Clinical utility of combinatorial pharmacogenomic testing in depression: A Canadian patient- and rater-blinded, randomized, controlled trial.

The pharmacological treatment of depression consists of stages of trial and error, with less than 40% of patients achieving remission during first medication trial. However, in a large, randomized-controlled trial (RCT) in the U.S. ("GUIDED"), significant improvements in response and remission rates were observed in patients who received treatment guided by combinatorial pharmacogenomic testing, compared to treatment-as-usual (TAU). Here we present results from the Canadian "GAPP-MDD" RCT. This 52-week, 3-arm, multi-center, participant- and rater-blinded RCT evaluated clinical outcomes among patients with depression whose treatment was guided by combinatorial pharmacogenomic testing compared to TAU. The primary outcome was symptom improvement (change in 17-item Hamilton Depression Rating Scale, HAM-D17) at week 8. Secondary outcomes included response (≥50% decrease in HAM-D17) and remission (HAM-D17 ≤ 7) at week 8. Numerically, patients in the guided-care arm had greater symptom improvement (27.6% versus 22.7%), response (30.3% versus 22.7%), and remission rates (15.7% versus 8.3%) compared to TAU, although these differences were not statistically significant. Given that the GAPP-MDD trial was ultimately underpowered to detect statistically significant differences in patient outcomes, it was assessed in parallel with the larger GUIDED RCT. We observed that relative improvements in response and remission rates were consistent between the GAPP-MDD (33.0% response, 89.0% remission) and GUIDED (31.0% response, 51.0% remission) trials. Together with GUIDED, the results from the GAPP-MDD trial indicate that combinatorial pharmacogenomic testing can be an effective tool to help guide depression treatment in the context of the Canadian healthcare setting (ClinicalTrials.gov NCT02466477).

Combinatorial pharmacogenomics and improved patient outcomes in depression: Treatment by primary care physicians or psychiatrists.

Failed medication trials are common in the treatment of major depressive disorder (MDD); however, the use of combinatorial pharmacogenomics to guide medication selection has been previously associated with improved outcomes in the psychiatric care setting. The utility of combinatorial pharmacogenomics in patients with MDD in primary care and psychiatric care settings was evaluated here. Patients enrolled in a naturalistic, open-label, prospective study [Individualized Medicine: Pharmacogenetics Assessment and Clinical Treatment (IMPACT)] with MDD were evaluated (N = 1871). Pharmacogenomic testing was performed for all patients and medications were categorized based on gene-drug interactions. Beck's Depression Inventory (BDI) was evaluated at baseline and follow-up (weeks 8-12). Symptom improvement (percent decrease in BDI), response (≥50% decrease in BDI), and remission (BDI≤10) at follow-up were evaluated according to provider type and whether medications were genetically congruent (little/no gene-drug interactions). There was a 27.9% reduction in depression symptoms at follow-up, as well as response and remission rates of 25.7% and 15.2%, respectively. Outcomes were significantly better among patients treated by primary care providers versus psychiatrists (symptom improvement 31.7% versus 24.9%, p < 0.01; response rate 30.1% versus 22.3%, p < 0.01; remission rate 19.5% versus 12.0%, p < 0.01). There was a 31% relative improvement in response rate among patients taking congruent versus incongruent medications, with slightly higher congruence among primary care providers (87.6%) versus psychiatrists (85.2%). Following combinatorial pharmacogenomic testing, outcomes were significantly improved among patients treated by primary care providers compared to psychiatrists, which supports the use of pharmacogenomics in broader treatment settings.

CCK(2) receptor nullification attenuates lipopolysaccharide-induced sickness behavior.

Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behavior after intraperitoneally delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CCK(2/gastrin) receptors (CCK(2)KO) and wild-type (WT) controls were administered LPS (50, 500, or 2,500 microg/kg; serotype 0111:B4; ip). Results indicate a role for CCK(2) receptor activation in the initiation and maintenance of LPS-induced sickness behavior. Compared with WT controls, CCK(2)KO mice were significantly less affected by LPS on measures of body temperature, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CCK(2) receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in nonvagal routes of immune-brain communication is suggested.

Metabotropic glutamate receptors mediate lipopolysaccharide-induced fever and sickness behavior.

Several mechanisms have been proposed for neuroimmune communication supporting the sickness syndrome (fever, anorexia, inactivity, and cachexia) following infection. We examined the role of glutamate as a neurochemical intermediary of sickness behavior induced by intraperitoneal lipopolysaccharide (LPS). Mice implanted with biotelemetry devices capable of detecting body temperature (Tb) were administered LPS (50 or 500 microg/kg i.p., serotype 0111:B4) with or without i.p. pretreatment with vehicle or broad-spectrum antagonists selective for N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic (AMPA)/kainite, or metabotropic glutamate (mGlu) receptors. While NMDA and AMPA/kainate receptor antagonism failed to attenuate LPS-induced sickness behavior, antagonism of metabotropic receptors with l(+)-AP3 reduced the febrile (0-11h: control: 37.32+/-0.16 degrees C, l(+)-AP3: 36.66+/-0.27), anorexic (control: -87+/-5%, l(+)-AP3: 48+/-12% scotophase food intake), and cachexic (control: -8.9+/-0.4%, l(+)-AP3: -6.1+/-1.3% body weight) effects of 500 microg/kg LPS, and produced a biphasic Tb effect in response to 50 microg/kg LPS (1h: -0.90+/-0.26; 6h: 1.78+/-0.35 degrees C relative to baseline). At this dose the Tb of l(+)-AP3-treated mice was 1.18 degrees C lower than controls 2h post-injection, and 0.68 degrees C greater that controls 8h post-injection. These results suggest a role for mGlu receptors in mediating fever, anorexia, and cachexia possibly via activation of extra-vagal pathways, since the attenuating effect of l(+)-AP3 increased with increasing dosages of LPS. Given the critical role ascribed to mGlu receptors in neurotransmitter release and astrocytic processes, it is possible that these observations reflect an l(+)-AP3-induced attenuation of these systems.

