Adult ADHD Controlled Medication Assessment

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Adult ADHDControlled Medication Assessment

MARCEL KINSBOURNE,a GUILLERMO B. DE QUIROS,bAND DOLORES TOCCI RUFOc

aNew School University, New York, New York 10003, USAbCEMIC, Buenos Aires, ArgentinacJackson School, Newton, Massachusetts, USA

ABSTRACT: Now is the time for all good men to come to the aid of the party.Now is the time for all good men to come to the aid of the party. Now is the timefor all good men to come to the aid of the party. Now is the time for all goodmen to come to the aid of the party. Now is the time for all good men to cometo the aid of the party. Now is the time for all good men to come to the aid ofthe party. Now is the time for all good men to come to the aid of the party. Nowis the time for all good men to come to the aid of the party. Now is the time forall good men to come to the aid of the party. Now is the time for all good mento come to the aid of the party. Now is the time for all good men to come to theaid of the party. Now is the time for all good men to come to the aid of the party.Now is the time for all good men to come to the aid of the party. Now is the timefor all good men to come to the aid of the party.

KEYWORDS: ADHD; etc.; etc.; etc.; etc.; etc.; etc.;

INTRODUCTION

In a companion article, we discuss the contribution of self-ratings to the diagnosisof adult ADHD.1 But diagnosing ADHD in adults would be of little use if no treat-ment recommendation results. Even more than in childhood, stimulant therapy isconsidered by far the most effective treatment modality in most adult cases. Indeed,there is a lack of controlled studies that support any non-medication treatment inadults,2 except as adjunct to the pharmacotherapy.

Studies of the response to methylphenidate therapy in adults all report significantsuccess, but in proportions of the samples that vary between 25% and 78%. Reasonsfor the extreme variability in reported outcome may include diverse diagnostic cri-teria, inadequate exploration of the dosage within the therapeutic range and ineffec-tive self-administered outcome measures (discussed in ref. 1). An open study of theeffects of Adderall, a mixture of l- and d-amphetamine showed benefit for 13 of 24adults with ADHD.3 While stimulant therapy is almost always well tolerated byadults, second-line drugs are available if stimulants are rejected by or contraindicat-ed in an individual patient. One such agent is desipramine. At an average daily dos-

Address for correspondence: Marcel Kinsbourne, M.D., New School University, 65 Fifth Ave-nue, New York, NY 10003, USA.

[email protected] or [email protected]

ADD10(kin).fm Friday, April 27, 2001 5:25 PM

2 ANNALS NEW YORK ACADEMY OF SCIENCES

age of 150 mg, Wilens and colleagues4 documented a 68% response. Bupropion atan average level of 360 mg. yielded a 74% response in an open study by Wender andReimherr.5 Ernst6 reported benefit from monoamine oxidase inhibitors. Effexor hasalso shown moderate benefit in open studies,7 and propanalol may be useful for tem-per outbursts associated with ADHD.8 Stimulants remain the drugs of choice forcore ADHD symptoms. Cormorbid psychiatric conditions often seen in adults areconcurrently, but independently, also addressed.9

The optimal stimulant drug dose level for ADHD varies widely between individ-uals, and there are no known external variables that accurately predict the optimaldose in a given patient. In particular, age, gender, height and weight have no predic-tive value, and there is no rationale for a mg/kg formulation.10,11 It is therefore nec-essary to compare the effect of several dose levels on each patient. This is usuallyaccomplished by a time-consuming procedure of prescribing different doses, andtracking the patient’s progress on each by means of various questionnaires. A con-trolled medication assessment streamlines this process, minimizes the time that a pa-tient spends on what turns out to be an ineffective or an excessive dose, is notvulnerable to placebo effects, and offers data which are quantitative and objective re-flections of performance, rather than impressionistic ratings of behavior.

CONTROLLED MEDICATION ASSESSMENT

Consistent with the continuity of ADHD throughout the life span, clinical expe-rience indicates that, as in children and in adolescents, stimulant therapy is effectivein adults with ADHD. This knowledge is accumulated from open and controlledfield trials,12 as well as clinical experience. Spencer and colleagues13 reported thatas many as 87% of their adult cohort responded favorably to stimulant therapy, asopposed to only a 13% response to placebo, based on rating scale scores. But theredo not appear to be any research publications on the results of controlled behaviorallaboratory testing in ADHD adults.

