A preliminary open study of the tolerability and effectiveness of nefazodone in major depressive disorder: comparing patients who recently discontinued an SSRI with those on no recent antidepressant treatment

Anecdotal evidence suggests that the recent discontinuation of an SSRI may confound the tolerability of the initiation of nefazodone treatment. We sought to determine whether recent discontinuation of an SSRI interferes with effectiveness and/or tolerability of nefazodone. Twenty-six depressed subjects, 21-63 years old, were recruited at the Massachusetts General Hospital. Thirteen subjects (50%) had discontinued an SSRI within 1-4 weeks due to ineffectiveness and/or side effects. Thirteen subjects (50%) had not taken antidepressants for the previous 6 months. Subjects were administered open nefazodone 50 mg p.o. b.i.d., and doses were increased as tolerated to a maximum of 600 mg/day. Subjects were followed for 12 weeks and were assessed for response and side effects using HAM-D-6 and clinical interviews. Both groups improved significantly on nefazodone; however, there was no statistically significant difference in response (>or=50% decrease in HAM-D-6) rates between completers with prior SSRI treatment (80%) and completers without recent exposure to antidepressants (67%). Response rates based on intent-to-treat (ITT) analysis were 31% for both groups. Association between prior SSRI treatment and discontinuation of nefazodone due to side effects or non-response was not statistically significant. Our study suggests that the rate of negative outcomes with nefazodone is no different whether patients have recently failed an SSRI.     

Cellular mechanisms of serotonin 5-HT2A receptor-mediated cGMP formation: the essential role of glutamate

The current study explores the mechanisms by which activation of serotonin(2A) (5-HT(2A)) receptors increase production of cyclic guanosine monophosphate (cGMP) in slices of rat frontal cortex. Contrary to results in cortical slices, stimulation of 5-HT(2A) receptors in cells stably expressing this serotonin receptor did not alter cGMP levels. In cortical slices, stimulation of cGMP formation by 2,5-dimethoxy-4-methylamphetamine (DOM), a 5-HT(2A/2C) receptor agonist, was blocked by tetanus toxin, a substance that prevents vesicular neurotransmitter release. However, this stimulation was not altered by tetrodotoxin, an agent that inhibits depolarization-induced neurotransmitter release. Addition of an N-methyl-d-aspartate (NMDA) receptor antagonist, d-AP-7, but not of an AMPA/kainate receptor antagonist CNQX, completely inhibited DOM-mediated cGMP production in the slices. Combined application of maximally effective concentrations of NMDA and DOM elicited a greater increase in cGMP content than either drug alone. The present study shows that 5-HT(2A) receptors do not directly stimulate cGMP formation, but rather that 5-HT(2A) receptor-mediated cGMP production is dependent on extracellular glutamate activating NMDA receptors. The results indicate that 5-HT(2A) receptor-mediated cGMP production could be at least partially attributed to potentiation of NMDA receptor-mediated cGMP formation.     

Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex

The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT(2A) antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT(2A/C) agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 microM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.     

Behavioral and emotional disturbances in the offspring of depressed parents with anger attacks

BACKGROUND: To examine the emotional and behavioral characteristics of the offspring of depressed parents with and without anger attacks. METHODS: Forty-three parents who met criteria for major depressive disorder (MDD) completed the Achenbach Child Behavior Checklist - Parent Report Version (CBCL) for each of their birth children (n = 58, age range 6-17 years). Unpaired t tests were used to evaluate the CBCL scale score differences between children of parents with and children of parents without anger attacks. Baseline demographics and clinical differences between the two groups of parents were also evaluated. RESULTS: Parents with anger attacks had a significantly younger age of onset of MDD. Offspring of depressed parents with anger attacks were found to have significantly lower social and school competency scale scores and higher scores for delinquency, attention problems, and aggressive behavior. In addition, this group was found to have a significantly higher total T score (a global measure of psychopathology). CONCLUSIONS: There are some important differences between offspring of depressed parents with and without anger attacks. This finding may be important in identifying and formulating intervention strategies for childhood problems in the offspring of depressed parents.     

Neonatal outcome of infants born at 500 to 800 grams from 1990 through 1998 in a tertiary care center.

OBJECTIVE: To assess if there have been changes in survival, demographic data, obstetric features, neonatal morbidity, and short-term neurologic/radiographic/neurosensory outcome of 500- to 800-g infants born in a tertiary care neonatal center from 1990 through 1998. STUDY DESIGN: Records of all 500- to 800-g infants born at North Shore University Hospital during 1990-1998 were reviewed to determine demographic data, survival by weight and gestational age (GA), obstetric features, neonatal morbidity, and short-term neurologic/radiographic/neurosensory outcome. Newborn infants were grouped into three triennia: 1990-1992, 1993-1995, and 1996-1998 and compared across time. RESULTS: Of the 173 infants admitted to the neonatal intensive care unit, 112 survived. Improved survival was documented: 40% in 1990-1992, 73% in 1993-1995, and 81% in 1996-1998 (p < 0.0001). Improved survival was also noted in each of the three weight cohorts, as well as in infants < or =26 weeks GA. An increased use of antenatal corticosteroids and increased number of deliveries by cesarean section (C/S) were noted across time. The incidence of 0 to 3 Apgar scores at both 1 and 5 minutes decreased across time. Necrotizing enterocolitis in survivors and expected short-term neurologic/radiographic/neurosensory outcome improved between 1990-1992 and 1996-1998, with a trend toward reduced IVH grade III to IV. The incidence of other neonatal morbidities did not change throughout the time period. CONCLUSIONS: The data document that survival rates continued to improve for 500- to 800-g infants throughout the 1990s. This was concurrent with an increase in "low-risk, expected normal" infants, increased number of deliveries by C/S, decreased incidence of low Apgar scores at both 1 and 5 minutes, and an increased use of antenatal corticosteroids.     

