An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [18F]-setoperone for 5-HT2 binding potential (BP) and [11C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [18F]-setoperone and with [11C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as >or=50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.     

Anger attacks in major depressive disorder and serum levels of homocysteine.

BACKGROUND: Increased levels of homocysteine have been associated with anger and depression separately. We investigated the association of anger attacks in major depressive disorder (MDD) with serum levels of homocysteine. METHODS: Homocysteine serum levels were measured in 192 outpatients with nonpsychotic MDD, mean age 39.9 +/- 10.7 (range 19-65), 53% women, at baseline of an open-trial antidepressant treatment. We used the Massachusetts General Hospital Anger Attacks Questionnaire to evaluate anger attacks, the Structured Clinical Interview for DSM-III-R Axis I Disorders-Patient Edition (SCID-I/P) to diagnose MDD and the 17-item Hamilton Rating Scale for Depression to measure depression severity. RESULTS: In the multiple regression analysis split by anger attacks adjusted for parameters of depression, creatinine, vitamin B(12), folate, age, smoking, and alcohol consumption, serum levels of homocysteine were positively correlated with length of current major depressive episode (t value, 3.01; 95% confidence interval [CI], .09 to .43; p = .004) and HAM-D-17 scores (t value, 2.48; 95% CI, .07 to 0.64; p = .016) in patients with anger attacks but not in those without anger attacks. CONCLUSIONS: Anger attacks in MDD may moderate the relationship of homocysteine serum levels with the severity and length of the depressive episode. Future studies are warranted to confirm and clarify the nature of this moderating effect.     

Antecedents, concomitants and consequences of anger attacks in depression

Anger attacks are episodes of intense anger with autonomic arousal, which occur in response to often trivial provocations. This study explores some of the antecedents, concomitants, and consequences of anger attacks in patients with depression. The sample comprised three groups: depression with anger attacks (n=20), depression without anger attacks (n=20) and normal controls (n=20). Subjects were administered the Mini International Neuropsychiatric Interview, the Anger Attack Questionnaire, Irritability, the Depression Anxiety Scale, the State-Trait Anger Expression Inventory, the Psychoticism Extraversion Neuroticism Inventory, the Hassles Scale, the World Health Organization Quality of Life-BREF Version and the Dysfunctional Analysis Questionnaire. Depressed patients with anger attacks exhibited more suicide-related phenomena and dysfunction scores in comparison to depressed patients without anger attacks. Depressed patients with anger attacks also had higher scores of anxiety, irritability, trait-anger, anger-out, anger expression, psychoticism, hassles, and poor quality of life in comparison to the other two groups. In conclusion, anger attacks adversely affect the lives of depressed patients and their family members and may serve as a qualifier for partially distinct syndrome of depression.     

PET findings in a brain abscess associated with a silent atrial septal defect

Brain abscesses are classical complications of congenital heart disease (CHD) in children and adolescents. This association is rarely observed in adults. We report a 46-year-old man presenting a fronto-parietal abscess associated with an asymptomatic atrial septal defect. Positron emission tomography (PET) study revealed high uptake of l-[methyl-¹¹C]methionine ([¹¹C]methionine) and 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) around the brain abscess. We suggest (1) to exclude a silent cardiac malformation in the presence of a cerebral abscess of unknown source occurring in adults; (2) to consider the diagnosis of brain abscess in cases of high uptake of [¹¹C]methionine and FDG in relation to a brain lesion.     

Anger attacks in bipolar depression: predictors and response to citalopram added to mood stabilizers

BACKGROUND: Of the 2 reports in the literature on anger attacks in bipolar depression, one found them to be uncommon (12%) compared with the rate in bipolar mixed states and unipolar depression (40%-60%), whereas the other found them to be common (62%). We examined anger attacks among participants in an 8-week trial of open-label citalopram added to mood stabilizer for the treatment of bipolar depression. We also examined trait anger, hypomanic symptoms, and depressive symptoms as predictors of anger attacks. We hypothesized that if anger attacks were related to hypomanic symptoms they would respond unfavorably to citalopram, whereas if they were related to trait anger or depressive symptoms they would respond favorably. METHOD: In 45 participants with a DSM-IV diagnosis of bipolar I or II depression, anger attacks, hypomanic symptoms, and depressive symptoms were assessed using a modified Anger Attacks Questionnaire, Young Mania Rating Scale, and Hamilton Rating Scale for Depression, respectively. Trait anger was measured using the State-Trait Anger Inventory. Posttreatment data were collected at the end of 8 weeks of treatment with citalopram or at dropout from the trial. The first participant study visit was in November 1998, and the final participant study visit was in December 2000. RESULTS: Before treatment with citalopram, 17 (38.6%) of 44 participants reported anger attacks (data on anger attacks were missing for 1 participant before treatment and 4 after treatment). Significantly fewer participants reported anger attacks after treatment (6 of 41, 14.6%; McNemar test, p <.05, 2-tailed). At pretreatment and post-treatment, trait anger was the only significant predictor of anger attacks (p <.05). CONCLUSIONS: These findings suggest that in bipolar depression anger attacks are common, may respond favorably to acute treatment with citalopram added to mood stabilizer, and are better predicted by trait anger than hypomanic or depressive symptoms. Further studies are needed to clarify the diagnostic and treatment implications of anger attacks in bipolar depression.     

