The Effects of Vortioxetine on Cognitive Function in Patients with Major Depressive Disorder: A Meta-Analysis of Three Randomized Controlled Trials.

BACKGROUND: Management of cognitive deficits in Major Depressive Disorder (MDD) remains an important unmet need. This meta-analysis evaluated the effects of vortioxetine on cognition in patients with MDD. METHODS: Random effects meta-analysis was applied to three randomized, double-blind, placebo-controlled 8-week trials of vortioxetine (5-20mg/day) in MDD, and separately to two duloxetine-referenced trials. The primary outcome measure was change in Digit Symbol Substitution Test (DSST) score. Standardized effect sizes (SES) versus placebo (Cohen's d ) were used as input. Path analysis was employed to determine the extent to which changes in DSST were mediated independently of a change in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Meta-analysis was applied to MADRS-adjusted and -unadjusted SES values. Changes on additional cognitive tests were evaluated (source studies only). RESULTS: Before adjustment for MADRS, vortioxetine separated from placebo on DSST score (SES 0.25-0.48; nominal p < 0.05) in all individual trials, and statistically improved DSST performance versus placebo in meta-analyses of the three trials (SES = 0.35; p < 0.0001) and two duloxetine-referenced trials (SES = 0.26; p = 0.001). After adjustment for MADRS, vortioxetine maintained DSST improvement in one individual trial ( p = 0.001) and separation from placebo was maintained in meta-analyses of all three trials (SES = 0.24; p < 0.0001) and both duloxetine-referenced trials (SES 0.19; p = 0.01). Change in DSST with duloxetine failed to separate from placebo in individual trials and both meta-analyses. Change in DSST statistically favored vortioxetine versus duloxetine after MADRS adjustment (SES = 0.16; p = 0.04). CONCLUSIONS: Vortioxetine, but not duloxetine, significantly improved cognition, independent of depressive symptoms. Vortioxetine represents an important treatment for MDD-related cognitive dysfunction.

Phospholipases A1 and A2 in lamellar inclusion bodies of the alveolar epithelium of rabbit lung.

1. A lamellar body-enriched fraction was prepared from rabbit lung and characterized by electron microscopy, surface activity studies, phospholipid assay and marker enzymes. 2. Both phospholipases A1 and A2 were found to be present in lamellar bodies. After these had been ruptured both enzymes were found to be principally in the soluble phase. 3. The possible roles for phospholipases in lamellar body development and in the respiratory distress syndrome of the newborn are discussed.

Rh/IGF-I/rhIGFBP-3 administration to patients with type 2 diabetes mellitus reduces insulin requirements while also lowering fasting glucose.

Administration of insulin-like growth factor-I to patients with diabetes enhances insulin action and reduces the degree of hyperglycemia but it is associated with a high rate of adverse events. Infusion of the combination of rhIGFBP-3 (the principal binding protein for IGF-I in plasma) with rhIGF-I to patients with type I diabetes improved insulin sensitivity and was associated with a low incidence in side effects. In this study, 52 patients with insulin-treated type 2 diabetes received recombinant human IGF-I plus rhIGFBP-3 in one of four dosage regimens for 14 days. The four groups were: (1) continuous subcutaneous infusion of 2 mg/kg/day; (2) the same 2 mg/kg dose infused subcutaneously over 6 h between 2000 and 0200 h; (3) 1 mg/kg twice a day by bolus subcutaneous injection; (4) a single bedtime subcutaneous injection of 1 mg/kg. Across these four groups rhIGF-I/rhIGFBP-3 decreased insulin requirements between 54% and 82%. Fasting glucose decreased by 32-37%. Mean daily blood glucose (4 determinations per day) declined in all 4 groups (range 9-23% decrease). Frequent sampling for total IGF-I, free IGF-I and IGFBP-3 was performed on days 0,1,7,14 and 15. The peak total IGF-I values were increased to 4.0-4.8-fold at 16-24 h. For free IGF-I the increase varied between 7.1 and 8.2-fold and peak values were attained at 16-20 h after administration. Both the time to maximum concentration (Tmax) and the maximum free IGF-I levels (Cmax) on day 1 for all groups were substantially less than previously published studies, wherein lower doses of rhIGF-I were given without IGFBP-3. The improvement in glucose values and the degree of reduction in insulin requirement were the greatest in groups 2 and 3 and the patients in those groups had the highest free IGF-I levels. The frequency of side effects such as edema, jaw pain and arthralgias was 4% which is less than that has been reported in previous studies wherein IGF-I was administered without IGFBP-3. We conclude that rhIGF-I/rhIGFBP-3 significantly lowers insulin requirements yet improves glucose values and these changes may reflect improvement in insulin sensitivity. Coadministration of IGFBP-3 with IGF-I produces lower free IGF-I (Tmax and Cmax) levels compared to administration of IGF-I alone and is associated with relatively low incidence of side effects during 2 weeks of administration.

