The symptoms of ADHD can present differently in patients at different ages. While hyperactivity is a main symptom in children, for example, this will frequently translate into internal restlessness in adults.

1. A and D – Incorrect. While ADHD has a strong genetic component, it is not advised to ask him first to compare himself to either his children or his parents. An accurate family history would be beneficial, however.

2. B – Correct. When trying to diagnose this adult patient with ADHD, it is preferable to first ask him to compare his behavior to that of other adults his age, as this will give a better idea of the severity of his symptoms at this time.

3. C – Incorrect. While it is important to obtain a medical history, the patient might not have the best recollection and might not be the best judge of his behaviors as a child.

1. C – Correct. In the DSM-5, the maximum age threshold for symptom onset for diagnosing ADHD changed from 7 to 12. Other revisions included the fact that, although symptoms must have been present prior to age 12, there does not have to have been impairment prior to age 12 when diagnosing someone who is older. The symptom count threshold also changed for adults (defined as age 17 and older), with five (instead of six) symptoms required in the inattention and/or hyperactive/impulsive categories.

2. A, B, and D – Incorrect.

1. A – Correct. Sustained attention is hypothetically modulated by the cortico-striatal-thalamic-cortical loop involving the dorsolateral prefrontal cortex (DLPFC). Inefficient activation of the DLPFC can lead to problems following through or finishing tasks, disorganization, and trouble sustaining mental effort; the patient exhibits all these symptoms. The dorsal anterior cingulate cortex is important in regulating selective attention, and is associated with behaviors such as losing things, being distracted, and making careless mistakes. This area is certainly also inefficient in this patient.

2. B – Incorrect. The prefrontal motor cortex hypothetically modulates behaviors such as fidgeting, leaving one’s seat, running/climbing, and having trouble being quiet.

3. C – Incorrect. The orbital frontal cortex regulates impulsivity, which includes symptoms such as talking excessively, blurting things out, and interrupting others.

4. D – Incorrect. Finally, the supplementary motor cortex is implicated in planning motor actions; thus, this brain area would be more involved in hyperactive symptoms.

ADHD is a neurodevelopmental disorder characterized by inattentive, hyperactive, and/or impulsive symptoms. Neuroimaging has been used to evaluate cortical maturation in children with ADHD compared to typically developing controls, specifically by comparing the age of attaining peak cortical thickness in children with and without ADHD.

1. A – Incorrect. Research shows that the pattern of cortical maturation is similar for children with and without ADHD. Specifically, the primary sensory and motor areas attain peak cortical thickness earlier in development than do high-order association areas such as the DLPFC.

2. B – Correct. There are differences in the timing of cortical maturation between children with and without ADHD that are apparent as early as age 7. That is, cortical maturation in children with ADHD seems to lag behind that of healthy children. In fact, the median age by which 50% of the cortical points achieve peak thickness is delayed by 3 years in children with ADHD. Delay is most prominent in the superior and dorsolateral prefrontal regions, which are particularly important for control of attention and planning. Delay is also seen in subcortical structures. A large cross-sectional mega-analysis demonstrated that the delay in brain maturation is not attributable to medication use.

   Interestingly, there is one brain region in which children with ADHD achieve peak cortical thickness earlier than typically developing controls: the primary motor cortex.

3. C and D – Incorrect.

1. A – Incorrect.

2. B – Correct. When norepinephrine and dopamine neurotransmission in the prefrontal cortex is optimally tuned, modest stimulation of postsynaptic alpha-2A receptors and dopamine 1 receptors allows for efficient cognitive functioning. If norepinephrine or dopamine neurotransmission is excessive, as in situations of stress or comorbid conditions such as anxiety or substance abuse, this can lead to overstimulation of postsynaptic receptors and consequently to cognitive dysfunction as well as other symptoms.

3. C – Incorrect.

4. D – Incorrect.

1. A – Incorrect. Immediate-release preparations have a duration of 4–6 hours. Decreasing the dose of immediate-release amphetamine (d, l) will have no therapeutic effect on helping the patient manage his symptoms later in the day.

2. B – Incorrect. Immediate-release preparations have a duration of 4–6 hours. Pharmacological actions of high-dose amphetamine are not linked to therapeutic action in ADHD, but to reinforcement, reward, and euphoria in amphetamine abuse. Increasing the dose of immediate-release formulations elicits pulsatile drug administration that causes immediate release of dopamine and could potentially lead to the highly reinforcing pleasurable effects of drug abuse, especially at high enough doses and rapid enough administration. For this reason, using immediate-release stimulants, especially in young adults, is increasingly being avoided.

3. C – Correct. Extended-release preparations have a duration ranging from 8 to 16 hours, depending on the formulation. Controlled-release (or extended-release) preparations for stimulants result in slowly rising, constant, steady-state levels of the drug. Under those circumstances, the firing pattern of dopamine will theoretically be mostly tonic, regular, and not at the mercy of fluctuating levels of dopamine. Some pulsatile firing is fine, especially when involved in reinforcing learning and salience.