Clinical descriptions of ADHD emphasize maladaptive behavior but focus less onthe cognitive consequences of ADHD. Yet it is very often underachievement in theclassroom that induces families to bring children to evaluation. Underachievementin ADHD has multiple potential sources, of which the frequently comorbid opposi-tional/defiant behavior is an obvious instance. But ADHD complicates learning evenfor compliant children, and improved learning is a desired outcome for stimulanttherapy. Sprague and Sleator14 questioned whether the dose of MPD that is mostbeneficial for control of behavior is also the best for most efficient learning. Theysuggested that doses that benefit classroom conduct tend to be too high for optimallearning. Their experimental design did not in fact permit this conclusion, in that thetimes at which learning and behavior were assessed were quite different and did nottap comparable periods during the short (four hour) time frame of efficacy of themedication. There has been no experimental confirmation of their claim, but it raisesa valid issue. It could be tempting to treat children whose behavior is troublesomewith relatively high doses, and thereby induce social withdrawal as a side effect. Thiswould certainly contain acting-out behavior, but would be detrimental for the child’smental functioning, and particularly for learning (so-called cognitive toxicity). The


3KINSBOURNE et al.: ADULT ADHD—MEDICATION ASSESSMENT

upshot is that the most desirable measure for determining the optimal level of stim-ulant therapy would be cognitive rather than behavioral. Controlled medication as-sessments can provide such measures. They also have the advantage of being free ofplacebo effects, in contrast to behavior ratings, which are much affected by the ob-server’s expectation and therefore by placebo. In addition, they save time. The par-adigm for medication assessment that we introduced15 uses a single administrationfor each level of the medication, and thus can be completed in three or four days. Incontrast, the customary titration procedure takes a number of weeks, and the risk ofthe patient discontinuing treatment is proportionately great. If the clinician titratestoo rapidly, patients may discontinue on account of side effects. If the clinician ti-trates too slowly, patients may discontinue because they have been taking a subther-apeutic dose for longer than they can tolerate. The medication assessment is likelyto zero in either on the clinically most effective dose, or a dose close to optimal.

A variety of dependent variables is used in medication assessments; memoryscanning, response inhibition, continuous performance tests (CPTs) are used, withthe latter being the most prevalent. CPTs challenge sustained attention in the face ofmonotony and boredom. They yield linear dose-response curves that lead to theadoption of higher doses than those may that serve the child best in the classroom.16

We have observed that children with ADHD are particularly handicapped on effort-ful tasks, and have found a task of effortful learning to be more useful clinically.Whereas even attentionally normal children may show some improvement on effort-less tasks such as CPTs when administered a stimulant drug,17 effortful new learningis actually impaired rather than assisted in normal people when they take a stimulantdrug.18 paired-associate learning is highly correlated with children’s I.Q. and aca-demic achievement.19 Conners et al.20 were the first to report that paired-associatelearning is deficient in ADHD and is enhanced by stimulant therapy. In addition toourselves in numerous publications, other investigators21–23 have documented thedifficulties that ADHD children experience on paired-associate learning, and thesensitivity of this procedure to the level of stimulant medication. The dose-responsecurve on paired-associate learning is U-shaped, not linear, defining an optimal dosethat is often quite low and generally conservative as compared to dose levels that arebased on the result of behavioral rather than cognitive dependent variables.24

We have used various formats of paired-associate learning in order to arrive at anestimate of an optimal dose that assures that the patient’s mental processes are ad-vantaged and not inhibited by the treatment regime. We regard our medication as-sessment as a safeguard against treating prospectively adverse responders with MPHand treating potentially favorable responders with excessively high doses, to whichthey respond adversely. This approach has not, until now, been applied to the adultADHD population.

We now supplement the rating scale literature with the results of the controlledmedication assessment of 17 patients with adult ADHD. The test procedure is onethat we have used extensively in ADHD children aged 5 and upward, on and off med-ication (as well as unmedicated control children) and have reported in numerouspublications. It consists of a learning test (paired-associates) which is presented inalternate forms in a controlled fashion at several levels of a medication (in this case,methylphenidate at levels 0 (placebo), 5, 10, and 20 mg.) Each patient is studied dou-ble blind as a single subject experiment.



