patients with a group of ADHD patients who had a variety of comorbid Axis I diagnoses, including depression, alcohol and drug abuse/dependence and antisocial personality disorder. They reported that patients with active comorbid Axis I disorders performed significantly worse than pure ADHD patients on an attentional capacity test. Other studies have reported high rates of depression among subjects with ADHD. Tzelepis, Schubiner, and Warbasse (1995) reported that in 114 adults with ADHD the lifetime prevalence for major depressive disorder (MDD) was 29%, and that the prevalence for dysthymia was 19%. ADHD symptoms of inattention, difficulty with concentration, irritability and susceptibility to frustration are often ascribed to depression. In fact, mood disorders are the most common diagnoses given in adults seen for treatment prior to the diagnosis of ADHD (Ratey, Greenberg, Bemporad, & Lindem, 1992). However, there are no known investigations examining the impact of active symptoms of depression alone on the neuropsychological profile of adults with ADHD. Although there have been a number of studies assessing the effectiveness of methylphenidate intervention on adult ADHD symptoms (Gualtieri et al., 1985; Mattes, Boswell, & Oliver, 1984; Spencer et al., 1995; Wender, Reimherr, Wood, & Ward, 1985; Wood, Reimherr, Wender, & Johnson, 1976), most have utilized various intellectual, academic achievement and cognitive measures only at baseline, presumably in an effort to aid in diagnosis and to rule out comorbid disorders (such as learning disorders). In one preliminary report (Huey et al., 1984), neuropsychological measures were administered both before and after methylphenidate treatment. The Lafayette Repeatable Battery was given to adult patients with ADHD, schizophrenia, depression and mania before and 3 weeks following a trial of methylphenidate. They reported that attentional deficits significantly decreased while motor performance improved 92% for ADHD subjects whereas non-ADHD subjects displayed an increase in attentional deficits as a result of methylphenidate treatment. However, the neuropsychological evaluation was not com-

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prehensive, and the ADHD patient group in this preliminary report was relatively small (n 5 7). Although Spencer et al. (1995) investigated the effectiveness of methylphenidate in ADHD patients with a past history of depression, there have been no studies of the effectiveness of methylphenidate in patients with active comorbid depressive symptoms. This is surprising given that cognitive dysfunction (i.e., inattention, an inability to sustain focus, distractibility, forgetfulness, disorganization) is considered a hallmark of this disorder, and that neuropsychological assessment has been shown to be an effective and reliable tool in assessing cognitive change following medication.

MATERIALS AND METHODS Patient Population The sample consisted of 40 patients diagnosed with adult ADHD drawn from a larger sample of 100 consecutive patients who presented to the ADHD Clinic at DartmouthHitchcock Medical Center with primary complaints of difficulty in attention/concentration. All patients completed a semistructured interview focusing on DSM-IV (APA, 1994) criterion of childhood and persistent symptoms of ADHD, as well as a symptom checklist based on DSM-IV criteria for the ADHD subtypes (predominantly inattentive, hyperactive-impulsive, or combined type). This interview was conducted by a board certified psychiatrist (LH) and the determination of diagnosis was supported by a second semistructured interview at the time of neuropsychological evaluation by one of the authors (HJR, LAF, SAF, KEC, AJS). This second interview was based on DSM-IV criteria, as well as a number of other persistent symptoms into adulthood, including task impersistence, and stress intolerance that interfered with occupational or social functioning. The initial semistructured interview queried symptoms of ADHD such as inattention, impulsivity, disorganization, procrastination, and distractibility according to DSM-IV criteria. The second semistructured interview (which was conducted by a neuropsychologist on the date of testing) consisted of a similar series of questions that were also developed to reflect DSM-IV criteria, as well as a comprehensive review of neurobehavioral symptomatology. Of these first 100 consecutive patients, 53 met DSM-IV criteria for adult ADHD. Thirteen patients who met criteria for adult ADHD were excluded from the present study because they were already taking medications for their mood disorder or attentional complaints at the time of the evaluation (n 5 11) or because of incomplete baseline neuropsychological testing (n 5 2). The remaining 40 patients were then classified into two groups based on their affective status. Patients with no current or past history of depression were assigned to the ADHD without depression group (ADHD) and those who also met DSM-IV criteria for dysthymia or a major depressive disorder currently were assigned to the ADHD with depression group (ADHD-D). This resulted in a group of 21 patients with ADHD alone and 19 patients with ADHD and active comorbid symptoms of depression. Of the latter 19 ADHD-D patients, nine had a prior history of treatment (pharmacologic and/or therapy) for their affective distress. Of the 40 patients who underwent neuropsychological testing at baseline, 26 were self-referred and 14 were referred by another physician or psychologist. There was no significant difference in referral source for the ADHD versus ADHD-D groups (x2 5 .05, p 5 .82). Of the forty patients tested at baseline, four did not return following treatment. Therefore, follow-up neuropsychological data were available for 19 patients with ADHD and 17 patients with ADHD-D.

