Mark Slifstein

Increased Serotonin 2A Receptor Availability in the Orbitofrontal Cortex of Physically Aggressive Personality Disordered Patients

BACKGROUNDnImpulsive physical aggression is a common and problematic feature of many personality disorders. The serotonergic system is known to be involved in the pathophysiology of aggression, and multiple lines of evidence have implicated the serotonin 2A receptor (5-HT(2A)R). We sought to examine the role of the 5-HT(2A)R in impulsive aggression specifically in the orbitofrontal cortex (OFC), given that our own studies and an extensive literature indicate that serotonergic disturbances in the OFC are linked to aggression. We have previously hypothesized that increased 5-HT(2A)R function in the OFC is a state phenomenon that promotes impulsive aggression.nnnMETHODSnSerotonin 2A receptor availability was measured with positron emission tomography and the selective 5-HT(2A)R antagonist radioligand [(11)C]MDL100907 in two groups of impulsively aggressive personality disordered patients-14 with current physical aggression, and 15 without current physical aggression-and 25 healthy control subjects. Clinical ratings of various symptom dimensions were also obtained.nnnRESULTSnOrbitofrontal 5-HT(2A)R availability was greater in patients with current physical aggression compared with patients without current physical aggression and healthy control subjects; no differences in OFC 5-HT(2A)R availability were observed between patients without current physical aggression and healthy control subjects. No significant differences in 5-HT(2A)R availability were observed in other brain regions examined. Among both groups of impulsively aggressive personality disordered patients combined, OFC 5-HT(2A)R availability was correlated, specifically, with a state measure of impulsive aggression.nnnCONCLUSIONSnThese findings are consistent with our previously described model in which impulsive aggression is related to dynamic changes in 5-HT(2A)R function in the OFC.

Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [11C]-(+)-PHNO

RationaleSecond-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.ObjectiveThe purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.MethodsUsing [11C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.ResultsA monotonic dose-occupancy relationship was observed for both receptor types. After 2xa0weeks of treatment, near complete (∼100xa0%) occupancies were observed for both receptors at a dose of 12xa0mg/day. At the lowest cariprazine dose (1xa0mg/day), mean D3 and D2 receptor occupancies were 76 and 45xa0%, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3xa0=xa03.84xa0nM and D2xa0=xa013.03xa0nM) in plasma after 2xa0weeks of dosing.ConclusionThis PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Striatal dopamine type 2 receptor availability in anorexia nervosa

The neurobiology of anorexia nervosa remains incompletely understood. Here we utilized PET imaging with the radiotracer [(11)C]raclopride to measure striatal dopamine type 2 (D2) receptor availability in patients with anorexia nervosa. 25 women with anorexia nervosa who were receiving treatment in an inpatient program participated, as well as 25 control subjects. Patients were scanned up to two times with the PET tracer [(11)C]raclopride: once while underweight, and once upon weight restoration. Control subjects underwent one PET scan. In the primary analyses, there were no significant differences between underweight patients (n=21) and control subjects (n=25) in striatal D2 receptor binding potential. Analysis of subregions (sensorimotor striatum, associative striatum, limbic striatum) did not reveal differences between groups. In patients completing both scans (n=15), there were no detectable changes in striatal D2 receptor binding potential after weight restoration. In this sample, there were no differences in striatal D2 receptor binding potential between patients with anorexia nervosa and control subjects. Weight restoration was not associated with a change in striatal D2 receptor binding. These findings suggest that disturbances in reward processing in this disorder are not attributable to abnormal D2 receptor characteristics, and that other reward-related neural targets may be of greater relevance.

Assessment of glutamate in striatal subregions in obsessive-compulsive disorder with proton magnetic resonance spectroscopy

Glutamatergic signaling abnormalities in cortico-striatal circuits are hypothesized to lead to the repetitive thoughts and behaviors of obsessive-compulsive disorder (OCD). To test this hypothesis, studies have used proton magnetic resonance spectroscopy (1H MRS) to measure glutamatergic compounds in the striatum of individuals with OCD. However, no studies have used methods that could measure glutamate minimally contaminated by glutamine and γ-aminobutyric acid (GABA) in striatal subregions. Therefore, in this study, a proton MRS imaging (1H MRSI) technique with relatively high spatial resolution at 3.0 T was used to measure minimally contaminated glutamate levels in three striatal subregions (i.e., dorsal caudate, dorsal putamen, and ventral striatum) in 15 unmedicated adults with OCD and 16 matched healthy control subjects. No significant group differences in glutamate levels were found in any of the three striatal subregions. In contrast, a study in unmedicated pediatric OCD patients that measured glutamatergic compounds in the dorsal caudate by MRS at 1.5 T found significant elevations. Further studies are warranted to assess whether these discrepant MRS findings are due to differences in subject age or MRS methodology, or potentially are associated with glutamatergic gene variants implicated in OCD.

Dopamine Release in Antidepressant-Naive Major Depressive Disorder: A Multimodal [11C]-(+)-PHNO Positron Emission Tomography and Functional Magnetic Resonance Imaging Study

BACKGROUNDnMesolimbic dopamine system dysfunction is believed to contribute to major depressive disorder (MDD), but molecular neuroimaging of striatal dopamine neurotransmission has yielded mixed results, possibly owing to limited sensitivity of antagonist radioligands used with positron emission tomography to assess dopamine release capacity. This study used an agonist radioligand with agonist challenge to assess dopamine release capacity and D2/D3 receptor availability in MDD.nnnMETHODSnTwenty-six treatment-naive adults with MDD and 26 healthy comparison participants underwent functional magnetic resonance imaging during a probabilistic reinforcement task, and positron emission tomography with the D3-preferring ligand [11C]-(+)-PHNO, before and after oral dextroamphetamine. MDD participants then received pramipexole treatment for 6 weeks.nnnRESULTSnMDD participants had trend-level greater dopamine release capacity in the ventral striatum, as measured by percent change in baseline binding potential relative to nondisplaceable compartment (ΔBPND) (-34% vs.xa0-30%; pxa0= .072, dxa0= 0.58) but no difference in D2/D3 receptor availability (BPND). Striatal and extrastriatal BPND and percent change in baseline BPND were not significantly associated with blood oxygen level-dependent response to reward prediction error in the ventral striatum, severity of depression and anhedonia, or antidepressant response to pramipexole (response ratexa0= 72.7%).nnnCONCLUSIONSn[11C]-(+)-PHNO demonstrated high sensitivity to displacement by amphetamine-induced dopamine release, but dopamine release capacity and D2/D3 availability were not associated with ventral striatal activation to reward prediction error or clinical features, in this study powered to detect large effects. While a preponderance of indirect evidence implicates dopaminergic dysfunction in MDD, these findings suggest that presynaptic dopamine dysregulation may not be a feature of MDD or a prerequisite for treatment response to dopamine agonists.