Long-Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study

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1 Basic & Clinical Pharmacology & Toxicology, 2016, 118, Doi: /bcpt MiniReview Long-Term Pharmacotherapy of Adults With Attention Deficit Hyperactivity Disorder: A Literature Review and Clinical Study Mats Fredriksen 1,2 and Dawn E. Peleikis 3 1 Division of Mental Health and Addiction, Vestfold Hospital Trust, Tonsberg, Norway, 2 University of Oslo, Oslo, Norway and 3 Department of Psychiatry, Akershus University Hospital, Grorud Outpatient Clinic, Lorenskog, Norway (Received 13 April 2015; Accepted 13 August 2015) Abstract: This MiniReview reports and discusses the main findings of the author s thesis including a literature study of longterm pharmacological treatment of adults with attention deficit hyperactivity disorder (ADHD), and a clinical study of 1-year medication. Electronic databases were systematically reviewed for original studies on pharmacotherapy of the defined duration, 24 weeks or more. Although few trials were found with limitations such as excluding comorbidities, treatment with stimulants and atomoxetine was reported tolerated and effective compared to non-treatment. The clinical study of the thesis was conducted on 250 medication-na ıve patients with ADHD referred to a specialized outpatient clinic. Comorbid psychiatric disorders were diagnosed among 75% of the patients. About 56% had not completed secondary school, and 51% had been unable to work the preceding year. Persisting inattentive symptoms and comorbid mental disorders in adulthood were related to long-term work disability. In the prospective observational study of the thesis, patients were treated with methylphenidate as first-line drug and atomoxetine or dexamphetamine as second-line drugs, according to current treatment guidelines. At 12-month follow-up, 232 patients completed evaluation and 70% persisted on medication. About 80% of these used methylphenidate. Sustained improvement of symptoms and functioning was related to continued medication. Comorbid mental disorders and side effects were related to lower effectiveness and adherence, and 12% stopped medication due to side effects. Summing up the MiniReview, treatment with stimulants and atomoxetine of adults with ADHD has long-term beneficial effects and is tolerated but more longitudinal studies should be performed. With stated limitations, the findings of the thesis should contribute to a relevant guidance for clinical practice. Persisting Attention Deficit Hyperactivity Disorder (ADHD) in Adulthood The present MiniReview reviews relevant findings reported in the clinically based thesis by Fredriksen [1] of long-term pharmacotherapy of adults with attention deficit hyperactivity disorder (ADHD) and discusses these findings in the light of recent research. The main aim of the reviewed thesis was to study advantages of prolonged drug treatment according to current pharmacotherapy. There were three objectives in the thesis: (i) to review original literature of adults with ADHD and identify direct and indirect effects of stimulant therapy on long-term outcome in adults addressing efficacy and tolerability of medical treatment, (ii) to examine dimensionally associations between childhood ADHD symptoms and characteristics and functional impairments as educational deficits and work disability in untreated ADHD adults and (iii) to examine prospectively the effectiveness of stimulant and nonstimulant medication of adult patients with ADHD during 1 year in a clinically relevant setting. Author for correspondence: Mats Fredriksen, Division of Mental Health & Addiction, Vestfold Hospital Trust, N-3101 Tonsberg, Norway (fax , mats.fredriksen@siv.no). Over the past decade, an increasing number of adults have been referred for the assessment or treatment of ADHD [2,3]. According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) [4] and the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) classification [5], the core symptoms of ADHD are inappropriate lack of attention and/or hyperactivity and impulsivity. ADHD is considered as a common childhood neurodevelopmental disorder with a high heritability [6], and the prevalence is estimated between 2% and 10% among children [7] and about 2 5% in adults [8 10]. Most children with ADHD do not recover fully [11], and ADHD affects them throughout their lifespan, often persisting in chronic but more covert adult ADHD symptoms in both sexes [12 14]. While hyperactivity and impulsivity often decline during adolescence, inattention tends to persist [11]. In addition, the functional requirements and tasks that arise in the transition to adulthood can reveal problems with functions that are previously compensated by parents or guardians and may lead to delayed detection [15,16]. Attention deficit hyperactivity disorder in adulthood is associated with psychological and social difficulties, and the prevalence of co-occurring psychiatric disorder is high (70 80%) [17 19]. Furthermore, somatic health problems such

