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Psychiatry Newsletter - Deficit Schizophrenia: A First Daisy in the Chain

Hopkins BrainWise Fall 2008

Deficit Schizophrenia: A First Daisy in the Chain

Date: October 12, 2010

The hunt for the biological basis for an uncommon form of schizophrenia.

Dr. Nicola Cascella
Nicola Cascella seriously believes biology’s behind the deficit disease.

Of those who go through life pressed under the thumb of schizophrenia, a smaller group is nearly flattened by it. They’re patients suffering deficit schizophrenia. It’s an add-on, really, to the disease’s usual disordered thinking, explains psychiatrist Nicola Cascella. People with “deficit” lack drive. Their emotional range is narrow; any sense of purpose that budded in their teens has withered. “Ask a patient what brings the greatest joy in life,” Cascella says, “and ‘I went for a walk this morning’ is what I’ll hear.”

Psychiatry sees deficit—it affects some 20 percent of schizophrenia patients—mostly as a difference of degree within the disorder’s spectrum of symptoms. But specialist Cascella thinks more might be at work. For one thing, a decade of his and others’ study consistently turned up telltale differences from the more common illness. And now, work out this fall by a mostly Hopkins team including Cascella suggests that deficit may have its own biology.

Besides the distinct symptoms, the epidemiology stands out, he says: People with common schizophrenia are typically born in the spring, most in March. But deficit patients’ birthdays fall in June or July. They tend to be medication-resistant. These patients are notorious for being hard to treat.

The reason may be tied to genetics. Four years ago, Cascella had his attention piqued by PCM1, a gene he’d come across during a Christmas holiday computer escape. Up popped a Hopkins study about an obscure genetic disorder, Bardet-Biedel syndrome, that linked the ailment to PCM1. Bardet-Biedel brings obesity and kidney damage. But, Cascella knew, patients also risk schizophrenia; it’s twice as common as in healthy folk.

Curious, Cascella sought PCM1’s particulars in an online database. The gene’s address was on chromosome 8, at spot 22 on its short arm. More clicks brought up a 1998 mammoth Hopkins study that had linked a mystery gene at 8p22 to schizophrenia. Excited, Cascella confided in colleague Akira Sawa, who directs molecular psychiatry.

 It took two years, but the two assembled a team that showed disrupting PCM1 in lab mice significantly flaws their brain development before birth (column, right);  the flaws mimic those brought about by a known schizophrenia gene Sawa has long researched. The implication? There’s a common mechanism for some forms of the disease.            

PCM1, then, has the makings of a new schizophrenia gene. But was there proof in people? A tie to deficit schizophrenia?

Fortunately, Hopkins psychogeneticist Ann Pulver had preserved blood samples from her earlier mammoth schizophrenia gene hunt. “Ann saw the promise of our search,” says Cascella, and soon they’d analyzed DNA from 32 volunteers with a strong family history of the disease. “When one family surfaced with a PCM1 mutation, and when we saw that only family members with schizophrenia had it, that finding was just fantastic,” Cascella grins.

 But there’s one more wrinkle. Last year, a British group tied abnormal PCM1 to a loss of brain volume, specifically in the orbitofrontal cortex. “We’re well aware of that area,” Cascella says, “because people with lesions there get an apathy that looks a lot like deficit schizophrenia. We know it’s speculation, but it’s tantalizing to think that flawed PCM1 might be a deficit schizophrenia gene.”

Of course repeat and expanded studies are in order. But the beauty of the work is that it sketches a possible outline for one sort of schizophrenia, from gene to cell to brain to person. That’s just the sort of daisy chain that psychiatrists pray for, the sort that inspires therapy. 

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