METHODS

Subjects

Seventeen adult patients, seven male, 10 female, with a mean age of 34 years(S.D. 10), were selected from a pool of consecutive adult clinic referrals, based onthe following criteria: (1) had a history of symptoms that meet DSM-IV criteria forADHD (at least six of nine inattentive and/or hyperactive/impulsive symptoms); (2)met full DSM-IV criteria for ADHD in childhood, in retrospect; (3) have no otherpsychiatric disorder that would explain why they have symptoms such as those thatcharacterize ADHD; and (4) gave informed consent to controlled medication testing.None of them had previously been diagnosed with ADHD, and none were currentlytaking psychoactive drugs. (The incidence of comorbid psychiatric disorders in ourpediatric neurology population is far lower than that which is typically reported bypsychiatric facilities.)

Continuous Paired-Associate Learning Test (CPALT)

The CPALT is a paired-associate learning task that uses consonant pairs as stim-ulus terms (S) and digits (0–9) as response terms (R). Swanson and Kinsbourne,15

Dalby et al.,25 Swanson et al.,26 Conte and Kinsbourne,27 Dalby et al.,28 Kins-bourne,29 and deQuiros et al.10 have reported findings with ADHD children usingearlier versions of this test. It is presented on an Apple-Macintosh microcomputer.At each session, the computer randomly generates the pairing of stimulus and re-sponse, and the sequence in which the pairs are presented. The subject is instructedto memorize the digit (R) associated with each pair of consonants (S). The task be-gins with the presentation of an S-R pair for study for 8 seconds, followed by a testsequence in which only the stimulus term is presented. The subject is allowed 5 sec-onds to key in the corresponding response term. If the response is correct, the S-Rpair is presented again simultaneously with a “YES”. Then a new S-R pair is pre-sented for study and added to the S-R pool. This sequence continues until an error ismade. If the response was incorrect or not forthcoming in the allotted time, the cor-rect answer is displayed. The earliest presented pair is then dropped from the activeS-R string and the subject is immediately tested on the remaining pairs. If two errorsare made, the two earliest presented pairs are dropped, and so forth. Although thepresentations are uninterrupted, this test format permits the subdivision of the totalblock of trials into a set of comparable epochs for subsequent scoring. The test con-tinues for 30 minutes. It is arbitrarily subdivided into 10 epochs, each of which lasts3 minutes.

SUBJECTS

There were 17 participants, eight men and seven women, mean age 34 years (SD10). All met DSM IV criteria for the diagnosis of ADHD, and none met criteria forany comorbid psychopathology. None of the subjects were taking any psychoactivedrugs. The purpose of the controlled medication trials was clinical, that is, to ascer-



tain a level of optimal learning performance, free of significant adverse side effects,as a guide to an appropriate starting dose for MPH therapy.

PROCEDURE

An acute double-blind drug-placebo crossover design was used to determine theADHD adult’s response to MPH. Each level of medication is represented by a singledose; a procedure that has previously been validated.15,26 Following a practice ses-sion to familiarize the patient with the computer task, the evaluation consisted offour sessions. Beginning at 9:00 A.M. on each day of assessment, the patient was test-ed at time zero (baseline condition) and at two hours (test condition) after adminis-tration of placebo and three levels of MPH (5, 10, and 20 mgs) in a randomizedsequence, counterbalanced across subjects. Both medication and placebo were en-closed in opaque gelatin capsules to mask their taste and appearance. The gelatindoes not dissolve until it comes into contact with the acid stomach contents. The sub-ject and the experimenter were both blind to the level of medication at each session.

Each testing session lasted 30 minutes. The computer generates independent S-Rsequences for each session to control for practice effects. Performance was measuredas (1) number of correct responses across all 10 epochs, (2) variability over time—the variance across epochs divided by the mean, which is the coefficient of variation(CV). Based on their performance (number of correct responses across conditions),subjects were classified as favorable responders or as non- or adverse-responders.The favorable responders were further classified with respect to the level of medica-tion that elicited their best (“optimal”) performance.

