Pharmacotherapy of Adult ADHD

By | April 8, 2015

Originally conceptualized as a disorder of childhood (), attention deficit hyperactivity disorder (ADHD) is increasingly recognized in adults. attention deficit hyperactivity disorder is estimated to affect 2-9% of school-age children and up to 5% of adults (). Although some investigators question the persistence of attention deficit hyperactivity disorder in adulthood (), long-term controlled follow-up studies of young adults diagnosed with attention deficit hyperactivity disorder in childhood demonstrate persistence of the syndrome in up to 60% (). While some clinicians remain skeptical of adult attention deficit hyperactivity disorder (), evidence supports the descriptive, face, predictive, and concurrent validity of the syndrome in adults (). Adults with attention deficit hyperactivity disorder present with a developmental derivation of symptoms similar to those of children, notably inattention/distractibility followed by hyperactivity-impulsivity. Comorbidity with mood, anxiety, substance use, and antisocial disorders are common in adults with ADHD.

Like children, pharmacotherapy is a mainstay of treatment for attention deficit hyperactivity disorder in adults. Despite the large amount of data on pharmacotherapy of attention deficit hyperactivity disorder in children, there is a limited number of medication studies in adults with the disorder. Most controlled investigations in adults with attention deficit hyperactivity disorder have studied the stimulants. As with children, there tends to be a dose-related improvement in attention deficit hyperactivity disorder symptoms with the stimulant medications in adults. This literature supports the stimulants as the most effective available treatment for attention deficit hyperactivity disorder symptoms in adults. Several nonstimulant alternatives have been investigated. Although these data are limited, medications with catecholaminergic activity appear to have efficacy, whereas those with predominately serotonergic properties appear ineffective in the treatment of core attention deficit hyperactivity disorder symptomology. Incases with psychiatric comorbidity, residual symptoms, or adverse effects, clinical experience, coupled with a small literature, supports combining medications, such as the stimulants and antidepressants. Often, cognitive/behavioral-based psychotherapies are necessary in conjunction with medication in order to fully address executive function deficits, dynamic issues (within individual and family), residual symptomatology, as well as comorbid psychopathology in adults with ADHD. Future controlled studies applying stringent diagnostic criteria and outcome methodology are necessary to enhance the range of pharmacotherapeutic options for adults with ADHD.

Overview of the neurobiology and genetics of adhd

The Neurobiology and genetics of attention deficit hyperactivity disorder includes the following characteristics.

  • Highly familial disorder with heritability estimated to be 0.8
  • Primary disturbance of catecholamine neurotransmission
  • Anterior cingulate, frontal cortex, basal ganglia, corpus callosum, and cerebellum manifest decreased size in ADHD
  • Variations in genes that code for dopamine transporter protein (DAT) and dopamine D4 receptor (DRD4) associated with distinct attention deficit hyperactivity disorder subtypes
  • No current role for neuroimaging or genetic testing in diagnosis of attention deficit hyperactivity disorder in clinical practice (but stay tuned)

The pharmacotherapy of attention deficit hyperactivity disorder is related directly to our understanding of its the pathophysiology. Although the exact neural and pathophysiological substrate remain unknown, an emerging neuropsychological and neuroimaging literature supports our understanding of attention deficit hyperactivity disorder as a disorder involving dysregulation of the frontal networks and/ or frontostriatal dysfunction. The neurochemical dysfunction in attention deficit hyperactivity disorder appears to be mediated by dopaminergic and adrenergic systems, with little direct influence by the serotonergic systems (). Stimulants, the most effective treatment for ADHD, block the reuptake of dopamine and norepinephrine presynaptically and simultaneously increase the release of these monoamines into the extraneuronal space (). Similar pharamcodynamic effects are reported with those antidepressants (tricyclic antidepressants and bupropion) effective for ADHD. While recent reports using data from animal models speculate on a role for serotonin in the pathophysiology of attention deficit hyperactivity disorder (), serotonergic dysregulation does not appear integral in the pathophysiology of ADHD. Additionally, medications, which increase serotonin, have not been shown to be useful for core attention deficit hyperactivity disorder symptomatology. Although cholinergic modulation of temporal memory has been investigated (), the effects of cholinergic-enhancing agents on ADHD, as well as dopaminergic and other neurotransmitter systems, are currently under investigation (). Regions of the brain, including the anterior cingulate, frontal cortex, basal ganglia, corpus callosum, and cerebellum, all show diminished size when individuals with attention deficit hyperactivity disorder are compared to individuals without the disorder. Similarly, functional-imaging studies in adults with attention deficit hyperactivity disorder demonstrate reduced global metabolism in catecholamine-rich areas of the brain (). Contributions from family, adoption, and twin studies strongly support the neurobiological basis of attention deficit hyperactivity disorder and suggest that genetic risk factors are operant in this disorder (). Recent work form molecular genetics focuses on the association of attention deficit hyperactivity disorder with various genes, including rare mutations in the human thyroid receptor-3 gene on chromosome 3 (), the D4 receptor gene on chromosome 11 (), as well as the dopamine transporter gene on chromosome 5 (). Conversely, increased density of presynaptic dopamine transporter proteins (DATs) has been associated with certain subtypes of ADHD, especially in patients with significant hyperactivity and impulsivity (). This increased density of DATs appears to be a trait that is transmittable across generations. Thus, ligands specific for DATs (e.g., Altropane and TRODAT-1) are being actively investigated. A recent letter describes significantly increased DAT density in a group of six adults with attention deficit hyperactivity disorder compared to controls. Similarly, Krause et al., using single photon emission tomography (SPECT) with the ligand TRODAT-1, demonstrated increased striatal DAT density in adults with ADHD, which was normalized using methylphenidate (). These exciting developments have implications for our understanding and identification of various subtypes of ADHD, in the diagnosis of ADHD, and perhaps as an a priori method of identifying the best medication for individual patients. However, at this time the use of genetic testing and neuroimaging is not necessary in clinical practice.

