Pharmacodynamic Properties of Stimulants

Stimulants increase intrasynaptic concentrations of dopamine (DA) and norepinephrine (NE).^25–29 MPH primarily binds to the DA transporter protein (DAT), blocking the reuptake of DA, increasing intrasynaptic DA.^26,29 While amphetamines diminish presynaptic reuptake of DA by binding to DAT, these compounds also travel into the DA neuron, promoting release of DA from reserpine-sensitive vesicles in the presynaptic neuron.^26,27 In addition, stimulants (amphetamine > MPH) increase levels of NE and serotonin (5-HT) in the interneuronal space.²⁵ Although group studies comparing MPH and amphetamines generally demonstrate similar efficacy,²⁰ their pharmacodynamic differences may explain why a particular patient may respond to, or tolerate, one stimulant preferentially over another. It is necessary to appreciate that while the efficacy of amphetamine and MPH is similar, their potency differs, such that 5 mg of amphetamine is approximately equally potent to 10 mg of MPH.

Clinical Use of Stimulants

Guidelines regarding the use of stimulant medications in children, adolescents, and adults in clinical practice have been published.²⁰ Treatment with immediate-release preparations generally starts at 5 mg of MPH or amphetamine once daily and is titrated upward every 3 to 5 days until an effect is noted or adverse effects emerge. Typically, the half-life of the short-acting stimulants necessitates at least twice-daily dosing, with the addition of similar or reduced afternoon doses dependent on breakthrough symptoms. In a typical adult, dosing of immediate-release MPH is generally up to 30 mg three to four times daily or amphetamine 15 to 20 mg three to four times a day. Currently, most adults with ADHD will be treated with a stimulant that has an extended delivery.²⁰

Side Effects of Stimulants

Although generally well tolerated, stimulants can cause clinically significant side effects (including anorexia, nausea, difficulty falling asleep, obsessiveness, headaches, dry mouth, rebound phenomena, anxiety, nightmares, dizziness, irritability, dysphoria, and weight loss).^20,64,65 Rates and types of stimulant side effects appear to be similar in ADHD patients, regardless of age. In patients with a current co-morbid mood/anxiety disorder, clinicians should consider whether an adverse effect reflects the co-morbid disorder, a side effect of the treatment, or an exacerbation of the co-morbidity. Moreover, while stimulants can cause these side effects, many ADHD patients experience these problems before treatment; therefore, it is important for clinicians to document these symptoms at baseline.⁶⁴ Recommendations about management of common side effects are listed in Table 49-2.

Table 49-2 Strategies in Challenging ADHD Cases

Medication Interactions with Stimulants

The interactions of stimulants with other prescription and nonprescription medications are generally mild and not a major source of concern.^83,84 Concomitant use of sympathomimetic agents (e.g., pseudoephedrine) may potentiate the effects of both medications. Likewise, excessive intake of caffeine may potentially compromise the effectiveness of the stimulants and exacerbate sleep difficulties. Although data on the co-administration of stimulants with tricyclic antidepressants (TCAs) suggest little interaction between these compounds,⁸⁵ careful monitoring is warranted when prescribing stimulants with either TCAs or anticonvulsants. Although administering stimulants with ATMX is common clinical practice, and appears to be safe, well tolerated, and effective based on clinical experience, to date only small samples have been studied; therefore, patients taking this combination should be monitored closely.⁸⁶ In fact, co-administration of stimulants with MAOIs is the only true contraindication.

Despite the increasing use of stimulants for patients with ADHD, many of them may not respond, experience untoward side effects, or manifest co-morbidity, which stimulants may exacerbate or be ineffective in treating.^18,87,88 Over the last 10 years ATMX has been systematically evaluated and is FDA-approved for the treatment of ADHD in children, adolescents, and adults.³⁰

Cardiovascular Safety of ADHD Treatments

The PDAC cited the baseline rate of sudden unexplained death in the pediatric population to range from 0.6 to 6 occurrences per 100,000 patient-years.¹⁰⁷ From the FDA’s research, the PDAC presented data indicating that the rates of sudden unexplained death in the pediatric population between 1992 and February 2005, treated with MPH, amphetamine, or ATMX, were 0.2, 0.3, and 0.5 cases per 100,000 patient-years, respectively. Based on these data, the PDAC rejected adding a black box warning, but recommended that current labeling language for amphetamine drugs on CV risks in patients with structural cardiac abnormalities should be extended to all medications approved for the treatment of ADHD. Details regarding these issues are provided in two recent reviews.^108,109

The American Heart Association has previously commented on CV monitoring of youths taking psychotropic medications.¹¹⁰ Despite the generally benign CV effects of these medications, caution is warranted in the presence of a compromised CV system (e.g., untreated hypertension, arrhythmias, and known structural heart defects). It remains prudent to monitor symptoms referable to the CV system (e.g., syncope, palpitations, and chest pain) and vital signs at baseline and with treatment in all patients with ADHD. For most pediatric patients it is not necessary to check an ECG at baseline or with treatment. In patients at risk for CV symptoms, it is important to collaborate with the patient’s primary care physician and to ensure that hypertension is not an issue. Recent data from an open-label study of ADHD treatment in adults suggest that if hypertension is well controlled, stimulants may be safely used in the short-term.¹¹¹ Safety remains the paramount concern; thus, in each case the physician and patient must weigh the risks and benefits of treatment.