The potential relationship between levels of perceived stress and subtypes of major depressive disorder (MDD)

OBJECTIVE: We wanted to explore whether major depressive disorder (MDD) subtypes (melancholic depression, atypical depression, double depression, and MDD with anger attacks) were related to levels of perceived stress, as measured by the Perceived Stress Scale (PSS). METHOD: Our sample [n = 298; female = 163 (55%); mean age 40.1 +/- 10.5 years] consisted of out-patients with MDD. The Structured Clinical Interview for DSM-III-R, the 17-item Hamilton Rating Scale for Depression, the Anger Attack Questionnaire, and the PSS were administered prior to initiating treatment. RESULTS: Depressed women had significantly higher levels of perceived stress (P = 0.02) than depressed men. Greater severity of depression at baseline was significantly related to higher levels of perceived stress (P < 0.0001). After adjusting for age, gender, and severity of depression at baseline, higher levels of perceived stress were significantly related to the presence of anger attacks (P < 0.0001; t = -4.103) as well as to atypical depression (P = 0.0013; t = 3.26). CONCLUSION: Out-patients with MDD who are more irritable and/or present with atypical features have higher levels of perceived stress, indicating a potential reactive component to their depression.     

Dopamine D2 receptor binding in drug-naïve patients with schizophrenia examined with raclopride-C11 and positron emission tomography

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D₂-like dopamine binding using the radioligand [¹¹C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D₂ binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D₂ BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D₂ BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D₂ BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D₂ BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [¹¹C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.     

Anger Attacks in Depressed Turkish Outpatients

Anger attacks have been described as sudden spells of anger accompanied by symptoms of autonomic activation and have been experienced by patients as uncharacteristic of them and inappropriate to the situations in which they had occurred. The aim of this study was to assess the prevalence of anger attacks in a non-Western depressed population. We also wanted to see whether depression in patients with anger attacks was qualitatively different from depression without anger attacks. The Anger Attacks Questionnaire, designed by Fava et al. to assess these attacks, was administered to 88 medication-free consecutive outpatients diagnosed as major depression according to DSM-IV criteria by two psychiatrists. The patients also were assessed by the Beck Depression Inventory, the Beck Anxiety Inventory, the Beck Hopelessness Scale, and the Spielberger's State-Trait Anger Expression Inventory. Forty-three (49%) of these patients had reported having anger attacks. The patients with anger attacks were significantly more depressed and anxious than patients without anger attacks. Anger-out and trait anger measures were significantly higher in depressed patients with anger attacks than patients without anger attacks. Patients with anger attacks also scored higher in hopelessness measure and there was a trend toward statistical significance. Our results are in line with previous literature which show, that anger attacks are prevalent in depressed patients. We also conclude that patients with anger attacks constitute a more depressed population than those without anger attacks. Severity of depression emerges as the strongest predictor of the presence of anger attacks in our study.     

Prevalence of anger attacks in depressive and anxiety disorders: Implications for their construct?

Aims: The present study explores anger attacks in depressive and anxiety disorders for their prevalence and some of the clinical and psychosocial correlates. Methods: The sample comprised of patients with ICD‐10‐diagnosed depressive and anxiety disorders (n = 328). All the subjects were given a demographic and clinical profile sheet, the Irritability Depression Anxiety Scale, World Health Organization Quality of Life – BREF Version and the Anger Attack Questionnaire. Using the Anger Attack Questionnaire they were divided into two groups – with anger attacks (n = 170) and without anger attacks (n = 158) – in order to study the differential profile of the two groups. Results: Anger attacks were associated with more anxiety and irritability, and poorer quality of life. Frequency of anger attacks had a positive correlation with depression, irritability and aggression, and a negative correlation with education, income, and quality of life. Panic attacks, somatic anxiety and psychological domain of quality of life predicted the categorization of subjects into those with and without anger attacks. Conclusion: Anger attacks are common among depressive and anxiety disorder cases and have a negative impact on quality of life. Status of anger attacks as either linked to anxiety and/or depression, or as an independent syndrome needs further study.     