Clinical features of ADHD in adults

Adults with attention deficit hyperactivity disorder typically present with the following clinical picture:

  • Problems with regulating attention and concentration
  • Disorganization, failure to plan ahead, forgetfulness
  • Poor time management skills
  • Difficulty initiating and completing tasks
  • Difficulties in job, parenting, marriage
  • While adults with attention deficit hyperactivity disorder usually can be relied on to accurately report their symptoms, additional informants often helpful

Adults with attention deficit hyperactivity disorder usually describe symptoms of poor attention, lack of concentration, easy distractibility, shifting activities, daydreaming, and forgetfulness (). They often begin one task and then find themselves in the middle of several projects. These patients appear to have a poorly developed sense of time and are often harried and late. They lose or misplace important personal items, such as keys and work and family projects. They usually avoid tasks that require high levels of concentration and patience, such as balancing a checkbook, filing tax returns, and helping children with homework. Projects are often put off until the last minute, at which time they often are highly motivated and are able to hyperfocus. Often these patients are drawn to novel stimuli, usually at the expense of the designated object of their attention. Their boredom or intrusiveness often compromises conversations with.25 coworkers, spouses, or children. Others frequently view adults with attention deficit hyperactivity disorder as either flighty or egotistical. Adults with attention deficit hyperactivity disorder seem to have difficulty regulating their attention, which leads to repeated problems as they attempt to manage affairs at work, home, or with friends.

Additionally, these patients report symptoms of impulsivity, impatience, boredom, fidgetiness, and intrusiveness (). These symptoms are often evident in the context of social situations. Frequently, adults with attention deficit hyperactivity disorder have long histories of social impairment and are often perceived as aloof (because they become easily bored) or as self-centered (because they interrupt or make socially inappropriate comments). Others are quite gregarious and talkative, “the life of the party,” almost an adult equivalent of the class clown. Adults with attention deficit hyperactivity disorder have a sense of urgency and immediacy to their lives and have little tolerance for frustration, delay, or planning. They are easily irritated while waiting in lines and often make decisions without proper consideration of alternatives. Collaboration with others is often a mutually frustrating experience. Also, young adults with attention deficit hyperactivity disorder experience increased rates of traffic accidents, traffic violations, and license suspensions (). Finally, symptoms of overt hyperactivity may be diminished, for many patients have developed compensatory strategies to diminish these symptoms. Recent data support the clinical observation that symptoms of hyperactivity-impulsivity decline over time while symptoms of inattention persist (). Overall, these investigators note that most patients with attention deficit hyperactivity disorder continue to struggle with a substantial number of symptoms and a high level of impairment.

Adults with attention deficit hyperactivity disorder are thought to have deficits of working memory, as exemplified by less ability to attend to, encode, or manipulate information (). Such deficits in working memory have recently been shown to decrease the ability to filter out distractions, and may contribute to symptoms of inattention in adults with attention deficit hyperactivity disorder (). Although less defined within ADHD, organizational difficulties and procrastination also appearcommon.

