Comparing ultrastable lasers at 7 × 10-17 fractional frequency instability through a 2220 km optical fibre network.

Ultrastable lasers are essential tools in optical frequency metrology enabling unprecedented measurement precision that impacts on fields such as atomic timekeeping, tests of fundamental physics, and geodesy. To characterise an ultrastable laser it needs to be compared with a laser of similar performance, but a suitable system may not be available locally. Here, we report a comparison of two geographically separated lasers, over the longest ever reported metrological optical fibre link network, measuring 2220 km in length, at a state-of-the-art fractional-frequency instability of 7 × 10-17 for averaging times between 30 s and 200 s. The measurements also allow the short-term instability of the complete optical fibre link network to be directly observed without using a loop-back fibre. Based on the characterisation of the noise in the lasers and optical fibre link network over different timescales, we investigate the potential for disseminating ultrastable light to improve the performance of remote optical clocks.

A clock network for geodesy and fundamental science.

Leveraging the unrivalled performance of optical clocks as key tools for geo-science, for astronomy and for fundamental physics beyond the standard model requires comparing the frequency of distant optical clocks faithfully. Here, we report on the comparison and agreement of two strontium optical clocks at an uncertainty of 5 × 10(-17) via a newly established phase-coherent frequency link connecting Paris and Braunschweig using 1,415 km of telecom fibre. The remote comparison is limited only by the instability and uncertainty of the strontium lattice clocks themselves, with negligible contributions from the optical frequency transfer. A fractional precision of 3 × 10(-17) is reached after only 1,000 s averaging time, which is already 10 times better and more than four orders of magnitude faster than any previous long-distance clock comparison. The capability of performing high resolution international clock comparisons paves the way for a redefinition of the unit of time and an all-optical dissemination of the SI-second.

Carrier-envelope phase stabilization with sub-10 as residual timing jitter.

We demonstrate carrier-envelope phase (CEP) stabilization of a mode-locked Ti:sapphire oscillator with unprecedented timing jitter of eight attoseconds. The stabilization performance is obtained by a combination of two different stabilization approaches. In a first step the drift of the CEP is stabilized with a conventional feedback loop by means of controlling the oscillator pump power with an acousto-optic modulator (AOM). In a second step we utilize a recently developed feed-forward type stabilization scheme which has a much higher control bandwith. Here an acousto-optic frequency shifter (AOFS) produces the stabilized output in the first diffraction order. Moreover, we present numerical results on the optimization of the length of the photonic crystal fiber, which is used to generate an octave-spanning spectrum, in order to optimize the sensitivity in the f-to-2f interferometers.

Deep brain stimulation of the posterior hypothalamic nucleus reverses akinesia in bilaterally 6-hydroxydopamine-lesioned rats.

Deep brain stimulation (DBS) of the basal ganglia motor circuitry is a highly effective treatment for the debilitating motor symptoms of Parkinson's disease (PD). However, recent findings have indicated promising potential for PD therapy with DBS in brain structures outside the basal ganglia. For example, high frequency stimulation of the posterior hypothalamic nucleus (PH) can reverse haloperidol-induced akinesia in rats [Jackson J, Young CK, Hu B, Bland BH (2008) High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. Exp Neurol 213:210-219]. In the current study, we used the bilateral 6-hydroxydopamine lesion model of Parkinsonian akinesia in male Long-Evans rats to further explore the efficacy of PH DBS. The application of PH DBS in lesioned animals reversed akinesia in an active avoidance paradigm with increased latency compared to pre-lesion performance. The dramatic reversal of akinesia in two models of rodent Parkinsonism by PH DBS warrants further exploration of its therapeutic potential.

Changes in energy during treatment of depression: an analysis of fluoxetine in double-blind, placebo-controlled trials.