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Fifteen normal control subjects were recruited from the community via newspaper advertisement and postings in the hospital and on campus. All control subjects completed a brief phone screen consisting of a semistructured interview and an ADHD checklist (Ward, Wender, & Reimherr, 1993). Of the 31 subjects screened for participation, 16 were excluded because they had a personal and/or familial history of neurological or psychiatric disorder, including adult ADHD. As indicated in Table 1, control subjects did not differ from either patient group in terms of age, sex, handedness, reading recognition score, or mean years of education. However, the control group had higher full scale IQ scores than either patient group. Medication All patients who were identified as having adult ADHD were placed on a trial of methylphenidate at a dosage of 0.5 mg/kg. There was no significant difference in medication duration between the two ADHD groups. On average, ADHD patients were on medication for 39 days (range: 20–107) before follow-up neuropsychological testing, and ADHD-D patients were on medication for an average of 38 days (range: 7–112) before repeat testing, F(1, 31) 5 0.02, p 5 .89. Neuropsychological Assessment A comprehensive battery of tests designed to reflect current theory and research on adult ADHD and assess overall neuropsychological functioning was administered to patients before and after treatment with methylphenidate and to control subjects both at baseline and after a yoked time interval. The average neuropsychological test-retest interval was 64 days (range: 26–140) for ADHD group, 79 days (range: 41–158) for ADHD-D and 63 days (range: 26–112) for the control group, F(2, 48) 5 1.40, p 5 .26. The battery took approximately 3.5 hours to administer and included well-established tests that measured intellectual as well as other cognitive processes and psychomotor functioning. All tests were administered by a trained neuropsychological technician or a postdoctoral fellow in neuropsychology.

TABLE 1 Mean (and Standard Deviation) Demographic Information for all Subject Groups

Mean age (years) Mean education (years) Gender (male/female) Handedness (right/left) Mean FSIQ Mean VIQ Mean PIQ Mean WRAT-3 reading

ADHD (n 5 21)

ADHD-D (n 5 17)

Controls (n 5 15)

F

31.8 (11.8) 14.6 (2.0) 17/4 18/3 105.6 (10.9) 105.0 (12.4) 106.2 (11.9) 104.3 (8.6)

32.7 (13.0) 14.3 (2.6) 11/8 18/1 103.4 (16.8) 105.1 (16.2) 99.7 (15.8) 102.6 (12.6)

36.5 (10.8) 16.0 (2.6) 7/8 12/3 118.9 (13.3) 117.1 (13.5) 117.5 (14.3) 106.2 (7.6)

0.73 2.50 x2 5 4.85 x2 5 1.71 6.03 3.97 6.75 0.53

p

0.49 0.09 0.09 0.42 0.004a,b 0.025a 0.0025b 0.59

Note. Standard deviations are shown in parentheses. ADHD 5 attention deficit hyperactivity disorder; ADHD-D 5 attention deficit hyperactivity disorder with depression; FSIQ 5 Full Scale Intelligence Quotient; VIQ 5 Verbal Intelligence Quotient; PIQ 5 Performance Intelligence Quotient; WRAT-3 5 Wide Range Achievement Test, 3rd edition. aADHD vs. controls. bADHD-D vs. controls.

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In an effort to control for Type I error given the large number of neuropsychological tests administered, a factor analysis was conducted. First, the raw data for all 100 patients who presented to the ADHD clinic with primary symptoms of difficulties in attention/concentration was z-transformed to a common metric based on published normative data (Cermak, Butters, & Goodglass, 1971; Denman, 1984; Lezak, 1995; Mesulam, 1985; Saykin et al., 1995; Spreen & Strauss, 1991). To calculate these Z scores, the normative mean was subtracted from each patient’s test score and this difference was divided by the standard deviation for the most appropriate normative sample. These Z scores were then entered into a principal components analysis, followed by varimax rotation, which yielded eight orthogonal factors with an eigenvalue greater than one. These factors were then utilized to compose unit weighted neuropsychological summary scales reflecting the various cognitive domains described below (see Table 2 for factor loadings). The following eight factors are presented in the order in which they were generated from the factor analysis. 1. Verbal Reasoning (VBL REAS): The verbal reasoning summary scale score was calculated by averaging age-corrected scaled scores for the Vocabulary, Information, Similarities, Comprehension, and Arithmetic subtests of the Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler, 1981). These tests are designed to assess general verbal abilities. 2. Verbal Memory (VBL MEM): The Verbal memory summary scale score was constructed from indices of the California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober, 1983) including the total number of items recalled for all trial presentations, the number of correctly recalled items after a short delay and the number of correctly recalled items after a twenty minute delay. Additionally, the number of items correctly recalled on a recognition format with a correction for false positive errors, and the number of semantic clusters were included in this summary scale. 3. Processing Speed (PROC SPEED): This factor summary scale was calculated using the three scores from the Stroop Color-Word Interference test (Golden, 1978), as well as the Digit Symbol subtest of the WAIS-R. In the Stroop test, the subject must name colors and color words as quickly as possible. Following this, incongru-

TABLE 2 Factor Analytical Loadings for Composite Neuropsychological Summary Scales Factor 1: Verbal Reasoning