RESULTS

Seventeen ADHD subjects were tested on the CPALT, and their performance onplacebo, 5, 10, and 20 mg was compared by repeated measures ANOVA. Groupmean performances and variabilities on the four levels of medication are presentedin TABLE 1. Both the number of correct responses, F (3, 48) = 2.92, p < .05, and thecoefficient of variation, F (3, 48) = 3.24, p < .05, differed significantly between pla-cebo and the three levels of medication.

Favorable response was defined as performance on one of the drug conditions25% or more above that on placebo. Adverse response was 25% below placebo. Out-comes between those extremes were recorded as non-response. Of the 17 subjects, 2(12%) were non-responders. Their best performance was on placebo. Of the 88% fa-vorable responders, 7 (41%) performed optimally at 5 mg, 2 (12%) at 10 mg and 6(35%) at 20 mg. The seven patients who responded best on 5 mg did so both in termsof mean performance and of coefficient of variation, and all but one generated in-verted U-shaped curves peaking at 5 mg across the four conditions, for both vari-ables. One met the criterion for adverse response both on 10 and 20 mg, and one metthat criterion on 20 mg only (again both for mean and CV).



DISCUSSION

The results in adults have much in common with results that we have repeatedlyobtained in children on paired-associate learning. Group performance on all threelevels of medication was significantly superior to that on placebo, and the perfor-mance was significantly less variable on all three levels of methylphenidate than onplacebo. It becomes clear that the problem of adults, though usually framed in be-havioral terms, has a reliable detrimental influence on learning, at least when thetask is effortful, monotonous, and protracted in duration, as it was intentionally de-signed to be in the case of the CPALT. In spite of the findings of Weiss andHechtman30 of far lower academic attainments by ADHD subjects followed fromchildhood than control subjects, the literature on adult ADHD is sharply biased to-ward the more psychiatric aspects of the disorder, and learning difficulties are un-derstated. In terms of the categories of attention nominated by Sohlberg andMateer,31 adult ADHD subjects fall short on focused attention (initial performance)as well as sustained attention (variability). However, their classification does nothighlight the effortful-effortless distinction, which our experience teaches us is im-portant in ADHD. Although rather effortless continuous performance testing (CPT)is customary; it is effortful learning that has consistently given us the most distinc-tive differentiation between levels of MPH. The importance of difficulty in learningis not well recognized in the adult ADHD literature.

Though adults perform better than children do in an absolute sense, the CPALTis so designed as not to be subject to the limitation of ceiling effects. The better thesubject remembers the associates, the more new pairs are presented. The list is short-ened instead to the extent that the subject makes mistakes. Furthermore, the blindwas effective in adults as it is in children. The patients were unaware of the medica-tion condition while performing; though sometimes they could infer it retrospective-ly from how well they had done on the learning test. Like the children, the adultpatients did not experience subjective markers of the presence or dosage of thedrug.32

Spencer et al.13 also reported a high proportion of favorable responders. Compar-ing the dose-response function that we obtained with the adults to that which we ob-tained with similar methodology on ADHD children (e.g., deQuiros et al.10 Swansonet al.26) we find a difference that had been foreshadowed in our clinical practice. Inthe children, 20 mg was more often the optimal dose than 10 mg, and 5 mg was rarelysufficient. Among the adults in this study, 5 mg was most often the optimal level, andin a number of patients, the higher doses were not as effective (though mostly stillsuperior to placebo). Swanson and Kinsbourne15 pointed out that the optimal doseof methylphenidate is not a function of age or body weight, and a measure in termsof absolute amount (mg) is preferable to a measure per unit weight (mg per kg). Thewide disparity between individuals in the dose that yields optimal performance maybe due to corresponding differences in bioavailability, (i.e., ratio of blood level to in-gested dose) as demonstrated by Chan et al.33 If so, this factor appears to be compa-rably relevant in adults with ADHD. We see that older, taller, and heavier individualsoften actually do better on lower doses than much younger children do.

