Comments on News and Primary Papers
Comment by: Brian Dean
Submitted 18 January 2010
Posted 18 January 2010
Serotonin2A Receptors and Schizophrenia: The Controversies Continue
A new study reporting decreased serotonin2A receptor (HTR2A) density in drug naïve first-episode schizophrenia (Rasmussen et al., 2010) has again raised the issue of the role of that receptor in the pathophysiology of the disorder.
The notion that the HTR2A is involved in pathophysiology and treatment of schizophrenia remains an open issue. The observation that a number of the atypical antipsychotic drugs are high-affinity antagonists at the receptor would suggest that blocking stimulation of the receptor can have some therapeutic benefit (Meltzer, 1995). It is also significant that, overall, available data from postmortem studies would suggest that the HTR2A is decreased in density in the cortex of subjects with schizophrenia (Dean, 2003). This could either be due to altered gene expression per se or an appropriate agonist induced downregulation of the receptor due to chronic overactivation (Rahimian et al., 1995). Recently, it has been suggested that different outcomes from the postmortem studies are due to differing methodologies (Dean et al., 2008); the differences being due to studies using particulate membrane separating a component in the cytosol which regulates receptor binding from the receptor protein. It is becoming clear that the HTR2A is part of protein complexes in the membrane (Gonzalez-Maeso et al., 2008), and, therefore, it could well be that further exploration of the interactions between the HTR2A and its membrane complexes as well as the cytosol are required to make postmortem data on the HTR2A more interpretable.
As with postmortem studies, positron emission tomography studies appear to be giving disparate outcomes regarding the levels of HTR2A in schizophrenia (Table 1). Clearly, in these studies different results cannot be accounted for by separating the receptor from intracellular regulatory proteins or membrane complexes. Moreover, whilst there are differences in the number of subjects in each study, an analysis of cohort sizes (Fisher exact test) shows this measure does not differ significantly across studies (p = 0.09). Finally, the radioligand used would not appear to be influencing outcomes, as studies using [18F]setoperone and [18F]altanserin have both given different outcomes in different studies of levels of HTR2A in subjects with schizophrenia.
One intriguing observation is that, if current studies are ranked by the mean age of the total cohort of subjects studied, then the two studies reporting decreases in the HTR2A in schizophrenia were completed on the youngest of the seven cohorts (Table 1). This raises the possibility that decreases in the HTR2A may be detectable by neuroimaging early in the disease process. If that is the case, could a decrease in cortical HTR2A be a potential prodromal marker to predict the transition from high risk to frank schizophrenia?
Rasmussen, H, et al., (2010) Decreased frontal serotonin2A receptor binding in antipsychotic-naive patients with first-episode schizophrenia, Arch. Gen. Psychiatry 67, 9-16. Abstract
Meltzer, HY, (1995) The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics, J. Clin. Psychopharmacol. 15, 2S-3S. Abstract
Dean, B, (2003) The cortical serotonin2A receptor and the pathology of schizophrenia: a likely accomplice, J. Neurochem. 85, 1-13. Abstract
Rahimian, R, et al., (1995) Possible role of protein kinase C in regulation of 5-hydroxytryptamine 2A receptors in rat brain, Can. J. Physiol Pharmacol. 73, 1686-1691. Abstract
Dean, B, et al., (2008) Evidence for altered post-receptor modulation of the serotonin 2a receptor in schizophrenia, Schizophr. Res. 104, 185-197. Abstract
Gonzalez-Maeso, J, et al., (2008) Identification of a serotonin/glutamate receptor complex implicated in psychosis, Nature 452, 93-97. Abstract
Ngan, ET, et al., (2000) Decreased serotonin 2A receptor densities in neuroleptic-naive patients with schizophrenia: A PET study using [(18)F]setoperone, Am. J. Psychiatry 157, 1016-1018. Abstract
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Trichard, C, et al., (1998) No serotonin 5-HT2A receptor density abnormality in the cortex of schizophrenic patients studied with PET, Schizophr. Res. 31, 13-17. Abstract
