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ABSTRACT: Serotonergic abnormalities are hypothesized to contribute to obsessive-compulsive disorder (OCD). This study used positron emission tomography with the radioligand [11C]MDL 100907 to examine whether the distribution of serotonin 2A (5-HT(2A)) receptors is altered in OCD.
Nineteen OCD subjects, free of psychiatric medications and depression, and 19 matched healthy subjects underwent positron emission tomography scans following injection of [11C]MDL 100907. Total distribution volumes were derived by kinetic analysis using the arterial input function. Two measures of 5-HT(2A) availability were computed: the ratio at equilibrium of specifically bound radiotracer either to nondisplaceable radiotracer in tissue (BP(ND)) or to unmetabolized tracer in arterial plasma (BP(p)). Groups were compared using a region of interest (ROI) analysis and voxelwise analysis of spatially normalized parametric maps. ROIs included cortical (orbitofrontal, dorsolateral prefrontal, medial prefrontal, anterior cingulate, temporal, parietal, occipital, and insular cortex) and limbic (entorhinal cortex, parahippocampal gyrus, and medial temporal lobe) regions.
No significant group differences were observed in [11C]MDL 100907 BP(ND) or BP(p) in the ROIs or in the voxelwise analysis of BP(ND) maps. There was a significant correlation in the orbitofrontal cortex between [11C]MDL 100907 binding and age of onset, with earlier age of onset associated with higher binding.
Adults with OCD are not characterized as a group by major changes in 5-HT(2A) availability in cortical or limbic brain regions. Further research is warranted to examine potential differences in 5-HT(2A) availability between early- and late-onset OCD and to assess 5-HT(2A) function in relation to other neurotransmitter systems implicated in OCD.
Biological psychiatry 08/2011; 70(9):897-904. · 8.93 Impact Factor
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ABSTRACT: The amphetamine challenge, in which positron emission tomography (PET) or single photon emission computed tomography radioligand binding following administration of amphetamine is compared to baseline values, has been successfully used in a number of brain imaging studies as an indicator of dopaminergic function, particularly in the striatum. [(18)F] fallypride is the first PET radioligand that allows measurement of the effects of amphetamine on D2/D3 ligand binding in striatum and extra-striatal brain regions in a single scanning session following amphetamine. We scanned 15 healthy volunteer subjects with [(18)F] fallypride at baseline and following amphetamine (0.3 mg/kg) using arterial plasma input-based modeling as well as reference region methods. We found that amphetamine effect was robustly detected in ventral striatum, globus pallidus, and posterior putamen, and with slightly higher variability in other striatal subregions. However, the observed effect sizes in striatum were less than those observed in previous studies in our laboratory using [(11)C] raclopride. Robust effect was also detected in limbic extra-striatal regions (hippocampus, amygdala) and substantia nigra, but the signal-to-noise ratio was too low to allow accurate measurement in cortical regions. We conclude that [(18)F] fallypride is a suitable ligand for measuring amphetamine effect in striatum and limbic regions, but it is not suitable for measuring the effect in cortical regions and may not provide the most powerful way to measure the effect in striatum.
Synapse 05/2010; 64(5):350-62. · 2.94 Impact Factor
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Lawrence S Kegeles,
Mark Slifstein,
W Gordon Frankle,
Xiaoyan Xu, Elizabeth Hackett,
Sung-A Bae,
Robyn Gonzales,
Jong-Hoon Kim,
Beatriz Alvarez,
Roberto Gil,
Marc Laruelle,
Anissa Abi-Dargham
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ABSTRACT: Positron emission tomography (PET) and the high affinity D(2/3) radiotracer [(18)F]fallypride allow the assessment of D(2/3) receptor occupancy of antipsychotic drugs in striatal and extrastriatal brain regions. We measured regional occupancy attained across a range of clinical dosing by the partial D(2) agonist aripiprazole using these methods. Twenty-eight PET scans were acquired on the ECAT EXACT HR+ camera in 19 patients with schizophrenia or schizoaffective disorder. Daily aripiprazole doses ranged from 2 to 40 mg, with a minimum of 10 days on steady dose. Mean regional occupancies, a model-independent estimate of aripiprazole effect on pituitary binding, and PANSS ratings changes were evaluated. Occupancy levels were high across regions of interest, ranging from 71.6+/-5.5% at 2 mg/day to 96.8+/-5.3% at 40 mg/day. Occupancy levels were higher in extrastriatal than striatal regions. Pituitary measures of aripiprazole effect correlated with doses and were unrelated to prolactin levels, which remained within the normal range under medication. PANSS positive (but not negative) symptom improvement correlated with striatal but not extrastriatal occupancies. These data show, for the first time, D(2) occupancy by aripiprazole in treated patients with schizophrenia in extrastriatal as well as striatal regions, with high occupancy for all doses. We discuss possible explanations for higher extrastriatal than striatal occupancy. Correlations of ratings of clinical improvement with regional occupancy suggest that aripiprazole, as do other antipsychotics, benefits positive symptoms of schizophrenia most directly through its modulation of striatal rather than cortical or other extrastriatal dopamine activity.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 05/2008; 33(13):3111-25. · 6.99 Impact Factor
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ABSTRACT: Whole-body radiation dosimetry of 11C-raclopride was performed in healthy human volunteers.
