Confusable diagnoses · PANCE / PANRE

Major Depressive Disorder vs Bipolar I Disorder

Written & clinically reviewed by Ryan Busch, PA-C · Updated August 2026 · Report an error

Major Depressive Disorder and Bipolar I Disorder are easy to mix up on the boards. Here's a side-by-side comparison — presentation, workup, imaging, and first-line treatment — drawn from our full outlines.

Major Depressive Disorder vs Bipolar I Disorder at a glance

  • Major Depressive Disorder: Persistent depressed mood or anhedonia >=2 weeks with neurovegetative and cognitive symptoms causing functional impairment.
  • Bipolar I Disorder: At least one lifetime manic episode; depressive and hypomanic episodes common but not required for diagnosis.

Try two board-style questions on Major Depressive Disorder vs Bipolar I Disorder

Real questions from the FirstPassPA bank, with the full explanation. Pick an answer — no signup, no email.

Question 1PsychiatryMedium
A 45-year-old female with major depressive disorder (MDD) has been on sertraline 100 mg daily for 3 years with good response. She is planning to conceive and asks how to safely stop sertraline. Which of the following approaches is most appropriate?
  • AGradual taper over weeks to months
  • BCross-taper to fluoxetine then stop
  • CAlternate-day dosing then stop
  • DTaper over three days then stop
Reveal answer & full explanation
Correct answer: A — Gradual taper over weeks to months
  • AGradual taper over weeks to months✓
  • BCross-taper to fluoxetine then stop
  • CAlternate-day dosing then stop
  • DTaper over three days then stop

Why Gradual taper over weeks to months is correct

  • Abrupt or rapid discontinuation of sertraline precipitates SSRI discontinuation syndrome
  • SSRI discontinuation syndrome is remembered by the mnemonic FINISH: Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances (electric shock sensations/brain zaps), Hyperarousal and anxiety
  • Recommended tapering rate is approximately 10% per 2-4 weeks
  • Because she is not yet pregnant, the patient and provider have time to complete a proper gradual taper

Why the others are wrong

  • Cross-taper to fluoxetine then stop — fluoxetine's long half-life makes it a rescue strategy when withdrawal occurs, not a routine planned-pregnancy taper (confused-with the rescue indication)
  • Alternate-day dosing then stop — does not constitute a proper gradual taper and can itself precipitate withdrawal (right-concept-wrong-method)
  • Taper over three days then stop — three days after a 3-year course behaves like abrupt cessation and falls far short of the roughly 10% per 2-4 weeks reduction needed to avoid discontinuation syndrome (right-concept-wrong-duration)

Additional high-yield points

  • Paroxetine carries the highest discontinuation risk among SSRIs due to its shortest half-life (~21 hours) plus cholinergic rebound
  • Untreated depression during pregnancy carries risks including premature birth and postpartum depression; sertraline is among the most commonly used SSRIs in pregnancy
Question 2PsychiatryMedium
A 40-year-old male with bipolar I disorder, currently euthymic on lithium (level 0.8 mEq/L), develops new hypertension requiring treatment. His primary care provider is reviewing antihypertensive options. Which of the following antihypertensives is most likely to cause lithium toxicity?
  • AMetoprolol
  • BDoxazosin
  • CHydrochlorothiazide
  • DAmlodipine
Reveal answer & full explanation
Correct answer: C — Hydrochlorothiazide
  • AMetoprolol
  • BDoxazosin
  • CHydrochlorothiazide✓
  • DAmlodipine

Why Hydrochlorothiazide is correct

  • Thiazide diuretics such as hydrochlorothiazide (HCTZ) reduce lithium renal clearance: sodium depletion triggers compensatory lithium reabsorption in the proximal tubule, increasing lithium levels 25-40%
  • This is a significant toxicity risk in a patient with a therapeutic lithium level of 0.8 mEq/L

Why the others are wrong

  • Metoprolol — beta-blockers (metoprolol, atenolol) are safe antihypertensives with lithium and do not significantly affect lithium levels
  • Doxazosin — alpha-blockers are safe antihypertensives with lithium
  • Amlodipine — calcium channel blockers (CCBs) such as amlodipine are safe antihypertensives with lithium

Additional high-yield points

  • NSAIDs also increase lithium levels 25-60% by reducing renal prostaglandin synthesis and lithium clearance
  • ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs) also reduce lithium clearance and raise lithium levels
  • Loop diuretics (furosemide) have less effect than thiazides on lithium levels
  • If a thiazide is required: reduce lithium dose 25-33% and check levels 5-7 days after starting the diuretic
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Side-by-side comparison

FeatureMajor Depressive DisorderBipolar I Disorder
At a glancePersistent depressed mood or anhedonia >=2 weeks with neurovegetative and cognitive symptoms causing functional impairment.At least one lifetime manic episode; depressive and hypomanic episodes common but not required for diagnosis.
Classic presentationSIG E CAPS mnemonic — Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicidality. Five of nine including depressed mood or anhedonia x 2 weeks.; Depressed mood most of the day, nearly every day (self-reported or observed); Markedly diminished interest or pleasure in nearly all activities (anhedonia); Significant…Manic patient with reduced need for sleep (e.g., sleeping 2-3 hours and feeling rested), spending sprees, hypersexuality, and grandiose business plans.; Manic episode: elevated, expansive, or irritable mood >=1 week with increased energy/activity; DIG FAST: Distractibility, Indiscretion (risky behaviors), Grandiosity, Flight of ideas,…
Workup / key labsDSM-5-TR: >=5 of 9 symptoms present for >=2 weeks, with at least one being depressed mood OR anhedonia. Symptoms must cause clinically significant distress/impairment, not be attributable to a substance or medical condition, and not be better explained by a psychotic or bipolar disorder. PHQ-9 >=10 supports diagnosis and tracks severity…DSM-5-TR Bipolar I: At least one lifetime manic episode — distinct period (>=7 days, or any duration if hospitalized) of elevated/expansive/irritable mood AND increased goal-directed activity/energy, with >=3 DIG FAST symptoms (>=4 if mood is only irritable), causing marked impairment or psychotic features. The episode is not…
ImagingNeuroimaging not routine; consider MRI brain if new focal neurologic findings, atypical features, or first episode after age 50Neuroimaging not routine; consider MRI if atypical features or first episode after age 50
First-line treatmentPsychotherapy — cognitive behavioral therapy (CBT) or interpersonal therapy (IPT); comparable to medication for mild-moderate episodes; SSRI — sertraline, escitalopram, fluoxetine (first-line pharmacotherapy; start low, titrate after 2-4 weeks; full effect at 6-8 weeks); SNRI — venlafaxine, duloxetine, desvenlafaxine (consider with…Mood stabilizer — lithium (gold standard, anti-suicide effect), valproate, or lamotrigine (bipolar depression and maintenance); Atypical antipsychotic — quetiapine, olanzapine, risperidone, aripiprazole, lurasidone, cariprazine; Acute mania: lithium OR valproate + atypical antipsychotic; add benzodiazepine for agitation; Bipolar…

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Full outlines

Major Depressive Disorder (MDD) Bipolar I Disorder All 514 diagnoses

Educational use only. This outline is a study aid for PA students and is not medical advice or a substitute for clinical judgment. FirstPassPA is an independent study tool and is not affiliated with, endorsed by, or sponsored by NCCPA or PAEA. PANCE® and PANRE® are registered trademarks of the National Commission on Certification of Physician Assistants; End of Rotation™ is a program of the Physician Assistant Education Association.