2 24 MATS FREDRIKSEN AND DAWN E. PELEIKIS MiniReview as obesity [20], smoking [21], drug abuse [22] and sleep disturbances [23] are more common among ADHD adults than in the general population. There is evidence that persistent ADHD has serious long-term costs [16,24 26], and impairments in areas of educational attainment and longterm work incapacity are often functional consequences of ADHD [27]. Impact of childhood ADHD symptom dimensions on functional outcome measures as educational achievements and work disability was one of the relevant issues in the thesis [1]. Several trials on pharmacological treatment of adults with ADHD have shown beneficial effects in treatment with shortterm duration [28,29]. In a meta-analysis of 19 studies on ADHD medications of adults including only randomized, controlled trials (RCTs) [28], the authors found that central stimulants such as methylphenidate and amphetamine, as well as the non-stimulant atomoxetine, were effective in studies lasting up to 12 weeks. A preliminary PubMed search included in the reviewed thesis identified no prior literature addressing long-term medication in adults with a defined duration above any certain time limit, and no consensus regarding the definition of long-term appeared in this field. Further, very few studies have systematically reviewed outcome measures of treatment of longer duration than 20 weeks in adults with ADHD [29,30]. Therefore, and for pragmatic reasons, prior to the systematical review of the literature, the thesis adopted the definition of long-term studies for treatments with a duration of 24 weeks or more [30,31]. In addition, although short-term RCTs have shown efficacy of ADHD medications, their clinical relevance is ambiguous, as the samples are typically small at end-points due to the high rates of drop-out, and selection bias is also likely as patients have typically had low rates of comorbid disorders [32]. To study the effectiveness of treatment, it is argued that variables such as treatment adherence, comorbidity, side effects and patient preferences should be included, in addition to the target symptoms [33]. Focusing on methodological issues, Hazell has argued that studies of long-term effects of stimulant medication of necessity should be naturalistic, and include characteristics such as adherence to treatment, and variation in the course of ADHD [34]. Few long-term, prospective, naturalistic studies have been conducted on adult patients with ADHD in a real-life clinical setting [33,35,36]. Bejerot et al. [35] examined outcome measures of adherence to stimulant treatment and side effects in a 2-year follow-up study. About 80% continued on stimulants at the 9-month follow-up, and 50% maintained on medication after 2 years. A significant proportion (19%) dropped out before 6 weeks for unknown reasons, and anxiety and depression were reported as common reasons for discontinuing treatment. In a naturalistic study of children and youths conducted by Powell et al. [37], comorbidity and younger age were significantly related to higher dosages of stimulants. However, a number of questions concerning outcome of pharmacological treatment seemed unresolved including tolerability, effects on different ADHD symptoms and psychiatric comorbidity, and issues of compliance. All this highlighted the question of knowledge about the benefits and safety of prolonged treatment with ADHD medications in adults. Relevant aspects of the background, methods and results of the thesis are reviewed in the following sections. A systematic Review of Long-Term Pharmacotherapy Methods. In the literature study of the thesis, efficacy and tolerability of medical treatment were addressed and reviewed systematically in electronic databases. Only original studies of adults with ADHD, using either prospective or retrospective designs, were included. Long-term treatment was defined as treatment with a duration of 24 weeks or more, and a systematic literature search was conducted by assistance from the librarian at the Norwegian Centre for Research, Education and Service using the following electronic databases: National Library of Medicine Pubmed site, EMBASE and PsycINFO until January Published articles for the last three decades were initially searched for making use of combinations of the selected search terms and restricted by a search strategy thoroughly described in the article published [38]. Results. The literature study identified only five articles of four separate RCTs with a duration 24 weeks [30,31,39 41] (table 1) and additionally 11 articles of 9 initially short-term RCTs which were followed by an open-label extension for a total duration of 24 weeks [42 52] (table 2). Only medication by methylphenidate, atomoxetine and