Long-term pharmacotherapy of adults with Attention-Deficit/Hyperactivity Disorder (ADHD): A literature review and clinical study
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AbstractBackground: ADHD in adulthood is associated with a wide range of clinical and psychosocial impairments, and the number of adults referred for medical treatment is considerable. Aims: The overall purpose of this thesis was to study clinically relevant aspects of long-term medical treatment of patients with adult ADHD. To achieve this, three aims were defined: 1) To systematically review the literature on long-term (= 24 weeks) pharmacological treatment of adults with ADHD (Study I); 2) To explore educational and occupational status as functional outcomes in previously not medicated adult ADHD patient (Study II); and 3) To assess outcomes of a 12 months first time medical treatment period of such patients (Study III). Materials and methods: In Study I we reviewed electronic databases to identify original studies of long-term effects of stimulant therapy in adults. Studies II and III were conducted on a sample of patients recruited at a specialized outpatient clinic for adult ADHD patients. Study II was a cross-sectional investigation of the impact of retrospectively retrieved childhood dimensional ADHD symptoms and characteristics as well as present state ADHD symptoms on the current level of basic education and current work status in medication-naïve adults with ADHD. Study III was an open-labeled prospective observational study of the 250 adults consecutively included and described in Study II, who received methylphenidate according to current guidelines with a titration-regime for 6 weeks, followed by a flexible-dose-regime. Patients, who did not respond or were non-tolerant for methylphenidate, were shifted to amphetamine or atomoxetine. Results: Study I: Most of published pharmacological studies reviewed were short-term randomized placebo-controlled trials (RCTs); four trials had intermediate duration between 24 weeks and one year. In contrast to findings in the short- and intermediate term (< 24 weeks) trials, where drug effects are well established, long-term effects (> 24 weeks) of medication on symptoms and functional outcomes, as well as side effects or complications, were less studied. We identified some open label extension studies from short term RCTs (n = 10) that evaluated outcome up to 52 weeks, except for one study on atomoxetine of three years. Study II: High number of childhood hyperactive-impulsive symptoms and overall severity of childhood ADHD-symptoms were significantly associated with high drop-out rates from school (OR = 3.0), while persisting ADHD inattentive symptoms (OR = 2.5) and comorbid mental disorders (OR = 1.6) in adulthood were more related to the proportion with long-term work disability. Study III: A total of 232 patients (93%) starting medical treatment completed examination at 12-months, and 70% of them persisted on medication, most commonly methylphenidate, while 30% had discontinued medication. Longitudinal analyses showed significant associations between sustained improvement of symptoms and global functioning measures, and staying on medication. Comorbid mental disorders and adverse effects of medication were related to both lower effectiveness, and reduced adherence to treatment. No serious adverse events were observed. Conclusions: Study I: The literature on long-term effects of ADHD-medication in adults was scarce and primarily naturalistic. The results suggested that pharmacological treatment of ADHD leads to less symptoms, better self-esteem, higher educational levels and occupational status, fewer accidents, and less delinquency compared to non-treatment, and medication was well tolerated. Study II: Higher levels of untreated childhood ADHD hyperactive-impulsive symptoms and overall severity of ADHD symptoms were associated with lower level of basic education. Persisting ADHD inattention symptoms and comorbid mental disorders in adulthood were more related to long-term work disability. Study III: Among stimulant-naïve adults with ADHD 70% continued on medication at one-year follow-up, and treatment with stimulants or atomoxetine was associated with a clinically significant reduction in ADHD symptoms and mental distress, and improvement on measure of global function. In a general clinical setting one-year treatment with ADHD medications were associated with significant improvements of patients who continued on medication compared with those who discontinued. Given the nature of an open-label uncontrolled design, this calls for more controlled studies on medical treatment in a longer time perspective.
List of papers
|Paper I: based on Study I. Fredriksen M, Halmoy A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: A review of controlled and naturalistic studies. Eur Neuropsychopharmacol 2013;23:508-27. The paper is not available in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.euroneuro.2012.07.016|
|Paper II: based on Study II. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Faraone SV, Peleikis DE. Childhood and persistent ADHD symptoms associated with educational failure and long-term occupational disability in adult ADHD. ADHD Atten Def Hyp Disord 2014 Jun;6(2):87-99. The published version is available at: https://doi.org/10.1007/s12402-014-0126-1|
|Paper III: based on Study III. Fredriksen M, Dahl AA, Martinsen EW, Klungsøyr O, Haavik J, Peleikis DE. Effectiveness of one-year pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD): An open-label prospective study of time in treatment, dose, side-effects and comorbidity. Eur Neuropsychopharmacol, submitted 2014. The paper is not available in DUO due to publisher restrictions.|