Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission.

OBJECTIVE: To determine the feasibility and safety of aripiprazole augmentation for incomplete response to sequential selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) pharmacotherapy in late-life depression. METHOD: This study was a 12-week, open-label pilot study of 24 patients (recruited from June 1, 2006, to June 1, 2007) aged 65 years and above (mean, 73.9 years) diagnosed with major depressive disorder (MDD) (according to DSM-IV) who responded partially (17-item Hamilton Rating Scale for Depression [HAM-D-17] score of 11 to 15) or not at all (HAM-D score > 15) to a 16-week trial of escitalopram (up to 20 mg/day), followed by either duloxetine (up to 120 mg/day) or venlafaxine (up to 225 mg/day) for 12 weeks. Subjects received 2.5 to 15 mg per day of adjunctive aripiprazole (mean dose, 9.0 mg/day) for 12 weeks. The criterion for remission during treatment with aripiprazole was a HAM-D score < or = 10 for 2 consecutive weeks. RESULTS: Of 24 subjects in the intent-to-treat study group, 19 completed 12 weeks of augmentation with aripiprazole, 12 of 24 (50%) met criteria for remission, and 2 of 24 discontinued due to side effects (sedation, akathisia). The mean (SD) HAM-D score decreased significantly by 6.4 (5.8) points (paired t test for means, p < .01, df = 16). There were no relapses among the 12 subjects who participated in continuation treatment over a median period of 27.6 weeks. CONCLUSIONS: In older adults with MDD with incomplete response to SSRI and SNRI pharmacotherapy, aripiprazole was well tolerated, and symptoms of depression improved significantly during treatment with aripiprazole. A randomized, double-blind, placebo-controlled trial of adjunctive aripiprazole for incomplete response in late-life depression is warranted to further evaluate benefit and risk. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00177671.

Sleeping well, aging well: a descriptive and cross-sectional study of sleep in "successful agers" 75 and older.

OBJECTIVES: To examine diary-based, laboratory-based, and actigraphic measures of sleep in a group of healthy older women and men (> or =75 years of age) without sleep/wake complaints and to describe sleep characteristics which may be correlates of health-related quality of life in old age. DESIGN: Cross-sectional, descriptive study. SETTING: University-based sleep and chronobiology program. INTERVENTION: None. PARTICIPANTS: Sixty-four older adults (30 women, 34 men; mean age 79). MEASUREMENTS: We used diary-, actigraphic-, and laboratory-based measures of sleep, health-related quality of life, mental health, social support, and coping strategies. We used two-group t-tests to compare baseline demographic and clinical measures between men and women, followed by ANOVA on selected EEG measures to examine first-night effects as evidence of physiological adaptability. Finally, we examined correlations between measure of sleep and health-related quality of life. RESULTS: We observed that healthy men and women aged 75 and older can experience satisfactory nocturnal sleep quality and daytime alertness, especially as reflected in self-report and diary-based measures. Polysomnography (psg) suggested the presence of a first-night effect, especially in men, consistent with continued normal adaptability in this cohort of healthy older adults. Continuity and depth of sleep in older women were superior to that of men. Diary-based measures of sleep quality (but not psg measures) correlated positively (small to moderate effect sizes) with physical and mental health-related quality of life. CONCLUSIONS: Sleep quality and daytime alertness in late life may be more important aspects of successful aging than previously appreciated. Good sleep may be a marker of good functioning across a variety of domains in old age. Our observations suggest the need to study interventions which protect sleep quality in older adults to determine if doing so fosters continued successful aging.

Incomplete response in late-life depression: getting to remission.

Incomplete response in the treatment of late-life depression is a large public health challenge: at least 50% of older people fail to respond adequately to first-line antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment-resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of empirical data on how best to manage TRLLD. A pilot study by our group on aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole, and that remission was sustained in all participants during 6 months of continuation treatment. In addition to controlled assessment, evidence is needed to support personalized treatment by testing the moderating role of clinical (e.g., comorbid anxiety, medical burden, and executive impairment) and genetic (eg, selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while also controlling for variability in drug exposure. Such studies may advance us toward the goal of personalized treatment in late-life depression.