amphetamine was found in the long-term defined studies, and methylphenidate was most frequently studied. We also included 18 treatment studies with naturalistic or cross-sectional design reporting other outcome measures or safety [38]. The majority of the controlled and extension studies were performed in the United States. Although the RCTs had fairly large sample size ( patients enrolled), high attrition rates among both drug-treated and placebo-treated patients (drop-out rates from 30% to 70%) led to difficulty with generalizing to the entire patient population (low external validity). Both sexes were represented in the study samples, and mean age ranged between 35 and 40 years. Comorbid mental disorders were exclusion criteria in most of the studies with initial RCT. Taking into account that in a clinical setting, most patients have at least one comorbid mental disorder, this raises unresolved questions about clinical validity of the RCT efficacy findings. All of the RCTs reported that ADHD medications were significantly more efficacious than placebo, and in the RCTs with open-label extension, the efficacy demonstrated during the placebo-controlled phase was either maintained or further improved during the extended follow-up period. In RCTs and extension studies, the medication was well tolerated by most patients, and most adverse effects occurred during the initial titration phase. Adrenergic-related effects

3 MiniReview LONG-TERM PHARMACOTHERAPY OF ADULTS WITH ADHD 25 Table 1. Randomized, double-blind, placebo-controlled trials with duration 24 weeks 1. Authors R osler et al. (2009) [30] Medication and duration Methylphenidate extended release (MPH-ER) 24 weeks Results 61% responders receiving MPH-ER versus 42% responders in the placebo group. Completers 69%. Premature termination (31%); 24% MPH-ER versus 43% placebo. Number-needed-to-treat statistics (NNT) was 6 R osler et al. (2010) [31] #Same trial above MPH-ER superior to placebo reducing emotional symptoms, significant from week 5, Cohen s d effect size 0.3 Biederman et al. (2010) [39] Osmotic-release oral system MPH (OROS MPH) 34 weeks Phase 1: 6 weeks Phase 2: 24 weeks Phase 3: 4 weeks Phase 1: OROS MPH group 62% responders versus placebo responders 37%. Phase 2: Rate of completers did not differ; OROS MPH responders were more likely to drop out due to adverse effects, and placebo responders by loss of effect. Phase 3: OROS MPH responders who completed phase 2 randomized for a 4-week, placebo-controlled discontinuation: the time-by-treatment interaction was statistically significant. Relapse rate did not differ (18% in both groups) Adler et al. (2009) [40] Young et al. (2011) [41] Atomoxetine (ATX) 6 months ATX 24 weeks Mean AISRS 2 total scores for ATX decreased from 38.2 at baseline to 21.4 at the 6-month end-point. Placebo from 38.6 to Completers: (38%) patients randomized to ATX and (45%) patients randomized to placebo completed the study CAARS-Inv:SV 3 Total score reduction was greater with ATX over placebo at 12 weeks ( 14.3 versus 10.1) and 24 weeks ( 16.4 versus 8.6; effect size, 0.6). Response: greater for ATX (68%) than placebo (42%) at 24 weeks. NNT was 4 1 Randomized, double-blind, placebo-controlled trials of ADHD medications with duration 24 weeks published until The Adult ADHD Investigator Symptom Rating Scale (AISRS). 3 The Conners Adult Attention Deficit/Hyperactivity Disorder (ADHD) Rating Scales (CAARS) Investigator Rated: Screening Version (CAARS- Inv:SV). such as decreased appetite, nausea, palpitations, mucosal dryness and dizziness were the side effects most frequently reported. Increased nervousness, irritability and sleep disturbance were the most common psychological adverse effects. Most frequent short-term adverse effects are well explained by adrenergic effects of the stimulant compounds and atomoxetine; however, long-term risk of such alterations is less studied. However, some large epidemiological studies of adverse effects of central stimulants did not report any significant associations with increased risk of serious cardiovascular events compared to non-users [53 55]. The Longitudinal Clinical Study Methods. The patients of the clinical study included in the thesis were recruited consecutively after they were referred to a specialized outpatient clinic for adults with ADHD. About half of the patients were referred from their general practitioner, and half from a specialist service psychiatrist, all with suspected undiagnosed ADHD persisting in adulthood. During ascertainment for participation, 620 patients were assessed for eligibility. Those having previously tried stimulant medication in adulthood or during the prior 5 years for patients 18 years of age were excluded. Further exclusion criteria were any medical contraindications for stimulant treatment such as hyperthyroidism, cardiovascular diseases or cardiac arrhythmias. Comorbid mental disorder