Vocabulary Information Similarities Comprehension Arithmetic

Factor 2: Verbal memory

.85 .83 .73 .72 .70

Factor 5: Visual Memory

ROCF Immediate ROCF Delay ROCF Copy

CVLT total Short Delay Long Delay Recognition Clusters

.88 .92 .92 .85 .80

Factor 6: Auditory Distract

84 83 65

ACT 3 ACT 18 ACT 9

.82 .78 .70

Factor 3: Processing Speed

Stroop Colors Stroop Words Interference Digit Symbols

.84 .83 .81 .61

Factor 7: Visual Scanning

Symbol cancel Letter cancel

.86 .82

Factor 4: Motor speed

CPT Vigilance RT Finger Tap Right CPT Distractibility RT Finger Tap Left CPT Simple RT

.84 .78 .74 .69 .69

Factor 8: Visual Distract

CPT Distractibility CPT Vigilance

.73 .71

Note. CVLT 5 California Verbal Learning Test; CPT 5 continuous performance test; RT 5 reaction time; ROCF 5 Rey-Osterreith Complex Figure; ACT 5 Auditory Consonant Trigrams Test.

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ent color-words are given and the subject must inhibit the attensive power of the reading stimuli and present a correct response indicating the color of the stimulus. Motor Speed (MOT SPEED): This summary scale included tests of reaction time from three conditions of the Continuous Performance Test (Gordon, 1986), as modified for adults (Saykin et al. 1995), as well as the Finger Tapping Test (Reitan & Wolfson, 1985). Three conditions of the CPT were utilized: Simple Reaction Time, in which the patient must respond to a target after a cue; Vigilance Reaction Time, in which the target stimulus is preceded by a particular number; and Distractibility Reaction Time, in which the patient must attend only to target stimuli in one portion of the display. Visual Memory (VIS MEM): This factor summary scale is composed of the three conditions of the Rey Osterrieth Complex Figure Test (Osterreith, 1944). This test involves the copying of a complex geometric figure followed by an immediate free recall drawing and a delayed recall after a 30-minute interval. Scoring was conducted using the Denman criteria (Denman, 1984) and converted to standard scores. Auditory Distractibility (AUD DIST): Three of the four conditions from the Auditory Consonant Trigram test (Peterson & Peterson, 1959) were utilized to construct this summary scale. These included the 3-second, 9-second, and 18-second interference conditions, all of which include a distractor component in which subjects must count backwards by threes between presentation of three consonants and free recall. Visual Scanning (SCANNING): This factor scale included the time to complete both the letter and symbol cancellation tasks (Mesulam, 1985). In these tasks, subjects must visually scan a page with random letters or symbols and cross out a target symbol, such as the letter A, as quickly as possible without missing any targets. Visual Distractibility (VIS DIST): Performance on the Vigilance and Distractibility conditions of the modified Gordon Continuous Performance Test (Gordon, 1986) were utilized to construct this factor summary scale. For all CPT conditions, the correct number of targets was calculated by subtracting the number of false positive errors from the total correct responses.

Other neuropsychological tests were included in the evaluation, but were not used for calculating neuropsychological summary scale scores as they did not load on any of the above factors. These include measures of language functioning (WRAT-3 Reading, Wilkinson, 1993; Controlled Oral Word Association Test, Benton & Hamsher, 1989; Sentence Comprehension from the Boston Diagnostic Aphasia Examination, Goodglass & Kaplan, 1983), other WAIS-R measures (Block Design, Digit Span, Picture Arrangement, Object Assembly, and Picture Completion), the number of targets achieved on the Simple Reaction time condition of the CPT, Trail Making Tests A and B, the zero second, no delay/no distractor condition of the ACT, and the number of intrusions, perseverations and items recalled on the distractor list from the CVLT. Additionally, measures of affective status, including the Beck Depression Inventory (BDI; Beck, 1987) and the State-Trait Anxiety Inventory (STAI; Spielberger, Montouri, & Luschene, 1970), were administered to all subjects. Finally, the Reading recognition subtest of the WRAT-3 and the Information, Vocabulary, Similarities, Comprehension, Picture Arrangement, Picture Completion, Object Assembly, Block Design were omitted from the follow-up assessment as performance on these tests is considered to be fairly stable over relatively short time periods. Self-reported measures of effectiveness of methylphenidate were provided by all patients upon follow-up neuropsychological testing. All patients were asked to estimate

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their degree of perceived change in ADHD symptomatology and overall global functioning (cognitive, emotional, social and occupational/academic) at follow-up neuropsychological testing. This outcome was coded on a 3-point scale incorporating reported functioning in occupational, social and academic domains. Patients who reported either an overall worsening or no change in ADHD symptoms or global functioning were coded as 0; patients who reported a mild improvement in ADHD symptoms or global functioning were coded as 1; and finally, patients who reported a significant improvement in ADHD symptoms or global functioning were coded as 2. In an effort to control for practice effects, alternate test forms were used at follow-up assessment whenever possible. For example, there are well established alternate forms of the CVLT, Trail Making Test, and verbal and semantic fluency. Additionally, the control group was retested at a yoked time interval to specifically assess the magnitude of practice effects; these could then be controlled for statistically, as necessary. Statistical Design and Analysis Statistical analyses were conducted using the SAS statistical package (SAS Institute, Inc., 1996). Univariate ANOVAs were used to test demographic and pre–post medication neuropsychological effects for ADHD and ADHD-D groups separately. MANOVA models were utilized to detect significant differences in neuropsychological profile level and shape among the ADHD, ADHD-D, and control groups at baseline, and for changes in performance following medication in a 3 3 8 mixed design with diagnosis as a between group factor and domain of functioning as a within subject factor. Omnibus MANOVA effects were then decomposed utilizing univariate ANOVA and Bonferroni corrected t tests.

