A 20-year-old female presents to student health at her university for excessive daytime sleepiness. She states that her sleepiness has caused her to fall asleep in all of her classes for the last semester, and that her grades are suffering as a result. She states that she normally gets 7 hours of sleep per night, and notes that when she falls asleep during the day, she immediately starts having dreams. She denies any cataplexy. A polysomnogram and a multiple sleep latency test rule out obstructive sleep apnea and confirm her diagnosis. She is started on a daytime medication that acts both by direct neurotransmitter release and reuptake inhibition. What other condition can this medication be used to treat?

Attention-deficit hyperactivity disorder

A 49-year-old woman presents to her primary care physician with fatigue. She reports that she has recently been sleeping more than usual and says her “arms and legs feel like lead” for most of the day. She has gained 10 pounds over the past 3 months which she attributes to eating out at restaurants frequently, particularly French cuisine. Her past medical history is notable for social anxiety disorder. She took paroxetine and escitalopram in the past but had severe nausea and headache while taking both. She has a 10 pack-year smoking history and has several glasses of wine per day. Her temperature is 98.6°F (37°C), blood pressure is 130/65 mmHg, pulse is 78/min, and respirations are 16/min. Physical examination reveals an obese woman with a dysphoric affect. She states that her mood is sad but she does experience moments of happiness when she is with her children. The physician starts the patient on a medication to help with her symptoms. Three weeks after the initiation of the medication, the patient presents to the emergency room with a severe headache and agitation. Her temperature is 102.1°F (38.9°C), blood pressure is 180/115 mmHg, pulse is 115/min, and respirations are 24/min. Which of the following is the mechanism of action of the medication that is most likely responsible for this patient’s symptoms?

Inhibition of amine degradation

Inhibition of serotonin and norepinephrine reuptake

Inhibition of the adrenergic alpha-2 receptor and serotonin-2 and -3 receptors

Inhibition of serotonin reuptake

Partial agonism of serotonin-1A receptor

A 51-year-old male presents to his primary care provider for a normal check-up. He reports that he “hasn’t felt like himself” recently. He describes feeling down for the past 8 months since his mother passed away. He has had trouble sleeping and has unintentionally lost 15 pounds. He feels guilty about his mother’s death but cannot articulate why. His performance at work has declined and he has stopped running, an activity he used to enjoy. He has not thought about hurting himself or others. Of note, he also complains of numbness in his feet and fingers and inability to maintain an erection. His past medical history is notable for diabetes. He is on metformin. His temperature is 98.6°F (37°C), blood pressure is 125/65 mmHg, pulse is 90/min, and respirations are 16/min. On exam, he is alert and oriented with intact memory and normal speech. He appears tired with a somewhat flattened affect. The best medication for this patient inhibits which of the following processes?

Norepinephrine and serotonin reuptake

Norepinephrine and dopamine reuptake

A 13-year-old boy has been suspended 5 times this year for arguing with teachers. He has presented a pattern of negativism and hostility that has lasted for about 8 months. When asked about the suspensions, he admits that he loses his temper easily and often blames the principal for not being fair to him. He usually finds an argument before finishing his homework. At home, he goes out of his way to annoy his siblings. He gets furious if his legal guardian finds out about it and confiscates his smartphone. Which of the following is the primary behavior characteristic of this patient's most likely diagnosis?

Hostile and disobedient behavior towards authority

Destruction of property and theft

Killing and/or harming small animals

A parent-teacher conference is called to discuss the behavior of a 9 year-old boy. According to the boy's teacher, he has become progressively more disruptive during class. When asked to help clean up or read out-loud, he replies with "You're not the boss of me." or "You can't make me." He refuses to participate in gym class, but will play the same games during recess. He gets along with and is well-liked by his peers. His mother reports that her son can "sometimes be difficult," but he is helpful around the house and is very good playing with his 7-year-old sister. What is the most likely diagnosis?

Antisocial personality disorder

Non-stimulant ADHD treatments — USMLE Lesson

Atomoxetine - The NRI Knockout

Mechanism: Selective Norepinephrine Reuptake Inhibitor (NRI).
- Increases both norepinephrine (NE) and dopamine (DA) primarily in the prefrontal cortex, a key region for executive function.
Key Features:
- Slow onset of action: Effects begin in 2-4 weeks, with full therapeutic benefit often taking 6-8 weeks.
- Not a controlled substance, making it a good option where substance abuse is a concern.
Side Effects:
- Most common: GI upset, sedation/fatigue, and decreased appetite.
- ⚠️ Monitor liver function tests (LFTs) due to rare but serious hepatotoxicity.

⭐ Black Box Warning: Increased risk of suicidal ideation in children and adolescents. Close monitoring is essential during the initial months of therapy.

Atomoxetine inhibition of norepinephrine reuptake

Alpha-2 Agonists - Calming the Storm

Central alpha-2 adrenergic agonists that modulate norepinephrine (NE) signaling in the prefrontal cortex (PFC), improving executive functioning. Particularly effective for hyperactivity, impulsivity, and aggression. Also useful for co-morbid tic disorders or oppositional defiant disorder.

Guanfacine mechanism of action in ADHD

Feature	Clonidine (Kapvay)	Guanfacine (Intuniv)
Selectivity	Non-selective (α2A, α2B, α2C)	More selective for α2A
Primary SEs	More sedation, hypotension	Less sedation, hypotension
Half-life	Shorter	Longer (once-daily dosing)

⚠️ Tapering is crucial! Abrupt discontinuation can cause severe rebound hypertension, especially with clonidine.

⭐ Rebound hypertension is a major risk if clonidine is stopped abruptly.

📌 Mnemonic: Guanfacine is more 'Fine-tuned' for the α2A receptor, leading to fewer side effects.

Treatment Strategy - The Non-Stim Playbook

⭐ A personal or strong family history of substance abuse is a key indication for using non-stimulants as a first-line agent over stimulants.

High-Yield Points - ⚡ Biggest Takeaways

Atomoxetine (SNRI) has a slower onset than stimulants and a black box warning for suicidal ideation.

Alpha-2 agonists (guanfacine, clonidine) are effective for ADHD with co-morbid tics or ODD.

Monitor for sedation, hypotension, and bradycardia with alpha-2 agonists.

Always taper alpha-2 agonists to prevent rebound hypertension.

Bupropion is contraindicated in patients with seizure or eating disorders.

Non-stimulants are second-line or preferred with a history of substance abuse.

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