Sputum cytokine levels in patients with pulmonary tuberculosis as early markers of mycobacterial clearance

Sputum and serum from patients with active pulmonary tuberculosis (TB), healthy purified protein derivative-positive adults, and patients with bacterial pneumonia were collected to simultaneously assess local immunity in the lungs and peripheral blood. To determine whether cytokine profiles in sputum from TB patients and control subjects were a reflection of its cellular composition, cytospin slides were prepared in parallel and assessed for the presence of relative proportions of epithelial cells, neutrophils, macrophages, and T cells. Gamma interferon (IFN-gamma) in sputum from TB patients was markedly elevated over levels for both control groups. With anti-TB therapy, IFN-gamma levels in sputum from TB patients decreased rapidly and by week 4 of treatment were comparable to those in sputum from controls. Further, IFN-gamma levels in sputum closely followed mycobacterial clearance. Although detected at fourfold-lower levels, IFN-gamma immunoreactivities in serum followed kinetics in sputum. TNF-alpha, interleukin 8 (IL-8) and IL-6 also were readily detected in sputum from TB patients at baseline and responded to anti-TB therapy. In contrast to IFN-gamma, however, TNF-alpha and IL-8 levels also were elevated in sputum from pneumonia controls. These data indicate that sputum cytokines correlate with disease activity during active TB of the lung and may serve as potential early markers for sputum conversion and response to anti-TB therapy.     

Characterization of the discriminative stimulus properties of centrally administered (-)-DOM and LSD

Despite the plausible assumption that the effects of hallucinogens predominantly arise in the central nervous system, most studies of these drugs in intact subjects have been conducted following systemic administration. The objective of the present investigation was to characterize the stimulus effects of (-)2,5-dimethoxy-4-methylamphetamine ((-)-DOM) following intracerebroventricular administration. Chronic indwelling cannulae were implanted into the lateral ventricle of male Fischer 344 rats trained to discriminate systemically administered (-)-DOM or lysergic acid diethylamide (LSD) from saline. Time-course and dose-response relationships for (-)-DOM and LSD administered intracerebroventricularly were established. For both LSD and (-)-DOM, central administration did not change the pretreatment times required for the maximal stimulus effects to occur. However, the onset of the stimulus effect was more rapid following intracerebroventricular administration. Following pretreatment periods that maximize drug-appropriate responding, central administration of (-)-DOM and LSD was approximately 2.4- and 1.5-times more potent, respectively, than systemic administration. The results of this study are consistent with the assumption that the stimulus effects of (-)-DOM and LSD are centrally mediated.     

Inhibition of mitochondrial Na+-Ca2+ exchanger increases mitochondrial metabolism and potentiates glucose-stimulated insulin secretion in rat pancreatic islets

The mitochondrial Na(+)-Ca(2+) exchanger (mNCE) mediates efflux of Ca(2+) from mitochondria in exchange for influx of Na(+). We show that inhibition of the mNCE enhances mitochondrial oxidative metabolism and increases glucose-stimulated insulin secretion in rat islets and INS-1 cells. The benzothiazepine CGP37157 inhibited mNCE activity in INS-1 cells (50% inhibition at IC(50) = 1.5 micro mol/l) and increased the glucose-induced rise in mitochondrial Ca(2+) ([Ca(2+)](m)) 2.1 times. Cellular ATP content was increased by 13% in INS-1 cells and by 49% in rat islets by CGP37157 (1 micro mol/l). Krebs cycle flux was also stimulated by CGP37157 when glucose was present. Insulin secretion was increased in a glucose-dependent manner by CGP37157 in both INS-1 cells and islets. In islets, CGP37157 increased insulin secretion dose dependently (half-maximal efficacy at EC(50) = 0.06 micro mol/l) at 8 mmol/l glucose and shifted the glucose dose response curve to the left. In perifused islets, mNCE inhibition had no effect on insulin secretion at 2.8 mmol/l glucose but increased insulin secretion by 46% at 11 mmol/l glucose. The effects of CGP37157 could not be attributed to interactions with the plasma membrane sodium calcium exchanger, L-type calcium channels, ATP-sensitive K(+) channels, or [Ca(2+)](m) uniporter. In hyperglycemic clamp studies of Wistar rats, CGP37157 increased plasma insulin and C-peptide levels only during the hyperglycemic phase of the study. These results illustrate the potential utility of agents that affect mitochondrial metabolism as novel insulin secretagogues.