Like children with ADHD, adults with the disorder may be stubborn and demoralized and have low self-esteem (). Relationships with family, friends, and employers are often conflicted, which may contribute to high rates of separation and divorce, as well as to the academic and occupational underachievement characteristic of these adults (). Compared to their non-ADHD peers, adults with attention deficit hyperactivity disorder have increased rates of anxiety, depression, and substance use disorders ().

Assessment and diagnosis of ADHD in adults

The assessment and diagnosis of attention deficit hyperactivity disorder in adults has the following features.

  • DSM-IV is the gold standard.
  • Several available scales and available to aid assessment, including the Brown Attention Deficit Disorder Scales, Conners Adult Attention Deficit Scale, DuPaul attention deficit hyperactivity disorder Rating Scale, and the Wender Utah Rating Scale.
  • Recent reports validate the reliability of data collected from adults with ADHD.
  • There is a potential for use of neuroimaging and genetic testing to identify certain subtypes of ADHD.
  • Disentangling comorbidities and associated impairments (e.g., executive functions) are a prime clinical challenge.

ADHD can be diagnosed in adults by carefully querying for developmentally appropriate criteria from the DSM-IV (American Psychiatric Association, 1994), attendingto achildhood onset of symptoms, persistence through adolescence, and current presence of symptoms as well as impairment. Self-report scales, such as the Brown-ADD Scale () and the DuPaul scale (), may assist in the evaluation and monitoring of attention deficit hyperactivity disorder in adults. Recently, the Conners Adult attention deficit hyperactivity disorder Rating Scale (CAARS) demonstrated high sensitivity and specificity, with an overall diagnostic efficiency of 85% (). These instruments have generally sound psychometric properties and may be used to aid in diagnosis as well as to assess treatment response. The Wender Utah Rating Scales may be used to aid diagnosis rather than to monitor treatment (). A variety of issues arise in the assessment and diagnosis of attention deficit hyperactivity disorder in adults. First, the appropriate diagnosis of attention deficit hyperactivity disorder in adults relies on the accurate recall of childhood symptoms and a reliable account of current symptoms and their impact. Some clinicians have questioned the reliability of adults with attention deficit hyperactivity disorder to accurately report this information (). Recently, Murphy and Schachar evaluated correlation of symptoms between adults with attention deficit hyperactivity disorder and other informants (). Diagnostic information is obtained from the patient and, whenever possible, from significant others, such as partners, parents, siblings, and close friends. If ancillary data are not available, information from an adult is acceptable for diagnostic and treatment purposes, because adults with ADHD, as with other disorders, are appropriate reporters of their own condition. Careful attention should be paid to the childhood onset of symptoms, the longitudinal history of the disorder, and a differential diagnosis, including medical/neurological as wellpsychosocial factors contributing to the clinical presentation. Neuropsychological testing should be used in cases in which learning disabilities are suspected or when learning problems persist in the presence of a treated attention deficit hyperactivity disorder adult ().

Differential Diagnosis

A variety of medical and psychiatric conditions should be considered as part of the evaluation of attention deficit hyperactivity disorder within adults. Such conditions include sleep disorders, headaches, visual and auditory disorders, seizure disorders, endocrine disorders; hepatic function; use of illicit substances as well as herbal remedies, impact of concurrent medications on cognition (e.g., anticholinergic or antihypertensive medications). Laboratory tests, such as thyroid studies, EEG, baseline EKG, and baseline hepatic function tests, are generally not necessary unless indicated by the patient’s symptoms or family history. Additionally, clinicians should obtain a history of anxiety disorders (including trauma), mood disturbances (including bipolar disorder), current and past substance use, aggression and impulse control problems, legal involvement, psychosis. In addition, current stresses as well as issues involving the patient’s adherence are important to the overall treatment plan.

Disentangling Comorbidities

In adults with ADHD, issues of comorbidity with learning disabilities and other psychiatric disorders need to be addressed (). Since alcohol and drug use disorders are frequently encountered in adults with attention deficit hyperactivity disorder (), a careful history of substance use should be completed. A Patient with ongoing substance abuse or dependence should generally not be treated until appropriate addiction treatments have been undertaken and the patient has maintained a drug and alcohol free period. Our experience attempting to treat adults with attention deficit hyperactivity disorder and ongoing substance use disorders indicates the necessity of addressing the comorbid substance use first and then reassessing and treating the ADHD. Other concurrent psychiatric disorders also need require evaluation. In subjects with attention deficit hyperactivity disorder plus bipolar mood-disorders, for example, the risk of mania needs be addressed and closely monitored during the treatment of the ADHD. In cases such as these, the conservative introduction of anti-ADHD medications along with mood-stabilizing agents should be considered.