was not an exclusion criterion unless assessed by a board-certified psychiatrist to be in immediate need of other treatment, such as current psychosis, major depression with melancholia or suicidal ideation, or alcohol or substance dependence during the last 3 months. Patients with any psychiatric comorbidity considered in need of treatment should undergo at least 3 months adequate therapy before inclusion, and those previously treated for chronic mental disorders were included despite no remission, except for psychotic disorders, chronic substance-use dependence or assessed acute suicidal risk. Those with an intelligence quotient (IQ) below 70 based on the Wechsler Adult Intelligence Scale IV or assessed with clinical symptoms and behaviours consistent with a pervasive developmental disorder were also excluded. In all, 250 adult patients were enrolled in the clinical study. Mean age was 32.6 (9.8) years, and 52% were females. Their ADHD symptoms in childhood and adulthood and achieved level of education and current employment status were investigated by interviews and questionnaires [56]. To obtain diagnoses in the clinical study, two board-certified psychiatrists examined each patient for inclusion criteria. The ADHD diagnosis was ascertained by a multisource procedure according to DSM-IV TR criteria [4]. To be diagnosed with ADHD, patients must have endorsed at least six of nine DSM- IV symptoms of inattention and/or hyperactivity/impulsivity in childhood, and currently have at least six of nine DSM-IV symptoms of inattention and/or hyperactivity/impulsivity for the last 6 months, and describe a chronic course from childhood to adulthood. In addition, patients with five of nine symptom criteria for each symptom domain in adulthood were included if they had met full symptom criteria in childhood corresponding to the DSM-5 criteria [5]. To examine comor-

4 26 MATS FREDRIKSEN AND DAWN E. PELEIKIS MiniReview Studies with short-term RCT and open-label extension phase. Authors Ginsberg & Lindefors (2012) [42] Buitelaar et al. (2011) [43] Marchant et al. (2010) [44] Wender et al. (2011) [45] Adler et al. (2009) [46] Biederman et al. (2005) [47] Weisler et al. (2005) [48] Ginsberg et al. (2011) [49] Adler et al. (2005) [50] Adler et al. (2008) [51] Marchant et al. (2011) [52] Medication and duration Osmotic-release oral system methylphenidate (OROS MPH) 52 weeks OROS MPH 52 weeks OROS MPH 6 months Immediate-release MPH (MPH-IR) 12 months Dex-MPH extended release (d-mph-er) 7 months Mixed amphetamine salts extended release (MAS-XR) 24 months MAS-XR #Same trial as above Up to 24 months Lisdexamphetamine dimesylate (LDX) 13 months Atomoxetine (ATX) Up to 97 weeks ATX #Extension of the trial above Up to 221 weeks ATX Up to 36 weeks Table 2. Results Improved ADHD symptoms (Cohen s d effect size 1.7 on ASRS 1 ). Response: 30% decrease in CAARS-O:SV 2 at week 5; 87% responded versus 0% for placebo; ASRS, CGI 3 and GAF 4 improved during open-label extension. Completers: 83% Mean CAARS:O-SV score decreased 1.9 from baseline. Small statistically significant improvements observed for CAARS-S, CGI-S and SDS. Completers: 63% Maintained improvement on WRAADDS dimensions 5 ; attention+ disorganization by 61%, hyperactivity impulsivity by 60%, emotional dysregulation 66% for all subgroups. Personality disordered patients were less likely to complete or improve. Completers: 44% In the RCT phase, more subjects in MPH-IR group responded (74% versus placebo 21%). During the open-label trial, symptom severity decreased by 80% from baseline. Average GAF improved significantly. Completers: 73% Significant mean improvement on ADHD-RS 6 ( 10.2) switching from placebo to d-mph-er, and ( 8.4) for those who maintained d-mph-er. Respective CGI-I responder rates were 95% and 95%. Completers: 60% ADHD symptoms significantly improved from baseline in mean ADHD-RS-IV total scores ( 7.2 unit points); this sustained for up to 24 months Completers: 34% Mean change in diastolic BP (1.3 mmhg), systolic BP (2.3 mmhg) and pulse (2.1 bpm) were small. On ECG, QTc (corrected by Bazett s formula) increased 7.2 msec observed at 24 months Clinical response related to level of severity (CGI-S = 4, 5 and 6, respectively): 79%, 84% and 88%. Symptomatic remission criteria by 64%, 65% and 72%, respectively. Increased mean change of ADHD symptoms with greater baseline symptom severity (5,6). Completers: 55% Significant improvement on ATX, mean CAARS-Inv:SV total ADHD symptom scores decreasing 33%. Completers: 33% CAARS-Inv:SV Total ADHD symptom scores decreased 30% during treatment. Significant decreases for the secondary efficacy measures, including the Sheehan Disability Scale total score, improved 25%. Completers: 18% Responders from the RCT phase achieved maximum response after 8 weeks of open-label medication; others continued to improve for 36 weeks. During open-label treatment, 39% of ATX double-blind non-responders became responders. Completers: 18% 1 The Adult ADHD Self-Report Scale (ASRS). 