More than two thirds of patients with depression present with symptoms of fatigue, low energy, and listlessness. Because daytime sedation may be a concern in such patients, a "nonsedating" antidepressant should be considered. The authors examined the effects of fluoxetine on depression-related disturbances in energy. Data from seven double-blind, placebo-controlled clinical trials in 2,075 patients with major depression were retrospectively analyzed. The Hamilton Rating Scale for Depression (HAM-D) Retardation factor score (total of items 1, 7, 8, and 14) was used as the primary measure of energy improvement, whereas the HAM-D-17 total score was used to assess changes in overall depression. Elderly patients (aged 60 years and older) were included in the overall group and were also analyzed separately. In addition, a subgroup analysis was performed using the HAM-D Retardation factor score to categorize patients as having low (score < 8) or high (score > or = 8) levels of retardation at baseline. Beginning at week 3, fluoxetine-treated patients experienced statistically significant reductions in their HAM-D Retardation factor score compared with placebo-treated patients. The reductions for the elderly subgroup were less than those for the overall population, but they were still statistically significant beginning at week 4. Patients in both the low and high baseline retardation groups improved significantly. HAM-D-17 total scores for fluoxetine-treated patients in all groups (total, elderly, high retardation, and low retardation) improved significantly compared with placebo-treated patients. These findings demonstrate that fluoxetine-treated patients experience an improvement in energy symptoms as their overall depression improves.

Fluoxetine versus sertraline and paroxetine in major depressive disorder: changes in weight with long-term treatment.

BACKGROUND: The effects of extended selective serotonin reuptake inhibitor (SSRI) treatment on weight are not well characterized. Also unknown is whether different agents have differential effects. To examine these questions, we assessed weight changes in patients randomly assigned to long-term treatment with fluoxetine, sertraline, or paroxetine. METHOD: Patients (N = 284) with major depressive disorder (DSM-IV) were randomly assigned to double-blind treatment with fluoxetine (N = 92), sertraline, (N = 96), or paroxetine (N = 96) for a total of 26 to 32 weeks. The mean percent change in weight was compared for each group, as was the number of patients who had > or = 7% weight increase from baseline. RESULTS: Patients (fluoxetine, N = 44; sertraline, N = 48; paroxetine, N = 47) who completed the trial were included in these analyses. Paroxetine-treated patients experienced a significant weight increase, fluoxetine-treated patients had a modest but nonsignificant weight decrease, and patients treated with sertraline had a modest but nonsignificant weight increase. The number of patients whose weight increased > 7% from baseline was significantly greater for paroxetine-treated compared with either fluoxetine-treated or sertraline-treated patients. CONCLUSION: Risk of weight gain during extended SSRI treatment differs depending on which SSRI is used.

Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: an updated meta-analysis.

BACKGROUND: A 1993 meta-analysis of US Investigational New Drug clinical trials of fluoxetine reinforced this agent's more favorable adverse-event profile compared with tricyclic antidepressants (TCAs). OBJECTIVES: The present meta-analysis sought to provide a reanalysis of updated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d compared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most commonly used effective dose of fluoxetine in MDD (20 mg) was also conducted. METHODS: Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spontaneously reported treatment-emergent adverse events, reasons for discontinuation, and events leading to discontinuation were compared between groups. RESULTS: The age of the 4016 randomized patients ranged from 12 to 90 years, with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ranged from 18 to 90 years, with a mean age of 54 years; as in the total population, most of these patients were white (92%), and 57% were female. The adverse-event profiles of fluoxetine and TCAs in these trials were consistent with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuation rate due to adverse events that was not statistically significantly different from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. However, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (> or = 2%) leading to discontinuation were asthenia, dizziness, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-treated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and tremor in TCA-treated patients. CONCLUSIONS: Data from this large series of clinical trials confirm that fluoxetine is well tolerated in the acute treatment of MDD in adults, especially at a dosage of 20 mg/d, and is better tolerated than the recommended doses of TCAs.

Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose.

BACKGROUND: The efficacy and safety of fluoxetine in adults with moderate-to-severe major depression are well established. However, most analyses combined dosages (20-80 mg/day) of the compound. We hypothesized that in patients taking 20 mg/day, efficacy would be maintained but the incidence of adverse events would be lower. We present a meta-analysis of efficacy and safety data for fluoxetine, 20 mg/day. METHOD: Data were from 3 double-blind studies (N = 417) that included patients with moderate-to-severe major depression (DSM-III or DSM-III-R criteria) who received placebo or fixed-dose 20-mg/day treatment with fluoxetine. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D; HAM-D-17 total score and anxiety/somatization, retardation, sleep disturbance, and cognitive disturbance factors) and response and remission rates. Safety assessments included treatment-emergent adverse events, reasons for discontinuation, and adverse events leading to discontinuation. Adverse events were evaluated to determine the emergence of activation and/or sedation. RESULTS: At 20 mg/day, fluoxetine-treated patients demonstrated significantly greater remission and response rates and mean changes on HAM-D-17 total score and anxiety/somatization, retardation, and cognitive disturbance factor scores than placebo-treated patients (p < .001). The incidence of specific adverse events leading to discontinuation and the frequency of study discontinuations due to adverse events were similar among fluoxetine-treated and placebo-treated patients (6.1% vs. 5.8%, p = .879). Several adverse events (insomnia, asthenia, somnolence, gastroenteritis, decreased libido, chills, and confusion) occurred significantly more frequently among fluoxetine-treated patients. A significant change in sedation, but not activation, occurred in patients in the fluoxetine 20-mg/day group compared with the placebo group. CONCLUSION: These data affirm that fluoxetine at 20 mg/day is efficacious, safe, and of similar activation potential when compared with placebo in patients with major depression.