Decreases in mediobasal hypothalamic and preoptic area opioid ([3H]naloxone) binding are associated with the progesterone-induced luteinizing hormone surge.

In view of evidence implicating hypothalamic opioid systems in the control of LH release, we have examined the binding of [3H]naloxone (NAL) to slices of mediobasal hypothalamus (MBH) and preoptic area (POA) during the induction of an afternoon LH surge (1630-1700 h) in estradiol benzoate (EB)-primed ovariectomized (OVX; day 0) rats by treatment with progesterone (P; day 2). Such a surge was invariably accompanied by a decrease from early morning (1000 h) values in the number of NAL-binding sites detectable in the MBH, while the affinity of the binding site was not affected over the course of the day. Time-course studies indicated that P injection at 1000 h on day 2 was followed by a transient midday elevation in the amount of NAL bound to slices of MBH; the binding decreased significantly before the onset of and during the LH surge. A similar diurnal change was not observed in MBH slices of either oil-treated OVX rats (controls) or EB-treated OVX rats, which displayed only a 2-fold increase in LH release in the afternoon. Further studies indicated a similar change in NAL binding to slices of the POA of EBP-treated rats. Since hypothalamic opioid systems inhibit LH release, the decrease in opioid binding to MBH as well as POA slices suggests that P may curtail the existing opioid inhibitory influence in these areas before and during the course of the afternoon LH surge.

Serum folate and chronic fatigue syndrome.

We assayed serum folate levels of 60 patients with chronic fatigue syndrome (CFS) and found that 50% had values below 3.0 micrograms/l. Some patients with CFS are deficient in folic acid.

Dynamic changes in neuropeptide y concentrations in the median eminence in association with preovulatory luteinizing hormone release in the rat.

Abstract Neuropeptide Y (NPY) stimulates luteinizing hormone (LH) release in the rat by a dual action, one in the hypothalamus to excite LH-releasing hormone (LHRH) release and the other at the level of pituitary gonadotrophs to activate and/or potentiate LH release induced by LHRH. Because NPY produces effects similar to norepinephrine with which it may comprise an excitatory hypothalamic circuit, it was hypothesized that NPY concentrations in the hypothalamus would change in a time- and site-specific manner in association with the preovulatory LH surge on proestrus. Concentrations of NPY in individual nuclei of the preoptic-tuberal pathway and serum LH levels were estimated by radioimmunoassays in rats during diestrus 2 and proestrus. On proestrus, serum LH levels were basal between 1000 and 1400 h, rose significantly at 1500 h and plateaued between 1600 and 1800 h. Of the five neural sites examined, only NPY in the median eminence displayed marked fluctuations in close association with the LH surge. NPY concentrations were low between 1000 and 1300 h, and rose abruptly at 1400 h (P<0.05) preceding the onset of LH rise at 1500 h. These elevated levels were maintained until 1600 h, during which time serum LH rose to a plateau and then fell at 1800 h to the low range seen between 1000 and 1300 h. In contrast, the pattern of changes in NPY levels in the arcuate nucleus, suprachiasmatic nucleus and medial preoptic area, three additional sites in the preoptic-tuberal pathway known to participate in the preovulatory LH surge, were markedly different from that seen in the median eminence. In each of these three sites, NPY levels rose significantly at 1800 h from the values at 1000 to 1200 h with a slightly different time-course of increment. None of these areas exhibited changes in NPY concentrations on diestrus 2; NPY concentrations also were unaltered on diestrus 2 or proestrus in the ventromedial nucleus. The present observations of site-specific, dynamic changes in NPY levels on proestrus, in a manner previously documented for LHRH, support the hypothesis that a subset of NPY neurons terminating in the median eminence may be a component of excitatory neural circuitry that either independently or in co-action with the adrenergic system is responsible for the induction of preovulatory LH release.