2 The Conners Adult Attention Deficit/Hyperactivity Disorder Rating Scales (CAARS) Observer: Short Version (CAARS-O:SV), CAARS-Self report (CAARS S), CAARS Investigator Rated:Screening Version (CAARS-Inv:SV). 3 The Clinical Global Impression (CGI). 4 The Global Assessment of Functioning (GAF). 5 The Wender Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). 6 The ADHD Rating Scale IV (ADHD-RS-IV). bid mental disorders, the MINI International Neuropsychiatric Interview Plus (M.I.N.I.-Plus) was conducted by the clinicians. Supplementary data to support evidence of childhood symptoms were collected from other informant sources such as school records and questionnaires rated by the parents, blinded for other informants ratings. Collateral information about current symptoms and impairment was also obtained from a close relative invited to participate during the interview with the patient. In the treatment segment of the clinical study included in the thesis, monitoring and observation with repeated measurements of symptom and functioning were conducted systematically [57]. Primary outcome measures measures for the assessment of treatment outcome measures were self-rated symptoms by the Adult ADHD Self-Report Scale version 1.1 (ASRS) and the investigator-rated Global Assessment of Functioning (GAF) Scale. The secondary outcome measures included the Clinical Global Impression (CGI) Scale and the Symptom Check List- 90-Revised [57]. The psychometric relevance of these scales is described by cited authors elsewhere [38,42,45,46]. All statistical analyses were carried out by The PASW statistics (version 17) for Windows package. Testing

5 MiniReview LONG-TERM PHARMACOTHERAPY OF ADULTS WITH ADHD 27 differences in the continuous outcome measures was performed with t-tests when the assumption of normal distribution was met, and otherwise with nonparametric tests. The level of significance was set at p < 0.01 because of many tests performed, and all tests were two-sided. Analyses of impaired work status were conducted adjusted for both age and gender. The specified independent variables were entered into logistic regression models initially unadjusted one at a time, and finally adjusted by entering age and gender together. Longitudinal analyses of treatment outcome measures were performed by linear mixed models to assess treatment effect on change over time of the defined measures. To assess a longitudinal dose response relationship of treatment, a cumulative dose covariate was constructed. Cumulative amount of side effect measures were also adjusted for to reduce potential selection bias. Procedures of medication and monitoring. As part of the open-label follow-up study, the patients and therapist knew that it was given medicine, but previous assessments of symptoms and functioning were masked for later assessments. According to the procedures of treatment, all patients were offered treatment with medicine following the national guidelines. Patients were offered MPH as first-line medication combined with psychosocial treatment as usual. Standard titration with immediate-release methylphenidate (MPH-IR) was prescribed for the first 6 weeks and 5 mg three times a day, stepwise increase until a maximum of 60 mg/day. Thereafter, a flexible dose titration was applied to optimize efficacy (maximum 120 mg/day). Shift into depot formulation/ extended-release methylphenidate (MPH-ER) was offered at the 3-month visit if patients reported difficulties with compliance, annoying fluctuations in effect, adrenergic side effects or otherwise wanted to try an easier administration form. If MPH was not tolerated or was ineffective, second-line medications were short-acting dextroamphetamine (damp) or atomoxetine (ATX). The dose of damp was escalated until a maximum of 50 mg/day and dose of ATX to a maximum of 120 mg. Patients were assessed for symptoms, functioning and side effects at scheduled follow-up time-points: 6 weeks and 3, 6 and 12 months. Associations between dimensional ADHD symptoms and functional impairments. In the sample, 55% of the patients had not completed secondary school equivalent to high school, and no significant difference between the sexes was observed. High levels of ADHD symptom severity in childhood measured by The Wender Utah Rating Scale 25 (WURS 25, third quartile with high severity, score 70) were significantly related to shorter duration of basic education and dropping out of high school (odds ratio = 3.0, 95% confidence interval [CI]: , p < 0.01). Also, higher numbers of hyperactive impulsive symptoms in childhood were significantly related to interrupted schooling (by each symptom criterion odds ratio = 1.2, CI: , p < 0.01). Work status was hardly related to differences in ADHD characteristics in childhood among the adult