A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

Increases in plasma sheet temperature with solar wind driving during substorm growth phases.

During substorm growth phases, magnetic reconnection at the magnetopause extracts ∼1015 J from the solar wind which is then stored in the magnetotail lobes. Plasma sheet pressure increases to balance magnetic flux density increases in the lobes. Here we examine plasma sheet pressure, density, and temperature during substorm growth phases using 9 years of Cluster data (>316,000 data points). We show that plasma sheet pressure and temperature are higher during growth phases with higher solar wind driving, whereas the density is approximately constant. We also show a weak correlation between plasma sheet temperature before onset and the minimum SuperMAG AL (SML) auroral index in the subsequent substorm. We discuss how energization of the plasma sheet before onset may result from thermodynamically adiabatic processes; how hotter plasma sheets may result in magnetotail instabilities, and how this relates to the onset and size of the subsequent substorm expansion phase.

Antidepressant use in pregnancy: a critical review focused on risks and controversies.

OBJECTIVE: Conflicting data have led to controversy regarding antidepressant use during pregnancy. The objectives of this study are to i) review the risks of untreated depression and anxiety, ii) review the literature on risks of exposure to antidepressants during pregnancy, iii) discuss the strengths and weaknesses of the different study designs used to evaluate those risks, and iv) provide clinical recommendations. METHOD: MEDLINE/PubMed was searched for reports and studies on the risk of first-trimester teratogenicity, postnatal adaptation syndrome (PNAS), and persistent pulmonary hypertension (PPHN) with in utero antidepressant exposure. RESULTS: While some individual studies suggest associations between some specific major malformations, the findings are inconsistent. Therefore, the absolute risks appear small. PNAS occurs in up to 30% of neonates exposed to antidepressants. In some studies, PPHN has been weakly associated with in utero antidepressant exposure, while in other studies, there has been no association. CONCLUSION: Exposures of concern include that of untreated maternal illness as well as medication exposure. It is vital to have a careful discussion, tailored to each patient, which incorporates the evidence to date and considers methodological and statistical limitations. Past medication trials, previous success with symptom remission, and women's preference should guide treatment decisions.

Energization of the Ring Current by Substorms.

The substorm process releases large amounts of energy into the magnetospheric system, although where the energy is transferred to and how it is partitioned remains an open question. In this study, we address whether the substorm process contributes a significant amount of energy to the ring current. The ring current is a highly variable region, and understanding the energization processes provides valuable insight into how substorm-ring current coupling may contribute to the generation of storm conditions and provide a source of energy for wave driving. In order to quantify the energy input into the ring current during the substorm process, we analyze Radiation Belt Storm Probes Ion Composition Experiment and Helium Oxygen Proton Electron ion flux measurements for H+, O+, and He+. The energy content of the ring current is estimated and binned spatially for L and magnetic local time. The results are combined with an independently derived substorm event list to perform a statistical analysis of variations in the ring current energy content with substorm phase. We show that the ring current energy is significantly higher in the expansion phase compared to the growth phase, with the energy enhancement persisting into the substorm recovery phase. The characteristics of the energy enhancement suggest the injection of energized ions from the tail plasma sheet following substorm onset. The local time variations indicate a loss of energetic H+ ions in the afternoon sector, likely due to wave-particle interactions. Overall, we find that the average energy input into the ring current is ∼9% of the previously reported energy released during substorms.

Omega-3 fatty acids and perinatal depression: a review of the literature and recommendations for future research.

INTRODUCTION: Perinatal depression refers to major depression in the context of pregnancy and postpartum. In consideration of its prevalence and consequences, the treatment and prevention of perinatal depression should be important public health priorities. Omega-3 fatty acids are attractive for consideration in perinatal women, due to known health benefits for the mother and baby. Antidepressant medications may pose risks in utero and in breastfeeding. METHODS: MEDLINE and manual searches were conducted. RESULTS: Epidemiological and preclinical data support a role of omega-3 fatty acids in perinatal depression. Two studies failed to support a role of omega-3 fatty acids for postpartum depression prophylaxis, although one included a small sample, and the other utilized a low dosage. Two pilot studies suggest good tolerability and potential efficacy in the acute treatment of perinatal depression. CONCLUSIONS: Further research studies are warranted to determine the role of omega-3 fatty acids in the treatment of perinatal depression.

