Management of adhd in adults

Management of ADHD in Adults
Lenard A. Adler, M.D., and Hong C. Chua, M.D.
Although first identified in children in the 19th century, attention-deficit/hyperactivity disorder Copyright 2002 Physicians Postgraduate Press, Inc.
(ADHD) in adults was not described in the literature until 1976. The symptoms of adult ADHD re-semble the symptoms of childhood ADHD, but symptom intensity, especially hyperactivity, may de-crease over time. However, due to the challenges and responsibilities of adulthood, a normal day isextremely complicated for the ADHD adult. Molecular genetics and neuroimaging studies confirmthat ADHD is a heterogeneous, neurobiological disorder, mainly of dopaminergic and noradrenergicpathways. Trials of pharmacologic treatments in adults with ADHD have produced mixed results dueto considerable variability in diagnostic criteria, dosing, and response. This article reviews the history,neurobiology, and pharmacologic management of adult ADHD.
(J Clin Psychiatry 2002;63[suppl 12]:29–35) ropsychiatric perspectives on syndromes of pathologic restlessness. Subsequent studies have implicated frontal Attention-deficit/hyperactivity disorder (ADHD) is lobe dysfunction in the pathophysiology of ADHD.4 Von characterized by inattentiveness, overactivity, and impul- Economo described formerly normal children becoming siveness. Although ADHD was first identified in children more talkative, importunate, impertinent, forward, and dis- in the 19th century, adult ADHD was not described in the respectful. Although his observations described children literature until 1976, when Wood et al.1 showed evidence predominantly with a conduct disorder, he also noted an in- of response to stimulants in a group of adults who pre- sented with the same symptoms as ADHD children.
Encephalitis lethargica, also called von Economo’s disease, has been used as a model of ADHD. After thepost–World War I pandemic of encephalitis lethargica In 1980, the third edition of the Diagnostic and Statis- (1916–1927), some children and adolescents had a post- tical Manual of Mental Disorders (DSM-III)5 was pub- encephalitic behavioral syndrome characterized by over- lished with 2 major changes in emphasis and terminology activity, lack of coordination, learning disability, impul- for what had been previously referred to as hyperkinetic sivity, and aggression.2,3 The children were reported as syndrome (Table 1).2 Attempts to include etiology within having minimal brain dysfunction–like behavior, and the the definition and diagnostic terminology were abandoned adults exhibited parkinsonian symptoms. The patients be- in favor of a phenomenological approach using operational came severely rigid with tremor, they had pathologic rest- criteria. Another change involved the consensus that inat- lessness and akathisia, and they developed formal basal tentiveness was a central criterion and that impulsiveness ganglia lesions. The basal ganglia lesions were the first was as important as overactivity. Therefore, DSM-III used clue that states of pathologic restlessness are not driven the classification attention-deficit disorder, which could be purely dynamically or in terms of conflict. This discovery diagnosed with or without hyperactivity (ADD-H or ADD).
represents a dividing point in the neurologic and the neu- Experts also agreed that the disorder often persisted intoadulthood but remained vague about the adult symptoms.
The later revision of DSM-III, DSM-III-R,6 allowed formalclassification into adulthood and required the symptomonset in childhood, but it also returned to placing more From the Department of Clinical Psychiatry and emphasis on overactivity, hence the change from ADD to Neurology, New York University School of Medicine, New York. ADHD. With the publication of the fourth edition of DSM Presented at the roundtable “Novel Treatments for Attention-Deficit/Hyperactivity Disorder in Children and (DSM-IV)7 in 1994, there remained a distinction between Adults,” which was held November 15–17, 2001, in Boston, inattention and the other symptom clusters, but impulsive Mass., and supported by an unrestricted educational grantfrom Eli Lilly and Company. and hyperactive symptoms remained in the same list, al- Corresponding author and reprint requests: Lenard A. though separately identified.2 The traits described by von Adler, M.D., Associate Professor of Clinical Psychiatry andNeurology, NYU School of Medicine, 530 First Avenue, Suite Economo in his observations of postencephalitic children 5A, New York, NY, 10016 (e-mail: [email protected]). still remain the criteria for diagnosis of ADHD in DSM-IV.