patients. However, statistically significantly more males (53%) than females (36%) were in paid work or attending ordinary studies, and more females (58%) than males (41%) received disability or rehabilitation pension. After adjusting for age and gender, persisting high levels of ADHD inattention symptoms by the Adult ADHD Self-Report Scale (ASRS, third quartile with high severity, score 24) in adulthood (odds ratio = 2.5, CI: , p < 0.05) and number of adult comorbid psychiatric disorders (odds ratio = 1.6, CI: , p < 0.001) were all associated with long-term work disability. Efficacy of 1-year pharmacotherapy. Among the 250 patients who started with medication in the clinical study, 232 (93%) completed examination at the 12-month follow-up, and 70% (n = 163) remained on medication, mostly on methylphenidate (80%). Some patients (n = 29) terminated their medication before the 6-week follow-up, and most of them (n = 20) did not switch to another medicine, here referred to as never-medicated at follow-up (fig. 1). The patients who continued on any ADHD medication had a statistically significant improvement of primary and secondary outcome measures at 1- year follow-up compared to their non-medicated baseline. Those who discontinued medication also experienced statistically significant improvements initially, but to a lesser degree. Comparing the primary outcome measures of those on medication to those off at 1-year follow-up, significantly greater improvements were found: percentage increased values of the clinician-rated Global Assessments of Symptoms and Functioning by the GAF-S and GAF-F (median 20% versus 2%, and 18% versus 6%, p < 0.001, respectively), and greater proportions of reductions in total ASRS scores (median 39% versus 13%, p < 0.001) including significant and corresponding reductions in both adult inattention and hyperactivity/impulsivity symptoms were observed (median 39% versus 13%, and median 39% versus 13%, p < 0.001, respectively). Corresponding improvements were reported on secondary outcome measures, such as mental distress by the measure of self-rated Global Severity Index of the Symptom Check List-90-Revised (mean 46% versus 23%, p < 0.007), and higher responder rate of the investigator-rated Clinical Global Impressions-Improvement Scale (CGI-I) by apriori response definition of the values of much or very much improved (CGI-I 2; median 87% versus 3%, p < 0.001). Frequencies of adverse effects were generally low. Of the 69 patients (28%) who had discontinued medical treatment before 12-month follow-up, 31 (12%) terminated due to side effects. Nine had to stop medication because of elevated blood pressure, and notably, all of these had a borderline high level at baseline. No serious adverse effects occurred, and there was no significant prolongation in electrocardiographic QT time. Longitudinal analyses showed significant associations between sustained improvement and being on medication at 12-month follow-up (fig. 1). Conversely, mental comorbidity and adverse effects were related to significantly lower effectiveness and more frequent termination of medication before 12-month follow-up. With the applied titration algorithm, higher dosage of medication over time (cumulative dose) was

6 28 MATS FREDRIKSEN AND DAWN E. PELEIKIS MiniReview associated with greater improvement on the primary outcome measures ASRS and GAF (p < 0.001). Discussion Never medicated Medicated Females Males Depressive episode No depression Fig. 1. Longitudinal outcome measures of Adult ADHD Self-Report Scale (ASRS) total score (0 72) paneled by group of adherence to medication, gender (n = 123 females) and depressive episode (n = 53) last year, respectively, for those patients who completed evaluation. The never-medicated group (n = 20): patients discontinued MPH treatment within first 6-week follow-up and never started up with any other ADHD medication. The medicated group (n = 140): patients who used any ADHD medication at every follow-up visit. Error bars: 95% confidence interval. Data adapted from the thesis by Fredriksen [1]. The reviewed results from the RCTs and RCT extension studies included in the thesis indicated favourable effects of ADHD medication maintained or further improved during the reported follow-up periods and acceptable tolerability. However, the systematic study of literature also revealed several issues for further study. Notably, no general consensus exists for what is regarded as a long-term study. Previously, at the time when ADHD was considered a self-limiting developmental disorder of childhood, studies of many years of duration were considered less relevant. In the thesis, a pragmatic compromise was adopted, including studies down to 24 weeks of duration, as otherwise there would be very little data left from RCTs. Besides being highly resource intensive, RCTs have limitations regarding clinical relevance of generalization to a clinical