What effect do substorms have on the content of the radiation belts?

Substorms are fundamental and dynamic processes in the magnetosphere, converting captured solar wind magnetic energy into plasma energy. These substorms have been suggested to be a key driver of energetic electron enhancements in the outer radiation belts. Substorms inject a keV "seed" population into the inner magnetosphere which is subsequently energized through wave-particle interactions up to relativistic energies; however, the extent to which substorms enhance the radiation belts, either directly or indirectly, has never before been quantified. In this study, we examine increases and decreases in the total radiation belt electron content (TRBEC) following substorms and geomagnetically quiet intervals. Our results show that the radiation belts are inherently lossy, shown by a negative median change in TRBEC at all intervals following substorms and quiet intervals. However, there are up to 3 times as many increases in TRBEC following substorm intervals. There is a lag of 1-3 days between the substorm or quiet intervals and their greatest effect on radiation belt content, shown in the difference between the occurrence of increases and losses in TRBEC following substorms and quiet intervals, the mean change in TRBEC following substorms or quiet intervals, and the cross correlation between SuperMAG AL (SML) and TRBEC. However, there is a statistically significant effect on the occurrence of increases and decreases in TRBEC up to a lag of 6 days. Increases in radiation belt content show a significant correlation with SML and SYM-H, but decreases in the radiation belt show no apparent link with magnetospheric activity levels.

Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.

BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

Mood stabilizer combinations: a review of safety and efficacy.

OBJECTIVE: Polypharmacy is common in the treatment of refractory bipolar disorder. The purpose of this article is to review the safety and efficacy of mood stabilizers in combinations. METHOD: A manual and computer (MEDLINE) search was performed for combinations of the most commonly used mood-stabilizing agents. RESULTS: The authors review safety and efficacy data on the more frequently encountered combinations of established and putative mood stabilizers. CONCLUSIONS: There have been few controlled studies of the use of combinations of mood stabilizers. The interactions of such combinations are sometimes complex, often very useful, and potentially dangerous. One general rule that may reduce the risks of toxic drug interactions is to add medication to the patient's current regimen in modest doses and increase the dose slowly. The safest and most efficacious mood stabilizer combinations appear to be the mixtures of anticonvulsants and lithium, particularly valproate plus lithium. Once the mechanisms of the mood stabilizers are identified, it is possible that a more rational approach to combination therapy will emerge, based on synergism at the sites of action.

Clinical picture and etiologic models of mixed states.

Although conceptualized as polar opposites, manic and depressive symptoms often co-occur in bipolar disorder. This article explores the clinical characteristics, prevalence, biologic features, and response to treatments of mixed states. Issues of diagnosis and cause are considered. The course is often protracted beyond acute episodes, psychotic symptoms are common, and suicide is a major risk. Bipolar mixed states are over represented in women. Mixed states respond poorly to lithium salts; mood stabilizers, particularly divalproex, are the mainstay of modern treatment. Electroconvulsive therapy is also effective, and can be used in severe cases.

Persistent sciatic artery. Report of three cases and literature review.

Persistence of the sciatic artery (SA) is a rare vascular anomaly, resulting from lack of regression of an embryonal artery to the lower extremity. Forty-nine cases have been published in the world literature since 1832. The persistent sciatic artery (PSA) is particularly prone to undergo aneurysm formation or atherosclerosis. It originates from the internal iliac artery, courses in close proximity to the sciatic nerve, and provides the main supply to the popliteal artery because a hypoplastic superficial femoral artery (SFA), contributing only collaterals to the knees, is usually associated with a PSA. This anomaly should be kept in mind in the clinical assessment of a pulsatile gluteal mass. It also presents a potential hazard during hip and renal transplant surgery.

Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression.