Since learning disabilities do not respond to pharmacotherapy, it is important to identify such deficits to help define remedial interventions. For instance, this evaluation may assist in the design and implementation of an educational plan for the adult who is considering returning to school, or serve as an aid for structuring the current work environment. Appropriate remedial strategies should be employed to address the morbidity of these factors at work and in school.

General principles of pharmacotherapy of ADHD in adults

Despite increased recognition that children with attention deficit hyperactivity disorder commonly grow up to be adults with the same disorder, the treatment of this disorder in adults remains under intense study. In addition, complicating the diagnostics and treatment strategy, many adults with attention deficit hyperactivity disorder have depressive and anxiety symptoms as well as histories of drug and alcohol dependence or abuse (). Thus, with the increasing recognition of the complex presentation of adults with ADHD, there is a need to develop effective pharmacotherapeutic strategies. In the following sections, guidelines for pharmacotherapy will be delineated, the available information on the use of medications for adult attention deficit hyperactivity disorder reviewed, and pharmacologic strategies suggested for the management of attention deficit hyperactivity disorder symptoms with accompanying comorbid conditions.

Pharmacotherapy should be part of a treatment plan in which consideration is given to all aspects of the patient’s life. Hence, it should not be used exclusive of other interventions. The administration of medication to adults with attention deficit hyperactivity disorder should be undertaken as a collaborative effort with the patient, with the physician guiding the use and management of efficacious anti-ADHD agents. The use of medication should follow a careful evaluation of the adult, including medical, psychiatric, social, and cognitive assessments.

Stimulants in the treatment of adults with ADHD

Nonstimulant medications in the treatment of adults with ADHD

Clinical strategies for the pharmacotherapy of ADHD in adults

Basic clinical strategies for the pharmacotherapy of adults with attention deficit hyperactivity disorder include the following.

  • Set clear, realistic treatment goals with the patient.
  • Stimulants are the first-line medications.
  • If the first stimulant is not effective or tolerated, consider an alternative stimulant.
  • When comorbidites are present, prioritize treatment.
  • Use additional therapies to support and complement the effects of medication.
  • Use remedial services to support the patient in work and educational settings.

Once you have established the diagnosis of attention deficit hyperactivity disorder as the primary current problem, patients should be familiarized with the risks and benefits of pharmacotherapy, the availability of alternative treatments, the likelihood of adverse effects, as well as the prognosis both with and without medications. Patient expectations need to be explored and realistic goals of treatment denned. Likewise, the clinician should educate the patient that each medication trial requires adherence to the dosing regimen as well as using clinically meaningful doses of the medication for a reasonable duration of time. Patients with substantial psychiatric comorbidity, who have residual symptomatology with treatment, or who report psychological distress related to their attention deficit hyperactivity disorder (i.e., self-esteem issues, self-sabotaging patterns, interpersonal disturbances) should be directed to appropriate psychotherapeutic intervention with clinicians knowledgeable in attention deficit hyperactivity disorder treatment.

Stimulant medications are considered the first-line therapy for attention deficit hyperactivity disorder in adults (). Given the high variability in effective dose, stimulants are typically started at low doses (e.g., Ritalin 5mg, Concerta 18mg, Metadate 10mg, Adderall 5 mg, Dexedrine 5 mg) in the morning and gradually titrated up. Tolerance of the medication as well as the time of effect should be noted by the patient. It is often clinically helpful for the adult to ask for observations from significant others regarding the effects of the medication; however, if no one is available, data from the patients can be relied on (). Decisions on how many doses a day and how many days of the week to take the medication should be tailored for each patient (). Consideration of another stimulant or class of agents is recommended if an attention deficit hyperactivity disorder adult is unresponsive or has intolerable side effects to the initial medication. The use of TCAs and bupropion can improve anti-ADHD response to the stimulants, whereas the SRI and other antidepressants can be used adjunctly for comorbid depression, anxiety, or obsessive-compulsive disorder. The effect of age, long-term adverse effects, and stimulant use in substance abusing subgroups of attention deficit hyperactivity disorder remains unstudied. Monitoring of routine side effects, vital signs, and the misuse of the medication is warranted.