The optimal dose level varies from individual to individual. Too high a dose con-fers less benefit on learning than the individually established correct dose. So when



a dose lower than 20 mg is optimal, that advantage does not necessarily carry overto the higher doses. In children, the performance dose-response curve often takes aquadratic, inverted U, form (Swanson et al.,26 Peeke et al.,34 Rapport et al.,23 Dou-glas et al.35). The present work is the first published demonstration of the U-shapedMPH dose-response function in adults with ADHD. Supraoptimal doses yield de-clining performance; in two of our cases the decline was so sharp that an adverse re-sponse was actually recorded at the 20 mg. level. Had these patients been given thehigher dose only, they would have been classified as adverse responders. Not onlytoo low, but also too high a dose of MPH generates a poor learner. Information froma previous treating physician that MPH did not work, or caused an adverse response,is uninterpretable unless the dose(s) used are known. If the dose that was previouslyused is not known, then the report that it did not work should not deter a trial ofMPH.

Our controlled demonstration of performance-enhancing medication effects fur-ther validates the use of methylphenidate in adult ADHD. It extends the applicabilityof stimulant therapy in adults to the cognitive/learning domain. The CPALT calls for30 minutes at a time of sustained effortful attention. The ADHD subjects end up witha lower mean total score in the unmedicated (placebo) condition. The increased vari-ability of the group’s performance, as indicated by the higher mean CV, is probablylargely the reason. It is not necessarily the case that the ADHD individual is a sub-normal learner. Rather, while he is able to maintain task orientation, he learns as ex-pected. But he relinquishes task orientation at frequent intervals. Why he does so isunclear, but it appears that even a brief time off task enables him to resume task ori-entation and full mental effort—for a time. We have found the increased variabilitythat characterized adult ADHD performance in many studies of children. Increasedvariability characterizes ADHD performance far better than decline of efficiencyacross the total period of the trial. In the seven subjects who produced their bestmean performance at the 5 mg dose level, the CV was also optimal at that level, andU-shaped functions were also obtained for the CV. The performance of the relativelyoverdosed subject becomes more variable. In three of the seven, the variability on 20mg was actually greater than on placebo.

Our findings show that the clinically observed benefits of MPH on adults withADHD cannot be ascribed to placebo effects and that they are systematic. The ben-eficial effects, both on mean score and on variability of performance, resemble thosethat we have found in children. They afford further evidence of the continuity be-tween the childhood and the adult phases of the condition.

While no single form of assessment suffices for determining and monitoring dos-age in stimulant therapy, controlled medication assessment has particular advantagesin the adult ADHD population. The widespread use of ratings during administrationof various levels of medication is usually not feasible, since reliable informants arehard to find. Even the patient’s compliance with instructions as to what dosage orcapsule to take, and at what time, cannot be relied upon. In contrast, the medicationassessment is carried out in the laboratory. There is no uncertainty about what dosethe patient has ingested, or when, or about its effects on his ability to learn paired-associates (an operational measure of attention). The CPALT output variables are notcontaminated by placebo effects. The result suggests a dose that is a suitable startingpoint for the therapy. This often saves substantial time, which would have been ex-



pended in trying out ineffective doses in the field. If a particular dose level of stim-ulant induces an adverse response, depressing performance below placebo levels, oradverse subjective effects (irritability, tearfulness, etc.) and then the clinician willavoid prescribing it. This will spare the patient the adverse effect for the days orweeks that it might otherwise have been experienced.

As compared to other behavioral laboratory measures, the CPALT has unique ad-vantages. It is controlled, not subject to ceiling effects (a frequent problem with thecontinuous performance tests that are sometimes used clinically in the adult popula-tion), and can be analyzed as a single subject experiment. In addition, as well as mea-suring mean performance, it has the advantage of offering a measure of performancevariability, the CV. This variable is particularly relevant in people with inconstant at-tention. Increased variability in the performance of ADHD children across diversetasks has been repeatedly noted, as early as Douglas36 and as recently as Rubia etal.,37 for reaction time and sequential motor behavior, respectively. Variability oflearning performance is a developmental variable, and decreases systematically be-tween ages six and 12 years.24 Does it represent a maturational lag in ADHD,38

which is ultimately corrected? To the contrary, in the present study we showed forthe first time that the CV is as effective in differentiating adult favorable from non-and adverse-responders as we have shown it to be in children. The CV was also ef-fective in demonstrating the level of stimulant medication at which the personal bestperformance was elicited.

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TABLE 1. Performance on the CPALT

Level of MPH Number of Correct Responses Coefficient of Variation

Placebo 100.24 0.895mg 126.41 0.29

10mg 117.35 0.3820mg 117.94 0.39


Adult ADHD Controlled Medication Assessment

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