A randomized controlled trial of cognitive-behavioral therapy, light therapy, and their combination for seasonal affective disorder

This first controlled psychotherapy trial for seasonal affective disorder (SAD) compared SAD-tailored cognitive-behavioral therapy (CBT), light therapy (LT), and their combination to a concurrent wait-list control. Adults (N = 61) with major depression, recurrent with seasonal pattern, were randomized to one of four 6-week conditions: CBT (1.5-hr twice-weekly group therapy), LT (10,000-lux for 90-min/day with administration time individually adjusted), combined CBT + LT, or a minimal contact/delayed LT control (MCDT; LT following 6 weeks of monitoring). CBT, LT, and CBT + LT significantly and comparably improved depression severity relative to MCDT in intent-to-treat and completer samples. CBT + LT (73%) had a significantly higher remission rate than MCDT (20%). Using prospectively measured summer mood status to estimate the "functional" population, CBT + LT also had a significantly larger proportion of participants with clinically significant change over treatment compared with MCDT. The LT condition outcomes virtually replicated results from prior trials. CBT, alone or combined with LT, holds promise as an efficacious SAD treatment and warrants further study. If replicated, CBT + LT's remission rate would represent a clinically meaningful improvement over the 53% observed across LT studies.     

The post illumination pupil response is reduced in seasonal affective disorder

Individuals with seasonal affective disorder (SAD) may have a decreased retinal sensitivity in the non-image forming light-input pathway. We examined the post illumination pupil response (PIPR) among individuals with SAD and healthy controls to identify possible differences in the melanopsin signaling pathway. We also investigated whether melanopsin gene (OPN4) variations would predict variability in the PIPR. Fifteen SAD and 15 control participants (80% women, mean age 36.7 years, S.D.=14.5) were assessed in the fall/winter. Participants were diagnosed based on DSM-IV-TR criteria. Infrared pupillometry was used to measure pupil diameter prior to, during, and after red and blue stimuli. In response to blue light, the SAD group had a reduced PIPR and a lower PIPR percent change relative to controls. The PIPR after the blue stimulus also varied on the basis of OPN4 I394T genotype, but not OPN4 P10L genotype. These findings may indicate that individuals with SAD have a less sensitive light input pathway as measured by the PIPR, leading to differences in neurobiological and behavioral responses such as alertness, circadian photoentrainment, and melatonin release. In addition, this sensitivity may vary based on sequence variations in OPN4, although a larger sample and replication is needed.     

Stability and comparative metabolism of selected felbamate metabolites and postulated fluorofelbamate metabolites by postmitochondrial suspensions

Evidence has been presented suggesting that a reactive metabolite, 2-phenylpropenal (ATPAL), may be responsible for the toxicities observed during therapy with the antiepileptic drug felbamate (FBM). Formation of ATPAL from its unstable immediate precursor, 3-carbamoyl-2-phenylpropionaldedhyde (CBMA) requires the loss of the hydrogen atom at position 2 in the propane chain, and it has been postulated that substitution of this atom with fluorine would prevent the formation of ATPAL. On the basis of this hypothesis, 2-fluoro-2-phenyl-1,3-propanediol dicarbamate (F-FBM) was synthesized and is presently undergoing drug development. To test this hypothesis, we compared the metabolism by human liver postmitochondrial suspensions (S9) in vitro of selected FBM and postulated F-FBM metabolites leading to formation of CBMA or 3-carbamoyl-2-fluoro-2-phenyl-propionaldehyde (F-CBMA). All S9 incubations included GSH as a trapping agent for any reactive metabolites formed. Our results indicated that, in phosphate buffer, pH 7.4, at 37 degrees C, the half-life for 4-hydroxy-5-phenyltetrahydro-1,3-oxazin-2-one (CCMF) was 2.8 and 3.6 h in the presence or absence of GSH, respectively; compared to 4-hydroxy-5-fluoro-5-phenyl-tetrahydro-1,3-oxazin-2-one (F-CCMF) which lost only 2.5% or 4.9% over 24 h under the same conditions. When incubated with S9 in the presence of the cofactor, NAD+, 2-phenyl-1,3-propanediol monocarbamate (MCF) was oxidized to CCMF which was further oxidized to 3-carbamoyl-2-phenylpropionic acid (CPPA). 2-Fluoro-2-phenyl-1,3-propanediol monocarbamate (F-MCF) under similar conditions was stable, and no metabolites were observed. When CCMF was incubated with S9 in the presence of NAD+ cofactor, oxidation to CPPA and reduction to MCF were observed. In addition, a new atropic acid GSH adduct (ATPA-GSH) was identified by mass spectrometry. When F-CCMF was incubated under the same conditions as CCMF, both reduced and oxidized metabolites, F-MCF and 3-carbamoyl-2-fluoro-2-phenylpropionic acid (F-CPPA), respectively, were formed but at significantly lower rates, and no GSH conjugates were identified. Our results support the hypothesis that F-FBM and F-CCMF are not metabolized by S9 in vitro to the known reactive FBM metabolite, ATPAL.     

CD14+ cells in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells induce secretion of interleukin-6 and G-CSF by marrow stroma

The ability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs) to induce secretion of cytokines in primary long-term marrow cultures (LTC) or in the human marrow stromal cell line HS23 was compared with that of marrow mononuclear cells. Equal numbers of G-PBMCs or marrow mononuclear cells were added to stromal cultures, supernatants were harvested at day 4 and levels of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, G-CSF, and tumor necrosis factor alpha (TNF alpha) were determined. G- PBMCs induced 21.4-fold higher levels of IL-6 and 12.5-fold higher levels of G-CSF in LTC cocultures compared with marrow mononuclear cells and induced 20.6-fold more IL-6 and 6.3-fold more G-CSF when added to HS23 cells. Experiments using sorted populations of CD20+, CD3+, and CD14+ cells showed that CD14+ cells within G-PBMCs were responsible for triggering the production of IL-6 and G-CSF. The effect did not require cell-cell contact and was inhibited when neutralizing antibodies to IL-1 alpha and IL-1 beta were used in combination. In these experiments, the greater stimulating ability of G-PBMCs is most likely attributable to the greater number of CD14+ cells in G-PBMCs (26.1+% +/- 2.3%) compared with marrow (2.5% +/- 0.8%), because equal numbers of CD14+ cells sorted from marrow and G-PBMCs showed comparable ability to induce IL-6 and G-CSF when placed directly on stromal cells.