Computer-based diagnostic reporting for serum electrolytes.

Desk-top computers equipped with 16K memory and programmed in BASIC can be used to produce interpretive reports of selected laboratory data by the assignment of a numerical code. A tetral algorithm is programmed in a three-dimensional matrix, charted by columns designating specific diagnostic considerations for serum electrolyte abnormalities (an adaptation of Dito's coding procedure for protein electrophoresis). The code consists of the numbers 4 (high), 2 (normal), and 1 (low), with no basis for borderline abnormal results. The program is easily updated with additions of diagnostic considerations (column headings) or with additional codes corresponding to such conditions (code listings under column headings). Diagnostic reports can be easily produced by the use of a tractor-feed printer or similarly interfaced printing equipment for use on the patient chart, and file copies are easily generated by a "rerun" loop incorporated into the software.

Mu-opioid ([3H]DAGO) binding in slices of rat brain: inhibition by sodium ions, guanyl-5'-yl imidodiphosphate and by the adrenergic neurotoxins DSP4 and xylamine.

We have characterized and quantified the specific binding of the mu-agonist [3H] DAGO to 300 microM slices of hypothalamus and cerebral cortex. The receptors have many of the opioid characteristics previously demonstrated in homogenate assays. Binding is reversible, saturable, stereospecific and of high affinity. The delta-opioids DTLET and DSLET are 36- and 30-fold respectively, less effective than DAGO in competing for the binding site. Assays can be routinely performed in the presence of physiological concentrations of sodium, though in TRIS buffer the affinity and the number of receptors is increased. Protection of the ligand against proteolytic degradation is unnecessary. Unexpectedly, we observed that GppNHp inhibits [3H] DAGO binding to brain slices. This suggests an allosteric modification of the mu-receptor in the membranes of intact cells. The mu-receptors are also blocked by the adrenergic neurotoxins DSP4 and xylamine. This re-emphasizes our contention that care should be exercised in the use of these drugs. The technique is simple, rapid and involves minimal disruption of tissue. It should provide new opportunities for the study of cell surface opioid receptor subtypes in intact tissue.

Rapid visualization of NMDA receptors in the brain: characterization of (+)-3-[125I]-iodo-MK-801 binding to thin sections of rat brain.

We have developed and characterized a method for the rapid autoradiographic determination of receptor sites for the non-competitive NMDA receptor antagonist, MK-801, using an iodinated form of the compound, (+)-3-[125I]-iodo-MK-801. The binding site was shown to exhibit those criteria necessary for its definition as a receptor site, i.e., the binding was saturable, of high affinity, easily reversible, and stereospecific. Saturation analysis of binding to thin brain sections revealed a Bmax of 108.1 +/- 10.5 fmol/mg protein and a Kd of 383 +/- 67 pM. The pharmacology of the interaction of the ligand with the binding site yielded good correlation between the potency of various substances to complete for the binding site and their ability to act as antagonists of NMDA. Autoradiographs of thin coronal brain sections using (+)-3-[125I]-iodo-MK-801 yielded high quality images in 24-48 h with a distribution of binding sites paralleling that reported for the tritiated form of the ligand, i.e., with high densities in the hippocampus, cerebral cortex and lateral septum. Other areas with significant binding included parts of the thalamus, the amygdala and the olfactory tubercules. Furthermore, due to its high specific activity, this ligand lends itself to the study of regions not rich in MK-801 binding sites, such as the diencephalon.

