Here are some important points regarding nonstimulants in the treatment of adults with ADHD.
- Tricyclic antidepressants and bupropion are second-line therapies.
- Antidepressant dosing of the agents appears necessary for attention deficit hyperactivity disorder efficacy.
- Serotonergic medications do not appear effective in the treatment of core attention deficit hyperactivity disorder symptoms but may be useful for comorbid anxiety and depression.
- Cholinergic-enhancing medications may have a role in improving areas of inattention, but data are limited.
- There is an empiric role for antihypertensives in aggression and tic disorders.
- Empiric use of combinations may be appropriate in refractory and comborbid patients.
Within the past two decades, the tricyclic antidepressants (TCAs) have been used as alternatives to the stimulants for attention deficit hyperactivity disorder in pediatrics (). Despite an extensive experience with children and adolescents (), there are only two studies of these agents in adult ADHD. Compared to the stimulants, TCAs have negligible abuse liability, once-daily dosing, and efficacy for comorbid anxiety and depression.
An initial chart review indicated that desipra-mine or nortriptyline, often in combination with other psychotropics including stimulants, resulted in moderate improvement that was sustained at one year (). A controlled trial of desipramine with a target dose of 200 mg daily resulted in significant reductions in attention deficit hyperactivity disorder symptoms in adults (). In that study, response was noted during the initial titration at two weeks, which continued to improve at the six-week endpoint. Whereas a minority of subjects responded to <100mg daily, the majority required more robust dosing (mean of 150 mg daily) for efficacy.
Generally, TCA daily doses of 50-250 mg are required, with a relatively rapid response to treatment (i.e., two weeks) when the appropriate dose is reached. Tricyclic antidepressants should be initiated at 25 mg and slowly titrated upward within dosing and serum level parameters until an acceptable response or intolerable adverse effects are reported. Common side effects of the TCAs include dry mouth, constipation, blurred vision, weight gain, and sexual dysfunction. While cardiovascular effects of reduced cardiac conduction, elevated blood pressure, and heart rates are not infrequent, if monitored they rarely prevent treatment. Because serum TCA levels are variable, they are best used as guidelines for efficacy and to reduce CNS and cardiovascular toxicity.
Recently, the atypical, stimulant-like antidepressant bupropion (Wellbutrin*) has been reported to be moderately helpful in reducing attention deficit hyperactivity disorder symptoms in children () and adults (). In an open study of 19 adults treated with an average of 360 mg of bupropion for 6-8 weeks, Wender and Reimherr () reported a moderate-to-marked response in 74% of adults in the study (five dropouts), with sustained improvement at one year noted in 10 subjects. Despite the small numbers of adults studied, bupropion may be helpful in ADHD, particularly when associated with comorbid mood instability or in adults with cardiac abnormalities (). Bupropion should also be started at very low doses (37.5 mg) and titrated upward weekly to a maximal dose of 450 mg per day. attention deficit hyperactivity disorder adults may benefit from the long-acting bupropion preparation. Bupropion appears to be more stimulating than other antidepressants, and it is associated with a higher rate of drug-induced seizures than other antidepressants (). These seizures appear to be dose related (>450mg/day) and elevated in patients with bulimia or a previous seizure history. Bupropion has also been associated with excitement, agitation, increased motor activity, insomnia, and tremor.
Monoamine Oxidase Inhibitors (MAOIs)
The monoamine oxidase inhibitor antidepressants have also been studied for the treatment of ADHD. Whereas open studies with pargyline and deprenyl in adult attention deficit hyperactivity disorder showed moderate improvements (), a more recent controlled trial of selegeline (Deprenyl) yielded less enthusiastic findings (). Ernst et al. reported dose-dependent improvements in attention deficit hyperactivity disorder symptoms on selegeline, which were not significant when compared to a high placebo response. Although a pilot child-based study demonstrated efficacy of the reversible monoamine oxidase inhibitor moclobemide, data of its effectiveness for attention deficit hyperactivity disorder are not available in adults. The monoamine oxidase inhibitors may have a role in the management of treatment-refractory, nonimpulsive adult attention deficit hyperactivity disorder subjects with comorbid depression and anxiety, who are able to comply with the stringent requirements of these agents. The concerns of diet- or medication-induced hypertensive crisis limit the usefulness and safety of these medications, especially in a group of attention deficit hyperactivity disorder patients vulnerable to impulsivity. Additionally, other adverse effects associated with the monoamine oxidase inhibitors include agitation or lethargy, orthostatic hypotension, weight gain, sexual dysfunction, sleep disturbances, and edema, often leading to the discontinuation of these agents ().