RESULTS Baseline Neuropsychological Test Performance As intellectual functioning was significantly higher for the control versus the ADHD and ADHD-D groups, full scale IQ was used as a covariate for all baseline neuropsychological analyses. A MANCOVA utilizing subjects as a between groups factor (ADHD, ADHD-D, controls) and the various neuropsychological summary scales (verbal reasoning, visual memory, verbal memory, scanning, motor speed, processing speed, visual distractibility and auditory distractibility) as a within subject repeated factor yielded a significant between groups effect, F(2, 50) 5 5.59, p 5 .006, but a nonsignificant within subject profile shape effect, F(7, 44) 5 1.95, p 5 .08, and a nonsignificant interaction between diagnosis and neuropsychological summary scales, F(14, 88) 5 1.54, p 5 .22. Please see Figure 1 for neuropsychological profiles of the three groups. As the ADHD and ADHD-D profiles were not significantly different at baseline, the two patient groups were combined and analyzed using the same MANCOVA design. This yielded similar results, with a significant between groups effect, F(1, 51) 5 8.57, p 5 .005, a nonsignificant within subject profile shape effect, F(6, 46) 5 1.27, p 5 .29, and a nonsignificant interaction between diagnosis and neuropsychological summary scales, F(6, 46) 5 1.61, p 5 .17. Changes in Neuropsychological Test Performance A MANOVA using diagnostic group as the between group factor and change in neuropsychological summary score over time (posttest score minus baseline score) as a

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FIGURE 1. Performance on neuropsychological summary scales for ADHD, ADHD-D, and control subjects.

within group factor was conducted. The neuropsychological summary scale of verbal reasoning was omitted from this analysis as subjects did not receive all of the tests which comprise this factor at follow-up assessment. This analysis failed to yield a significant within subject effect of change in profile shape, F(6, 42) 5 1.51, p 5 .20, or an interaction of change in profile by diagnostic group, F(12, 84) 5 0.78, p 5 .67. However, a significant between groups effect was noted, F(2, 47) 5 4.75, p 5 .013. Please see Figure 2 for profile of neuropsychological change scores for all three groups. As there was no significant difference between change scores for both patient groups, the ADHD and ADHD-D patient groups were combined into one group and a second MANOVA was conducted on the combined patient group versus the control group. This yielded a similar pattern of results, with a significant between group effect, F(1, 48) 5 9.15, p 5 .004, a nonsignificant within subjects effect for change in profile shape, F(6, 43) 5 1.11, p 5 .37, and a nonsignificant interaction, F(6, 43) 5 1.27, p 5 .29. To assess the potential contribution of practice effects on neuropsychological change scores (from baseline to follow-up), a series of univariate analyses were conducted for each neuropsychological summary scale individually. No significant change score differences from zero were found on any factor over time for the control subjects, suggesting that practice effects were minimal and did not significantly influence these results. In contrast, both patient groups demonstrated significant improvements on neuropsychological summary scales of motor speed, processing speed, visual distractibility and auditory distractibility. The ADHD group also exhibited significant improvement on the visual memory scale, while the ADHD-D group demonstrated significant improvement on the verbal memory scale (please refer to Table 3 for actual means, F, and p values for neuropsychological summary scales).

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FIGURE 2. Changes in performance on neuropsychological summary scales for ADHD, ADHD-D, and control subjects following methylphenidate treatment.

An examination of the individual neuropsychological test scores from baseline to postmedication follow-up yielded numerous pre–post effects for each patient group. (Please refer to Table 4 for pre- and postmedication means and standard deviation of individual neuropsychological test scores for each group). In contrast to the significant improvement seen on numerous individual neuropsychological tests for both patient groups, the control group exhibited a significant improvement only on three neuropsychological tests (Rey Osterrieth Complex Figure Immediate and Delayed conditions, p , .02 and p , .002, respectively, and the Arithmetic subtest of the WAIS-R, p , .04). TABLE 3 Comparison of Baseline and Follow-up Composite Neuropsychological Summary Scores for All Subject Groups ADHD Without Depression Composite Summary Scores

Visual Memory Verbal memory Scanning Motor speed Processing speed Visual Distractibility Auditory Distractibility