Gonadotropin suppression with oral contraceptives before in vitro fertilization.

One hundred eighty-one stimulation cycles in which gonadotropin suppression with oral contraceptives (OCs) preceded induction of follicle stimulation (study group) and 113 stimulation cycles without pituitary suppression (control group) were compared. The mean length of ovarian suppression was 35.3 +/- 0.9 days. No spontaneous luteinizing hormone (LH) surges occurred when the use of OC preceded ovarian hyperstimulation, whereas in the control group the incidence of LH surges was 19.5%. The mean amount of human menopausal gonadotropin required was significantly lower in the study group than in the control group (8.9 +/- 0.4 and 10.9 +/- 0.4 ampules, respectively). Significantly more follicles greater than or equal to 1.5 cm in diameter were seen on the day before oocyte retrieval and significantly more oocytes were retrieved per attempt in the group with OC pretreatment. Our data clearly demonstrate that OCs are useful in vitro fertilization stimulation protocols to facilitate scheduling of cycles and to prevent spontaneous LH surges.

Endometrial thickness and growth during ovarian stimulation: a possible predictor of implantation in in vitro fertilization.

The present study was undertaken to evaluate endometrial thickness and the amount of endometrial growth (delta) in patients who conceived during in vitro fertilization (IVF) (n = 36) compared with matched women who did not conceive (n = 72). Estradiol (E2) and endometrial thickness were measured daily from cycle day 10 to the day after human chorionic gonadotropin (hCG). Mean endometrial thickness and E2 levels on cycle day 10 did not differ. On the day before ovum retrieval, significantly thicker endometrium was observed in the pregnant than in the nonpregnant women (8.6 +/- 0.3 [SEM] and 7.1 +/- 0.3 mm, respectively; P less than 0.0005), whereas the mean E2 levels did not differ. The delta endometrial growth was greater in the women who conceived than in the nonpregnant group (4.3 +/- 0.2 and 2.5 +/- 0.2 mm, respectively; P less than 0.0005). The fertilization rate and serum E2 levels did not correlate with endometrial thickness nor with delta endometrial growth. Our data suggest that the amount of endometrial growth during ovarian hyperstimulation and the endometrial thickness on the day before oocyte retrieval deserve further study as possible predictive parameters for implantation.

A multicenter study on the use of pulsed low-intensity direct current for healing chronic stage II and stage III decubitus ulcers.

BACKGROUND AND DESIGN: Pulsed low-intensity direct current (300 to 600 microA) has been used in a double-blind placebo multicenter study in the treatment of stage II and stage III chronic decubitus ulcers. RESULTS: Seventy-four ulcers were treated in four centers. Forty-three patients were selected for the experimental group, and 31 control subjects used the sham instrument (placebo group). In the treated group, 25 ulcers (58%) healed in 8 weeks, whereas in the placebo group, only one ulcer (3%) healed and most ulcers increased in size. Statistical analysis, based on surface area and ulcer depth before and after treatment, showed that low-intensity direct current had a significant influence on the healing rates for these ulcers (P < .0001). Experiments with guinea pigs (n = 10) showed that pulsed low-intensity direct current caused a rapid calcium flux in the epidermis. CONCLUSIONS: Pulsed low-intensity direct current represents a useful approach for the treatment of stage II and stage III chronic decubitus ulcers by increasing the healing rate. The growth of fibroblasts and keratinocytes may be enhanced by pulsed low-intensity direct current due to changes in calcium homeostasis.

Brain slices in radioligand binding assays: quantification of opiate, benzodiazepines and beta-adrenergic ([3H] CGP-12177) receptors.