Many of the adults with ADHD suffered from comorbid Table 1. Evolving Diagnostic Criteria for ADHDa
psychiatric disorders and showed clinically significant Name changed from hyperkinetic syndrome to impairments, such as histories of school failure, occupa- tional problems, and traffic accidents. Family history is important in diagnosis because there is a strong genetic More emphasis on impulsivenessCan be diagnosed without hyperactivity component with about a 50% concordance rate for ADHD Required symptom onset in childhoodMore emphasis on overactivityName changed to attention-deficit/hyperactivity disorder Copyright 2002 Physicians Postgraduate Press, Inc.
Impulsive and hyperactive symptoms in same list but Data from molecular genetics and neuroimaging stud- Distinction between inattention and other symptom ies also support the validity of ADHD in adults. Several studies have reported that ADHD is a heterogeneous dis-order11,12 that has been associated with the 10-repeat alleleof the 40 bp at the dopamine transporter gene (DAT1)13–16 and the 7-repeat allele of the 48 bp in exon III of the dopa-mine D receptor gene (DRD4).13,14,17–19 In adults, the symptoms of ADHD are seen not in the That ADHD is a neurobiological disorder, mainly of school setting as with children but in the workplace. The dopaminergic and noradrenergic pathways, is supported symptoms also have to be present in one other setting, by evidence from single-photon emission computed such as at home, according to DSM-IV criteria.7 When tomography/positron emission tomography (SPECT/PET) comparing childhood with adult ADHD, the symptoms a studies20–23 and magnetic resonance imaging (MRI) stud- patient has as a child are the symptoms the patient tends to ies.24–26 Ernst et al.21 used PET with [fluorine-18] fluoro- have as an adult. Symptom intensity, especially hyper- dopa ([18F] FDOPA) to assess the integrity of dopaminer- activity, may decrease over time, and while there may be gic presynaptic function in ADHD. Data obtained through cases of unrecognized ADHD until adulthood, adult onset this process reflect DOPA decarboxylase activity and is not thought to occur. Despite a decrease in ADHD dopamine storage processes. They found that adults with symptom intensity in adulthood, everyday life continues ADHD have abnormally low DOPA decarboxylase activ- to become more complex. Adults without ADHD have a ity in the prefrontal cortex, particularly in the medial and very full, challenging day, but an adult with ADHD is left lateral areas. By using PET with [18F] fluoro-2-deoxy- particularly challenged by a normal day’s activities. Not D-glucose, Zametkin et al.22 were able to measure the re- only do adults with ADHD have to get themselves up and gional glucose metabolism in the brains of adults with functioning in the morning, make it to work on time, and ADHD. Their results confirmed previous imaging study be productive, but they also have to get their children, who findings of abnormal regional and global glucose metabo- many times have ADHD themselves, out of bed and func- lism in the brains of adults with ADHD since childhood.
tioning in the morning and off to school. After a full day of The largest areas of reduction in glucose metabolism were work, ADHD adults must manage homework and dinner, the premotor cortex and the superior prefrontal cortex— get the children to bed, and somehow try to find some time areas earlier shown to be involved in the control of atten- for themselves. With all the problems these patients have tion and motor activity. Impaired executive function has with executive functioning and time management, what been associated with damage in the frontal lobes,2 and seems like a very normal day to the average individual is excessive motor activity has been associated with damage an extremely complicated task for the adult with ADHD.
For this reason, clinicians who treat adults with ADHDmust examine whole-life issues.
Although educational therapy and psychotherapy are often beneficial for developing skills to cope with the chal- In determining the validity of adult ADHD as a diagno- lenges of ADHD, pharmacologic treatment is the mainstay sis, many clinical correlates must be considered. Faraone of treatment for children and adults with ADHD. The MTA et al.8 reviewed clinical, family, psychopharmacologic, Cooperative Group study28 of long-term (14-month) treat- neurobiological, and outcome studies. They found that ments for children with ADHD found significant improve- family history, treatment response, course and outcome, ment with stimulant medication treatment, with or without molecular genetics, and neuroimaging combine to tell a psychosocial treatments compared with intensive behav- very interesting story. The reports described adults with ioral treatment and/or community care alone. Far more clinical features highly reminiscent of childhood ADHD.
medication trials have been conducted with children and Table 2. Stimulant Trials in Adult ADHDa
Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Copyright 2002 Physicians Postgraduate Press, Inc.
