Limbic-frontal circuitry in major depression: a path modeling metanalysis.

This paper reports the results of an across lab metanalysis of effective connectivity in major depression (MDD). Using FDG PET data and Structural Equation Modeling, a formal depression model was created to explicitly test current theories of limbic-cortical dysfunction in MDD and to characterize at the path level potential sources of baseline variability reported in this patient population. A 7-region model consisting of lateral prefrontal cortex (latF9), anterior thalamus (aTh), anterior cingulate (Cg24), subgenual cingulate (Cg25), orbital frontal cortex (OF11), hippocampus (Hc), and medial frontal cortex (mF10) was tested in scans of 119 depressed patients and 42 healthy control subjects acquired during three separate studies at two different institutions. A single model, based on previous theory and supported by anatomical connectivity literature, was stable for the three groups of depressed patients. Within the context of this model, path differences among groups as a function of treatment response characteristics were also identified. First, limbic-cortical connections (latF9-Cg25-OF11-Hc) differentiated drug treatment responders from nonresponders. Second, nonresponders showed additional abnormalities in limbic-subcortical pathways (aTh-Cg24-Cg25-OF11-Hc). Lastly, more limited limbic-cortical (Hc-latF9) and cortical-cortical (OF11-mF10) path differences differentiated responders to cognitive behavioral therapy (CBT) from responders to pharmacotherapy. We conclude that the creation of such models is a first step toward full characterization of the depression phenotype at the neural systems level, with implications for the future development of brain-based algorithms to determine optimal treatment selection for individual patients.

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

Dizocilpine prevents the development of tolerance to ethanol-induced error on a circular maze test.

Dizocilpine [(+)MK-801] and ketamine, in doses that disrupt learning and memory, also prevent the development of tolerance to the motor impairing effects of ethanol (EtOH). However, dizocilpine itself affects motor behavior. In order to separate the possible influence of these two effects on the development of tolerance to EtOH, food-reinforced performance on a circular maze test was used in two different experiments. EtOH alone (1.2 g/kg) tended to increase the error score and reduce number of runs per trial, running speed, and total distance run, but on chronic administration of EtOH, tolerance developed progressively to all these effects. Dizocilpine also increased the error score, but had a biphasic effect on measures of running: low and intermediate doses (0.009 and 0.075 mg/kg, IP) increased running distance, whereas a high dose (0.15 mg/kg) decreased running speed and distance. When combined with EtOH, dizocilpine tended to overcome the effect of EtOH on running activity, but not on error score. Chronically, dizocilpine (0.075 and 0.15 mg/kg) prevented the development of tolerance to the effect of EtOH on error score, even though the lower dose of dizocilpine permitted tolerance to the effects of EtOH on running. These results suggest that NMDA receptor antagonists selectively inhibit tolerance to cognitive effects of ethanol even when the antagonists do not affect motor performance.

Interaction of 3'-azido-3'-deoxythymidine with the organic base transporter in a cultured renal epithelium.

In humans and various animal species, 3'-azido-3'-deoxythymidine (AZT) is in part eliminated by the kidneys, where it undergoes significant tubular secretion. The goal of this project was to develop, in a continuous renal epithelial cell line (LLCPK1), a model of AZT transport in which mechanisms of drug interactions could be investigated. Transport properties of H3-AZT were studied in LLCPK1 cells grown as monolayers on permeable filters. This system provides access to the basolateral and apical surfaces of the epithelium and allows the determination of substrate transepithelial flux from the basolateral side to the apical side (B-->A/secretory direction) and apical to basolateral side (A-->B/reabsorptive direction). The B-->A flux of AZT was significantly greater than B-->A flux of mannitol (a nontransported substrate) and was temperature dependent (37 degrees C >> 4 degrees C). The AZT A-->B flux was significantly smaller than the B-->A flux, indicating that the drug is predominantly secreted in this renal epithelium. The B-->A flux was significantly inhibited by the organic bases cimetidine, quinine, quinidine, and trimethoprim. Log concentration dose studies indicate that quinine is a weak inhibitor (IC50 = 9.61 mM) of AZT B-->A flux, and that AZT is a moderate inhibitor (IC50 = 0.69 mM) of the organic base cimetidine. These results suggest that AZT may share the organic base transporter in the renal epithelium, and that this model can be used successfully to study transport properties and renal drug-drug interactions of AZT.