We have characterized and quantified specific binding of [3H]-flunitrazepam (FNZ; (benzodiazepine), [3H]-naloxone (NAL; (opiate) and [3H] CGP-12177(CGP; (beta-adrenergic) to thick slices (230-400 micron) of mouse and rat brain. The binding sites are stereospecific, saturable and of high affinity. In all cases, the binding of the ligands is readily reversible and demonstrates the appropriate drug specificity. In mouse brain [3H]-NAL binding is elevated by chronic treatment with naloxone (via capsules). We have been unsuccessful in quantifying beta adrenoreceptors with the archetypal ligand [3H]-dihydroalprenolol (DHA). However, the use of [3H]-CGP 12177 enabled us to detect high-affinity beta adrenoreceptors in brain slices. [3H]-CGP also permits the demonstration of rapid and reversible agonist-induced down-regulation (internalization) of beta binding sites. We have been successful in quantifying beta adrenergic sites in single pineal glands of rat and hamster.

Opiate ([3H]-naloxone) binding to hypothalamic and cerebral cortical slices of mouse brain.

We have characterized the binding of [3H]-naloxone to thick (400 microns) slices of hypothalamus and cerebral cortex from mouse brain. Binding is reversible, saturable, stereospecific, thermolabile, readily displaceable by opiates and sensitive to phenoxybenzamine and phentolamine. Values for KD and Bmax are very close to published figures obtained in brain homogenates. Metabolic inhibitors (ouabain and azide) have no effect on specific binding. The assay is rapid, simple and involves minimal tissue preparation.

Effects of the noradrenergic neurotoxin DSP4 on growth and the gonadal steroid- and PMSG-induced release of LH in the prepubertal female rat.

We have examined the effect of DSP4 treatment on PMSG-induced ovulation. A marked attenuation of the stimulatory effects of PMSG (7.5 I.U.) by DSP4 was evidenced by the significantly lower number of corpora lutea present in the ovaries of those animals which ovulated compared to controls. In addition, ovarian weight was lower in the DSP4 group. In a further experiment, we examined the effect of DSP4 on the induction of an LH surge by progesterone (P) in estradiol benzoate (EB) primed rats. DSP4 administration 2 hours prior to P eliminated the LH surge seen in controls. In view of our previous observations that DSP4 can interact with opioid receptors, we attempted to block its inhibitory effect on PMSG and EB/P stimulations. Coinjection of naloxone, an opioid antagonist, only partially prevented the influence of DSP4. It seems likely, therefore, that opioid receptors are not involved in the inhibitory effects of DSP4 described here. In further experiments, we studied the effects of DSP4 on spontaneous sexual maturation in female rats. DSP4 was administered (50 mg/kg, IP) on either day 5, day 23, day 29, or both day 24 and day 26 of life. Growth was inhibited and vaginal opening (VO) was significantly delayed in all except the day 29 group. However, VO occurred at the same body weight as the controls. By the end of the experiment, hypothalamic noradrenaline levels were not significantly different between control and DSP4-treated animals. The lack of an effect of DSP4 on the progression to puberty may be due to sufficient recovery of the central noradrenergic systems during the time course of the experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

The noradrenergic neurotoxins DSP4 and xylamine bind to opiate receptors.

DSP4 and xylamine compete with [3H]-naloxone for opiate binding sites with IC50 values of approximately 1 microM. This effect can be blocked by excess naloxone but not by the noradrenaline uptake inhibitors cocaine or desipramine. Other drugs containing the 2-chloroalkylamine structure--phenoxybenzamine, dibenamine, chloroethyl clonidine, the cholinotoxin AF-64 and 2-dimethylaminoethyl chloride--were similarly tested. Phenoxybenzamine and dibenamine were also able to compete with [3H]-naloxone for binding at the opiate receptor. Experiments in vivo demonstrated that DSP4, like other opiates, can rapidly reduce LH secretion in the rat. This effect is prevented by naloxone but not by desipramine. These data suggest the use of caution in interpreting the results of experiments in which DSP4 and xylamine are used as "specific" noradrenergic uptake inhibitors or as neurotoxins.

Benzodiazepine ([3H])-flunitrazepam) binding sites in cerebellar and cerebral cortical slices of mouse brain.