Aggression during Treatment with ADHD Medications

From the FDA’s research, the PDAC presented data reporting episodes of aggression with all ADHD medications during clinical trials and in postmarketing surveillance. However, aggression in patients with ADHD usually responds to stimulant treatment.¹¹² During clinical trials, rates of aggression were observed to be similar with active and placebo treatment. The PDAC recommended that the decision about whether to continue therapy following an aggression event is complex and that the physician and parent should evaluate whether the risks outweigh the benefits that the child obtains from the treatment.

Psychotic or Manic Symptoms during Treatment with ADHD Medications

The FDA has received hundreds of reports of psychotic or manic symptoms, particularly hallucinations, associated with ADHD medication use in children and adolescents. FDA drug-safety analysts recommended adding warnings to ADHD medication-labeling advising that ADHD medications should be stopped if a patient experiences signs and symptoms of psychosis or mania. A recent review of stimulant trials revealed that psychotic-like or manic-like symptoms might occur in approximately 0.25% of children (or 1 in 400) treated with stimulant medications.¹¹³

In conclusion, the PDAC recommended that a medication guide be issued for all ADHD medications describing the potential psychiatric, aggression, and CV risks and that these risks be clearly elucidated in the product labeling of all ADHD medications. However, the PDAC concluded that potential episodes of psychosis, aggression, suicidality, and cardiac events during treatment with ADHD medications in children do not warrant a black box warning.

Currently the only black box warning for stimulants warns about the potential for substance abuse.

Bupropion

Bupropion hydrochloride (Wellbutrin), a unicyclic aminoketone, approved for treatment of depression and as an aid for smoking cessation in adults,³⁰ has been reported to be moderately helpful in reducing ADHD symptoms in children, adolescents,^114–116 and adults.^117–119 Although helpful, the magnitude of effect of bupropion is less than that seen with either stimulants or ATMX. Bupropion is often used in patients with ADHD and co-morbidities and has been studied in small groups of adolescents with ADHD and nicotine dependence,¹²⁰ substance use and mood disorders,¹¹⁷ substance abuse and conduct disorder,¹²¹ and depression.¹²² In light of the high rates of marijuana use in patients with ADHD,¹²³ it is important for clinicians to note that adolescents treated with bupropion may experience increased irritability during marijuana withdrawal.¹²⁴ In addition, bupropion has been helpful in ADHD adults with bipolar disorder¹²⁵ or with coexisting cardiac abnormalities.¹²⁶

Bupropion modulates both norepinephrine and DA. It appears to be more stimulating than other antidepressants, may cause irritability, has been reported to exacerbate tics,¹²⁷ and is associated with higher rates of drug-induced seizures than other antidepressants.³⁰ These seizures appear to be dose-related (> 450 mg/day) and more likely to occur in patients with bulimia or seizure disorder, and thus should be avoided in patients with these problems. In ADHD adults, bupropion IR and SR should be given in divided doses, with no single dose of the IR exceeding 150 mg, or SR 200 mg. Dosing for ADHD appears to be similar to that for depression.¹²⁸

Tricyclic Antidepressants

Although controlled trials in ADHD youths¹²⁹ and adults¹³⁰ demonstrate TCAs’ efficacy, the effects are less robust than with stimulants. Compared to the stimulants, TCAs have negligible abuse liability, have once-daily dosing, and may be useful in patients with co-morbid anxiety, ODD,¹³¹ tics,¹³² and, theoretically, depression (adults). However, given concerns about potential cardiotoxicity and the available of ATMX, use of the TCAs has been significantly curtailed.

Before treatment with a TCA, a baseline ECG should be obtained (as well as inquiry into any family history of early-onset or sudden cardiac arrhythmias).¹³³ Dosing for ADHD appears to be similar to that for depression. ECGs should be obtained as the dose is increased. Monitoring serum levels of TCAs is more helpful in avoiding toxicity than it is in determining optimal levels for response.