ADHD With Depression

Controls

F

p

F

p

F

p

11.00 2.50 0.71 6.77 22.18 4.89 19.18

.004* .13 .41 .02* .0002* .04* .0004*

1.38 4.96 3.48 8.91 11.66 7.81 9.26

.26 .04* .08 .009* .004* .01* .008*

4.37 0.35 0.65 0.07 0.57 1.68 0.00

.06 .56 .43 .80 .46 .22 1.00

Note. ADHD 5 attention deficity hyperactivity disorder. *p # .05

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TABLE 4 Mean (and Standard Deviation) Comparison of Individual Neuropsychological Scores for the ADHD, ADHD-D, and Healthy Control Groups ADHD (N 5 19)

ADHD-D (N 5 17)

Controls (N 5 15)

Baseline Scores

Posttreatment Scores

Baseline Scores

Posttreatment Scores

Baseline Scores

Follow-up Testing

8.96 (2.01) 11.21 (3.10) 9.79 (2.18)

10.26 (2.28) 10.94 (2.84) 11.53 (2.09)

9.29 (3.16) 10.47 (3.73) 9.53 (2.29)

9.59 (3.10) 10.76 (3.68) 11.00 (2.18)

11.27 (3.20) 12.13 (1.81) 13.12 (2.80)

11.67 (2.69) 13.20 (2.21) 13.07 (3.53)

11.44 (0.86)

11.73 (0.59)

10.69 (1.40)

10.82 (1.42)

11.73 (0.46)

11.67 (0.49)

36.5 (8.23) 55.74 (7.45)

40.44 (8.11) 54.47 (7.75)

35.53 (11.43) 53.70 (10.92)

39.12 (11.44) 54.88 (12.67)

49.00 (10.12) 59.07 (9.77)

CVLT, Short Delay CVLT, Long Delay CVLT, Recognition ROCF Copy ROCF Immediate ROCF Delay Trail Making, Part A

10.68 (2.65) 10.95 (2.97) 13.32 (2.36) 9.78 (3.59) 11.06 (2.26) 10.11 (2.61) 28.79 (8.46)

11.89 (2.49) 12.26 (2.33) 14.42 (1.46) 10.17 (2.31) 12.50 (2.64) 12.22 (2.58) 23.84 (6.65)

11.00 (3.53) 11.35 (3.26) 13.47 (2.45) 9.35 (3.52) 8.53 (4.46) 7.35 (4.51) 30.35 (12.60)

12.59 (3.02) 13.06 (3.13) 14.82 (1.59) 8.53 (3.95) 9.47 (3.64) 9.41 (3.55) 24.65 (10.02)

Trail Making, Part B

71.32 (19.06)

55.74 (14.15)

70.88 (21.62)

77.76 (30.07)

Test

WAIS-R Digit Span WAIS-R Arithmetic WAIS-R Digit Symbol Sentence Comprehension Phonemic Fluency CVLT, Total 1–5

Finger Tapping, RH 45.00 (8.1) 46.03 (5.97) Finger Tapping, LH 42.59 (6.24) 44.43 (5.12) Letter Cancellation 123.39 (55.32) 113.61 (41.04) Time Symbol Cancellation 81.89 (39.44) 81.50 (35.95) Time ACT 0 Percent 98.95 (2.5) 99.65 (1.53) Correct ACT 3 Percent 77.89 (14.41) 86.32 (12.86) Correct ACT 9 Percent 59.30 (22.43) 75.09 (20.94) Correct ACT 18 Percent 49.47 (25.75) 64.56 (26.2) Correct CPT Simple Correct 28.89 (1.52) 28.74 (1.73) CPT Simple RT 352.26 336.58 (97.62) (122.54) CPT Vigilance 25.59 (7.18) 28.79 (1.96) Correct CPT Vigilance RT 432.37 387.74 (90.43) (149.97) CPT Distractibility 18.84 (9.49) 26.32 (8.00) CPT Distractibility 474.22 386.42 (57.16) RT (126.56) Stroop Word 89.42 (13.31) 94.00 (14.58) Naming Stroop Color 65.42 (11.73) 72.05 (11.11) Naming Stroop Interference 36.32 (10.02) 43.10 (9.18)

44.00 (7.31) 48.25 (6.95) 40.96 (6.87) 44.58 (6.72) 130.18 (29.85) 120.8 8(37.26) 86.76 (20.46) 100.00 (0.0) 69.41 (23.34)

74.70 (16.54) 99.22 (3.23) 78.43 (20.62)

44.60 (9.83) 59.40 (11.67) 12.33 (2.50) 12.40 (3.64) 12.27 (2.81) 13.47 (3.20) 15.40 (1.24) 15.57 (0.83) 10.93 (1.67) 10.27 (3.03) 8.80 (3.14) 10.53 (3.58) 8.20 (3.21) 10.33 (3.20) 23.13 (8.77) 21.87 (10.06) 49.87 (19.73) 55.67 (17.90) 49.38 (6.62) 48.04 (4.73) 46.51 (5.27) 45.25 (4.79) 85.80 (23.96) 99.47 (61.12) 66.07 (20.54) 67.07 (37.41) 100.00 (0.0) 99.11 (3.44) 88.89 (10.29)