Getting better, getting well: understanding and managing partial and non-response to pharmacological treatment of non-psychotic major depression in old age.

In general, the pharmacological treatment of non-psychotic major depressive disorder in old age is only partially successful, with only approximately 50% of older depressed adults improving with initial antidepressant monotherapy. Many factors may predict a more difficult-to-treat depression, including coexisting anxiety, low self-esteem, poor sleep and a high coexisting medical burden. Being aware of these and other predictors of a difficult-to-treat depression gives the clinician more reasonable expectations about a patient's likely treatment course. If an initial antidepressant trial fails, the clinician has two pharmacological options: switch or augment/combine antidepressant therapies. About 50% of patients who do not improve after initial antidepressant therapy will respond to either strategy. Switching has several advantages including fewer adverse effects, improved treatment adherence and reduced expense. However, as a general guideline, if patients are partial responders at 6 weeks, they will likely be full responders by 12 weeks. Thus, changing medication is not indicated in this context. However, if patients are partial responders at 12 weeks, switching to a new agent is advised. If the clinician treats vigorously and if the patient and clinician persevere, up to 90% of older depressed patients will respond to pharmacological treatment. Furthermore, electroconvulsive therapy is a safe and effective non-pharmacological strategy for non-psychotic major depression that fails to respond to pharmacotherapy. Getting well and staying well is the goal; thus, clinicians should treat to remission, not merely to response. Subsequently, maintenance treatment with the same regimen that has been successful in relieving the depression strongly improves the patient's chances of remaining depression free.

Late-onset major depression: clinical and treatment-response variability.

OBJECTIVE: To explore clinical and treatment-response variability in late-onset vs early-onset non-bipolar, non-psychotic major depression. METHODS: We grouped patients from a late-life depression treatment study according to illness-course characteristics: those with early-onset, recurrent depression (n = 59), late-onset, recurrent depression (n = 27), and late-onset, single-episode depression (n = 95). Early-onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late-onset was defined as having a first episode of major depression at age 60 or later. We characterized the three groups of patients with respect to baseline demographic, neuropsychological, and clinical characteristics, use of augmentation pharmacotherapy to achieve response, and treatment outcomes. RESULTS: Rates of response, remission, relapse, and termination were similar in all three groups; however, patients with late-onset, recurrent major depression took longer to respond to treatment than those with late-onset, single-episode depression (12 weeks vs 8 weeks) and had more cognitive and functional impairment. Additionally, patients with recurrent depression (whether early or late) were more likely to require pharmacotherapy augmentation to achieve response than patients with a single lifetime episode. CONCLUSION: Late-onset, recurrent depression takes longer to respond to treatment than late-onset single-episode depression and is more strongly associated with cognitive and functional impairment. Further study of biological, neuropsychologic, and psychosocial correlates of late-onset, recurrent depression is needed.

WRN helicase and FEN-1 form a complex upon replication arrest and together process branchmigrating DNA structures associated with the replication fork.

Werner Syndrome is a premature aging disorder characterized by genomic instability, elevated recombination, and replication defects. It has been hypothesized that defective processing of certain replication fork structures by WRN may contribute to genomic instability. Fluorescence resonance energy transfer (FRET) analyses show that WRN and Flap Endonuclease-1 (FEN-1) form a complex in vivo that colocalizes in foci associated with arrested replication forks. WRN effectively stimulates FEN-1 cleavage of branch-migrating double-flap structures that are the physiological substrates of FEN-1 during replication. Biochemical analyses demonstrate that WRN helicase unwinds the chicken-foot HJ intermediate associated with a regressed replication fork and stimulates FEN-1 to cleave the unwound product in a structure-dependent manner. These results provide evidence for an interaction between WRN and FEN-1 in vivo and suggest that these proteins function together to process DNA structures associated with the replication fork.

Inhibition of Werner syndrome helicase activity by benzo[c]phenanthrene diol epoxide dA adducts in DNA is both strand-and stereoisomer-dependent.