Pemoline and mixed amphetaminesSpencer et al37 Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover aAbbreviations: ADHD = attention-deficit/hyperactivity disorder, RDC = Research Diagnostic Criteria of Spitzer et al.31 Symbols: + = ≥ 50% of allpatients taking study medication showed a positive response, – = < 50% of all patients taking study medication showed a positive response,+/– = mixed results.
adolescents than with adults; however, similar medications methylphenidate and placebo, 26 of the 61 completers had are used for both children and adults with ADHD. Wilens a childhood diagnosis of ADD-H according to DSM-III et al.29 reviewed comprehensively the available literature criteria, and 35 comparators had similar adult symptoms on pharmacologic treatment of adult ADHD in 2002.
but no history of childhood ADD-H. At endpoint, only Stimulants such as methylphenidate, pemoline, or am- 25% of the patients were considered responders.
phetamine preparations or antidepressants such as norepi- Wender et al.33 had more favorable results for methyl- nephrine reuptake inhibitors, norepinephrine-serotonin phenidate. The mean dose of methylphenidate after 14 reuptake inhibitors, or norepinephrine-dopamine reuptake days was 43.2 mg/day. Of the 37 completers, 21 (57%) inhibitors make up the most widely used treatments for experienced a moderate-to-marked treatment response ADHD. Data from those studies, in addition to the results during the methylphenidate condition, 12 (32%) demon- of subsequent trials, are bringing clinicians closer to un- strated little or no change during either treatment condi- derstanding and effectively treating adults suffering from tion, and 4 (11%) demonstrated a moderate-to-marked response to placebo and either no benefit or mild worsen-ing with methylphenidate. In a study of methylphenidate conducted by Gualtieri et al.,34 8 patients showed a A review of 11 stimulant trials conducted between 1976 mild-to-moderate response after 2 weeks of treatment, and 2001 in adults (N = 300) with ADHD shows response while Iaboni, using a similar study design, but over 4 rates that are less consistent than the response rates in weeks, showed moderate improvement in 30 patients similar trials with children (Table 2).30 The results of the (as reviewed in Wilens et al.29). Another double-blind, earlier studies were inconsistent, which could be the result placebo-controlled study by Spencer et al.35 found a of using lower stimulant doses and less stringent inclusion marked therapeutic response in 18 (78%) of 23 patients criteria than were used in later trials.
while taking methylphenidate, compared with 1 patient Methylphenidate. In one of the earliest trials of phar-
(4%) while taking placebo. In this study, 23 adult patients macologic treatment of ADHD in adults, Wood et al.1 con- were treated with relatively high doses of 1 mg/kg/day. In ducted a double-blind trial of methylphenidate in 11 of 15 an open-label study by Shekim et al.,36 methylphenidate patients, and an open trial of pemoline, imipramine, or produced a favorable response in 78% of the 33 patients amitriptyline in all 15 patients. Patients were diagnosed with minimal brain dysfunction according to the Research Pemoline and mixed amphetamine salts. Other clini-
Diagnostic Criteria of Spitzer et al.31 Eight of the 11 pa- cal trials on pharmacologic treatments for adult ADHD tients taking methylphenidate showed a significant re- have focused on the use of pemoline and mixed amphet- sponse to the double-blind trial of methylphenidate. Of all amine salts. In a trial of mixed amphetamine salts, Spen- 15 patients participating in the open trial of pemoline, cer et al.37 examined 27 adults satisfying full DSM-IV cri- imipramine, or amitriptyline, 8 showed a good response to teria for ADHD. The 7-week, randomized, double-blind, stimulants or tricyclic antidepressants, 2 showed a moder- placebo-controlled, crossover study used approximately ately favorable response, and 5 were unresponsive to drug 54 mg/day of mixed amphetamine. Of the 27 patients tak- therapy. In another double-blind crossover trial32 with ing mixed amphetamine, 19 (70%) showed improvement Table 3. Nonstimulant Trials in Adult ADHDa
Antidepressants: norepinephrine, dopamine, serotonin reuptake inhibitorsWilens et al42 Adler et al48 Copyright 2002 Physicians Postgraduate Press, Inc.
