Treating the Elusive, Disabling ‘Flatness’ of Schizophrenia

John A was a junior in college when things fell apart. He was 20, a typical age for schizophrenia to come crashing down, and had begun to suspect that his roommate was poisoning his food. John A stopped eating and began hearing voices—they told him to kill the roommate before the roommate killed him. The roommate reported John's behavior to school officials who contacted his parents. He was hospitalized and put on a regimen of risperidone, a classic atypical antipsychotic medication.

The hallucinations, delusions, and paranoia washed away. You wouldn't say they washed away easily; risperidone is, like even the best current antipsychotics, prone to side effects. But the really alarming, dangerous stuff washed away. This is what antipsychotic medication excels at—nuking the most outward, obvious symptoms of schizophrenia. The stuff we might call "losing touch."

John A didn't miraculously bounce back from the episode as if his psychotic episode were a toothache. He didn't return to school. Instead, he lives with his parents, mostly locked away in his room. He rarely emerges, eating and showering only when pushed. He has few interests or activities or friends. The psychosis was gone, but schizophrenia was still there in the form of so-called "negative symptoms." Psychologically, it's like being buried in a wet pile of leaves.

The case study of John A (requires login) could be repeated an endless number of times across schizophrenia patients. Sometime in their mid-20s someone who seems to be doing pretty well suddenly steps off a mental cliff, is treated for psychotic symptoms, and then left to dangle. This isn't the fault of doctors or caregivers, but is a consequence of the simple reality that schizophrenia is mostly untreatable.

This might be about to change, however: At a conference this week, researchers presented results from a phase III trial of what is poised to be the first-ever treatment for the negative symptoms of schizophrenia. While the effects are not exactly night and day, just by existing it's a medication that could change everything for the illness, much like the advent of antipsychotic medication freed patients from a terrifying unreal world that often left them to languish in institutions. The next step, which could still be a ways away, is FDA approval.

So, schizophrenia is divided into three distinct symptom sets. Different combinations of these sets make schizophrenia an extremely varied illness. The negative symptoms all generalize to a form of all-consuming "flatness." It sounds a bit like depression, but in a sense it's before depression, a neutralization or paralysis of the part of the mind that becomes depressed.

"The negative symptoms of schizophrenia include constructs such as asociality (disengagement from others), avolition (reduced initiation or persistence in goal directed behavior), anhedonia (a putative reduction in the ability to experience pleasure), alogia (a reduction in speech output), and blunted or flat affect (a reduction in the display of affect in facial expressions, voice prosody, and gesture)," summarizes a recent editorial in the American Journal of Psychiatry.

There are some slight treatments that can be offered for negative symptoms—stimulants, SSRIs—but they don't amount to much. Same goes for a somewhat more vague schizophrenia symptom category consisting of general cognitive impairments. Schizophrenia remains one of a small handful of diagnoses that are near by-definition disabling, even with sustained antipsychotic treatment.

"The majority of people with schizophrenia do not attain 'normal' milestones in social functioning, productivity, residence, and self-care," explains a 2012 Social Security Administration report. "Further, people with schizophrenia typically underperform compared to expectations based on the achievements of family members and their own functioning prior to diagnosis. These impairments are present early in the illness and are clearly detectable at the time the diagnosis of schizophrenia is confirmed. These impairments also are stable and are not produced in most cases by psychosis, per se, in that disability can be present even during periods when symptoms of psychosis are controlled."

This new drug is called cariprazine and it's technically an antipsychotic. Its targets are two dopamine receptors in the brain, known as D2 and D3. Other antipsychotics tend to act as dopamine receptor antagonists, which means that they block dopamine activity in the brain. That's thought to be a feature of schizophrenia: dopamine receptor overstimulation. Cariprazine works a bit different, however, and rather than just block receptors, it regulates activity both up and down. When receptors are overstimulated, it blocks them; when activity is low, it does the opposite and instead it works to stimulate the receptors. The exact mechanisms are still being investigated.

The latest trial took 461 men and women from around the world and put them in a randomized, double-blind trial comparing cariprazine and risperidone, which is an existing and widely used antipsychotic treatment. Patients were treated for 26 weeks and about three-quarters of participants remained in the trial until the end.

The researchers assessed symptoms using a variation of the common PANSS scale (Positive and Negative Syndrome Scale), focused on negative symptoms. On average, the difference was significant, albeit not huge. What's more, side effects were limited: Between 5 and 10 percent of subjects experienced "insomnia, headache, akathisia, worsening of schizophrenia symptoms, anxiety and somnolence," according to a news release from Gedeon Richter, the pharmaceutical maker behind the drug.

The fate of cariprazine, which is also being evaluated as a treatment for bipolar manic episodes, is now in the FDA's hands. The agency extended its review period earlier this year by three months, which means the decision could come by the end of the year.