population, and naturalistic long-term clinical studies are also warranted. The clinical study of the thesis was able to correlate the severity of childhood ADHD symptoms and a high number of childhood hyperactive impulsive symptoms with school dropout and interrupted education in the untreated patients. It is noted that adult inattentive symptoms were associated with occupational impairment and that adult comorbidity predicted work disability. In contrast to prior literature with similar findings, our analyses were dimensional as per current DSM trends. A dimensional approach to symptoms and behaviours rather than categorical was useful to elucidate aspects of ADHD such more like a spectrum disorder. The defined categorical functional impairments of dropping out of high school and being out of work last year may be influenced by various conditions, not only ADHD behaviours. These outcome measures also lack information about the mode of impairment of each patient; data that could be essential to understand the impact of ADHD and other conditions on these outcome measures. Furthermore, those patients with most hyperactivity impulsivity in childhood related to interrupted schooling were also most severely affected with more symptoms and higher score on the WURS, and had accompanying high levels of inattentive symptoms as well. Intercorrelations between number of childhood inattention and hyperactivity impulsivity symptoms made some difficulties to separation between these dimensional symptoms in the analyses. The clinical treatment study included in the thesis was a large single-site prospective study performed on medicationna ıve adults and was implemented in a specialized outpatient setting. A high proportion completed evaluation at 1-year follow-up, and the majority of the patients remained on medication. The large clinical cohort with ADHD adults followed prospectively and, with a low proportion of drop-outs, provided a clinically relevant basis for longitudinal analyses. The reduction in self-rated ADHD symptoms (ASRS) corresponded well with the clinician-rated improvement of functioning (GAF) and assessment of response to treatment (CGI), indicating clinical relevance of the changes. The differences in effectiveness between being on and off medication appeared early on in treatment, with an overall increase during the follow-up visits, and higher dose of medication was associated with greater improvement, while adverse effects and comorbidities were related to less effectiveness. About half of the drop-outs from treatment occurred within

7 MiniReview LONG-TERM PHARMACOTHERAPY OF ADULTS WITH ADHD 29 first 6 weeks, and most of them did not continue on another drug. This is a somewhat lower rate than expected from a recent nationwide study from Denmark reporting early discontinuation of 20% among 18- to 49-year-olds [58]. Although the findings may be seen as replications of results from the previous small number of intermediate and 1-year RCT extension studies, this study complemented such findings on a broader clinical sample, including comorbid patients and patients with various medication dosages and adherence, and to some extent, the longitudinal model adjusted for such confounding factors in treatment. In a specialized outpatient setting, application of a current medication regimen for ADHD adults was associated with long-term reduction in ADHD symptoms and improvement of function and mental distress among those who used the medication, and adverse effects were within expected incidences. These results may provide realistic guidance for clinicians with regard to medical treatment in everyday practice and should supplement previous knowledge regarding the effectiveness of ADHD medication regimens. Cmorbid anxiety and bipolar disorders were associated with less effectiveness adjusted for age, gender and dosage. Retrospective studies have found comorbidity related to less adherence to medication [59,60], and this corresponds with our findings with less comorbidity among those adherent to treatment. Medication dosages were in line with other medication studies in adults with ADHD [36,44,45]. Similar to what was reported in a study from a younger patient population (aged 9 21 years) [37], we found variations in dosages across time and individuals, although patients with the highest dosages tended to have the best responses. The flexible dose regimen allowed for individualized dosing, thus taking into account both tolerability and optimizing efficacy. Conclusions To sum up this MiniReview of the thesis, efficacy in up to 6- month duration of treatment was found in the sparse literature of controlled studies of ADHD medications, and the results were kept in open extension studies for up to 1 year. In the clinical study of previously untreated patients of the thesis, hyperactive impulsive ADHD symptoms and severity of ADHD symptoms in childhood were related to not having completed high school. Sustained attention difficulties in adulthood and co-occurring psychiatric disorders were related to long-term work incapacity. In a clinically relevant setting at 1-year follow-up, a majority of patients preferred to use their ADHD medications. Adherence to ADHD medication was associated with significant reduction in ADHD symptoms, improvement in the general functioning and psychological symptoms. No serious adverse events were recorded, and the side effects were for most acceptable. 