Specific norepinephrine reuptake inhibitorsSpencer et al50 Double-blind placebo-controlled crossover Cholinergic agents and nicotineConners et al55 Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover Double-blind placebo-controlled crossover aAbbreviations: ADHD = attention-deficit/hyperactivity disorder, SR = sustained-release, WURS = Wender Utah Rating Scale. Symbols: + = ≥ 50%of all patients taking study medication showed a positive response, – = < 50% of all patients taking study medication showed a positive response,+/– = mixed results, … = unknown.
of ADHD symptoms, compared with 2 (7%) of 27 patients studied in relation to the treatment of ADHD in children, taking placebo. In an open-label 16-week trial using dex- and again, the results of clinical trials of these nonstimu- troamphetamine/amphetamine, Horrigan and Barnhill38 re- lant medications on adult patients with ADHD are gener- ported that of 24 adult patients with ADHD, as measured ally reflective of findings in the pediatric studies.
by the Clinical Global Impressions-Improvement (CGI-I) Antidepressants. Antidepressants have been used as
scale scores, 13 (54%) were considered responders. The alternative pharmacologic agents for the treatment of mean end-dose of the responders was 10.77 mg/day, and ADHD in children, and various classes of antidepressants, the study also reported acute anxiety symptoms in 4 of 7 including the tricyclics, monoamine oxidase inhibitors, patients with comorbid anxiety disorders.
and selective serotonin reuptake inhibitors, have produced The use of pemoline for the treatment of adult ADHD variable results in the patients studied.
was studied in 2 trials. Wilens et al.,39 reported positive The earliest group of antidepressants studied for use response rates in 42 patients treated in a double-blind in the treatment of ADHD in adults were the tricyclics. A placebo-controlled study. A later study40 utilized the same 1995 chart review by Wilens et al.42 suggested that desip- design with 35 patients diagnosed with DSM-IV ADHD, ramine, which is mostly noradrenergic in its mechanism of but higher mean doses of 2.2 mg/kg/day resulted in only a action, and nortriptyline, a norepinephrine and serotonin moderate (50%) response rate, defined by a 30% reduction reuptake inhibitor, used in combination with stimulants of ADHD symptoms. The modest clinical utility of pemo- and other psychotropics were able to moderately improve line is overshadowed by the association of this agent with the symptoms of the 37 adult ADHD patients reviewed. A double-blind, parallel trial of desipramine43 in 43 patients The studies reviewed in this section demonstrate the showed moderate responses, but only at higher doses.
efficacy of stimulants in adults with ADHD. In general, Wender and Reimherr44 conducted an open-label trial of efficacy was somewhat greater in the later studies, which bupropion, an atypical catecholaminergic (dopamine and used more consistent diagnostic criteria and higher doses norepinephrine) antidepressant, in 14 adults with ADHD.
The patients had received maintenance stimulant medica-tion or monoamine oxidase inhibitors for an average of 3.7 years. The mean ± SD dose of bupropion was 359 ± 118 Trials of nonstimulants in adults include a variety mg/day (range, 150–450 mg/day). After 6 to 8 weeks of of agents with dopaminergic and/or noradrenergic action bupropion treatment, 8 of the 14 patients were considered (Table 3). Many of the agents described below have been very much improved, 6 were considered much improved, and 10 chose to continue bupropion treatment. Wilens physicians, which adds a further measure of control. Entry et al.45 conducted a double-blind, placebo-controlled, ran- into the study required meeting DSM-IV ADHD criteria domized, parallel, 6-week trial comparing sustained- and either having corroborated childhood symptoms by release bupropion (up to 200 mg b.i.d.) with placebo. The report of the patient or having current symptoms reported 38 patients who completed the study met DSM-IV criteria for ADHD, and 16 (76%) of the patients taking bupropion Potential advantages of atomoxetine, compared with responded positively versus 7 (37%) of the patients taking stimulants, include a longer duration of action, a lower risk of rebound, and a lower risk of induction of tics or In trials of other antidepressant agents, there have been psychosis. If the FDA does not require scheduling for ato- Copyright 2002 Physicians Postgraduate Press, Inc.
small, open-label studies in adults with venlafaxine, an moxetine, additional advantages over stimulants would be antidepressant with both serotonergic and noradrenergic the ease of prescribing and lower abuse liability in patients properties. In these trials, patients reported better tolerance with ADHD and comorbid substance abuse disorders.
with venlafaxine than with other drugs. Findling et al.46 Antihypertensive agents. The use of antihypertensive
studied 10 adult patients who met DSM-IV criteria for pharmacologic agents in adult patients with ADHD has ADHD in an 8-week open trial of venlafaxine. Patients focused on the ability of these agents to reduce the aggres- were started on an initial dose of 37.5 mg b.i.d., which was siveness, temper outbursts, and marked hyperactivity increased to 75 mg b.i.d. as needed. On the basis of a priori features of ADHD. In an open study of propranolol,52 13 criteria, 7 of the 9 completers were considered responders.
