UPDATED January 21, 2015 // Young people at clinical high risk (CHR) who progress to full psychosis have increased reductions in prefrontal gray matter that may be driven by neuroinflammation, new research suggests.

The study also showed that this cortical loss, which was more pronounced in those whose prodromal symptoms were of shorter duration, was inversely associated with plasma levels of proinflammatory cytokines, suggesting the presence of systemic neuroinflammation. Importantly, the investigators note, the tissue loss was not accounted for by exposure to antipsychotic medications.

Individuals at CHR "who convert to psychosis show a steeper rate of thinning in prefrontal cortex, an effect that is independent of exposure to antipsychotic drugs and is predicted by plasma analytes indicative of an inflammatory process," the investigators, led by Tyrone Cannon, PhD, professor of psychology and psychiatry at Yale University, in New Haven, Connecticut, write.

The article was published in the January 15 issue of the journal Biological Psychiatry.

Antipsychotic Naïve

Previous neuroimaging research has established that individuals who convert to psychosis have more rapid and more pronounced gray matter loss compared with those who do not convert and with healthy persons.

The long-term effects of antipsychotic medications on cortical gray matter are not well understood, and because nearly all patients are treated with these medications, it has been difficult to distinguish the effects of antipsychotic drug treatment from the progression of schizophrenia, the authors note.

To determine whether these brain changes reflect processes associated with the pathophysiology of schizophrenia or exposure to antipsychotics, investigators conducted a longitudinal, multicenter MRI study at eight US sites.

The study included 274 CHR, antipsychotic-naïve individuals whose average age was 18.8 years at baseline and 135 healthy control persons, all of whom had undergone MRI at baseline and at 1-year follow-up.

Of the CHR participants, 35 converted to psychosis, and 239 did not convert. There were no significant differences between those who converted, those who did not, and healthy control persons in terms of age, sex, site of origin, and socioeconomic class.

There were also no significant differences at baseline between the groups in terms of cortical thickness or subcortical or ventricular volumes.

Compared with both nonconverters and control persons, and after correcting for multiple comparisons, those who converted had a steeper rate of gray matter loss in right superior frontal, middle frontal, and medial orbitofrontal cortical regions of the brain. Those who converted also had a greater rate of expansion of the third ventricle compared with other participants.

Changes in gray matter thickness were unaffected by exposure to antipsychotic medication. The results also showed that these changes were not significantly correlated with the duration or dosage of antipsychotic medication or with the interval between conversion to psychosis and the follow-up scan.

Causal Relationship?

However, it was observed that among those who converted, the cortical changes were more pronounced in those whose prodromal symptoms were of shorter duration than in those with symptoms of longer duration.

It is tempting to suggest that these findings represent a "hardwiring" of psychosis into the brain. Dr Cannon agreed that this is one way of looking at the process, "although that way of phrasing it might imply a permanency that may overstate it, because we think of these processes relating to synaptic density and dendritic processes and neurons as reflecting mechanisms that have ongoing plasticity throughout the lifespan."

"These elements of neurons can regenerate and are constantly being modified with experience and so forth throughout life; whereas we are not growing more actual cell bodies, we are constantly modifying the synaptic contacts of existing cells, and that's the nature of the pathology that we think underlies this loss," he added.

The team also found that at baseline, there were no significant differences in mean levels of inflammatory or proinflammatory cytokines in the blood. However, the rate of prefrontal cortical thinning was significantly associated with higher levels of proinflammatory cytokine markers, with the inverse correlation significantly greater among those who convertered than other participants.

This finding reinforces a growing body of evidence suggesting a connection between psychosis and schizophrenia and inflammatory processes.

"The field is becoming quite taken by this notion. Perhaps there's some kind of immune- or autoimmune-related process that results in inflammation, and the inflammation could be driving this gray matter loss, in the sense that cytokines activate microglia in the brain, and the microglia are involved in pruning-type processes," said Dr Cannon.

"It's not entirely clear yet whether the signal we've detected in this study reflects that kind of feed-forward causal relationship where inflammation occurs first and you get the gray matter loss, or whether the inflammation is more like a secondary signal," he added.

Anti-inflammatories to Treat, Prevent Psychosis?

Dr Cannon believes that it may eventually be possible to use anti-inflammatory medications in treating the onset of psychosis.

"If we can establish a causal link with inflammation, then that would clearly motivate intervention approaches with anti-inflammatories," said Dr Cannon.

"One of the great things about that if it works out that way is these drugs are available, they're relatively low toxicity in terms of side effects, and dosing is probably favorable to avoid the side effects that do exist."

"There are lots of reasons to be optimistic that this class of drug could be helpful, if it turns out that the inflammatory mechanism is a causal one," he added.

Although Dr Cannon believes that it may eventually be possible to use anti-inflammatory medications in treating the onset of psychosis, he pointed out that previous randomized, controlled trials of anti-inflammatory drugs in schizophrenia patients have yielded inconclusive results.

"You would think that if the mechanism relates to the initial causes of this gray matter loss, then if that's already occurred in people who are fully ill, your ability to affect the course of that change is much more limited," he said.

"You could expect, then, that maybe the window of opportunity of using them in this preventive mode is somewhere prior to the onset of full symptoms, and that's something that hasn't been tested yet," Dr Cannon concluded.

Tipping Point

William T Carpenter Jr, MD, professor of psychiatry and pharmacology, University of Maryland School of Medicine, in College Park, welcomed the study, describing it as "important."

"The gray matter changes in the brain show that there's a progression, and because the second scans were after a fairly short period of time, meaning the person had progressed onto a psychosis and then got retested, it suggests that the onset is shortly before conversion to full psychosis," he told Medscape Medical News.

"For the field, it's important for us to know when different types of brain changes are taking place. Some may take place very early in life...some may take place as you move towards psychosis," Dr Carpenter added.

"There are always limitations to any single study, but if this is a valid finding, it would suggest that there's an aspect of brain change that starts shortly before psychosis, it progresses during that period, and then, of course, we'll need to find out if it continues to progress or if it's just for a short period of time."

One obvious application of the finding of progressive brain changes is as a potential risk factor for psychosis.

"Clinically, that might not be necessary, because it may be that symptoms are increasing, and just knowing the change in the clinical picture might be sufficient to warn you that a relapse is coming," said Dr Carpenter.

"But from a scientific point of view and understanding what's going on in the brain, this kind of longitudinal study is very important," he added.

John Krystal, MD, editor of Biological Psychiatry, said the findings suggest that "neuroinflammation may be a process that in some cases 'tips people over' from the at-risk state into psychosis."

"Inflammation," he added, "is increasingly recognized as a contributing factor to the emergence of progression of disease in every organ of the body."

This study was supported by a collaborative U01 award from the National Institute of Mental Health (NIMH) at the National Institutes of Health, as well as grants from the NIMH and the Commonwealth of Massachusetts. The authors have reported no relevant financial relatinships.

Biol Psychiatry. 2015;77:147-57. Abstract