An open study of triiodothyronine augmentation of selective serotonin reuptake inhibitors in treatment-resistant major depressive disorder

OBJECTIVE: In an open trial, we investigated the efficacy of triiodothyronine (T(3)) adjuvant to selective serotonin reuptake inhibitors (SSRIs) in subjects with major depressive disorder (MDD) resistant to SSRI treatment. METHOD: Twenty subjects who met DSM-IV criteria for MDD (mean +/- SD age = 44.3 +/- 10.3 years; 55% [N = 11] women) and had failed to respond to a course of treatment of at least 8 weeks with an SSRI antidepressant were enrolled in a 4-week open-label augmentation treatment with T(3) 50 microg/day. Atypical and melancholic sub-types of MDD were diagnosed using Structured Clinical Interview for DSM-IV Axis I Disorders criteria. We administered the 17-item Hamilton Rating Scale for Depression (HAM-D-17) 4 times during the study (which was conducted between 2001 and 2003). RESULTS: During T(3) augmentation, the severity of depression decreased from an initial mean +/- SD HAM-D-17 score of 20.5 +/- 3.6 to a final HAM-D-17 score of 14.0 +/- 7.1 (p < .001). Seven subjects (35.0%) were treatment responders (HAM-D-17 reduction >or= 50%), and 6 subjects (30.0%) achieved clinical remission (final HAM-D-17 相似文献   

Evidence for defective incorporation of proteins in myelin of the quaking mutant mouse

The defect in myelinogenesis present in the Quaking mutant mouse was investigated using a double radioisotope technique for comparing the incorporation of amino acid into myelin proteins of normal and mutant mice. Quaking mice and littermate controls recieved intracranial injections of 150 μCi [³H]glycine and 25 μCi of [¹⁴C]glycine respectively. After 2 h their brains were combined and jointly processed to obtain subcellular fractions. The ³H/¹⁴C ratio for the myelin subfraction was 1.88 as compared to a ³H/¹⁴C ratio of 3.0 for the other subfractions, indicating a 40% decrease in glycine incorporation into myelin of Quaking mice. Myelin proteins were separated by discontinuous gel electrophoresis in the presence of sodium dodecyl sulfate (SDS) and the ³H/¹⁴C ratios determined in each gel slice. In contrast to the microsomal subfractions which gave a ³H/¹⁴C ratio of 2.6 across the gel, the ³H/¹⁴C ratio of myelin showed large variations with values ranging from 0.54 for proteolipid protein to 2.0 for some of the high molecular weight proteins. During development, the Quaking mutant exhibited a preferential depression in glycine incorporation into proteolipid protein in 18-day-old mice, while in older animals (32–54 days) the fast migrating basic protein, as well as the proteolipid protein, was labeled to a significantly lesser extent.     

Amino acid transport in cerebral microvessels during plasmodium yoelii infection in mice

Plasmodium yoelii infected cerebral microvessels of mice had an enhanced time-dependent, temperature-sensitive, and saturable uptake of [¹⁴C]-amino acid. viz. leucine, valine and glycine. Metabolic inhibitors caused a noticeable inhibition of amino acid uptake in normal microvessels as compared to infected cerebral microvessels indicating that the uptake of [¹⁴C]-L-leucine, [¹⁴C]-L-valine and [¹⁴C]-glycine is an energy dependent process.     

