A mental health volunteer is interviewing locals as part of a community outreach program. A 46-year-old man discloses that he has felt sad for as long as he can remember. He feels as though his life is cursed and if something terrible can happen to him, it usually will. He has difficulty making decisions and feels hopeless. He also feels that he has had worsening suicidal ideations, guilt from past problems, decreased energy, and poor concentration over the past 2 weeks. He is otherwise getting enough sleep and able to hold a job. Which of the following statement best describes this patient's condition?

The patient has double depression.

The patient may have symptoms of mania or psychosis.

The patient is likely to show anhedonia.

The patient likely has paranoid personality disorder.

The patient should be started on an SSRI.

A 46-year-old male presents with his wife to his primary care provider for depression and strange movements. His wife reports that her husband has not been himself for the last two months. Whereas he was previously outgoing and “the life of the party,” the patient is now irritable and withdrawn. He is a partner at an accounting firm, but his colleagues are threatening his job if he continues to perform poorly at work. The patient cannot explain the recent changes to his mood and tearfully admits he fears there is something seriously wrong with him. His wife says that she thinks he is getting worse. The patient’s past medical history is significant for hypertension, for which he takes lisinopril. His family history is unknown as he was adopted. The patient met his mother once, and never knew his father but was told he died in his 50's. He drinks a few glasses of wine per week and has never smoked. On physical exam, the patient has a flat affect with facial grimace and sudden jerky movements of his upper extremities. Which of the following is most likely to be seen on further workup?

Dorsal striatum atrophy on head CT

Alpha-synuclein aggregates on brain biopsy

Neurofibrillary tangles on brain biopsy

Frontotemporal atrophy on head CT

A 24-year-old woman comes to the physician because she feels sad and has had frequent, brief episodes of crying for the last month. During this period, she sleeps in every morning and spends most of her time in bed playing video games or reading. She has not been spending time with friends but still attends a weekly book club and continues to plan her annual family reunion. She stopped going to the gym, eats more, and has gained 4 kg (8.8 lb) over the past 4 weeks. Three weeks ago, she also started to smoke marijuana a few times a week. She drinks one glass of wine daily and does not smoke cigarettes. She is currently unemployed; she lost her job as a physical therapist 3 months ago. Her vital signs are within normal limits. On mental status examination, she is calm, alert, and oriented to person, place, and time. Her mood is depressed; her speech is organized, logical, and coherent. She denies suicidal thoughts. Which of the following is the most likely diagnosis?

Persistent Depressive Disorder (Dysthymia)

A 29-year-old man presents to his primary care provider complaining of not being able to get enough rest at night. He goes to bed early enough and has otherwise good sleep hygiene but feels drained the next day. He feels he is unable to perform optimally at work, but he is still a valued employee and able to complete his share of the work. About a month ago his wife of 5 years asked for a divorce and quickly moved out. He has cut out coffee after 12 pm and stopped drinking alcohol. He also exercises 3 days per week. Today, his blood pressure is 120/80 mm Hg, heart rate is 95/min, respiratory rate is 25/min, and temperature is 37.0°C (98.6°F ). On physical exam, his heart has a regular rate and rhythm and his lungs are clear to auscultation bilaterally. A CMP, CBC, and thyroid test are negative. Which of the following statements best describes this patient’s condition?

Symptoms typically resolve within 6 months after the stressor ends

Symptoms are usually self-limited and may persist for 2 years

Symptoms develop within 3 months of the stressor

Symptoms may be persistent if the stressor is chronic

Symptoms represent a maladaptive response to an identifiable stressor

A 42-year-old female presents to her primary care provider for an annual checkup. She reports feeling sad over the past few months for no apparent reason. She has lost interest in swimming, which she previously found enjoyable. Additionally, she has had trouble getting a full night’s sleep and has had trouble concentrating during the day. She has lost 15 pounds since her last visit one year prior. Which of the following sets of neurotransmitter levels is associated with this patient’s condition?

Decreased norepinephrine, decreased serotonin, decreased dopamine

Decreased acetylcholine, normal serotonin, normal dopamine

Decreased GABA, decreased acetylcholine, increased dopamine

Increased norepinephrine, decreased serotonin, decreased GABA

Increased acetylcholine, increased serotonin, decreased dopamine

A 33-year-old man visits his psychiatrist with feelings of sadness on most days of the week for the past 4 weeks. He says that he is unable to participate in his daily activities and finds it hard to get out of bed on most days. If he has nothing scheduled for the day, he sometimes sleeps for 10–12 hours at a stretch. He has also noticed that on certain days, his legs feel heavy and he finds it difficult to walk, as though there are bricks tied to his feet. However, he is still able to attend social events and also enjoys playing with his children when he comes home from work. Other than these simple pleasures, he has lost interest in most of the activities he previously enjoyed. Another troubling fact is that he had gained weight over the past month, mainly because he eats so much when overcome by these feelings of depression. His is prescribed a medication to treat his symptoms. Which of the following is the mechanism of action of the drug he was most likely prescribed?

