Many of us have known a dog on Prozac. We've also witnessed the eye rolls that come with canine psychiatry. Doting pet owners—myself included—ascribe all sorts of questionable psychological ills to our pawed companions. But the science does suggest that numerous non-human species suffer from psychiatric symptoms. Birds obsess; horses on occasion get pathologically compulsive; dolphins and whales—especially those in captivity—self-mutilate. And that thing when your dog woefully watches you pull out of the driveway from the window—that might be DSM-certified separation anxiety. "Every animal with a mind has the capacity to lose hold of it from time to time" wrote science historian and author Dr. Laurel Braitman in "Animal Madness."

But there’s at least one mental malady that, while common in humans, seems to have spared all other animals: schizophrenia. Though psychotic animals may exist, psychosis has never been observed outside of our own species; whereas depression, OCD, and anxiety traits have been reported in many non-human species. This begs the question of why such a potentially devastating, often lethal disease—which we now know is heavily genetic, thanks to some genomically homogenous Icelanders and plenty of other recent research—is still hanging around when it would seem that genes predisposing to psychosis would have been strongly selected against. A new study provides clues into how the potential for schizophrenia may have arisen in the human brain and, in doing so, suggests possible treatment targets. It turns out psychosis may be an unfortunate cost of our big brains—of higher, complex cognition.  

The study, led by Mount Sinai researcher Dr. Joel Dudley, proposed that since schizophrenia is relatively prevalent in humans despite being so detrimental—the condition affects over 1% of adults—that it perhaps has a complex evolutionary backstory that would explain its persistence and exclusivity to humans. Specifically they were curious about segments of our genome called human accelerated regions, or HARs. HARs are short stretches of DNA that while conserved in other species, underwent rapid evolution in humans following our split with chimpanzees, presumably since they provided some benefit specific to our species. Rather than encoding for proteins themselves, HARs often help regulate neighboring genes. Since both schizophrenia and HARs appear to be for the most part human-specific, the researchers wondered if there might be a connection between the two.

To find out, Dudley and colleagues used data culled from the Psychiatric Genomics Consortium, a massive study identifying genetic variants associated with schizophrenia. They first assessed whether schizophrenia-related genes sit close to HARs along the human genome—closer than would be expected by chance. It turns out they do, suggesting that HARs play a role in regulating genes contributing to schizophrenia. Furthermore, HAR-associated schizophrenia genes were found to be under stronger evolutionary selective pressure compared with other schizophrenia genes, implying that the human variants of these genes are beneficial to us in some way despite harboring schizophrenia risk.

To help understand what these benefits might be, Dudley’s group then turned to gene expression profiles. Whereas gene sequencing provides an organism’s genome sequence, gene expression profiling reveals where and when in the body certain genes are actually active. Dudley's group found that HAR-associated schizophrenia genes are found in regions of the genome that influence other genes expressed in the prefrontal cortex, a brain region just behind the forehead involved in higher order thinking—impaired PFC function is thought to contribute to psychosis.

They also found that these culprit genes are involved in various essential human neurological functions within the PFC, including the synaptic transmission of the neurotransmitter GABA. GABA serves as an inhibitor or regulator of neuronal activity, in part by suppressing dopamine in certain parts of the brain, and it’s impaired transmission is thought to be involved in schizophrenia. If GABA malfunctions, dopamine runs wild, contributing to the hallucinations, delusions and disorganized thinking common to psychosis. In other words, the schizophrenic brain lacks restraint. 

“The ultimate goal of the study was to see if evolution may help provide additional insights into the genetic architecture of schizophrenia so we can better understand and diagnose the disease,” says Dudley. Identifying which genes are most implicated in schizophrenia and how they’re expressed could lead to more effective therapies like, say, those influencing the function of GABA.

But the findings also offer a possible explanation for why schizophrenia arose in humans in the first place, and why it doesn’t seem to occur in other animals. “It’s been suggested,” Dudley explains, “that the emergence of human speech and language bears a relationship with schizophrenia genetics, and incidentally also autism. Indeed, language dysfunction is a feature of schizophrenia, and GABA is critical to speech, language and many other aspects of higher-order cognition. The fact that our evolutionary analysis converged on GABA function in the prefrontal cortex seems to tell an evolutionary story connecting schizophrenia risk with intelligence.”

Put another way, with complicated, highly social human thought—and the complicated genetics at the root of higher cognition—perhaps there’s just more that can go wrong: complex function begets complex malfunction.

Dudley is careful not to exaggerate the evolutionary implications of his work. “It is important to note that our study was not specifically designed to evaluate an "evolutionary trade-off,” he says, “but our findings support the hypothesis that evolution of our advanced cognitive abilities may have come at a cost—a predisposition to schizophrenia.” He also acknowledges that the new work didn’t identify any “smoking gun genes” and that schizophrenia genetics is profoundly complex. Still, he feels that evolutionary genetic analysis can help identify the most relevant genes and pathologic mechanisms at play in schizophrenia, and possibly other mental illnesses that preferentially affect humans as well—specifically neurodevelopmental disorders related to higher-cognition and GABA activity, including autism and ADHD.

In fact, a new study published in Molecular Psychiatry reports a link between gene variants associated with autism spectrum disorder and better cognitive function in people without the disorder. The findings may help explain why those with autism sometimes exhibit extraordinary skill at certain cognitive abilities. They also support Dudley’s speculation that higher cognition might have come at a price. As we broke away from our primate cousins our genomes—HARs especially—hastily evolved, granting us an increasing cache of abilities that other species lack. In doing so, they may have left our brains prone to occasional  complex dysfunction—but also capable of biomedical research aimed at one day, hopefully, curing the ailing  brain. As Dudley and others untangle the genetic underpinnings of schizophrenia and other mental illnesses in search of improved diagnosis and treatment, at least our pugs, poodles and pot-bellied pigs seem to be psychosis free.

Bret Stetka is an Editorial Director at Medscape (a subsidiary of WebMD) and a freelance health, science and food writer. He received his MD in 2005 from the University of Virginia and has written for WIRED, Slate and Popular Mechanics about brains, genomics and sometimes both. Follow Bret on Twitter @BretStetka.

Are you a scientist who specializes in neuroscience, cognitive science, or psychology? And have you read a recent peer-reviewed paper that you would like to write about? Please send suggestions to Mind Matters editor Gareth Cook, a Pulitzer prize-winning journalist at the Boston Globe. He can be reached at garethideas AT or Twitter @garethideas.