Imaging of [C]-labelled RO 15-1788 binding to benzodiazepine receptors in the human brain by positron emission tomography

The benzodiazepine antagonist Ro 15-1788 was labelled with [¹¹C] and examined for possible use as ligand for PET scan studies on benzodiazepine receptors in the brain of cynomolgus monkeys and human subjects. [¹¹C] Ro 15-1788 allowed the in vivo visualization of benzodiazepine receptor binding in cerebral and cerebellar cortical areas as well as in basal brain nuclei in PET scan images. [¹¹C] Ro 15-1788 exhibited a high ratio of specific benzodiazepine receptor binding (cerebral cortex) to non-specific binding (pons) and the kinetics of binding should be satisfactory for quantitative clinical PET scan studies using [¹¹C]. The in vivo binding of [¹¹C] Ro 15-1788 in the cerebral cortex of cynomolgus monkeys and healthy human subjects was reduced by approximately 90% within 10 min after the intravenous injection of a high dose of unlabelled Ro 15-1788 (0.5 mg/kg i.v.). Different areas of the healthy human brain showed an approximately 10-fold variation in maximal [¹¹C] Ro 15-1788 binding that corresponded to the previously known distribution of benzodiazepine receptors in these regions. The highest degree of binding was obtained in the medial occipital cerebral cortex followed by frontal cortex, cerebellum, thalamus, striatum and pons. Two psychiatric patients with anxiety syndromes who had been treated for a long time with high doses of benzodiazepines had roughly the same degree of maximal [¹¹C] Ro 15-1788 binding in brain regions as the healthy subjects but the rate of decline of [¹¹C] Ro 15-1788 in the brain was higher. This indicates that there is measurable competition between [¹¹C] Ro 15-1788 binding and clinical benzodiazepine concentrations in the body fluids of psychiatric patients. The results demonstrate that [¹¹C] Ro 15-1788 should be a valuable tool for quantitative analyses of benzodiazepine receptor characteristics and receptor occupancy in the brain of patients with neuropsychiatric disorders.     

Fenfluramine challenge in unipolar depression with and without anger attacks

We have previously hypothesized that patients with major depression and anger attacks may have a greater central serotonergic dysregulation than depressed patients without such attacks. We wanted to compare the prolactin response to fenfluramine challenge, as an indirect measure of central serotonergic function, in depressed patients with and without anger attacks. We recruited 37 outpatients (22 men and 15 women; mean age: 39.5+/-10.5) with DSM-III-R major depressive disorder, diagnosed with the SCID-P. Their initial 17-item Hamilton Rating Scale for Depression score was >/=16. Patients were classified as either having or not having anger attacks with the Anger Attacks Questionnaire. All patients received a single-blind placebo challenge followed by a fenfluramine challenge (60 mg orally) the next day. Plasma prolactin measurements were obtained with double antibody radioimmunoassay before and after both placebo and fenfluramine challenges, and fenfluramine and norfenfluramine blood levels after each challenge were determined by gas chromatography. Of the 37 study participants, 17 (46%) were classified as having anger attacks. There were no significant differences in age, gender, fenfluramine, or norfenfluramine blood levels between depressed patients with and without anger attacks. Depressed patients with anger attacks showed a significantly blunted prolactin response to fenfluramine challenge compared to patients without anger attacks. As previous studies have shown blunted prolactin responses to fenfluramine in impulsive aggression among patients with personality disorders, our results support our hypothesis that depressed patients with anger attacks may have a relatively greater serotonergic dysregulation than depressed patients without these attacks.     

Functional neuroanatomical correlates of eye movements during rapid eye movement sleep in depressed patients

In depressed patients, REM density, or the number of rapid eye movements (REMs) per minute of REM sleep, is a correlate of depression severity and clinical outcomes. We investigated the functional neuroanatomical correlates of average REM counts (RC), an automated analog of REM density, in depression. Thirteen medication-free depressed patients underwent all night polysomnography and positron emission tomography (PET) scans using [¹⁸F]fluoro-2-deoxy- -glucose ([¹⁸F] FDG) during REM sleep. Regression analyses were conducted with Statistical Parametric Mapping (SPM-99). Average RC significantly and positively correlated with relative regional cerebral metabolic rate of glucose (rCMRglc) bilaterally in the striate cortex, the posterior parietal cortices, and in the medial and ventrolateral prefrontal cortices. Average RC were negatively correlated with rCMRglc in areas corresponding bilaterally to the lateral occipital cortex, cuneus, temporal cortices, and parahippocampal gyri. The areas where average RC was positively correlated with rCMRglc appear to constitute a diffuse cortical system involved in the regulation of emotion-induced arousal. The observed pattern of correlations suggests that average RC may be a marker of hypofrontality during REM sleep in depressed patients.     