We have characterized and quantified the specific binding of [3H]-flunitrazepam ( FNZ ) to thick (230 micron) slices of mouse brain. The binding site has the characteristics of a benzodiazepine receptor, i.e., binding of FNZ is reversible, stereospecific, saturable and of high affinity. Clonazepam, but not R05 -4864, readily displaces the label. In contrast to results from homogenate assays, neither GABA nor bicuculline has any effect on [3H]- FNZ binding. However, as previously reported, the slice assay confirms the lower number of benzodiazepine receptors in "emotional" mouse brain. In addition, we have confirmed that the neurotoxin DSP4 can modify [3H]- FNZ binding though in our hands this compound elevates rather than reduces binding. The speed, simplicity and minimal tissue preparation involved suggests that this slice assay could be a valuable addition to neurochemical studies of neurotransmitter receptors.

Tissue slices in radioligand binding assays: studies in brain, pineal and muscle.

The use of tissue homogenates in receptor binding assays raises serious questions as to the physiological value of a preparation which examines receptors (binding sites) in disrupted tissue. In order to usefully study the regulatory properties of neurotransmitter receptors under physiological conditions, the necessity for tissue preparations which retain some degree of cellular integrity is clear. We review here the experiments which have utilized intact tissue - largely in the form of thick slices - to perform radioligand binding assays. There are many reports which note marked differences between studies in intact versus broken cell preparations. For example, significant discrepancies in KD and Bmax values are apparent for [3H] quinuclidinyl benzilate (muscarinic) and [3H] ouabain (Na+/K+-ATP ase, sodium pump) sites in brain and muscle respectively. A further example is the well-described stimulatory effect of GABA on benzodiazepine binding sites which is not seen in tissue slices. Other examples are highlighted. For all ligands so far examined, binding to slices is reversible, stereospecific, saturable, displaceable by appropriate drugs and of high affinity (nM). The method developed in our own laboratory is inexpensive, rapid and involves a minimum of tissue preparation. The technique is so simple as to allow many workers to enter this field who would not otherwise have done so. We suggest that metabolically active tissue slices offer the simplest approach to the study of cell-surface receptor regulation in living tissue.

Use of the Milwaukee brace for progressive idiopathic scoliosis.

One hundred and two (92 per cent) of 111 immature patients in whom idiopathic scoliosis had been treated with a Milwaukee brace were followed to determine the effectiveness of the brace in preventing progression of the scoliosis. The average time from cessation of bracing until the latest radiographs were made for the patients who were managed non-operatively was six years and four months. The average progression of the curve, from the time of initial bracing until use of the brace was stopped, in the eighty-eight patients who were included in the statistical analysis was 4 degrees. The curve continued to progress an average of 5 degrees after use of the brace was stopped in the patients who did not have an arthrodesis. Forty-two patients (48 percent) had more than 5 degrees of progression at the time that use of the brace was stopped. Thirty-seven patients (42 per cent) had an operation or a curve of sufficient magnitude to warrant operative intervention. The maximum correction of the Cobb angle in the brace had prognostic importance for progression of the curve. The patients in whom the curve did not progress or who did not need operative intervention had had an average correction of 20 per cent, while the patients who had a failure had had an average correction of 8 per cent. The patients who eventually had the indications for an arthrodesis were on the average, one year younger (eleven years and none months) and had a curve of a larger magnitude at the time of bracing than the patients who did not need an arthrodesis. The findings of this study do not agree with previously reported favorable results with bracing and raise questions about whether the natural history of progressive idiopathic scoliosis is truly altered by use of the Milwaukee brace.

Serum folate in viral and mycoplasmal infections.

The concentration of serum folate in 260 patients with viral and mycoplasmal infections was determined (305 samples). In 60% the serum folate concentrations were found to be below 3 micrograms/l. The incidence of low serum folate varied slightly. According to the infections diagnosed, low values were: for influenza A 50% (50 patients), influenza B 42% (45 patients), human parvovirus 67% (76 patients), rubella 62% (13 patients), infectious mononucleosis 60% (15 patients), Mycoplasma pneumoniae 73% (45 patients). For a group of undiagnosed rashes it was 81% (16 patients). The cause of low concentrations of serum folate in these patients is discussed.