In vivo PET study of 5HT2A serotonin and D2 dopamine dysfunction in drug-naive obsessive-compulsive disorder
Introduction
Obsessive compulsive disorder (OCD) is defined by the presence of recurrent thoughts or images (obsessions), intrusive and distressing, and ritualistic behaviours (compulsions) typically engaged to neutralize obsessive thoughts (according to the Diagnostic and Statistical Manual of Mental Disorder criteria)(American Psychiatric Association, 1994).
Advances in brain imaging, neurophysiology and pharmacology have provided growing evidences for a neurological basis of OCD (Friedlander and Desrocher, 2006).
The prevalent neurobiological model proposes that OCD is associated with a dysfunction of the cortico-striatal–thalamic–cortical pathway, including orbitofrontal cortex, cingulate gyrus, striatum, globus pallidus and thalamus (Insel, 1992). The involvement of the cortico-striatal–thalamic–cortical pathway was primarily revealed by anatomo-clinical observations showing that subjects with focal lesions in cerebral structures within this neural circuit suffered by obsessive-compulsive symptoms (see for review Coetzer, 2004). These evidences are also supported by neuroimaging steady-state studies of cerebral perfusion and metabolism, providing consistent data about the dysfunction of this system in OCD (see for review Whiteside et al., 2004). In the same direction, MRI structural data have shown changes of regional grey matter density in cortical and subcortical structures belonging to the cortico-striatal–thalamic–cortical circuit in OCD patients (Pujol et al., 2004).
The involvement of specific neurotransmitters in OCD pathophysiology is still unclear, but there are several indirect evidences suggesting serotonergic and dopaminergic abnormalities.
The earliest indication of the importance of serotonin was the observation that OCD patients responded to clomipramine, a tricyclic antidepressant which is mainly a serotonin reuptake inhibitor (Rack and Chir, 1970). Nowadays, antidepressant drugs with selective serotonergic properties such as SSRIs are effectively used in the treatment of patients suffering from OCD (see for review Dell'Osso et al., 2005). Finally, neurobiological studies demonstrated that OCD is associated with decreased levels of plasmatic serotonin (Delorme et al., 2005).
Both preclinical and clinical evidences support the relevance of the dopaminergic system in the pathogenesis of OCD (Denys et al., 2004a). Experimental studies in animals demonstrated that an increase of dopaminergic activity through the administration of dopamine-agonist drugs, such as amphetamine, bromocriptine, apomorphine and l-dopa, induces stereotyped behaviours (Pitman, 1989). The D2 receptors seem to be of primary interest since rats treated with quinpirole, a selective D2/3 receptor agonist, develop repetitive checking behaviour (Tizabi et al., 2002).
Clinical evidences for the role of dopamine in OCD are provided by the observation that basal ganglia infarcts might be associated with OCD behaviour (Carmin et al., 2002), and by the fact that patients who do not show significant improvement after SSRIs treatment, may benefit from addition of antipsychotics (Cavedini et al., 2004, Denys et al., 2004a).
Neurological diseases associated with dopaminergic dysfunction and presenting with OCD symptoms, such as Tourette's syndrome, Sydenham's chorea and Von Economo's encephalitis, provide another indirect strong evidence of the role of dopamine in OCD. In addition, the co-morbidity of Tourette's Syndrome and OCD, mainly in the childhood-onset forms, suggests possible common neurobiological mechanisms and genetic factors for the two disorders (Lochner et al., 2005, Pauls et al., 1986, Pauls et al., 1995).
Previous neuroimaging studies addressed the serotonergic and dopaminergic systems in OCD, with inconsistent results that could be explained by the type of tracers and different analysis methods, as well as by the inclusion of previously treated, instead of drug-naive subjects (Adams et al., 2005, Denys et al., 2004a, Denys et al., 2004b, Hasselbalch et al., 2007, Hesse et al., 2005, Pogarell et al., 2003, Simpson et al., 2003, Stengler-Wenzke et al., 2004, Zitterl et al., 2007, van der Wee et al., 2004).
Despite the growing evidences for contributions of the serotonergic and dopaminergic systems in the pathophysiology of OCD, to date there are no available PET studies addressed to the postsynaptic activity on the same group of OCD subjects, naive to any kind of psychotropic drugs. We support an a-priori hypothesis of a combined serotonergic and dopaminergic dysfunction in OCD.
We used PET and the selective antagonists [11C]MDL 100,907 ([11C]MDL) and [11C]Raclopride ([11C]RAC) to assess respectively 5-HT2A and D2 receptor availability in the same group of clinically homogeneous drug-naive OCD patients. We also evaluated the correlations with the major clinical symptoms of the disease.
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Subjects
Nine drug-naive OCD patients (3 females and 6 males, age range 20–45 years) and 15 age-matched healthy subjects (3 females and 12 males, age range 21–55 years) participated in the study. (see Table 1 for details).
The patients were consecutively recruited from the OCD inpatient unit at the San Raffaele Hospital, Milan. They were diagnosed according to standard criteria for OCD (DSM-IV) by experienced research psychiatrists. The severity of OCD symptoms was clinically assessed using the
Voxel-based analysis
The SPM analysis revealed significant clusters areas of reduced [11C]MDL-BP in OCD patients compared to control subjects. These differences were located bilaterally in the frontal lobes, involving the dorsolateral, frontal polar, and medial frontal cortex. Significant BP reductions were also evident in the anterior and middle cingulate cortex and in the parietal and temporal associative cortex (see Fig. 1 and Table 2).
We did not find any clusters of significantly higher [11C]MDL-BP in OCD
Discussion
One of the critical issues in research on OCD is examining the neurological correlates of the disorder. Here we provide the first in vivo PET evidence of associated dysfunctions in both serotonergic and post-synaptic dopaminergic systems in OCD. We found significant reductions of both [11C]MDL- and [11C]RAC-BP in OCD patients, as compared with control subjects. The reduction of the [11C]MDL-BP in OCD group was prominent in the frontal and cingulate cortex, but involved also parietal and
Acknowledgments
We thank Mrs. L. Bonaldi and A. Compierchio for assistance in PET study acquisition and data analysis and Lucia Pietra for assistance in data analysis.
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