Megaloblastic Madness

In 1960, a now-landmark article titled “Megaloblastic Madness” appeared in the British Medical Journal, describing patients with severe psychiatric and neurological symptoms—delusions, hallucinations, personality changes, cognitive decline—all linked not to a primary mental illness, but to a deficiency in vitamin B12. This was a wake-up call: the mind can be hijacked by the body’s biochemistry long before anemia shows up on a lab report.

Yet more than 60 years later, this wake-up call has largely gone unanswered.

Megaloblastic madness, now understood as the neuropsychiatric manifestation of pernicious anemia, remains underrecognized and misdiagnosed—despite its devastating potential.

A clinician shared her mother’s story with us. She asked us to share information about Pernicious Anemia as her mother had suffered greatly with misdiagnoses for years. Her goal is to bring visibility to Pernicious Anemia so that others can avoid what her mother endured.

What Is Pernicious Anemia?

Pernicious anemia is an autoimmune disorder in which the body mistakenly attacks the stomach’s parietal cells or the intrinsic factor protein they produce. Intrinsic factor is essential for absorbing vitamin B12 in the small intestine. Without it, even a nutrient-rich diet or oral supplements can’t get B12 into the bloodstream.

The result? A slow but profound malabsorption of B12, which gradually affects nerve function, mood regulation, and cognition—often before traditional lab markers, like red blood cell changes or anemia, appear.

Patients may suffer for years with depression, memory issues, or unexplained fatigue and neurological symptoms before anyone thinks to check B12—or worse, before it’s correctly understood that the patient cannot absorb B12 without bypassing the digestive system.

This failure of the clinical system to catch B12 deficiency early—especially in the context of pernicious anemia—is one of modern psychiatry’s quiet tragedies.

DSM-III: What Went Wrong?

In shifting toward a descriptive, symptom-based model in DSM-III (1980), psychiatry unintentionally severed its link to biology. Symptoms became the focus; causes became secondary. What was once recognized as an organic psychosis—a condition with clear physiological roots—became a “disorder of mood” or “cognition” to be managed with pharmaceuticals.

This symptom-first approach has defined mainstream psychiatry for decades. And it’s why so many patients, like the woman whose story inspired this piece, continue to suffer through years of misdiagnoses, invasive procedures, and ineffective medications, when the root cause may be as simple as a missing nutrient.

What Functional Psychiatry Gets Right

At Psychiatry Redefined, our mission is to shift this paradigm. Root-cause diagnosis isn’t just more effective—it’s essential.

Dr. James Greenblatt, a pioneer in Functional Psychiatry, has spent over 30 years treating patients with complex psychiatric symptoms using a model that integrates biochemistry, nutrition, and genetics. Through this lens, vitamin and nutrient deficiencies, toxic burden, methylation imbalances, and gut health are not peripheral issues—they are central to brain health.

In the case of B12 deficiency, the neurological and psychiatric symptoms can appear long before anemia is evident. These may include:

• Memory loss and brain fog
• Depression and irritability
• Anxiety or panic attacks
• Psychosis or hallucinations
• Peripheral neuropathy or movement issues

Yet many of these patients are told they are “just anxious” or “depressed.” They’re given medications. They’re labeled. But they’re not investigated. Functional Psychiatry flips that script.

Why An Integrative Model of Care Matters More Than Ever

We are living in a time when the rates of mental illness are skyrocketing—and so is the demand for a more personalized, integrative model of care. Misdiagnoses like those seen in megaloblastic madness are not just relics of history; they are happening now, every day, in hospitals and clinics across the country.

What would happen if every psychiatrist screened for B12 in patients with treatment-resistant depression? Or ruled out methylation disorders before prescribing SSRIs? Or considered nutrient absorption in patients on long-term PPIs or metformin? What if we stopped chasing symptoms and started investigating causes?

A Legacy Ignored—and a Legacy Rekindled

Few people know that James B. Duke—the man who funded the founding of Duke University—died of pernicious anemia. His death was part of what brought attention to this condition nearly a century ago. And yet, despite his legacy, the deeper lessons of megaloblastic madness have been largely lost in the modern psychiatric playbook.

We believe it’s time to reclaim them.

Functional Psychiatry doesn’t just offer better outcomes—it offers answers. It provides the context and the curiosity to ask the right questions. And it holds the promise of a future in which stories like this one—of misdiagnosis, of pain, of being dismissed—are no longer common.

If you’re a clinician looking to deepen your understanding of Functional Psychiatry and nutrient-based interventions for mental health, we invite you to explore what trainings we offer are right for you and your career growth in functional and nutritional psychiatry. Schedule a 1:1 with one of our educational consultants to determine what is best for you.