A 31-year-old male presents to the emergency room following an altercation with patrons at a local grocery store. He is acting aggressively toward hospital staff and appears to be speaking to non-existent individuals. On examination he is tachycardic and diaphoretic. Horizontal and vertical nystagmus is noted. The patient eventually admits to taking an illegal substance earlier in the evening. Which of the following mechanisms of action is most consistent with the substance this patient took?

Biogenic amine reuptake inhibitor

A 7-year-old boy is brought in to clinic by his parents with a chief concern of poor performance in school. The parents were told by the teacher that the student often does not turn in assignments, and when he does they are partially complete. The child also often shouts out answers to questions and has trouble participating in class sports as he does not follow the rules. The parents of this child also note similar behaviors at home and have trouble getting their child to focus on any task such as reading. The child is even unable to watch full episodes of his favorite television show without getting distracted by other activities. The child begins a trial of behavioral therapy that fails. The physician then tries pharmacological therapy. Which of the following is most likely the mechanism of action of an appropriate treatment for this child's condition?

Decreases synaptic reuptake of norepinephrine and dopamine

Increases the frequency of GABAa channel opening

Increases the duration of GABAa channel opening

A 65-year-old woman presents with memory problems for the past few weeks. Patient vividly describes how she forgot where she put her car keys this morning and did not remember to wish her grandson a happy birthday last week. Patient denies any cognitive problems, bowel/bladder incontinence, tremors, gait problems, or focal neurologic signs. Patient mentions she wants to take Ginkgo because her friend told her that it can help improve her brain function and prevent memory loss. Past medical history is significant for an acute cardiac event several years ago. Current medications are aspirin, carvedilol, and captopril. Patient denies any history of smoking, alcohol or recreational drug use. Patient is a widow, lives alone, and is able to perform all activities of daily living (ADLs) easily. No significant family history. Patient is afebrile and vital signs are within normal limits. Physical examination is unremarkable. Which of the following would be the most appropriate response to this patient’s request to take Ginkgo?

"No, taking ginkgo will increase your risk for bleeding."

"Yes, ginkgo is widely used for improving brain function and memory."

“No, you have Alzheimer's disease and need to start donepezil.”

“No, herbal preparations are unsafe because they are not regulated by the FDA.”

Yes, ginkgo may not help with your memory, but there is no risk of adverse events so it is safe to take.

A 12-year-old boy is brought by his mother to a neurologist for continuing evaluation of seizures. His seizures were previously well-controlled on medication but over the last month he has been having seizures several times per week. The boy is non-verbal and has had severe developmental delays and cognitive disability since birth. On exam, the boy is found to be enthusiastically playing with the toys in the office and laughing at almost any stimulus. Furthermore, his movements are found to be uncoordinated with a wide based gait. Previous genetic testing has revealed an abnormality in an E3 ubiquitin ligase gene. Compared to unaffected individuals, which of the following patterns of gene expression is most likely seen in this patient?

Abnormally decreased expression of the gene from the maternal chromosome

Abnormally increased expression of the gene from the maternal chromosome

Abnormally decreased expression of the gene from both chromosomes

Abnormally decreased expression of the gene from the paternal chromosome

Abnormally increased expression of the gene from the paternal chromosome

Pharmacotherapy for cognitive disorders for USMLE Step 1: High-Yield Psychiatry Lessons

Cholinesterase Inhibitors - Brainy Boosters

Mechanism: Centrally acting, reversible inhibition of acetylcholinesterase → ↑ cortical acetylcholine.
Indications: Mild to moderate dementia (Alzheimer's, Lewy body, vascular).
Side Effects (Cholinergic): 📌 DUMBELS (Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Emesis, Lacrimation, Salivation/Sweating).

Synaptic Transmission Process

Drug	Dosing (Oral)	Administration	Specific Notes
Donepezil (Aricept)	5-10 mg daily	Once daily	Long half-life, fewer GI effects.
Rivastigmine (Exelon)	6-12 mg/day	Twice daily or Patch	Also inhibits butyrylcholinesterase.
Galantamine (Razadyne)	16-24 mg/day	Twice daily or ER	Modulates nicotinic receptors.

NMDA Receptor Antagonists - Glutamate Guards

Mechanism: A non-competitive NMDA receptor antagonist. It selectively blocks chronic, low-level glutamate excitotoxicity while permitting normal synaptic function.
Drug: Memantine (Namenda).
Indication: Moderate to severe Alzheimer's disease. Often added to a cholinesterase inhibitor.
Side Effects: Well-tolerated; can cause dizziness, confusion, headache, hallucinations.

Memantine: NMDA Receptor Antagonist Mechanism and Effect

⭐ Memantine's lower affinity for the NMDA receptor compared to Mg²⁺ allows it to selectively block pathological activation without disrupting normal neurotransmission.

Neuropsychiatric Symptoms - Calming the Storm

Management begins with identifying and addressing triggers. Prioritize non-pharmacologic strategies before considering medication.

Pharmacologic Options (if non-pharm fails):
- Antipsychotics for severe agitation or psychosis (e.g., Risperidone, Olanzapine).
- Antidepressants (SSRIs) for depression or anxiety (e.g., Citalopram, Sertraline).
⚠️ Avoid Benzodiazepines: High risk of sedation, confusion, falls, and paradoxical disinhibition.

⭐ BLACK BOX WARNING: Antipsychotics are associated with an increased risk of all-cause mortality in elderly patients with dementia-related psychosis. Use the lowest effective dose for the shortest possible duration.

Emerging Therapies - Plaque Busters

Class: Anti-amyloid monoclonal antibodies.
Drugs:
- Aducanumab (Aduhelm)
- Lecanemab (Leqembi)
Mechanism: Target amyloid-beta (Aβ) plaques, promoting their clearance from the brain.
Indication: For patients with Mild Cognitive Impairment (MCI) or mild-stage Alzheimer's disease.
Major Side Effect: ⚠️ Amyloid-Related Imaging Abnormalities (ARIA).
- ARIA-E: Edema (vasogenic).
- ARIA-H: Hemorrhage (microhemorrhages, superficial siderosis).
- Requires baseline and periodic MRI monitoring.

⭐ High-Yield Fact: These therapies are indicated only after amyloid pathology is confirmed via PET scan or CSF analysis. They are not for advanced dementia.

High-Yield Points - ⚡ Biggest Takeaways

Cholinesterase inhibitors (e.g., Donepezil) are first-line for mild-to-moderate Alzheimer's disease.

Memantine, an NMDA antagonist, is used for moderate-to-severe Alzheimer's, often as combination therapy.

These drugs offer modest symptomatic benefit but do not halt neurodegeneration or cure the disease.

The most common side effects of cholinesterase inhibitors are gastrointestinal (nausea, diarrhea, vomiting).

For severe behavioral symptoms, use antipsychotics cautiously due to a black box warning for increased mortality.

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