Helicases are among the first enzymes to encounter DNA damage during DNA processing within the cell and thus are likely to be targets for the adverse effects of DNA lesions induced by environmental chemicals. Here we examined the effect of cis- and trans-opened 3,4-diol 1,2-epoxide (DE) DNA adducts of benzo[c]phenanthrene (BcPh) at N6 of adenine on helicase activity. These adducts are derived from the highly tumorigenic (-)-(1R,2S,3S,4R)-DE as well as its less carcinogenic (+)-(1S,2R,3R,4S)-DE enantiomer in both of which the benzylic 4-hydroxyl group and epoxide oxygen are trans. The hydrocarbon portions of these adducts intercalate into DNA on the 3' or the 5' side of the adducted deoxyadenosine for the 1S- and 1R-adducts, respectively. These adducts inhibited the human Werner (WRN) syndrome helicase activity in a strand-specific and stereospecific manner. In the strand along which WRN translocates, cis-opened adducts were significantly more effective inhibitors than trans-opened isomers, indicating that WRN unwinding is sensitive to adduct stereochemistry. WRN helicase activity was also inhibited but to a lesser extent by cis-opened BcPh DE adducts in the displaced strand independent of their direction of intercalation, whereas inhibition by the trans-opened stereoisomers in the displaced strand depended on their orientation, such that only adducts oriented toward the advancing helicase inhibited WRN activity. A BcPh DE adduct positioned in the helicase-translocating strand did not sequester WRN, nor affect the rate of ATP hydrolysis relative to an unadducted control. Although the Bloom (BLM) syndrome helicase was also inhibited by a cis-opened adduct in a strand-specific manner, this helicase was not as severely affected as WRN. Because BcPh DEs form substantial amounts of deoxyadenosine adducts at dA, their adverse effects on helicases could contribute to genetic damage and cell transformation induced by these DEs. Thus, the unwinding activity of RecQ helicases is sensitive to the strand, orientation, and stereochemistry of intercalated polycyclic aromatic hydrocarbon adducts.

The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein.

Exonuclease 1 (EXO-1), a member of the RAD2 family of nucleases, has recently been proposed to function in the genetic pathways of DNA recombination, repair, and replication which are important for genome integrity. Although the role of EXO-1 is not well understood, its 5' to 3'-exonuclease and flap endonuclease activities may cleave intermediates that arise during DNA metabolism. In this study, we provide evidence that the Werner syndrome protein (WRN) physically interacts with human EXO-1 and dramatically stimulates both the exonucleolytic and endonucleolytic incision functions of EXO-1. The functional interaction between WRN and EXO-1 is mediated by a protein domain of WRN which interacts with flap endonuclease 1 (FEN-1). Thus, the genomic instability observed in WRN-/- cells may be at least partially attributed to the lack of interactions between the WRN protein and human nucleases including EXO-1.

Biochemical characterization of the WRN-FEN-1 functional interaction.

Werner Syndrome is a premature aging disorder characterized by chromosomal instability. Recently we reported a novel interaction of the WRN gene product with human 5' flap endonuclease/5'-3' exonuclease (FEN-1), a DNA structure-specific nuclease implicated in pathways of DNA metabolism that are important for genomic stability. To characterize the mechanism for WRN stimulation of FEN-1 cleavage, we have determined the effect of WRN on the kinetic parameters of the FEN-1 cleavage reaction. WRN enhanced the efficiency of FEN-1 cleavage rather than DNA substrate binding. WRN effectively stimulated FEN-1 cleavage on a flap DNA substrate with streptavidin bound to the terminal 3' nucleotide at the end of the upstream duplex, indicating that WRN does not require a free upstream end to stimulate FEN-1 cleavage of the 5' flap substrate. These results indicate that the mechanism whereby WRN stimulates FEN-1 cleavage is distinct from that proposed for the functional interaction between proliferating cell nuclear antigen and FEN-1. To understand the potential importance of the WRN-FEN-1(1) interaction in DNA replication, we have tested the effect of WRN on FEN-1 cleavage of several DNA substrate intermediates that may arise during Okazaki fragment processing. WRN stimulated FEN-1 cleavage of flap substrates with a terminal monoribonucleotide, a long 5' ssDNA tract, and a pseudo-Y structure. The ability of WRN to facilitate FEN-1 cleavage of DNA replication/repair intermediates may be important for the role of WRN in the maintenance of genomic stability.