   The goal is to enhance phasic dopamine neurotransmission with low to moderate, continuous drug delivery, trying to increase mostly tonic dopamine firing and only judiciously increase phasic dopamine firing. To achieve prudent and therapeutic improvement of tonic and phasic dopamine neurotransmission, without increases in phasic dopamine neurotransmission that could potentially lead to abuse and addiction, sustained delivery is what is wanted.

4. D – Incorrect. Not changing anything will have no therapeutic effect on helping the patient manage his symptoms later in the day.

Atomoxetine is a selective norepinephrine reuptake inhibitor.

1. A – Incorrect. In the nucleus accumbens there are only a few NE neurons and NE transporters (NET). Inhibiting NET in the nucleus accumbens will not lead to an increase in norepinephrine or dopamine.

2. B – Correct. The prefrontal cortex lacks high concentrations of dopamine transporters (DAT), so in this brain region, dopamine gets inactivated by NET. Therefore, inhibiting NET in the prefrontal cortex increases both dopamine and norepinephrine. As only a few NET exist in the nucleus accumbens, atomoxetine does not induce an increase in dopamine and norepinephrine in the nucleus accumbens, the reward center of the brain; thus, atomoxetine does not have abuse potential.

3. C – Incorrect. Atomoxetine does not modulate serotonin levels.

4. D – Incorrect. The orbitofrontal cortex and the anterior cingulate cortex are not brain areas involved in reward.

1. A – Incorrect. Methylphenidate binds to the DAT and to the norepinephrine transporter, in both cases acting as an allosteric modulator. That is, it binds to each transporter at a different site than the neurotransmitter itself binds. When it does so, it stops the action of the transporters, preventing reuptake and thus allowing dopamine and norepinephrine to accumulate in the synapse. Methylphenidate itself is not taken up into the presynaptic neuron.

2. B – Incorrect. Atomoxetine is an inhibitor of the norepinephrine transporter and, like methylphenidate, it binds at a site distinct from where monoamines bind. It does not have actions at the DAT.

3. C – Correct. Like methylphenidate, amphetamine blocks the transporters for both dopamine and norepinephrine. However, unlike methylphenidate, which acts as an allosteric modulator, amphetamine is a pseudosubstrate and a competitive inhibitor at these receptors. That is, it binds to the same site as the substrate – either dopamine or norepinephrine – thus competing with the neurotransmitters and preventing them from being taken up into the terminal. In addition, because amphetamine is a pseudosubstrate, it is actually transported into the presynaptic nerve terminal. This is important, because amphetamine is also a pseudosubstrate and competitive inhibitor at the vesicular monoamine transporter (VMAT). VMAT is a proton pump that exchanges dopamine for protons, packaging the dopamine into synaptic vesicles where it is stored for subsequent reuse. When amphetamine binds to VMAT, it not only blocks the further transport of dopamine into synaptic vesicles but is actually packaged into vesicles itself, where it has the ability to displace stored dopamine – or norepinephrine – back into the cytoplasm. This occurs only at high doses of amphetamine, as in cases of amphetamine abuse.

1. A – Incorrect. Investigational and recently available medications for ADHD largely still target the dopamine and/or norepinephrine system.

2. B – Correct. The majority of approved treatments for ADHD, and specifically new agents approved recently, still target the norepinephrine and/or dopamine system. There are numerous formulation variations of either amphetamine or methylphenidate, and their differences lie not in the active ingredient but rather in how that active ingredient is delivered (i.e., release mechanism). Modified-release formulations are designed to release drug in a controlled and predictable manner that allows for a particular efficacy and safety profile. Modifying the release of drug can improve tolerability by eliminating peaks and troughs in plasma concentration, and can improve efficacy by increasing duration of action as well as by eliminating peaks and troughs. Other approved treatments include the norepinephrine reuptake inhibitors atomoxetine and viloxazine (which also has some actions at serotonin receptors), and the alpha-2 agonists clonidine and guanfacine.

There are two direct-acting agonists for alpha-2 receptors used to treat ADHD, guanfacine and clonidine. Guanfacine is relatively more selective for alpha-2A receptors than for other subtypes, whereas clonidine binds to alpha-2A, alpha-2B, and alpha-2C receptors. Clonidine also has actions on imidazoline receptors, which is thought to be responsible for some of clonidine’s sedating and hypotensive actions.

1. A – Incorrect. Although the actions of clonidine at alpha-2A receptors exhibit therapeutic potential for ADHD, its actions at other receptors may increase side-effect. By contrast, guanfacine is 15–60 times more selective for alpha-2A receptors than for alpha-2B and alpha-2C receptors. Additionally, guanfacine is ten times weaker than clonidine at inducing sedation and lowering blood pressure. Thus, guanfacine is better tolerated than clonidine.

