Can psychiatric medications cause a high-anion-gap metabolic acidosis with a serum bicarbonate of 16 mmol/L and an anion gap of 22 mEq/L?

Can Psychiatric Medications Cause This Acid-Base Disturbance?

Psychiatric medications are not a common cause of high-anion-gap metabolic acidosis (bicarbonate 16 mmol/L, anion gap 22 mEq/L), and you should urgently investigate the standard life-threatening causes—diabetic ketoacidosis, lactic acidosis, toxic ingestions, and renal failure—before attributing this to psych meds. 1, 2

Understanding Your Patient's Acid-Base Status

Your patient has:

• Serum bicarbonate 16 mmol/L (normal 22-26 mmol/L) = metabolic acidosis 1
• Anion gap 22 mEq/L (normal 10-12 mEq/L) = high anion gap 2, 3

This combination defines a high-anion-gap metabolic acidosis, which indicates accumulation of unmeasured organic anions such as lactate, ketoacids, uremic toxins, or toxic metabolites. 1, 2, 3

Psychiatric Medications and Metabolic Acidosis: The Reality

Atypical Antipsychotics (e.g., Risperidone)

• Atypical antipsychotics can cause hyperglycemia and diabetic ketoacidosis (DKA), which would produce exactly this pattern—high anion gap metabolic acidosis. 4
• The FDA label for risperidone explicitly warns: "Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including RISPERIDONE." 4
• This is an indirect mechanism: the medication causes hyperglycemia → DKA → high anion gap acidosis, not a direct drug-induced acidosis. 4

Carbonic Anhydrase Inhibitors

• Drugs like topiramate (sometimes used for mood stabilization) cause normal anion gap (hyperchloremic) acidosis, not high anion gap. 5
• This does not match your patient's presentation. 5

Other Psychiatric Medications

• Most psychiatric medications (SSRIs, SNRIs, benzodiazepines, mood stabilizers like lithium or valproate) do not typically cause high-anion-gap metabolic acidosis. 5
• Lithium or barium can actually artificially lower the anion gap. 2

Urgent Differential Diagnosis You Must Rule Out

Before blaming psychiatric medications, systematically exclude these life-threatening causes: 1, 6, 7

1. Diabetic Ketoacidosis (DKA)

• Check: plasma glucose, serum ketones (beta-hydroxybutyrate preferred), urine ketones 6
• DKA criteria: glucose >250 mg/dL, pH <7.3, bicarbonate <15 mEq/L, ketones positive 1
• Euglycemic DKA can occur with SGLT2 inhibitors (glucose may be "normal") 2
• If your patient is on an atypical antipsychotic, this is the most likely connection to their psych meds 4

2. Lactic Acidosis

• Check: serum lactate (use prechilled fluoride-oxalate tubes, transport on ice) 6
• Lactate >5 mmol/L is abnormal; >10 mmol/L is life-threatening 6
• Causes: sepsis, shock, tissue hypoxia, metformin, HIV antiretrovirals 6, 7

3. Toxic Ingestions

• Methanol or ethylene glycol: anion gap >27 mmol/L warrants emergent hemodialysis 2, 6
• Check: serum osmolality, urinalysis for calcium oxalate crystals (ethylene glycol) 6
• Salicylate toxicity 7

4. Renal Failure

• Check: BUN, creatinine 6
• Uremic acidosis from advanced kidney disease 1, 7

5. Rare Causes

• 5-oxoproline (pyroglutamic) acidosis: associated with chronic acetaminophen use, malnutrition 3, 7
• Propylene glycol (IV medication vehicle) 7

Immediate Diagnostic Workup

Order these tests now: 1, 6

1. Arterial or venous blood gas (pH, PaCO₂) 1, 6
2. Plasma glucose 6
3. Serum and urine ketones (beta-hydroxybutyrate preferred) 6
4. Serum lactate 6
5. BUN, creatinine 6
6. Complete metabolic panel (Na⁺, K⁺, Cl⁻, HCO₃⁻) 6
7. Serum osmolality (if toxic ingestion suspected) 6
8. Urinalysis (calcium oxalate crystals if ethylene glycol suspected) 6

Management Principles

If DKA is Confirmed (Most Likely Psych Med Connection)

• Isotonic saline 15-20 mL/kg/h during first hour 1, 6
• Continuous IV regular insulin 0.1 U/kg/h after confirming K⁺ >3.3 mEq/L 1
• Add 20-30 mEq/L potassium to IV fluids once urine output established 1
• Bicarbonate is NOT indicated unless pH <6.9-7.0 1, 6
• Monitor electrolytes every 2-4 hours 1, 6

If Toxic Ingestion (Anion Gap >27 mmol/L)

• Immediate hemodialysis for ethylene glycol/methanol with anion gap >27 mmol/L 2, 6
• Fomepizole to block toxic metabolism 6

If Lactic Acidosis

• Treat underlying cause: restore tissue perfusion, treat sepsis 1, 7
• Bicarbonate does not improve outcomes in lactic acidosis 1, 7

Critical Pitfalls to Avoid

1. Don't assume it's the psych meds without ruling out DKA first—atypical antipsychotics cause DKA, not direct acidosis 4
2. Don't give bicarbonate empirically—it's contraindicated in most high-anion-gap acidosis unless pH <6.9-7.0 1, 6
3. Don't miss severe hypertriglyceridemia—can cause pseudo-hypobicarbonatemia and falsely elevated anion gap 8
4. Don't forget to correct anion gap for albumin—hypoalbuminemia lowers the measured anion gap 3
5. Don't overlook euglycemic DKA—glucose may be normal with SGLT2 inhibitors 2

Bottom Line Algorithm

1. Check glucose and ketones immediately → If positive, treat as DKA 6, 4
2. If negative, check lactate → If elevated, treat underlying shock/sepsis 6, 7
3. If negative, check renal function → If elevated, consider uremic acidosis 6, 7
4. If negative, consider toxic ingestion → Check osmolality, urinalysis 6
5. Only after excluding all of the above, consider rare causes like 5-oxoproline 3, 7

The psychiatric medication connection is most likely through atypical antipsychotic-induced hyperglycemia leading to DKA, not a direct drug effect on acid-base balance. 4