81.78 (17.54) 53.72 (21.53) 68.63 (22.70) 73.33 (19.02) 74.67 (18.89) 43.53 (28.78) 60.00 (26.77) 51.56 (23.97) 59.11 (27.47) 27.41 (3.71) 29.29 (0.92) 29.60 (0.63) 29.27 (1.43) 373.53 350.35 (72.82) 332.07 321.73 (109.16) (114.09) (68.59) 24.88 (7.17) 28.35 (3.48) 29.60 (1.55) 29.67 (0.62) 436.41 (98.11) 399.12 (52.48) 404.80 393.53 (112.47) (106.51) 15.56 (10.61) 26.12 (5.71) 26.67 (6.56) 27.80 (3.12) 517.06 431.76 (82.03) 421.60 387.47 (103.49) (109.54) (61.15) 87.18 (17.95) 97.18 (17.54) 105.53 (17.76) 108.53 (18.92) 62.29 (15.39) 69.12 (12.28) 79.27 (15.19) 81.00 (14.27) 33.88 (11.77) 41.41 (7.34) 49.00 (17.88) 49.20 (14.89)

Note. ADHD 5 attention deficit hyperactivity disorder; ADHD-D 5 attention deficit hyperactivity disorder with depression; WAIS-R 5 Wechsler Adult Intelligence Scale-Revised; CVLT 5 California Verbal Learning Test; ROCF 5 Rey-Osterreith Complex Figure; RH 5 right hand; LH 5 left hand; CPT 5 continuous performance test; RT 5 reaction time.

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Affective Status By design, there were significant differences on self-report measures of affective status between the three groups at baseline. An ANOVA on BDI scores for the three groups yielded a significant between groups effect, F(2, 51) 5 18.61, p 5 .0001. A similar effect was seen for the State Trait Anxiety Inventory (STAI) for measures of both state, F(2, 51) 5 6.41, p 5 .004, and trait anxiety, F(2, 51) 5 11.86, p 5 .0001. Specifically, the ADHD-D group endorsed more symptoms of depression than the other two groups, and more symptoms of state and trait anxiety than control subjects. ADHD only patients also endorsed more trait anxiety than control subjects. Change in affective status (from baseline to follow-up) was also analyzed using separate ANOVAs for each subject group in a repeated measures design. Significant differences were seen for both ADHD and ADHD-D patient groups on the BDI and STAI trait anxiety scale, with both patient groups endorsing fewer symptoms of depression and anxiety on follow-up testing. Additionally, the ADHD only group endorsed significantly fewer symptoms of STAI state anxiety on follow-up. No significant differences from baseline to follow-up were noted for control subjects on any affective measures. Despite their reported improvement in affective status, the ADHD-D group continued to endorse more symptoms of depression than control subjects, and more trait anxiety than both the control subjects and ADHD patients at follow-up. (Please see Table 5 for group means, standard deviations, F, and p values for all three groups). Self-Report Outcome Measures Eighteen of the 36 patients (50%) reported significant improvement in ADHD symptoms, 15 patients (42%) reported mild improvement and three patients (8%) reported no noticeable change in ADHD. There was no significant difference in self-reported outcome by patient group, with ADHD-D patients reporting similar outcomes to the ADHD patients (x2 5 0.825, p 5 .662). All patients, regardless of their prior grouping, were then divided into two groups based on their self-report of improvement in ADHD symptoms. The first group was composed of the patients who reported either no change or mild improvement in ADHD symptoms (n 5 18), whereas the second group was composed of patients who reported significant improvement in ADHD symptoms (n 5 18). A MANOVA using outcome as the between groups factor and change in various neuropsychological summary scales as the within group factor yielded a significant between TABLE 5 Comparison of Affective Status for All Subjects at Baseline and Follow-Up Assessment

ADHD without depression

ADHD with depression

Controls

Test

Baseline Scores

Follow-Up Scores

F

p

Beck Depression Inventory State Anxiety Trait Anxiety Beck Depression Inventory State Anxiety Trait Anxiety Beck Depression Inventory State Anxiety Trait Anxiety

5.67 (2.72) 43.44 (8.66) 42.06 (8.24) 14.00 (7.46) 47.35 (14.27) 47.76 (11.32) 3.13 (2.56) 33.87 (9.85) 32.07 (8.57)

3.22 (2.92) 37.78 (8.74) 31.78 (7.95) 6.24 (4.71) 40.59 (10.66) 40.70 (9.62) 2.93 (2.94) 34.01 (10.15) 31.67 (8.02)

9.31 4.31 33.06 16.82 3.92 5.44 0.07 0.02 0.06

0.007* 0.05* 0.001* 0.0008* 0.06 0.033* 0.79 0.90 0.81

Note. ADHD 5 attention deficit hyperactivity disorder. *p # .05

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groups effect, F(1, 33) 5 6.53, p 5 .02, with subjects reporting improved outcome demonstrating more cognitive improvement, but no significant within subject effect for neuropsychological function, F(6, 28) 5 1.63, p 5 .18, or function by group interaction, F(6, 28) 5 1.47, p 5 .23. There was no significant correlation between outcome measures for patient groups (either separately or combined) and BDI scores at baseline or at followup. Additionally, there was no significant correlation between outcome and measures of state or trait anxiety.