2. B – Correct. Guanfacine is better tolerated than clonidine.

3. C – Incorrect. Guanfacine is 25 times more potent in enhancing prefrontal cortical function. Thus, it can be said that guanfacine exhibits therapeutic efficacy with a reduced side-effect profile compared to clonidine.

4. D – Incorrect. There are no head-to-head comparisons to establish that guanfacine has superior efficacy to clonidine in ADHD.

1. A – Correct. Multiple meta-analyses assessing the effects of stimulant medications have shown that, as a class, nonstimulants have smaller effect sizes than stimulants. Due to differences in study design, these meta-analyses do not address potential differences in efficacy among specific medications.

2. B and C – Incorrect.

1. A and C – Incorrect. While anxiety and depression are common comorbidities in patients with ADHD, they are more often found in girls compared to boys.

2. B – Correct. Argumentative, disobedient, and aggressive behaviors are often seen in patients suffering from ADHD and oppositional symptoms. The presence of comorbid disruptive behavior disorders such as oppositional defiant disorder, or conduct disorder, within children with ADHD has been well established. About 5 in 10 children with ADHD have a behavior or conduct problem and this is seen at a higher rate in boys than in girls in studies.

1. A – Incorrect. Dose response studies of stimulant medications suggest that the optimal dose varies across individuals and depends somewhat on the domain of function. Specifically, higher doses may lead to greater improvement of some domains (e.g., vigilance, attention) but not executive function (e.g., planning, cognitive flexibility, inhibitory control).

2. B – Correct. If medication dose is high enough to substantially diminish symptoms of inattention and distractibility, then executive function needs to be addressed independently and will not likely respond to higher medication dosing.

1. A and B – Partially correct.

2. C – Correct. Comparisons have been made between aerobic/nonaerobic and acute vs. chronic exercise on cognitive and behavioral symptoms in children with ADHD. Numerous published studies on exercise and cognition in children with ADHD have shown that aerobic exercise appears to be the most effective for improvements in executive function (EF). Both acute and chronic exercise have beneficial effects on behavioral and cognitive measures in children with ADHD, when assessed immediately after exercise. Cognitive measures include improved response inhibition, cognitive control, attention allocation, cognitive flexibility, processing speed, and vigilance.

   Physical exercise is beneficial as adjunctive treatment, but there is not enough evidence to suggest that it is a stand-alone treatment. There is some evidence to indicate that exercise may be particularly effective for youth. The literature is promising; however, the most challenging complications for these types of studies are random assignment, blinded raters, and adequate control groups.

3. D – Incorrect.

1. A – Incorrect. Because ongoing substance abuse can hinder the treatment progress of other disorders, in many cases it may be necessary to address this problem first. However, these are general guidelines in the ordering of treatment, and one should be careful that this prioritization of symptoms/conditions does not lead to the neglect of ADHD treatment in adults. In fact, there is an evidence base for prescribing ADHD medication for patients in early sobriety from an alcohol use disorder. Specifically, atomoxetine, which is approved for adult ADHD, has been shown to be effective for ADHD and to decrease both alcohol cravings and heavy drinking days. Atomoxetine is not contraindicated in patients with acute alcohol use disorder or in patients with liver impairment, so the patient’s alcohol use would not require medication discontinuation. It is an appropriate treatment choice; however, it is not the only appropriate treatment choice.

2. B – Incorrect. Long-acting stimulant medications are not contraindicated in patients with acute alcohol use disorder, although they do carry a black box warning indicating caution in patients with history of substance dependence. In general, nonstimulant options may be preferable to stimulants in patients with substance use disorders, but long-acting stimulants should remain as a second-tier option.

3. C – Correct. Nonstimulant and long-acting stimulant medications are both options for ADHD co-occurring with substance use disorders; however, nonstimulants may be preferred as the first-line approach. If a stimulant is prescribed to a patient in early sobriety from substance use and/or continued low-level substance use, then he/she should be monitored closely for misuse of the prescribed medication.

1. A – Correct. Current recommendations from the American Heart Association (AHA) are that it is reasonable but not mandatory to obtain an ECG prior to prescribing a stimulant to a child. The American Academy of Pediatrics (AAP) does not recommend an ECG prior to starting a stimulant for most children.

2. B – Incorrect. According to recommendations, it is at the physician’s discretion whether to obtain an ECG; however, in this case there is no evidence of cardiovascular disease in either the family history or patient exam.

3. C – Incorrect. According to AHA and AAP recommendations, treatment with a stimulant should not be withheld because an ECG is not obtained.

4. D – Incorrect. There is no reason why a stimulant would not be a reasonable choice for this patient.