Subjects (n = 6) were scanned with PET. Subjects received single-bolus injections of 11C-raclopride (S-(-)-3,5-dichloro-N-[(1-ethyl-2-pyrrolidinyl)]methyl-2-hydroxy-6-methoxybenzamide) (533 +/- 104 MBq) and were scanned for approximately 110 min with a 2-dimensional whole-body protocol. Regions of interest were placed over all visually identifiable organs and time-activity curves were generated. Residence times were computed as the area under the curve of the time-activity curves, normalized to injected activities and standard values of organ volumes. Absorbed doses were computed according to the MIRD schema with MIRDOSE3.1 software.
Organs with the highest radiation burden were gallbladder wall, small intestine, liver, and urinary bladder wall.
On the basis of the estimated absorbed dose, the maximum allowable single study dose under U.S. federal regulations for studies performed under Radiation Drug Research Committee is 1.58 GBq (42.8 mCi). This is still considerably higher than the doses of 11C-raclopride commonly used in research PET (370-555 MBq).
Journal of Nuclear Medicine 03/2006; 47(2):313-9. · 6.38 Impact Factor
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ABSTRACT: Repeated treatment with the psychostimulant amphetamine produces behavioral sensitization that may represent the neural adaptations underlying some features of psychosis and addiction in humans. In the present study we investigated the role of adenosine A(2A) receptors in psychostimulant-induced locomotor sensitization using an A(2A) receptor knockout (A(2A) KO) model. Daily treatment with amphetamine for 1 week resulted in an enhanced motor response on day 8 (by two-fold compared to that on day 1), and remained enhanced at day 24 upon rechallenge with amphetamine. By contrast, locomotor sensitization to daily amphetamine did not develop in A(2A) KO mice on day 8 or 24, and this absence was not the result of a nonspecific threshold effect. The absence of behavioral sensitization was selective for amphetamine since daily treatment with the D(1) agonist SKF81297 (2.5 mg/kg) or the D(2) agonist quinpirole (1.0 mg/kg) produced similar behavioral sensitization in both WT and A(2A) KO mice. Furthermore, coinjection of SKF81297 and quinpirole also resulted in indistinguishable locomotor sensitization in A(2A) KO and WT mice, suggesting normal D(1) and D(2) receptor responsiveness. Finally, at the cellular level A(2A) receptor inactivation abolished the increase in striatal dynorphin mRNA induced by repeated amphetamine administration. The selective absence of amphetamine-induced behavioral sensitization in A(2A) KO mice suggests a critical role of the A(2A) receptor in the development of psychostimulant-induced behavioral sensitization, and supports the pharmacological potential of A(2A) adenosinergic agents to modulate adaptive responses to repeated psychostimulant exposure.
Neuropsychopharmacology 07/2003; 28(6):1086-95. · 7.99 Impact Factor
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ABSTRACT: Obsessive-compulsive disorder (OCD) typically begins early in life and has a chronic course. Despite the need for long-term treatment, the authors found no placebo-controlled studies that have examined the relapse-prevention efficacy of maintenance therapy.
Patients who met criteria for response after 16 and 52 weeks of a single-blind trial of sertraline were randomly assigned to a 28-week double-blind trial of 50-200 mg/day of sertraline or placebo. Primary outcomes after the double-blind trial were full relapse, dropout due to relapse or insufficient response, or acute exacerbation of OCD symptoms.