The antidepressants, namely, TCAs and bupropion, are less well studied, appearing useful for stimulant nonresponders or adults with concurrent psychiatric disorders, including depression, anxiety, and active or recent substance abuse (). Comparative data between the antidepressants and stimulants coupled with studies in children support that stimulants are generally more effective in reducing attention deficit hyperactivity disorder symptoms (). In addition, the response to the stimulants is rapid (), while antidepressants demonstrate improvement up to four weeks after titration (). Although some adults may respond to relatively low doses of the TCAs (), the majority of adults appear to require solid antidepressant dosing of these agents (i.e., desipramine >150mg daily). Selegiline, a short-acting MAO-B inhibitor used primarily for Parkinson’s disease, has some potential benefit in adults with ADHD. Monoamine oxidase inhibitors are mildly effective and are generally reserved for treatment-refractory adults who can reliably follow the dietary requirements. The antihypertensives may be useful in adults with attention deficit hyperactivity disorder and aggressive outbursts (), tic disorders, impulse control disorders, or bipolar disorder or those with adverse effects to first- and second-line medications. The amino acids have not been shown effective, and the cholinergic-enhancing compounds remain to be studied comprehensively in attention deficit hyperactivity disorder adults.

Combined pharmacotherapy

Although systematic data assessing the efficacy and safety profile of combining agents for attention deficit hyperactivity disorder in adults are lacking, empiric use of combination treatment may be necessary in those who have residual symptomatology with single agents or psychiatric comorbidity. For example, in a recent naturalistic report on TCAs for adults with ADHD, 84% of adults were receiving additional psycho-active medications, with 59% receiving adjunctive stimulants (). These findings are similar to controlled data in juvenile ADHD, in which the combination of methylphenidate and desipramine improved the attention deficit hyperactivity disorder response more than either agent singly (). The use of methylphenidate conjointly with fluoxetine has been reported to be well tolerated and useful in improving depression in attention deficit hyperactivity disorder adolescents () and appears useful in adults with the same comorbidity. In cases of partial response or adverse effects with stimulants, the addition of low-dose SRIs, TCAs, or beta-blockers has been reported to be helpful). While the stimulants appear to be well tolerated with TCAs and SRIs (), clinicians should consider potential drug interactions as have been described between TCAs and some SRIs ().

Managing Suboptimal Responses

Despite the availability of various agents for adults with ADHD, there appears to be a number of individuals who either do not respond or are intolerant of the adverse effects of medications used to treat their ADHD. In managing difficult cases, several therapeutic strategies are available (). If adverse psychiatric effects develop concurrent with a poor medication response, alternate treatments should be pursued. Severe psychiatric symptoms that emerge during the acute phase can be problematic, irrespective of the efficacy of the medications for ADHD. These symptoms may require reconsideration of the diagnosis of attention deficit hyperactivity disorder and careful reassessment of the presence of comorbid disorders. For example, it is common to observe depressive symptoms in an attention deficit hyperactivity disorder adult that are independent of the attention deficit hyperactivity disorder or treatment. If reduction of dose or change in preparation (i.e., regular vs. slow-release stimulants) does not resolve the problem, consideration should be given to alternative treatments. Neuroleptic medications should be considered as part of the overall treatment plan in the face of comorbid bipolar disorder or extreme agitation. Concurrent nonpharmacologic interventions such as behavioral or cognitive therapy may assist with symptom reduction.

Combining Psychotherapies with Medications

Although the efficacy of various psychotherapeutic interventions remains to be established, a retrospective assessment of adults with attention deficit hyperactivity disorder indicated that traditional insight-oriented psychotherapies were not helpful for attention deficit hyperactivity disorder adults (). A cognitive therapy protocol adapted for adults with attention deficit hyperactivity disorder has been developed that preliminary data suggest is effective when used with pharmacotherapy ().

Pharmacotherapy of Adult ADHD: Summary

The aggregate literature supports the notion that pharmacotherapy provides an effective treatment for adults with ADHD. Effective pharmacological treatments for attention deficit hyperactivity disorder adults to date have included the use of the psychostimulants and anti-depressants, with unclear efficacy of cognitive enhancers. Structured psychotherapy may be effective when used adjunctly with medications. Groups focused on coping skills, support, and interpersonal psychotherapy may also be very useful for these adults. For adults considering advanced schooling, educational planning and alterations in the school environment may be necessary. Further controlled investigations assessing the efficacy of single and combination agents for adults with attention deficit hyperactivity disorder are necessary, with careful attention to diagnostics, symptom and neuropsychological outcome, long-term tolerability and efficacy, and use in specific attention deficit hyperactivity disorder subgroups.

 

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.