Downregulation of Brain Phosphodiesterase Type IV Measured with 11C-(R)-Rolipram Positron Emission Tomography in Major Depressive Disorder

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland.
Biological psychiatry (Impact Factor: 10.26). 06/2012; 72(7):548-54. DOI: 10.1016/j.biopsych.2012.04.030
Source: PubMed


Phosphodiesterase type IV (PDE4), an important component of the cyclic adenosine monophosphate (cAMP) cascade, selectively metabolizes cAMP in the brain to the inactive monophosphate. Basic studies suggest that PDE4 mediates the effects of several antidepressants. This study sought to quantify the binding of (11)C-(R)-rolipram, a PDE4 inhibitor, as an indirect measure of this enzyme's activity in the brain of individuals with major depressive disorder (MDD) compared with healthy control subjects.
(11)C-(R)-Rolipram brain positron emission tomography scans were performed in 28 unmedicated MDD subjects and 25 age- and gender-matched healthy control subjects. Patients were moderately depressed and about one half were treatment-naive. (11)C-(R)-Rolipram binding in the brain was measured using arterial (11)C-(R)-rolipram levels to correct for the influence of cerebral blood flow.
Major depressive disorder subjects showed a widespread, approximately 20% reduction in (11)C-(R)-rolipram binding (p = .002), which was not caused by different volumes of gray matter. Decreased rolipram binding of similar magnitudes was observed in most brain areas. Rolipram binding did not correlate with the severity of depressive or anxiety symptoms.
This study is the first to demonstrate that brain levels of PDE4, a critical enzyme that regulates cAMP, are decreased in unmedicated individuals with MDD in vivo. These results are in line with human postmortem and rodent studies demonstrating downregulation of the cAMP cascade in MDD and support the hypothesis that agents such as PDE4 inhibitors, which increase activity within the cAMP cascade, may have antidepressant effects.

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Available from: Sami S Zoghbi
    • "Enzymes in the PDE4 family catalyze the hydrolysis of cyclic AMP (cAMP) and have a critical role in controlling the intracellular concentration of cAMP and increasing phosphorylation of cAMP-response element-binding protein (Li et al, 2009). PDE4s are found throughout the brain (Perez-Torres et al, 2000), but their levels are decreased in unmedicated depressed individuals (Fujita et al, 2012). This reflects a downregulation of the cAMP cascade that can potentially be restored using PDE4 inhibitors (Duman et al, 1999), an idea which is supported by an increasing number of animal studies that indicate the potential of PDE4 inhibitors for novel treatments of anxiety and depression (Halene and Siegel, 2007; Li et al, 2009). "
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    ABSTRACT: The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people, and subsequently by European colonial farmers as a psychotropic in tincture form. Over the last decade the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals, and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin(®)) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin(®) administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind placebo-controlled cross-over design 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin(®). Follow-up connectivity analysis on the emotion-matching task showed that amygdala-hypothalamus coupling was also reduced. These results demonstrate for the first time the attenuating effects of Sceletium tortuosum on the threat circuitry of the human brain, and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.Neuropsychopharmacology accepted article preview online, 1 August 2013. doi:10.1038/npp.2013.183.
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    • "The greater number of samples may also explain the marginally more accurate results obtained with IDIF compared to PBIF (Table 5). Finally, using both PBIF and IDIF, we were able to demonstrate a widespread decrease in [ 11 C](R)-rolipram binding in depressed patients as compared to healthy subjects, proving that the clinical results obtained with full arterial input function (Fujita et al., 2012) can be obtained using either technique. "
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    ABSTRACT: Quantitative PET studies of neuroreceptor tracers typically require that arterial input function be measured. The aim of this study was to explore the use of a population-based input function (PBIF) and an image-derived input function (IDIF) for [(11)C](R)-rolipram kinetic analysis, with the goal of reducing - and possibly eliminating - the number of arterial blood samples needed to measure parent radioligand concentrations. A PBIF was first generated using [(11)C](R)-rolipram parent time-activity curves from 12 healthy volunteers (Group 1). Both invasive (blood samples) and non-invasive (body weight, body surface area, and lean body mass) scaling methods for PBIF were tested. The scaling method that gave the best estimate of the Logan-V(T) values was then used to determine the test-retest variability of PBIF in Group 1 and then prospectively applied to another population of 25 healthy subjects (Group 2), as well as to a population of 26 patients with major depressive disorder (Group 3). Results were also compared to those obtained with an image-derived input function (IDIF) from the internal carotid artery. In some subjects, we measured arteriovenous differences in [(11)C](R)-rolipram concentration to see whether venous samples could be used instead of arterial samples. Finally, we assessed the ability of IDIF and PBIF to discriminate depressed patients (MDD) and healthy subjects. Arterial blood-scaled PBIF gave better results than any non-invasive scaling technique. Excellent results were obtained when the blood-scaled PBIF was prospectively applied to the subjects in Group 2 (V(T) ratio 1.02±0.05; mean±SD) and Group 3 (V(T) ratio 1.03±0.04). Equally accurate results were obtained for two subpopulations of subjects drawn from Groups 2 and 3 who had very differently shaped (i.e. "flatter" or "steeper") input functions compared to PBIF (V(T) ratio 1.07±0.04 and 0.99±0.04, respectively). Results obtained via PBIF were equivalent to those obtained via IDIF (V(T) ratio 0.99±0.05 and 1.00±0.04 for healthy subjects and MDD patients, respectively). Retest variability of PBIF was equivalent to that obtained with full input function and IDIF (14.5%, 15.2%, and 14.1%, respectively). Due to [(11)C](R)-rolipram arteriovenous differences, venous samples could not be substituted for arterial samples. With both IDIF and PBIF, depressed patients had a 20% reduction in [(11)C](R)-rolipram binding as compared to control (two-way ANOVA: p=0.008 and 0.005, respectively). These results were almost equivalent to those obtained using 23 arterial samples. Although some arterial samples are still necessary, both PBIF and IDIF are accurate and precise alternatives to full arterial input function for [(11)C](R)-rolipram PET studies. Both techniques give accurate results with low variability, even for clinically different groups of subjects and those with very differently shaped input functions.
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