Antipsychotic-Related Brain Loss: Does Class Matter?

Deborah Brauser

February 26, 2015

Depending on drug class, some antipsychotics may be associated with cortical gray matter (GM) deficits in schizophrenia, whereas others may be neuroprotective, new research suggests.

Dr Antonio Vita

A meta-analysis of 18 MRI studies, with more than 2000 adults, showed that participants with schizophrenia had significantly greater loss of total cortical GM volume compared with their counterparts who did not have the disorder, a finding that was "related to cumulative antipsychotic intake during the interval between scans."

Further analysis showed that more progressive brain volume loss was associated with higher mean daily intake in those receiving at least one first-generation antipsychotic (FGA). On the other hand, patients receiving second-generation antipsychotics (SGAs) had less progressive GM loss with higher mean daily intake.

"The role played by antipsychotic treatment on the pathophysiologic trajectory of brain abnormalities in schizophrenia is currently a matter of lively debate [but] we obtained clear-cut results," Antonio Vita, MD, PhD, from the University of Brescia School of Medicine, in Italy, told Medscape Medical News.

He noted that the study's main conclusion is that the contributory role of antipsychotics in reducing GM volume in schizophrenia "cannot be generalized and appears to be far less evident for SGAs." In fact, he noted, SGAs may be associated with less brain tissue loss.

"A stable, therapeutic mean daily dose of SGAs taken may contrast the trajectory of progressive cortical GM loss detected in schizophrenia," said Dr Vita.

The study was published online February 16 in Biological Psychiatry.

SGAs Neuroprotective?

The researchers evaluated data on 18 MRI longitudinal studies that examined gray matter changes over time and were published between 2002 and March 2014. A total of 1155 patients with schizophrenia and 911 age- and sex-matched adults who acted as healthy control individuals participated in the studies.

In addition, subgroup meta-analyses were conducted to examine patients treated with FGAs and/or SGAs during MRI scan intervals.

Results showed that whole-brain gray matter volume loss was significantly higher in the group with schizophrenia than in the healthy control group (-0.24 vs -0.10, respectively; P = .02).

There were no significant between-group differences in frontal lobe, temporal lobe, or parietal lobe gray matter changes over time.

Subgroup analyses showed that schizophrenia patients who received FGAs alone or with SGAs had significant decreases in whole-brain, frontal, temporal, and parietal lobe gray matter volume over time.

Those receiving only SGAs had no volume decreases in whole-brain and parietal lobe GM levels. Interestingly, GM volume increased over time in the frontal and temporal lobe for this group; but this increase was not statistically significant.

In addition, "the greater the exposure to antipsychotics [overall] during the interscan interval the greater the reduction in GM volume," report the investigators.

Plus, the effect size of whole-brain GM changes was negatively affected by the cumulative exposure to and mean daily dose of antipsychotics for those treated with FGAs.

However, not only did the patients receiving only SGAs show no association between cumulative exposure to the drugs and whole brain GM volume change but the higher the mean daily dose, the less the volume decreased.

"These findings add useful information to the controversial debate on the brain structural effects of antipsychotic medication and may have both clinical relevance and theoretical implications," write the investigators.

However, they add that any interpretation of the medication class results "are speculative at this time," especially because there were so few studies with these specific comparisons.

Still, "it has been hypothesized that SGAs may have a neuroprotective effect," they write.

"Conversely, the excessive reduction in cortical GM observed in patients treated with FGAs may be attributable to a direct neurotoxic effect secondary to oxidative stress and/or excitotoxic phenomena."

Dr Vita noted that there are "many issues" that need to be addressed in future research, including whether antipsychotics' effects on the brain vary as a function of age and stage of illness.

"More longitudinal studies specifically designed to directly test the hypothesis of a different effect on regional brain volumes of FGAs vs SGAs are warranted," he said.

"Clarification of these issues will have crucial importance in the clinical management of schizophrenia and will allow a better understanding of the mechanisms."

Clinically Relevant?

David Glahn, PhD, professor of psychiatry at Yale University, in New Haven, Connecticut, and from the Olin Neuropsychiatry Research Center, at Hartford Hospital, told Medscape Medical News that although the results are interesting, he would have also liked information on whether there were changes in the patients' functional activity, symptom profile, or cognitive ability.

Dr David Glahn

"Because you would expect that if you're seeing a progressive gray matter loss, you would see those comparable changes as well. And if you're not seeing that, then we need to ask: is the amount of gray matter loss we're seeing here really clinically relevant?" he asked.

"And unfortunately, that's not addressed in this particular paper. But it could possibly be addressed in some of the larger-scale databases that are out there. I think that would be a wonderful follow-up to this type of work."

Dr Glahn, who was not involved with this research, has written about GM anomalies in schizophrenia.

"I have had data over the years that have suggested that there is cortical change in gray matter when we're looking at individuals with schizophrenia who have been taking certain classes of medication," he said.

However, "I've had those same exact patients come back at later times on the same medications and not found that effect. It's a question of whether there is truly an effect of the medication or are there other things that are sequelae of the illness that are the critical things that are going on."

Dr Glahn said these questions are "difficult to untangle" because research rarely examines untreated patients with this disorder.

"It is possible that antipsychotics are having an effect and reducing cortical thickness over time, which is what this paper suggests. However, instead of comparing class of medication, it would be better if there was a group of patients who weren't being medicated at all who were doing the same scans. But that can be hard to find."

He added that SGAs have been a breakthrough in psychiatry and have really helped patients who were not being helped by FGAs.

"But having said that, there are a lot of things going on, and there are a lot of questions that need to be addressed. I think this should spur us to have a conversation," said Dr Glahn.

The authors have reported several potential conflicts, which are fully listed in the original article. Dr Glahn reports no relevant financial relationships.

Biol Psychiatry. Published online February 16, 2015. Abstract

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