Serotonin-reuptake inhibitors (SRIs). The selective serotonin-reuptake inhibitors do not appear to be effective for attention deficit hyperactivity disorder (); however, venlafaxine, an antidepressant with both serotonin and noradrenergic properties, may have anti-ADHD efficacy. In three open studies totaling 41 adults, 75% of adults who tolerated venlafaxine had a measurable reduction in their attention deficit hyperactivity disorder at doses of 75-150 mg daily (). Although further controlled trials are necessary to determine its optimal dosing and efficacy, venlafaxine is generally titrated from 25 mg daily to more typical anti-depressant dosing of between 150 and 225 mg daily for attention deficit hyperactivity disorder control. Side effects to venlafaxine in adults include nausea, gastrointestinal distress, anorgasmia, and concerns of elevated blood pressure at relatively higher dosing. Patients may experience discontinuation symptoms if the medication is stopped rapidly. Venlafaxine is often used conjointly with stimulants for control of attention deficit hyperactivity disorder in adults.
The antihypertensives clonidine and guanfacine have been used in childhood ADHD, especially in cases with a marked hyperactive or aggressive component (). However, because of a lack of efficacy data and concerns of their sedative and hypotensive effects, their use in adults remains dubious. Beta-blockers may be helpful in adult attention deficit hyperactivity disorder but remain unstudied under controlled conditions (). One small open study of propranolol for adults with attention deficit hyperactivity disorder and temper outbursts indicated improvement in both the attention deficit hyperactivity disorder symptoms and outbursts at daily doses of up to 640mg/day (). Beta-blockers when added to stimulants have also been reported to be helpful for attention deficit hyperactivity disorder in three adults (), although it may be that this combination was helpful by reducing the stimulant-induced adverse effects.
Trials with the amino acids were in part undertaken with the assumptions that attention deficit hyperactivity disorder may be related to a deficiency in the catecholaminergic system and that administration of precursors of these systems would reverse these deficits. The results of open studies with L-DOPA and tyrosine and controlled studies of phenylalanine in adults with attention deficit hyperactivity disorder have generally been disappointing, despite robust dosing and adequate trial duration (). In these studies, transient improvement in attention deficit hyperactivity disorder was lost after two weeks of treatment.
More recently, the relationship of nicotine and attention deficit hyperactivity disorder has attracted attention, including findings of higher-than-expected overlap of cigarette smoking in attention deficit hyperactivity disorder children () and adults (). One small study of two days’ duration showed a significant reduction in attention deficit hyperactivity disorder symptoms in adults wearing standard-size nicotine patches (). Moreover, the authors have observed the efficacy of the nicotine patch in reducing attention deficit hyperactivity disorder symptoms in smokers who report the emergence of attention deficit hyperactivity disorder symptoms with cigarette cessation. Donepezil, a cholinesterase inhibitor, increases the bioavailability of acetylcholine and has been found to improve memory and attention in Trisomy-21 and traumatic brain injury (). Data on donepezil in attention deficit hyperactivity disorder are limited to case series in children and adolescents (). ABT-418 is a selective and potent nicotinic cholinergic agonsit. In the one published study, symptoms of inattention improved preferentially over symptoms of impulsivity and hyperactivity. The effect was more gradual than with methylphenidate and it was associated with some dizziness. Although compelling, the role of cholinergic medications in treatment of attention deficit hyperactivity disorder remains to be further defined.
Modfanil is a nonstimulant medication used in the treatment of narcolepsy. Its main effects appear to be on the hypothalamus rather than on central dopaminergic or noradrenergic pathways. Despite anecdotal reports of its usefulness in ADHD, initial trials demonstrated no benefit over placebo, and manufacture-sponsored trials were discontinued. It may have a role in cases of refractory ADHD.
Medications Under Investigation
Tomoxetine, an investigational antidepressant with selective noradrenergic-reuptake inhibitor properties, is under study for the treatment of attention deficit hyperactivity disorder in children, adolescents, and adults (). In one controlled trial with adults, average daily doses of 76 mg were well tolerated and moderately effective in reducing core attention deficit hyperactivity disorder symptomology. Full therapeutic benefit may have been compromised by the short duration of the study (). Although time to response with tomoxetine appears longer compared to the stimulants, it will likely provide an excellent alternative to the stimulants in patients with comorbid mood, anxiety, and/or substance use disorders. Reboxetine, a highly selective noradrenergic-reuptake inhibitor, is expected to be available in the United States soon. Although it has not been formally studied for the treatment of ADHD, clinicians may consider using it as an alternative for the treatment of attention deficit hyperactivity disorder with comorbid mood, anxiety, and substance use disorders. The investigational antidepressants S-adenosylmethionine and nomifensen have also been shown to be effective for attention deficit hyperactivity disorder in adults, although they remain unstudied under controlled conditions (). GW320659 is a relatively short-acting noradrenergic/dopaminergic-reuptake inhibitor under study for attention deficit hyperactivity disorder in children and adolescents (). Although it remains unstudied in adults with ADHD, Phase II trials demonstrated reductions of 20% in Conners Teachers Rating Scales and a half-life of 7 hours with linear pharmacokinetics.
Selections from the book: “Clinician’s Guide to Adult ADHD: Assessment and Intervention (Practical Resources for the Mental Health Professional)”. Edited by Sam Goldstein and Anne Teeter Ellison, 2002.