DISCUSSION These results are consistent with the notion that adults with ADHD have a distinct neuropsychological profile before medication which approximates that seen in children with this disorder (Biederman et al., 1993). This profile is marked by relatively intact verbal reasoning and visual memory, but impaired performance on measures of verbal memory, motor and processing speed, visual scanning, and auditory and visual distractibility. The patient group with active comorbid depressive symptoms (ADHD-D) exhibited a strikingly similar neuropsychological profile to the ADHD only group. There was some evidence to suggest that the ADHD-D group exhibited more impairment across all neuropsychological measures, suggesting additive neuropsychological dysfunction in patients who have ADHD and active comorbid depressive symptoms. Although the patient groups performed significantly more poorly than comparison adults, the differences were not very large, lending support to Biederman et al.’s (1993) findings related to the magnitude of impairment in this patient population. Following treatment, both patient groups exhibited increases on numerous neuropsychological measures. It is interesting to note that the ADHD-D group had relatively poorer performance at baseline and exhibited a relatively greater improvement following treatment. In comparison, the neuropsychological test performance for the control subjects remained relatively stable over time, suggesting that practice effects did not significantly contribute to the improvement seen in either patient group. Change in neuropsychological functioning was relatively unaffected by gender. In fact, the only significant difference for male versus female patients on change in neuropsychological performance was seen for the ADHD-D group on a measure of visual distractibility, with males exhibiting significantly more improvement (2.6 SD) than female (0.4 SD) patients (t 5 2.33, p , .05). This gender effect was not seen on any other neuropsychological or affective change measure. Neuropsychological differences at baseline and following treatment were also not associated with the referral status of patients (i.e., whether patients were self-referred or referred by another caregiver). It has been suggested that clinically referred patients with ADHD are more likely to be ill and to seek treatment from other professionals. In our sample, 65% of the patients were selfreferred to the Adult ADHD clinic, and 35% were referred from another caregiver, usually a physician or psychologist. MANOVA analyses failed to reveal any significant differences between nonreferred and referred patients on either baseline neuropsychological and affective measures, or between the two groups on changes in neuropsychological and affective functioning following methylphenidate intervention. This lends support to Biederman et al. (1993) who reported that referred and nonreferred adults with ADHD were similar to one another on cognitive and psychological measures, but more impaired than subjects without ADHD. Although a large improvement was seen for both patient groups on measures of visual distractibility, there were no significant profile shape differences between patients

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and controls (i.e., improvement in cognitive functioning was not specific to any individual functional domain). This is consistent with Matochik et al. (1993) who reported that acute treatment of adult ADHD with methylphenidate or dextroamphetamine produce changes in behavior and in regional glucose metabolism that were not specific to any single region. Rather, stimulants may act by a widespread pattern of increases and decreases in metabolism, and therefore may improve a variety of cognitive functions, as seen here. In an effort to characterize the effects of methylphenidate on self-reported measures of affective distress and its role in cognitive change, an examination of mood was performed before and after treatment. As expected, at baseline the ADHD-D group endorsed more symptoms of depression than the other two groups, and more symptoms of state and trait anxiety than control subjects. Following treatment, both patient groups endorsed less affective distress and more specifically, the ADHD-D group’s score on the BDI was clinically within normal limits (but significantly higher than control subjects’ scores). It is important to note that improvement in depressive symptoms for all patients correlated with change on only two neuropsychological summary scales: visual scanning (r 5 .35, p 5 .04) and motor speed (r 5 .36, p 5 .04), suggesting that change in mood was generally unrelated to change in higher cognitive processing. The positive correlations between depression and motor speed and visual scanning is not unexpected, as both of these summary scales are comprised of timed tests, and depression is known to result in psychomotor slowing. Further, there was no significant correlation between depression and a self-reported measure of outcome. The majority of patients (92%) reported improved cognitive and social functioning following methylphenidate treatment. This is higher than previous reports, which have indicated improvement in 25 to 78% of subjects (Gualtieri et al., 1985; Mattes et al., 1984; Spencer et al., 1995; Wender et al., 1985; Wood et al., 1976). This discrepancy may be due to the nature of our outcome assessment measure, which was simply a general subjective rating regarding response to medication. There was no significant difference between the two patient groups on self-report measures of outcome, suggesting that both groups subjectively benefited equally from methylphenidate treatment. Many patients who reported significant improvement actually exhibited significant objective increases on a number of neuropsychological domains, such as verbal and visual memory, processing speed, and visual distractibility, suggesting that patients are able to accurately assess the effects of medication on their cognitive functioning. As collateral information is often not available in adult patients with ADHD, accuracy of self-assessment is an important issue in both diagnosis and in assessing the efficacy of treatment. These results confirm Spencer et al.’s (1995) assumption that adult ADHD subjects can provide accurate information with regard to their current symptomatology and changes following treatment. Some authors have questioned whether adult ADHD is a valid diagnostic entity, and it has been suggested that this disorder may reflect a special case of atypical depression or the prodrome of another psychiatric disorder (Biederman et al., 1993). The striking similarities between the neuropsychological profiles of this adult sample before and after medication to that of children with ADHD (Biederman et al., 1993) lend support to the validity of this disorder in adults. Questions have also been raised as to whether adult ADHD with and without comorbid psychiatric disorder (such as depression) should be classified as two discrete disorders or as different manifestations of the same disorder. Active depressive symptoms are commonly thought to conceal or significantly distort ADHD symptoms, making it difficult to accurately diagnose adult ADHD. The similarities of neuropsychological profiles, and objective and subjective response to treatment for both ADHD patients groups support the inclusion of the two sets of symp-