Fluoxetine vs. tricyclic antidepressants in women with major depressive disorder.

Major depressive disorder and dysthymia are twice as prevalent in women as in men, and the lifetime risk of a woman's developing a major depressive disorder is about 20%. Yet depression is often unrecognized or misdiagnosed in women, and only about one quarter of women who meet criteria for major depressive disorder receive appropriate therapy. Until recently, women were generally excluded from clinical drug trials because of concerns of inadvertent pregnancy and risk of teratogenicity. Thus, information on safety and efficacy in those most likely to require antidepressant therapy is lacking. Studies have shown that the antidepressant fluoxetine, a selective serotonin reuptake inhibitor (SSRI) has a more tolerable side effect profile than do tricyclic amine (TCA) antidepressants, but few data have been reported on the efficacy and tolerability of fluoxetine or other SSRIs in female patients. In this study, a retrospective analysis of 11 randomized, double-blind, well-controlled trials was done to compare data from 427 female patients on fluoxetine and 423 female patients on TCAs. Both fluoxetine and TCAs significantly reduced the HAMD17 total mean score from baseline to end point, week 5 (fluoxetine, 24.35 to 14.37; TCAs, 24.57 to 14.43; p < 0.001). Both treatment groups were associated with significant reductions in the HAMD17 anxiety/somatization and insomnia subfactor scores. Abnormal vision, constipation, dizziness, dry mouth, and somnolence occurred more frequently (p < 0.05) in the TCA group. Insomnia and nausea were the only adverse events more common (p < 0.05) in the fluoxetine group. This study demonstrates that fluoxetine is an effective and tolerable agent for the treatment of major depressive disorder in women.

Fluoxetine and concomitant centrally acting medication use during clinical trials of depression: the absence of an effect related to agitation and suicidal behavior.

Concomitant use of psychoactive medications is a common practice in most clinical trials of antidepressant medications. However, the relative therapeutic impact of such use on trial results has not been the subject of much attention. We conducted a meta-analysis to determine whether concomitant use of psychoactive medications confounded the efficacy or safety results of a series of fluoxetine trials. Data were evaluated from 25 randomized, double-blind clinical trials comparing fluoxetine with placebo or a tricyclic antidepressant (TCA) in 4,016 patients with major depression. We compared incidence rates of concomitant use of anxiolytics, sedatives, and antipsychotics between treatments. In addition, we compared the change in total score for the 21-Item Hamilton Depression Rating Scale (HAMD21): incidence rates of any worsening, emergence, or improvement in psychomotor agitation; and incidence of suicidal acts and any worsening, emergence, or improvement in suicidal ideation between treatment groups among patients taking/not taking a sedative. Anxiolytic and antipsychotic drug use was uncommon (8.3% and 0.9% overall use, respectively) and did not substantially increase over time. Sedative drugs were used most often (29.6% overall), but only 29.8% of the fluoxetine-treated patients took one or more doses. Regarding efficacy, fluoxetine was superior to placebo in decreasing HAMD21 total scores among patients taking/not taking sedatives. Effects on safety were assessed by examining agitation and suicidal ideation. Use of sedatives did not affect the change in the HAMD agitation score; scores were similar in patients receiving fluoxetine, placebo, and TCAs. In all treatment groups, anxiolytic use tended to increase as the HAMD anxiety score increased. Fluoxetine was superior to placebo in treating suicidal ideation, and the concomitant use of sedatives did not influence this effect. Overall, concomitant use of psychotropic medications in the fluoxetine depression clinical trials was uncommon. Our meta-analysis demonstrated that the clinical efficacy and safety of fluoxetine were not confounded by the concomitant use of medications.