Vascular lipoxygenase activity: synthesis of 15-hydroxyeicosatetraenoic acid from arachidonic acid by blood vessels and cultured vascular endothelial cells

Although indirect pharmacologic evidence has suggested the presence of a lipoxygenase pathway of arachidonic acid (AA) metabolism in blood vessels, direct biochemical evidence has been difficult to demonstrate. We have investigated lipoxygenase metabolism in both fresh vessel preparations and cultured vascular cells from various sources and species. Lipoxygenase-derived [³H]HETE (composed of 12-HETE, 15-HETE and 5-HETE), which was abolished by ETYA but not by aspirin, was formed when [³H]AA was incubated with fresh sections of rat aorta. Lipoxygenase activity was lost following deendothelialization. A single peak of [³H]15-HETE was produced by cultured bovine aortic and human umbilical vein endothelial cells (EC) in response to exogenous [³H]AA or from [³H]AA released by ionophore A23187 from endogenous EC membrane phospholipid pools. Cultured bovine, rabbit or rat aorta smooth muscle cells had no detectable 15-lipoxygenase activity. ¹⁴C]Linoleic acid was converted by EC to its 15-lipoxygenase metabolite, [¹⁴C]13-hydroxyoctadecadienoic acid. These results indicate that blood vessels from different sources and species have a 15-lipoxygenase system, and this activity resides predominantly in the endothelial cells.     

Dopamine metabolism in characterised neurones ofPlanorbis corneus

A sensitive chromatographic procedure was used to study the metabolism of [¹⁴C]tyrosine, [³H]DOPA and [³H]dopamine in 3 defined cell-types situated in the nervous system ofPlanorbis corneus. One of the cell-types contains dopamine (GDC), the other serotonin (GSC) and the other neither amine (GC). The GDCs metabolise [¹⁴C]tyrosine to form DOPA and dopamine while the other two cells lack this ability. In contrast, the GDCs and the GSC, but not the GCs, metabolise [³H]DOPA to form dopamine. In addition the GDCs incorporate radioactivity from [³H]DOPA into DOPAC, homovanillic acid and methoxytyramine. After incubation of cells in [³H]dopamine, only the GDCs metabolise it to form DOPAC, homovanillic acid and methoxytyramine. In no instance did the GDCs form significant amounts of noradrenaline from the incorporated radioactive substances.

These results, together with data on the amine histochemistry of the individual cell-types following pretreatment of animals with drugs known to affect specific enzymes in the synthesis of amine transmitter substances, clearly demonstrate that the GDCs alone have the enzymes requisite for the biosynthesis and catabolism of dopamine, but not noradrenaline.     

Transport, uptake, and metabolism of blood-borne vasopressin by the blood-brain barrier

Transport, binding, and metabolism of [phenylalanyl-3,4,5-³H(N)]arginine vasopressin (AVP) by the blood-brain barrier (BBB) was studied in adult guinea-pigs by means of a novel vascular brain perfusion (VBP)/capillary depletion technique and HPLC. A time-dependent, progressive brain uptake of ³H-radioactivity was measured over the 10 min period of VBP both in brain homogenates and in brain tissue depleted of cerebral microvessels. The unidirectional blood-to-brain transport constant, K_IN, estimated by multiple-time tissue uptake analysis of the homogenate and postcapillary supernatant, indicated that the BBB transfer rat ffor [³H]AVP (K_IN = 2.37±0.25 μl min⁻¹ per gram brain homogenate) was almost 10 times higher than for simultaneously perfused [¹⁴C]sucrose, a cerebrosvascular space marker. In contrast to homogenate and postcapillary supernatant, the [³H]radioactivity determined in the vascular pellet after dextran density centrifugation of the brain homogenate was very low and only somewhat higher than for [¹⁴C]sucrose. HPLC analysis of the perfused brain tissue revealed time-dependent degradation of the blood-borne neuropeptide. The percentage of intact [³H]AVP as determined in the postcapillary supernatant progressively declined during brain perfusion, from 49% at 1 min to 11.9% at 10 min. The major detectable labeled metabolite was [³H]phenylalanine, the labeled amino acid residue of [³H]AVP. The aminopeptidase inhibitor bestatin (0.5 mM), perfused simultaneously with [³H]AVP by the VBP technique, did not alter tissue uptake of [³H]AVP, indicating that there was no significant hydrolysis of peptide by the luminal BBB surface. The results suggest that rapid in vivo metabolism of AVP occurs after BBB transport in the brain parenchyma with no evidence of significant capillary sequestration, or degradation of AVP by the BBB.     

