16 January 2010. The frontal cortex in people with schizophrenia contains abnormally low levels of the 5-HT2A type of serotonin receptor, according to a new report in Archives of General Psychiatry. Hans Rasmussen and colleagues at the Copenhagen University Hospital in Denmark found that this abnormality may be related to psychotic symptoms, but not to the cognitive problems of schizophrenia. Among male patients, the lower the amount of 5-HT2A receptor detected, the more pronounced their psychosis. Similar correlations were not found between 5-HT2A receptor levels and measures of working memory, problem-solving, or attention.
These findings further implicate the neurotransmitter serotonin and its receptors in schizophrenia (see SRF related news story). Several serotonin receptors, particularly the G protein-coupled ones like 5-HT2A that initiate a cascade of intracellular events, are targets of atypical antipsychotic drugs. Indeed, the hypothesis that 5-HT2A occupancy was responsible for the enhanced effectiveness of clozapine over typical antipsychotics helped spur the development of the "me-too" atypicals (see SRF related news story). Postmortem studies have found depleted levels of 5-HT2A receptor binding in brain tissue from people with schizophrenia. Studies in living human brains, however, have been mixed.
Getting to the roots
Using positron emission tomography (PET), Rasmussen and colleagues detected a radiolabeled ligand called altanserin that binds selectively to 5-HT2A receptors, revealing their location in the brain. They did this in 30 people who had recently gone through their first episode of schizophrenia, but who hadn't yet taken antipsychotic medications. Imaging patients after an initial episode, but before treatment, can potentially get to the root problems in the brain in schizophrenia before medications or chronic illness bring about their own changes in the brain. Previous PET studies of serotonin receptors in living human brains either suffered from these confounds, used a less selective ligand, or had small sample sizes.
The new study found that, compared to a case-control population matched by age, sex, and parental socioeconomic status, those with schizophrenia had decreased 5-HT2A receptor binding in a number of cortical brain areas, especially those located in the frontal cortex, which controls higher mental functions. These included the orbitofrontal cortex, the medial inferior frontal cortex, the superior frontal cortex, and the anterior cingulate cortex.
The study did not uphold a previous result showing lower 5-HT2A receptor binding in the caudate nucleus, a subcortical region, in a pilot study of 15 patients conducted by the same group (Erritzoe et al., 2008). Although these same patients were included in the current study, the earlier study did not detect low levels of 5-HT2A receptors in the frontal cortex.
What it might mean
To try to get at what depleted 5-HT2A receptor levels in the frontal cortex could mean, the researchers compared their PET results for each study participant to extensive measurements of their symptom severity and cognitive abilities. Among the 23 male participants with schizophrenia, there was a negative correlation between the amount of 5-HT2A receptor binding in the frontal cortex and their scores for positive symptoms of schizophrenia. This relationship extended to subscores for delusions and suspiciousness, with decreasing levels of 5-HT2A receptors in the frontal cortex associated with increasing delusional behavior or suspiciousness.
The picture was different in the cognitive domain. Although the study participants with schizophrenia performed less well than controls in a battery of cognitive tests, including those probing spatial working memory and executive functions like problem solving, no correlations emerged between these and other cognitive test scores and 5-HT2A receptor binding.
Although this study of first-episode, antipsychotic-naïve people with schizophrenia points to an irregularity in serotonin receptors as a primary disturbance in the brain in schizophrenia, the authors caution that the low 5-HT2A receptor binding could instead reflect a compensation by the brain in response to other primary abnormalities, like altered serotonin levels, hyperactive second messenger systems, or disruptions in other neurotransmitter systems that, in turn, interact with serotonin.—Michele Solis.
Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LJ, Baaré W, Svarer C, Lublin H, Knudsen GM, Glenthoj B. Decreased frontal serotonin2A receptor binding in antipsychotic-naïve patients with first-episode schizophrenia. Arch Gen Psychiatry. 2010 Jan; 67: 9-16. Abstract