Association between intellectual functioning and age in children and young adults with Duchenne muscular dystrophy: further results from a meta-analysis.

This study used meta-analytical techniques to explore the association between intelligence and age in children with Duchenne muscular dystrophy (DMD). The sample comprised 1224 children and young adults with DMD (mean age 12 y 3 mo, SD 4 y; range 2 y to 27 y). Standardized measures including the Wechsler Intelligence Scales (WIS) and the Stanford-Binet Intelligence Scales were used to estimate intelligence. No age-related difference was noted for Full-scale and Performance intelligence quotients (IQ). However, Verbal IQ increased significantly with age. Age-related increases were noted for the WIS Information, Similarities, Arithmetic, Comprehension, Digit Span, Picture Arrangement, Block Design, and Coding subscales. These results support the notion that younger children with DMD have deficits in verbal reasoning and verbal processing. Older children with DMD, particularly those of 14 years and older, were less likely to present with these problems. Implications of these findings and possible future research directions are discussed.

The effect of lipopolysaccharide on cholecystokinin in murine plasma and tissue.

Several mechanisms have been proposed for neuroimmune communication supporting sickness behavior (fever, anorexia, inactivity, and cachexia) following infection. We examined the role of cholecystokinin as a neurochemical intermediary of sickness behavior by determining plasma, duodenum, hypothalamus, and brainstem cholecystokinin concentrations 30 and 60 min and 12 h following intraperitoneal lipopolysaccharide (LPS) (0.25 and 2.5 mg/kg). Hypothalamic cholecystokinin was significantly lower in LPS- versus saline-treated mice 30 min (0.25 and 2.5 mg/kg) and 12 h (2.5 mg/kg) post-injection. Plasma cholecystokinin of LPS-treated mice was significantly lower than that of controls 1 and 12 h post-injection, a finding consistent with a non-endocrine action of peripheral cholecystokinin.

The role of CCK2 receptors in energy homeostasis: insights from the CCK2 receptor-deficient mouse.

The present study explored the contribution of type 2 cholecystokinin (CCK) receptors in energy regulation. A total of 78 CCK2 receptor-deficient mice and 80 wild-type controls were acclimated to a 12:12 light-dark cycle at 30 +/- 1 degrees C. Using a computer-monitored biotelemetry system, circadian patterns of body temperature, food intake, and activity were monitored for 4 days. Body weight and water consumption were manually recorded during this period. Results indicate that CCK2 receptor invalidation produces elevated body temperature during both the photophase and scotophase (by 0.38 and 0.12 degrees C, respectively), increased body weight (29.3 +/- 0.2 vs. 26.8 +/- 0.2 g) and water consumption (4.1 +/- 0.1 vs. 3.2 +/- 0.1 ml), and decreased scotophase locomotor activity (WT: 7.0 +/- 0.2 vs. KO: 6.1 +/- 0.2 counts/min). These findings suggest an important role for CCK2 receptors in processes underlying energy regulation during basal and possibly pathological states.

The role of conditioning and verbal expectancy in the placebo response.

Both conditioning and expectancy models have been offered in recent years as explanations for the placebo response. Following our earlier work on conditioning placebo responses in human subjects the current study examined the relative contribution made by conditioning and verbal expectancy. Group 1 received a Combined Expectancy and Conditioning Manipulation; group 2 received Expectancy Alone; group 3, Conditioning Alone; and group 4 was the control group. Subjects' responses were compared with and without a placebo cream, using iontophoretic pain stimulation. The results suggest that conditioning was more powerful than verbal expectancy in creating a placebo response.

Conditioned response models of placebo phenomena: further support.

Following our earlier research, we further investigated a model that conceptualizes placebo phenomena as the result of conditioning and attempted to extend and replicate the finding that placebo responses can be conditioned in human subjects. Two groups of 10 subjects were told that they were receiving an analgesic which was in fact a placebo. During the conditioning, placebo administration was surreptitiously paired with an increase in the painful stimulus for half of the subjects and with a decrease for the other half. Subjects were tested pre and post conditioning for a placebo response. A second type of experimental pain was also used to determine stimulus generalization. The results confirmed a previous finding that placebo responses can be conditioned in human subjects. The implications for clinical practice of a learning model of placebo behavior are discussed.