Erritzoe, D, et al., (2008) Cortical and subcortical 5-HT2A receptor binding in neuroleptic-naive first-episode schizophrenic patients, Neuropsychopharmacology 33, 2435-2441. Abstract
Lewis, R, et al., (1999) Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects, Am. J. Psychiatry 156, 72-78. Abstract
Verhoeff, NP, et al., (2000) A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia, Psychiatry Res. 99, 123-135. Abstract
View all comments by Brian DeanComment by: Albert Adell
Submitted 18 January 2010
Posted 18 January 2010
The search for biomarkers in complex psychiatric disorders such as schizophrenia has been a crucial goal in clinical research, but remains to be fully accomplished. Serotonin 5-HT2A receptors have been associated with the pathophysiology and pharmacotherapy of schizophrenia for two main reasons: 5-HT2A receptor agonists such as LSD elicit hallucinogenic states in humans and second-generation, atypical antipsychotics are effective 5-HT2A receptor antagonists. However, 5-HT2A receptor agonists usually evoke visual hallucinations, whereas those associated with schizophrenia are commonly auditory (Hollister, 1962). Contradictory changes in 5-HT2A receptor density in cortical areas of the brain have been detected in several postmortem studies. The case-control study of Rasmussen and coworkers (Rasmussen et al., 2010) shows decreased 5-HT2A binding in the frontal cortex of antipsychotic-free, first-episode schizophrenics. Although similar findings were previously observed (Ngan et al., 2000; Erritzoe et al., 2008), the present study used the largest sample of patients to date, which gives further strength and validity to the results.
A question that remains to be answered is, What causes this reduced 5-HT2A binding? Although a hyperactive serotonergic transmission in the prefrontal cortex has been implicated in schizophrenia (Meltzer, 1989), the precise role of cortical serotonin on this effect is not fully understood. It has been shown in an animal model of the illness that antagonists of the NMDA glutamate receptor increased serotonin release in prefrontal cortex (Adams and Moghaddam, 2001; Amargós-Bosch et al., 2006; López-Gil et al., 2007), an effect prevented by atypical but not typical antipsychotic drugs (López-Gil et al., 2007; 2010). If these changes also occur in schizophrenia, the decreased 5-HT2A binding might be a compensatory effect resulting from increased cortical serotonergic transmission. Interestingly, although negative symptoms are usually thought to be associated with impaired serotonergic transmission in schizophrenia (Reynolds, 2004), the present study found a significant negative correlation between 5-HT2A binding in the frontal cortex and positive symptoms in the group of male patients. A study with a larger population is likely needed to draw unequivocal conclusions on that matter. Also, an important point not to be missed is that PET measures were performed, for obvious reasons, in a resting state. Differences in serotonergic changes may thus exist, depending on the pathological phase of the illness.
From a pharmacological point of view, it is worth noting that blockade of 5-HT2A receptors alone does not confer antipsychotic activity. Thus, clinical evaluation of the selective 5-HT2A antagonist, M100907, failed to demonstrate therapeutic efficacy (de Paulis, 2001), despite the high level of 5-HT2A receptor occupancy achieved in frontal cortex (Offord et al., 1999). With the exception of dopamine D2 receptor antagonists (Seeman et al., 1976), no other monoamine receptor antagonist has been shown to possess antipsychotic activity per se. Therefore, there is a clear need for targeting different transmitter receptors in order to achieve better treatment (as well as a lower side effect profile) of schizophrenia. What the study by Rasmussen and coworkers clearly points out is that 5-HT2A receptors in the frontal cortex are involved in the pathophysiology of schizophrenia, and this region plays a role in the pharmacological effects of antipsychotic drugs.
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Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J. Decreased frontal serotonin2A receptor binding in antipsychotic-naïve patients with first-episode schizophrenia. Arch Gen Psychiatry. 2010;67:9-16. Abstract
Reynolds GP. Receptor mechanisms in the treatment of schizophrenia. J Psychopharmacol. 2004;18:340-345. Abstract
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View all comments by Albert Adell