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8 30 MATS FREDRIKSEN AND DAWN E. PELEIKIS MiniReview 19 Torgersen T, Gjervan B, Rasmussen K. ADHD in adults: a study of clinical characteristics, impairment and comorbidity. Nord J Psychiatry 2006;60: Cortese S, Angriman M, Maffeis C, Isnard P, Konofal E, Lecendreux M et al. Attention-deficit/hyperactivity disorder (ADHD) and obesity: a systematic review of the literature. Crit Rev Food Sci Nutr 2008;48: Kollins SH, McClernon FJ, Fuemmeler BF. Association between smoking and attention-deficit/hyperactivity disorder symptoms in a population-based sample of young adults. Arch Gen Psychiatry 2005;62: Wilens TE, Martelon M, Joshi G, Bateman C, Fried R, Petty C et al. Does ADHD predict substance-use disorders? A 10-year follow-up study of young adults with ADHD. J Am Acad Child Adolesc Psychiatry 2011;50: Gau SS, Kessler RC, Tseng WL, Wu YY, Chiu YN, Yeh CB et al. Association between sleep problems and symptoms of attention-deficit/hyperactivity disorder in young adults. 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A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry 2010;71: Torgersen T, Gjervan B, Rasmussen K. Treatment of adult ADHD: is current knowledge useful to clinicians? Neuropsychiatr Dis Treat 2008;4: Rosler M, Fischer R, Ammer R, Ose C, Retz W. A randomised, placebo-controlled, 24-week, study of low-dose extended-release methylphenidate in adults with attention-deficit/hyperactivity disorder. Eur Arch Psychiatry Clin Neurosci 2009;259: Rosler M, Retz W, Fischer R, Ose C, Alm B, Deckert J et al. Twenty-four-week treatment with extended release methylphenidate improves emotional symptoms in adult ADHD. World J Biol Psychiatry 2010;11: Weiss MD, Gadow K, Wasdell MB. Effectiveness outcomes in attention-deficit/hyperactivity disorder. J Clin Psychiatry 2006;67 (Suppl 8): Weiss MD, Gibbins C, Goodman DW, Hodgkins PS, Landgraf JM, Faraone SV. Moderators and mediators of symptoms and quality of life outcomes in an open-label study of adults treated for attention-deficit/hyperactivity disorder. J Clin Psychiatry 2010;71: Hazell P. Review of new compounds available in Australia for the treatment of attention-deficit hyperactivity disorder. Australas Psychiatry 2004;12: Bejerot S, Ryden EM, Arlinde CM. Two-year outcome of treatment with central stimulant medication in adult attention-deficit/hyperactivity disorder: a prospective study. J Clin Psychiatry 2010;71: Adler LA, Orman C, Starr HL, Silber S, Palumbo J, Cooper K et al. Long-term safety of OROS methylphenidate in adults with attention-deficit/hyperactivity disorder: an open-label, dose-titration, 1-year study. J Clin Psychopharmacol 2011;31: Powell SG, Thomsen PH, Frydenberg M, Rasmussen H. Long-term treatment of ADHD with stimulants: a large observational study of real-life patients. J Atten Disord 2011;15: Fredriksen M, Halmoy A, Faraone SV, Haavik J. 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9 MiniReview LONG-TERM PHARMACOTHERAPY OF ADULTS WITH ADHD Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med 2011;365: Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;306: Schelleman H, Bilker WB, Kimmel SE, Daniel GW, Newcomb C, Guevara JP et al. Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry 2012;169: Fredriksen M, Dahl AA, Martinsen EW, Klungsoyr O, Faraone SV, Peleikis DE. Childhood and persistent ADHD symptoms associated with educational failure and long-term occupational disability in adult ADHD. Atten Defic Hyperact Disord 2014;6: Fredriksen M, Dahl AA, Martinsen EW, Klungsoyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): an openlabel prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol 2014;24: Pottegard A, Bjerregaard BK, Kortegaard LS, Zoega H. Early discontinuation of attention-deficit/hyperactivity disorder drug treatment: a Danish nationwide drug utilization study. Basic Clin Pharmacol Toxicol 2015;116: Lensing MB, Zeiner P, Sandvik L, Opjordsmoen S. Four-year outcome in psychopharmacologically treated adults with attention-deficit/hyperactivity disorder: a questionnaire survey. J Clin Psychiatry 2013;74: Torgersen T, Gjervan B, Nordahl HM, Rasmussen K. Predictive factors for more than 3 years duration of central stimulant treatment in adult attention-deficit/hyperactivity disorder: a retrospective, naturalistic study. J Clin Psychopharmacol 2012;32: