Do we still need to check B12 (Vitamin B12), Folate, and iron levels in a patient with anhedonia in the absence of macrocytic or microcytic anemia?

Should You Check B12, Folate, and Iron in Anhedonia Without Anemia?

Yes, you should check vitamin B12 levels in a patient with anhedonia even without anemia, as neuropsychiatric symptoms including anhedonia can occur before hematologic manifestations develop. 1 However, routine folate screening is not indicated given its extremely low prevalence in the general population, and iron studies are only warranted if there are specific clinical indicators beyond anhedonia alone.

Vitamin B12 Testing - Recommended

B12 deficiency can cause neuropsychiatric symptoms including depression and anhedonia without any anemia or macrocytosis. 1 This is a critical clinical pitfall that many providers miss.

• Neurological and psychiatric disorders have been documented in patients with vitamin B12 deficiency even in the complete absence of anemia 1
• The absence of macrocytosis does not exclude B12 deficiency - patients can present with normocytic anemia, no anemia at all, or even microcytic anemia if concurrent iron deficiency exists 2, 1
• Anhedonia falls within the spectrum of neuropsychiatric manifestations that warrant B12 evaluation regardless of hematologic findings 1

Testing approach:

• Measure serum vitamin B12 level initially 3
• If borderline (typically 150-400 pmol/L), confirm with methylmalonic acid (>271 nmol/L confirms deficiency) 3
• This prevents irreversible neurological damage that can occur if deficiency progresses untreated 4

Folate Testing - Generally Not Indicated

Routine folate screening is not recommended in the absence of anemia or specific risk factors. 5

• Since 1998 FDA grain fortification, folate deficiency prevalence dropped to less than 1% in the general population 5
• In cancer patients specifically screened, 0% had folate deficiency and 80% actually had elevated folate levels 5
• Testing should be reserved for patients with increased MCV, neurological symptoms suggesting combined deficiency, or when planning erythropoiesis-stimulating agent therapy 5

Exception: If B12 deficiency is confirmed, consider checking folate as these deficiencies can coexist, but always treat B12 first to prevent precipitating subacute combined degeneration of the spinal cord 3, 4

Iron Studies - Not Indicated Without Additional Context

Iron testing is not warranted based solely on anhedonia without anemia or other clinical indicators. 5

• Iron deficiency testing should be guided by presence of microcytic anemia, documented blood loss, malabsorption syndromes, or inflammatory conditions 5
• In the absence of anemia and without specific risk factors (heavy menstrual bleeding, gastrointestinal blood loss, malabsorption), routine iron screening lacks clinical utility
• If inflammatory conditions are present, ferritin can be falsely elevated despite true iron deficiency, requiring transferrin saturation assessment 3, 4

Clinical Algorithm

For a patient presenting with anhedonia and normal CBC:

1. Check vitamin B12 level - this is the single most important test given neuropsychiatric manifestations can precede hematologic changes 1
2. Do not routinely check folate - prevalence is <1% in general population without specific risk factors 5
3. Do not check iron studies - unless additional clinical indicators present (dietary restrictions, blood loss, malabsorption, inflammatory disease) 5
4. If B12 is low or borderline, confirm with methylmalonic acid and initiate treatment promptly 3

Important Caveats

• Macrocytosis is NOT required for B12 deficiency diagnosis - this is a common misconception that delays diagnosis 2, 1
• Concurrent iron deficiency can mask macrocytosis by normalizing the MCV, resulting in a normal or even low MCV despite B12 deficiency 5, 6
• Elevated RDW can be a clue to mixed deficiencies when MCV appears normal 5, 3
• Always treat B12 deficiency before folate if both are present to prevent neurological complications 3, 4