Gepirone extended-release treatment of anxious depression: evidence from a retrospective subgroup analysis in patients with major depressive disorder

OBJECTIVE: To evaluate the efficacy and tolerability of gepirone extended-release (ER) tablets in patients with major depressive disorder (MDD) and high ratings of anxiety (anxious depression). METHOD: This subgroup analysis was derived from an 8-week, double-blind, placebo-controlled study of gepirone ER in patients with MDD. Male and female patients 18 to 69 years of age who met DSM-IV criteria for MDD and had high ratings of anxiety (Hamilton Rating Scale for Depression [HAM-D-17] total score > or = 20 and HAM-D-17 factor I [anxiety/somatization] score > 6) were included in this subgroup analysis. Eligible patients with anxious depression were randomly assigned to receive either placebo or gepirone ER, 20 mg to 80 mg daily. Patient assessments were performed at weeks 1, 2, 3, 4, 6, and 8. Treatment efficacy was evaluated by mean HAM-D-17 total scores and mean changes from baseline in (1) HAM-D-17 total scores, (2) HAM-D-17 factor I (anxiety/somatization) scores, and (3) HAM-D-17 item 12 (anxiety, psychic) scores. All statistical tests were 2-sided and considered statistically significant if the p value was <.05. Between-group comparisons were analyzed using least-squares analysis of variance on the change from baseline at each visit with the last observation carried forward (LOCF). The Cochran-Mantel-Haenszel test adjusting for center was also performed on the percentage of patients in each treatment group at each visit (LOCF) who met the response criterion on the HAM-D-17 (> or = 50% decrease from baseline) or remission criterion (HAM-D-17 total score < or = 7). RESULTS: Gepirone ER-treated patients (N = 58) experienced a statistically significant (p <.05) reduction in mean HAM-D-17 total score at week 3, 6, and 8 compared with placebo-treated patients (N = 75). A statistically significant effect (p <.05) in favor of gepirone ER was observed in mean change from baseline in HAM-D-17 total scores and for HAM-D factor I (anxiety/somatization) scores from week 2 onward. A statistically significant (p < or =.01) effect in favor of gepirone ER was observed in HAM-D-17 item 12 (anxiety, psychic) scores throughout the 8-week trial. There were significantly more patients in the gepirone ER group compared with the placebo group who were HAM-D-17 responders (p <.05) at endpoint and who met the criteria for HAM-D-17 remission at week 3 (p <.05) and weeks 6 and 8 (p <.01). Overall, gepirone ER was well tolerated, with rates of weight gain and sexual dysfunction comparable to placebo. Adverse events were generally mild to moderate. The most commonly reported adverse events were dizziness and nausea. CONCLUSIONS: Gepirone ER is an effective and well-tolerated treatment for patients with anxious depression.     

A radioisotopic method for the simultaneous quantitation of regional cerebral blood flow and glucose utilization in small dissected samples: Validation studies and values in the nitrous oxide-anesthetized rat

A method is described for the simultaneous determination of the rates of regional cerebral blood flow (rCBF) and regional cerebral glucose utilization (rCMRgl) in 6–7 mg brain samples dissected from multiple areas of interest. The method utilizes [¹³¹I]-iodoantipyrine ([¹³¹l]IAP) to measure rCBF by indicator fractionation, and [¹⁴C]2-deoxyglucose to measure rCMRgl. [¹³¹I]IAP was synthesized with specific activity exceeding 350 Ci/mmol and radiochemical purity greater than 99.5% by the radioiodination of antipyrine with Na¹³¹I. A triple-counting strategy was developed to quantitate¹⁴C activity of the dissected brain samples in the presence of¹³¹I. The factors contributing to the propagated error of the double-label separation strategy were defined and optimal assay parameters were determined. The separation strategy was validated by measuring rCBF simultaneously with both [¹³¹I]IAP (x) and [¹⁴C]IAP (y) in a series of rats. The equation of the regression line was y = 1.025 x −0.065 (correlation coefficient 0.985), denoting excellent agreement. In another series of 5 normocapnic rats anesthetized with nitrous oxide, rCBF and rCMRgl were measured simultaneously. In individual animals, the rates of rCBF within 14–16 brain areas were closely coupled to their respective rates of glucose metabolism. For the group data, the linear regression equation relating rCBF (y) to rCMRgl (x) was y = 1.76 x + 0.13 (correlation coefficient 0.93,P < 0.001). These studies provide direct evidence, based upon data obtained in the same brain, of a close coupling of regional metabolic rate and blood flow.