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toms under one diagnostic entity. Thus, ADHD does not appear to be simply an artifact of symptoms shared with common comorbid disorders (such as depression), nor are these comorbid disorders themselves an artifact of overlapping symptoms of ADHD. Adult ADHD patients with active comorbid symptoms of depression appear equally likely to benefit from methylphenidate intervention for their ADHD as patients who do not have active symptoms of depression. Although many clinicians choose the pharmacologic treatment of comorbid symptoms of depression before or after an initial trial of methylphenidate or another psychostimulant, this study suggests that the decision to initiate supplemental treatment with an antidepressant medication should be made after an extended assessment (e.g., 1 to 3 months) of the effects on mood of the psychostimulant alone. In some cases, if the comorbid depression is of sufficient clinical concern, a trial of one of the antidepressants having demonstrated efficacy in the treatment of adult ADHD (e.g., desipramine or buproprion) might be employed in lieu of the psychostimulant or possibly in combination (Barrickman et al., 1995; Wilens, Biederman, Mick, & Spencer, 1995; Wilens et al., 1996). In our paradigm, we use methylphenidate as the initial “standard” intervention medication as part of the initial assessment of medication effect. If a patient shows clear signs of improvement as determined by neuropsychological testing, self-report, and in some cases the report of family or friends, a decision is made to continue the methylphenidate or switch to some other medication. Little data is available regarding preliminary treatment of these patients with antidepressant medication followed by psychostimulant supplement. Patient profile treatment order matching warrants future investigation. There are several factors that limit the generalizability of these results to the larger population of patients with adult ADHD. First, and most importantly, it was impossible to implement a double blind placebo cross over design to reliably and accurately assess the role of methylphenidate in this patient sample as these patients were clinically referred for evaluation from the Adult ADHD Clinic. The results were also based on a relatively small sample size and both the patient and control groups were relatively highly educated. Although these factors limit the generalizability of our results, other measures were taken to help validate our findings. For example, multiple diagnostic criteria were also utilized by independent raters to ensure diagnostic reliability of this sample. Further, an effort was made to assess practice effects by including a group of normal controls (who were similar in terms of age, education and gender) that were tested at a yoked time interval to the patient groups. In the current study, only seven patients (3 ADHD, 4 ADHD-D) had a prior diagnosis and treatment of ADHD as children. However, previous studies (Biederman et al., 1993, 1990) have demonstrated similar patterns of epidemiological characteristics in retrospectively diagnosed adults to those followed prospectively from childhood, suggesting that a reliable diagnosis can be made without clear childhood evidence. A related problem in studies such as this one is the reliance on self-report measures for diagnosis. Unlike children with ADHD, it is often not possible to obtain collateral evidence of ADHD symptomatology in adults. Practically, it is often not possible to interview spouses, co-workers or parents, resulting in a need to rely primarily on self-report measures by patients who may have a bias in recalling events (especially for symptoms before the age of seven). However, Spencer, Biederman, Wilens, and Faraone (1994) reported that a reliable diagnosis can be made by interview which is not significantly affected by recall bias. Both patient groups rated their response to medication as successful, consistent with the objective results of neuropsychological measures; that is, there was a significant difference between those patients who reported no or mild improvement versus those who reported substantial improvement.

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Currently, there is very little data on the differential response of medication in comorbid ADHD, and on the effects of combined pharmacotherapy or combined pharmacotherapy and psychotherapy (Spencer et al., 1995). In the present study, measures of self-report of treatment outcome were limited to the assessment of changes following medication alone. It is possible that some of the patients also followed advice from popular texts on treatment of ADHD. It will be important to include nonmedication treatment (such as group or individual therapy, etc.) as well for comparison purposes in future studies. The focus of this study was on measuring change in neuropsychological and affective functioning only. It will be equally important to establish accurate measures of change in family, social (i.e., social skills), and occupational functioning, as well as gather data on frequency and intensity of ADHD symptoms, to assess the effectiveness of medication intervention in this population. Future studies should attempt to identify biological mechanisms that may help differentiate different subtypes of ADHD (based on severity of symptoms and DSM-IV criteria) as well as medication responders from nonresponders. For example, Filipek et al. (1997) reported that morphometric MRI measures could help predict responders to psychostimulants. In addition to cerebral structural variables, functional cerebral measures should also be investigated in an attempt to elucidate the underlying pathophysiological mechanisms involved in the development and persistence of ADHD symptoms, the mechanisms of drug action, and their relationship of these variables to treatment response. Emphasis should be placed on how descriptive variables such as neuropsychological and morphological measures can be used in the development of new approaches to the etiology, classification and treatment of this disorder.

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