adults with a DSM-III diagnosis of residual ADD were Wilens et al.47 reported on 2 cases of adult ADHD that given a maximum dose of 160 mg/day. Of the 13 patients, were successfully treated with venlafaxine after failure 11 demonstrated improvement in symptoms of ADD.
with stimulants and antidepressants among other medica- Taylor and Russo53 conducted a double-blind, cross- tions. Two other clinical trials of venlafaxine48,49 reported over, 7-week trial of guanfacine, an α-adrenergic agonist, significant reductions in ADHD symptoms, although 38% in 17 adults with ADHD. The results showed that guanfa- of patients enrolled in the 2 studies were unable to tolerate cine was well-tolerated and improved the neuropsychiatric the relatively high doses of venlafaxine used.
functioning of all 17 patients, as compared with placebo Specific norepinephrine reuptake inhibitors. Atomox-
etine is a nonstimulant, selective norepinephrine reuptake Amino acids. The use of the amino acids L-dopa and
inhibitor that is currently being investigated for the treat- L-tyrosine for the treatment of adult ADHD in the 1980s ment of ADHD in children, adolescents, and adults.59 It is was based on the theory that the symptoms of ADHD currently under review by the U.S. Food and Drug Admin- could be related to deficiencies in the catecholaminergic istration (FDA) for the treatment of both children and system. Reimherr et al.54 conducted an 8-week open trial of L-tyrosine in 12 patients with ADD, residual type, The original examination of atomoxetine for ADHD according to DSM-III diagnostic criteria. The dose of was in a trial by Spencer and colleagues50 in 1998. They L-tyrosine was rapidly titrated from 50 mg/kg/day to 150 conducted a double-blind, placebo-controlled, crossover mg/kg/day with only minor side effects. In the initial trial of atomoxetine in 22 adults who met DSM-III-R crite- phase, patients appeared to stabilize at 4 weeks, at which ria for ADHD. Of the 22 patients, 1 patient dropped out time there was marked improvement in 2 patients, moder- due to adverse effects. The mean dose of atomoxetine at ate improvement in 6, slight or no improvement in 2, and week 3 was 76 mg/day. Using a preestablished definition slight worsening in 2. Although there remained significant of improvement of ≥ 30% reduction in symptoms, they effects from baseline to week 8, clinical regression oc- found that 11 of 21 patients showed improvement in curred between the subjects’ best responses and their re- ADHD symptoms while receiving atomoxetine, compared with 2 who improved while receiving placebo.
Cholinergic agents and nicotine. The observation that
A trial consisting of 2 parallel, identical studies was re- cigarette smoking appeared to have a pathoplastic effect cently completed by Michelson et al.51 in 536 adult pa- on the adult ADHD population led to a short 2-day trial of tients with ADHD. The primary objective of the study was a nicotine patch in 11 patients.55 All patients demonstrated to examine the efficacy of atomoxetine at doses of 60 to significantly reduced ADHD symptoms and improved 120 mg/day in 2 equally divided doses compared with pla- cebo for up to 10 weeks. The study design consisted of an The Abbott Laboratories (Abbott Park, Ill.) compound initial screening with a washout and entry period and 2 ABT-418 is a novel cholinergic agonist (nicotinic analog).
weeks of placebo lead-in followed by 10 weeks of acute A double-blind, placebo-controlled, randomized, cross- active treatment. The initial active treatment dose was over trial was conducted by Wilens et al.56 that compared a 30 mg/day b.i.d. and titrated to a maximum dose of 75-mg transdermal patch of ABT-418 with a placebo patch 60 mg/day b.i.d. An interesting aspect of the study is that it in adults who met DSM-IV criteria for ADHD. The 29 used blinded rating investigators and non-blinded treating completers participated in a 3-week treatment period, followed by 1 week of washout and an additional 3-week pion, desipramine, guanfacine, imipramine, modafinil, nortriptyline, treatment period. At the endpoint of each active arm (last propranolol, venlafaxine, ABT-418, atomoxetine, L-dopa, and L-tyrosineare not approved by the U.S. Food and Drug Administration for the observation carried forward), 40% of patients taking treatment of attention-deficit/hyperactivity disorder (ADHD); and dex- ABT-418 were considered improved, compared with 13% troamphetamine/amphetamine, methylphenidate, and pemoline are not of patients taking placebo. Similarly, at endpoint there was approved for the treatment of ADHD in adults.
a significantly greater reduction in ADHD symptom Antinarcoleptic/alertness medications. Among the
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