Of 649 patients at baseline, 232 completed 52 weeks of the single-blind trial and met response criteria. Among the 223 patients in the double-blind phase of the study, sertraline had significantly greater efficacy than placebo on two of three primary outcomes: dropout due to relapse or insufficient clinical response (9% versus 24%, respectively) and acute exacerbation of symptoms (12% versus 35%). Sertraline resulted in improvement in quality of life during the initial 52-week trial and continued improvement, significantly superior to placebo, during the subsequent 28-week double-blind trial. Long-term treatment with sertraline was well tolerated. Over the entire study period, less than 20% of the patients stopped treatment because of adverse events.
Sertraline demonstrated sustained efficacy among patients responding to treatment and was generally well tolerated during the 80-week study. During the study's last 28 weeks, sertraline demonstrated greater efficacy than placebo in preventing dropout due to relapse or insufficient clinical response and acute exacerbation of OCD symptoms.
American Journal of Psychiatry 02/2002; 159(1):88-95. · 12.54 Impact Factor
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ABSTRACT: Objective: To investigate the long-term efficacy, prevention of relapse and safety of sertraline in the treatment of panic disorder.Method: This study consisted of 52 weeks of open-label sertraline treatment (n=398) followed by a 28 weeks of a double-blind, placebo-controlled discontinuation trial (n=183).Results: Ninety-three patients were randomized to sertraline and 90 were randomized to placebo. Discontinuation due to insufficient clinical response occurred in 23.6% of placebo-treated patients and 12.0% of sertraline-treated patients (log-rank test, P=0.040). Thirty-three per cent of placebo-treated patients had an exacerbation of panic symptomatology, versus 13% of sertraline-treated patients (log-rank test, P=0.005). Abrupt cessation of sertraline resulted in dizziness (4.3% sertraline vs. 16.9% placebo; P=0.007) and insomnia (4.3% sertraline vs. 15.7% placebo; P=0.013) occurring at significantly higher rates.Conclusion: Long-term sertraline treatment was effective in preventing relapse of panic disorder, well tolerated and associated with minimal discontinuation symptoms.
Acta Psychiatrica Scandinavica 09/2001; 104(4):289 - 298. · 4.22 Impact Factor
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Jiang-Fan Chen,
Rosario Moratalla,
Francesco Impagnatiello,
David K. Grandy,
Beatriz Cuellar,
Marcelo Rubinstein,
Mark A. Beilstein, Elizabeth Hackett,
J. Stephen Fink,
Malcolm J. Low,
Ennio Ongini,
Michael A. Schwarzschild
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ABSTRACT: The A2AR is largely coexpressed with
D2Rs and enkephalin mRNA in the striatum where it modulates
dopaminergic activity. Activation of the A2AR antagonizes
D2R-mediated behavioral and neurochemical effects in the
basal ganglia through a mechanism that may involve direct
A2AR–D2R interaction. However, whether the
D2R is required for the A2AR to exert its
neural function is an open question. In this study, we examined the
role of D2Rs in A2AR-induced behavioral and
cellular responses, by using genetic knockout (KO) models (mice
deficient in A2ARs or D2Rs or both). Behavioral
analysis shows that the A2AR agonist
2–4-(2-carboxyethyl)phenethylamino-5′-N-ethylcarboxamidoadenosine
reduced spontaneous as well as amphetamine-induced locomotion in
both D2 KO and wild-type mice. Conversely, the nonselective
adenosine antagonist caffeine and the A2AR antagonist
8-(3-chlorostyryl)caffeine produced motor stimulation in mice lacking
the D2R, although the stimulation was significantly
attentuated. At the cellular level, A2AR inactivation
counteracted the increase in enkephalin expression in striatopallidal
neurons caused by D2R deficiency. Consistent with the
D2 KO phenotype, A2AR inactivation partially
reversed both acute D2R antagonist (haloperidol)-induced
catalepsy and chronic haloperidol-induced enkephalin mRNA expression.
Together, these results demonstrate that A2ARs elicit
behavioral and cellular responses despite either the genetic deficiency
or pharmacological blockade of D2Rs. Thus,
A2AR-mediated neural functions are partially independent of
D2Rs. Moreover, endogenous adenosine acting at
striatal A2ARs may be most accurately viewed as a
facilitative modulator of striatal neuronal activity rather than simply
as an inhibitory modulator of D2R neurotransmission.
Proceedings of the National Academy of Sciences 02/2001; 98(4):1970-1975. · 9.68 Impact Factor
