Arch Gen Psychiatry. 2010;67(1):9-16.
Hans Rasmussen, PhD; David Erritzoe, MD, PhD; Rune Andersen, MSc; Bjorn H. Ebdrup, MD; Bodil Aggernaes, MD, PhD; Bob Oranje, PhD; Jan Kalbitzer, MD; Jacob Madsen, PhD; Lars H. Pinborg, MD, DMSc; William Baaré, PhD; Claus Svarer, PhD; Henrik Lublin, MD, DMSc; Gitte M. Knudsen, MD, DMSc; Birte Glenthoj, MD, DMSc
Context: Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin2A receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin2A binding in schizophrenic patients. However, in vivo studies of serotonin2A binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin2A binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear.
Objectives: To assess in vivo brain serotonin2A binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions.
Design: Case-control study.
Setting: University hospital, Denmark.
Participants: A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects.
Interventions: Positron emission tomography with the serotonin2A-specific radioligand fluorine 18-labeled altanserin and administration of a neuropsychological test battery.
Main Outcome Measures: Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing.
Results: Schizophrenic patients had significantly lower serotonin2A binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin2A binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin2A binding.
Conclusion: The results suggest that frontal cortical serotonin2A receptors are involved in the pathophysiology of schizophrenia.
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What primarily differentiates an atypical antipsychotic vs. a typical antipsychotic is serotonin 2A binding in atypical antipsychotics. Atypicals block serotonin2A receptor, typicals do not.
Blockade of serotonin 2A receptors (which are primarily presynaptic receptors which control dopamine signaling in the frontal cortex), increases dopamine signaling in the frontal cortex.
Interestingly, a pure serotonin 2A receptor blocker/antagonist can work well as an antipsychotic medication. However, such a medication has never come to market past initial studies.
The study brings up an increasing question: Why is serotonin signaling lower in the frontal cortex in patients with schizophrenia? Serotonin has not been a neurotransmitter much discussed in the pathophysiology of schizophrenia. Dopamine, Norepinephrine, and Glutamate have taken the lion’s share of speculation.
Another question: Are there different results for the different types of schizophrenia? For example, paranoid schizophrenia, to me, consists of a psychotic disorder AND a mood disorder (with fear/anxiety being the primary mood). I would expect this to possibly have different serotonin 2A binding compared to those with disorganized schizophrenia (where the disorder is primarily a psychotic disorder).
And a third question: What serotonin 2A binding in patient with mood disorders versus schizophrenia? This is cogent given the recent rash of using atypicals as augmenting agents for the treatment of major depressive disorder.