OBJECTIVE: Postpartum depression (PPD) affects 10-15% of mothers. Omega-3 fatty acids are an intriguing potential treatment for PPD. METHOD: The efficacy of omega-3 fatty acids for PPD was assessed in an 8-week dose-ranging trial. Subjects were randomized to 0.5 g/day (n = 6), 1.4 g/day (n = 3), or 2.8 g/day (n = 7). RESULTS: Across groups, pretreatment Edinburgh Postnatal Depression Scale (EPDS) and Hamilton Rating Scale for Depression (HRSD) mean scores were 18.1 and 19.1 respectively; post-treatment mean scores were 9.3 and 10.0. Percent decreases on the EPDS and HRSD were 51.5% and 48.8%, respectively; changes from baseline were significant within each group and when combining groups. Groups did not significantly differ in pre- or post-test scores, or change in scores. The treatment was well tolerated. CONCLUSION: This study was limited by small sample size and lack of placebo group. However, these results support further study of omega-3 fatty acids as a treatment for PPD.

Bipolar disorder in women: reproductive events and treatment considerations.

OBJECTIVE: Bipolar disorders are prevalent in women. Women with bipolar disorder often present with different clinical features than men. Reproductive events and hormonal treatments may impact the course of bipolar disorder. Our main objectives are to i) assess the impact of reproductive events on the course of the disorder, and ii) to discuss the relationships between reproductive events and psychiatric treatments. METHOD: A literature search was conducted of MEDLINE journals from 1965 to present. Manual literature searches were also conducted. We review the presentation, clinical course, and treatment considerations of bipolar disorder in women, with emphasis on treatment considerations in the context of reproductive events. Treatment-related issues such as teratogenicity, breastfeeding, polycystic ovarian syndrome, weight gain and obesity, and medication interactions with oral contraceptives are reviewed. RESULTS: Women with bipolar disorder may be more vulnerable to mood episodes in the context of reproductive events, particularly postpartum. In women of reproductive age, mood stabilizers must be selected with teratogenic risks in mind, with the highest reported risks in pregnancy with valproate, and the greatest concern during breastfeeding with lithium use. In the areas of the perimenopause and polycycstic ovarian syndrome, more data are needed to advise treatment decisions. CONCLUSION: We urgently need further study in these areas to deliver care that is appropriate to women with bipolar disorder.

Omega-3 fatty acids in psychiatry: a review.

Omega-3 fatty acids are long-chain, polyunsaturated fatty acids found in plant and marine sources. Unlike saturated fats, which have been shown to have negative health consequences, omega-3 fatty acids are polyunsaturated fatty acids that have been associated with many health benefits. Omega-3 fatty acids may prove to be efficacious in a number of psychiatric disorders. Mood disorders have been associated with abnormalities in fatty acid composition. Several lines of evidence suggest that diminished omega-3 fatty acid concentrations are associated with mood disorders. Clinical data are not yet available regarding omega-3 fatty acids in the treatment of major depression. However, one double-blind treatment trial has been conducted in bipolar disorder. Also, substantial evidence does exist supporting a potential role of omega-3 fatty acids in schizophrenia, although treatment data are needed. A case has been reported in which a patient with schizophrenia was successfully treated with omega-3 fatty acids. Controlled studies are necessary to explore the potential treatment of schizophrenia with omega-3 fatty acids. Omega-3 fatty acids may also be helpful in the treatment of dementia. Furthermore, omega-3 fatty acids may prove to be a safe and efficacious treatment for psychiatric disorders in pregnancy and in breastfeeding.

Renal artery embolization to control urinary cutaneous fistula after partial resection of a horseshoe kidney.

We describe a patient with a chronic urinary cutaneous fistula following partial nephrectomy of a previously separated horseshoe kidney, who was treated successfully by stainless steel coil embolization of the renal artery. Thus, a major reoperation was avoided.

Transcatheter embolization of the dorsal pancreatic artery to control massive postoperative bleeding.

We report a severely traumatized patient who developed massive bleeding through surgical drains in the postoperative period. Superselective dorsal pancreatic arteriography demonstrated extravasation of contrast material in the pancreatic bed. Embolization with Gel-foam particles successfully controlled this severe bleeding. Transcatheter embolization is the procedure of choice for controlling pancreatic bleeding in acutely traumatized patients.

Ewing sarcoma of the skull with an unusual pattern of reactive sclerosis: MR characteristics.

A case of primary Ewing sarcoma involving the occipital bone with an unusual radiographic feature--markedly thickened bone--is described. Magnetic resonance imaging was more helpful than CT in determining the lesion extent due to lack of bone artifact and since it showed the precise relationship of the neoplasm to the tentorium on direct coronal imaging.