Plenty of us have known a dog on Prozac. We have also witnessed the eye rolls that come with the mention of canine psychiatry. Doting pet owners—myself included—ascribe all kinds of questionable psychological ills to our pawed companions. But in fact, the science suggests that numerous nonhuman species do 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 Laurel Braitman in her 2014 book Animal Madness.

But at least one mental malady, while common in humans, seems to have spared other animals: schizophrenia, which affects an estimated 0.4 to 1 percent of adults. Although animal models of psychosis exist in laboratories, and odd behavior has been observed in creatures confined to cages, most experts agree that psychosis has not typically been seen in other species, whereas depression, obsessive-compulsive disorder and anxiety traits have been reported in many nonhuman species.

This raises the question of why such a potentially devastating, often lethal disease is still hanging around plaguing humanity. We know from an abundance of recent research that schizophrenia is heavily genetic in origin. One would think that natural selection would have eliminated the genes that predispose to psychosis. A study published earlier this year in Molecular Biology and Evolution provides clues as to how the potential for schizophrenia may have arisen in the human brain and, in doing so, suggests possible treatment targets. It turns out that psychosis may be an unfortunate cost of having a big brain that is capable of complex cognition.

Hotspots in the Human Genome

The study, led by Joel Dudley, a genomics professor at the Icahn School of Medicine at Mount Sinai, proposes that because schizophrenia is relatively prevalent in humans, it perhaps has a complex evolutionary backstory that would explain its persistence and apparent exclusivity to humans. Specifically, Dudley and his colleagues were curious about segments of our genome called human accelerated regions, or HARs, first identified in 2006. HARs are short stretches of DNA that were conserved in other species but underwent rapid evolution in humans following our split with chimpanzees, presumably because they provided some benefit specific to our species. Rather than encoding for proteins themselves, HARs often help to regulate neighboring genes. Because 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 his 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, by comparing the patterns of change in humans and chimpanzees, it was revealed that HAR-associated schizophrenia genes were under stronger evolutionary selective pressure than other schizophrenia genes. This observation implies that the human variants of these genes are essential to us in some way, despite the risk they harbor.

To help understand what these benefits might be, Dudley's group then turned to gene expression profiles. Gene sequencing provides an organism's genome sequence, but gene expression profiling reveals where and when in the body certain genes are active. Dudley's team 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 that is involved in higher-order thinking. Impaired function in the prefrontal cortex is thought to contribute to psychosis.

They also found that these culprit genes are involved in various key human neurological functions within the prefrontal cortex, including the transmission of the neurotransmitter GABA across a synapse from one neuron to another. GABA serves as an inhibitor or regulator of neuronal activity, in part by suppressing dopamine in certain parts of the brain. In schizophrenia, GABA appears to malfunction, and dopamine runs wild, contributing to the hallucinations, delusions and disorganized thinking that are 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 that we can better understand and diagnose the disease,” Dudley explains. Identifying which genes are most implicated in schizophrenia and how they are expressed could lead to more effective therapies such as those influencing the function of GABA.

When Bigger Isn't Better

Dudley's findings offer a possible explanation for why schizophrenia arose in humans in the first place and why it does not 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, autism.” Indeed, language dysfunction—typified by disorganized speech or jumping from one topic to another—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 is 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 observes, “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 did not identify any “smoking gun genes” and that schizophrenia genetics is profoundly complex. Still, Dudley feels that evolutionary genetic analysis can help identify the most relevant genes and pathological mechanisms at play in schizophrenia and possibly other mental illnesses that preferentially affect humans—that is, neurodevelopmental disorders related to higher cognition and GABA activity, including autism and attention-deficit/hyperactivity disorder.

In fact, a study published online this past March in Molecular Psychiatry reported a link between gene variants associated with autism spectrum disorder and better cognitive function in the general population—specifically, enhanced general cognitive ability, memory and verbal intelligence. “It would suggest that some of these variants can have beneficial effects on cognition,” says lead author Toni-Kim Clarke of the University of Edinburgh. The findings might also help explain why individuals with autism sometimes exhibit unusual cognitive gifts.

Clarke's findings 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 curing the ailing brain.