Inhibit the uptake of serotonin and norepinephrine at the presynaptic cleft

Activates the γ-aminobutyric acid receptors

Works as an antagonist at the dopamine and serotonin receptors

Non-selectively inhibits monoamine oxidase A and B

Stimulates the release of norepinephrine and dopamine in the presynaptic cleft

Neurobiological basis of depression for USMLE Step 1: High-Yield Psychiatry Lessons

Monoamine Hypothesis - The Chemical Imbalance

Core Idea: Depression results from a functional deficiency of key monoamine neurotransmitters in the CNS.
Primary Amines Implicated:
- Serotonin (5-HT): Regulates mood, sleep, and appetite.
- Norepinephrine (NE): Affects alertness, energy, and attention.
- Dopamine (DA): Modulates pleasure, reward, and motivation.
Supporting Evidence: The mechanism of action of most antidepressants involves increasing monoamine levels (e.g., SSRIs, SNRIs, MAOIs).

Dopamine Synapse: Reuptake and Degradation

⭐ The 2-4 week therapeutic lag for antidepressants suggests that the acute increase in neurotransmitters is not the sole mechanism. The clinical effect likely involves downstream adaptations, such as changes in receptor sensitivity and gene expression.

Neurotrophic Hypothesis - Stunted Brain Growth

Core Idea: Depression is linked to ↓ levels of Brain-Derived Neurotrophic Factor (BDNF), a key protein for neuron growth, survival, and neurogenesis.
Pathophysiology:
- Chronic stress → ↑ cortisol → ↓ BDNF synthesis.
- Low BDNF leads to atrophy and reduced connectivity in the hippocampus and prefrontal cortex.
- This impairs mood regulation, memory, and executive function.
Antidepressant Action:
- Most antidepressants ↑ BDNF levels over time.
- This stimulates neurogenesis and repairs neuronal connections.

BDNF signaling pathways in depression

⭐ The delayed therapeutic effect of many antidepressants (weeks) is thought to reflect the time required for BDNF levels to rise and exert their neurogenic and synaptogenic effects.

HPA Axis Dysregulation - The Stress Connection

Chronic stress leads to a hyperactive Hypothalamic-Pituitary-Adrenal (HPA) axis, causing elevated cortisol levels (hypercortisolemia).
Core Defect: Impaired negative feedback. Glucocorticoid receptors (GR) in the hippocampus & hypothalamus become desensitized to cortisol.
This dysregulation leads to persistently high levels of CRH and ACTH, creating a vicious cycle.
Sustained ↑ cortisol is neurotoxic, contributing to hippocampal atrophy and decreased neurogenesis seen in depression.

⭐ The Dexamethasone Suppression Test (DST) can reveal this faulty feedback loop. In many depressed patients, cortisol levels are not suppressed after a dose of dexamethasone, indicating HPA axis hyperactivity.

Gut-Brain Axis, HPA Dysregulation, and Depression

Neuroinflammation - A Brain on Fire

Chronic stress and systemic inflammation ↑ pro-inflammatory cytokines (IL-6, TNF-α, IL-1β).
These cytokines cross the blood-brain barrier, activating microglia (the brain's immune cells).
Activated microglia drive neuroinflammation, which promotes depression by:
- Shifting tryptophan metabolism away from serotonin synthesis (↑ kynurenine pathway).
- ↓ Brain-Derived Neurotrophic Factor (BDNF), impairing neurogenesis.
- ↑ Oxidative stress, leading to neuronal damage.

⭐ Elevated C-Reactive Protein (CRP), a peripheral inflammatory marker, is associated with a poorer response to traditional SSRIs.

Neuroinflammation in depression: early vs. late stages

High-Yield Points - ⚡ Biggest Takeaways

The monoamine hypothesis is central, postulating deficiencies in serotonin (5-HT), norepinephrine (NE), and dopamine (DA).

Chronic depression leads to structural brain changes, including decreased hippocampal volume and reduced frontal lobe metabolic activity.

HPA axis hyperactivity is common, resulting in elevated cortisol levels and impaired negative feedback.

Inflammation plays a key role, with increased levels of pro-inflammatory cytokines.

Brain-Derived Neurotrophic Factor (BDNF) levels are often decreased, impairing neuroplasticity and neurogenesis.

Continue reading on Oncourse

CONTINUE READING — FREE

or get the app

App Store|Google Play