Common short-term adverse consequences of the TCAs include dry mouth, blurred vision, orthostasis, and constipation. Since the anticholinergic effects of TCAs limit salivary flow, they may cause dental problems. Following the sudden death of a number of children receiving desipramine (DMI), concerns were raised regarding the possible cardiac toxicity of TCAs in children.¹³⁴ However, epidemiological evaluation of the association between DMI and sudden death in children has not supported a causal relationship.¹³⁵ TCAs predictably increase heart rate and are associated with conduction delays, usually affecting the right bundle, thus requiring ECG monitoring.¹³⁶ However, these effects, when small, rarely seem to be pathophysiologically significant in noncardiac patients with normal baseline ECGs. In patients with documented congenital or acquired cardiac disease, pathological rhythm disturbances (e.g., atrioventricular block, supraventricular tachycardia, ventricular tachycardia, and Wolff-Parkinson-White syndrome), family history of sudden cardiac death or cardiomyopathy, diastolic hypertension (> 90 mm Hg), or when in doubt about the CV state of the patient, a complete (noninvasive) cardiac evaluation is indicated before initiation of treatment with a TCA to help determine the risk-benefit ratio of such an intervention. A serious adverse event associated with use of TCAs is overdose. Hence, close supervision of the administration and storage of TCAs is necessary.

Alpha-Adrenergic Agonists

Clonidine, an imidazoline derivative with alpha-adrenergic agonist properties, has been primarily used in the treatment of hypertension.¹³⁷ At low doses, it appears to stimulate inhibitory, presynaptic autoreceptors in the CNS.¹³⁸ Although clonidine reduces symptoms of ADHD,¹³⁹ its overall effect is less than the stimulants,¹⁴⁰ and likely smaller than ATMX, TCAs, and bupropion. Clonidine appears to be particularly helpful in patients with ADHD and co-morbid CD or ODD,^141–143 tic disorders,^144,145 ADHD-associated sleep disturbances,^75,146 and may reduce anxiety and hypervigilance in traumatized children.¹⁴⁷

Clonidine is a relatively short-acting compound with a plasma half-life ranging from approximately 5.5 hours (in children) to 8.5 hours (in adults). Therapy is usually initiated at the lowest manufactured dose of a half or quarter tablet of 0.1 mg. Usual daily doses ranges from 3 to 10 mcg/kg given generally in divided doses, bid, three times daily (tid), or four times daily (qid), and there is a transdermal preparation.¹⁴⁸ The most common short-term adverse effect of clonidine is sedation, which tends to subside with continued treatment. It can also produce, in some cases, hypotension, dry mouth, vivid dreams, depression, and confusion. Overdoses of clonidine in children under 5 years of age may have life-threatening consequences.¹⁴⁹ Since abrupt withdrawal of clonidine has been associated with rebound hypertension, slow tapering is advised.^150,151 In addition, extreme caution should be exercised with the co-administration of clonidine with beta-blockers or calcium channel blockers.¹⁵² Concerns about the safety of co-administration of clonidine with stimulants have been debated.¹⁵³ Current guidelines are to monitor blood pressure when initiating and tapering clonidine, but ECG monitoring is not usually necessary.¹¹⁰

Guanfacine, a more selective, alpha₂-adrenergic agonist compound, has been used as an alternative to clonidine for the same indications.^154,155 Possible advantages of guanfacine over clonidine include less sedation and a longer duration of action. Anecdotal information suggests that guanfacine may be more useful in improving the cognitive deficits of ADHD. School-age children with ADHD and co-morbid tic disorder, treated with guanfacine in doses ranging from 0.5 mg bid to 1 mg tid, showed reduction in both tics and ADHD.^156,157 Guanfacine treatment is associated with minor, clinically insignificant decreases in blood pressure and pulse rate. The adverse effects of guanfacine include sedation, irritability, and depression. Several cases of apparent guanfacine-induced mania have been described, but the impact of guanfacine on mood disorders remains unclear.¹⁵⁸ An extended formulation of guanfacine is currently being studied.⁶³

Modafinil

Modafinil, a novel stimulant that is distinct from amphetamine, is approved for the treatment of narcolepsy.¹⁵⁹ Unlike the broad activation observed with amphetamine, modafinil appears to activate specific hypothalamic regions.^160,161 Although initial trials in adults were negative, in three recent trials in children modafinil demonstrated efficacy in the treatment of ADHD.^162–164 The FDA PDAC voted that modafinil is “not approvable” for pediatric ADHD due to possible Stevens-Johnson syndrome (SJS) in pediatric patients (see www.fda.gov). It may be reasonable to consider combining modafinil with stimulants,^165,166 and clinicians should be aware of the potential to exacerbate mania.¹⁶⁷ Given the cognitive enhancing properties of nicotine,¹⁶⁸ Wilens and colleagues have studied a novel cholinergic activating agent, ABT-418,¹⁶⁹ and more recently a nicotine receptor partial agonist, ABT-089.¹⁷⁰ At this time the role of nicotinic agents remains investigational.

Although compelling based on efficacy in Alzheimer’s disease, positive initial experience in ADHD patients¹⁷¹

Related posts:

31: Psychiatric Illness during Pregnancy and the Postpartum Period 11: Brief Psychotherapy: An Overview 87: Emergency Psychiatry 65: Aggression and Violence 91: Coping with the Rigors of Psychiatric Practice 63: Genetics and Psychiatry

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