Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty.

Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories.

Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.

Analysis of the rhodopsin cycle in limulus ventral photoreceptors using the early receptor potential.

The early receptor potential (ERP) was recorded intracellularly from Limulus ventral photoreceptors. The ERP in cells dissected under red light was altered by exhaustive illumination. No recovery to the original wafeform was observed, even after 1 h in the dark. The ERP waveform could be further altered by chromatic adaptation or by changes in pH. The results indicate that at pH 7.8 there are two interconvertible pigment states with only slightly different lambdamax, whereas at pH 9.6 there are two interconvertible states with very different lambdamax. Under all conditions studied the ERPs were almost identical with those previously obtained in squid retinas. This strongly suggests that light converts Limulus rhodopsin to a stable photoequilibrium mixture of rhodopsin to a stable photoequilibrium mixture of rhodopsin and metarhodopsin and that, as in squid, the lambdamax of metarhodopsin depends on pH. This conversion at pH 7.8 is associated with a small (0.7 log unit) decrease in the maximum sensitivity of the late receptor potential. Thus the component of adaptation linked to changes in rhodopsin concentration is unimportant in comparison to the "neural" component.

Properties of the pH-sensitive site that controls the lambda max of Limulus metarhodopsin.

A pH-sensitive site controls the lambda max of Limulus metarhodopsin. The properties of this site were examined using intracellular recordings of the early receptor potential (ERP) as a pigment assay. ERPs recorded over a range of extracellular pHs indicate that the apparent pK of the site is in the range of 8.3-8.6. Several lines of evidence indicate that the site responds directly to changes in extracellular pH (pHo) rather than to changes in intracellular pH(pHi) that follow as a secondary result of changing pHo : (a) the effect of changing pHo was rapid (less than 60 s); (b) when pHo was raised, the simultaneous rise in pHi, as measured with phenol red, was relatively small; (c) raising pHi by intracellular injection of pH 10 glycine buffer did not affect the site; and (d) the effect of changing pH0 could not be blocked by increasing the intracellular pH buffering capacity. It is concluded that the pH-sensitive site on metarhodopsin is on the extracellular surface of the plasma membrane.

Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet.

BACKGROUND: To examine the relationship between binding parameters of the platelet central serotonergic (5-HT) transporter and measures of aggression and impulsivity in adult human subjects. METHODS: Maximal number of platelet tritiated paroxetine binding sites (Bmax) and dissociation constant (Kd) values were measured in patients with personality disorder (n = 24) and healthy volunteers (n = 12). Measures of aggression and impulsivity included the total score and aggression subscale of the Life History of Aggression, the Motor Aggression factor and the assault subscale of the Buss-Durkee Hostility Inventory, and the total score and motor impulsivity subscale of the Barratt Impulsiveness Scale. RESULTS: The Bmax, but not Kd, values of platelet tritiated paroxetine binding was inversely correlated with the Life History of Aggression total score and aggression score and with the Buss-Durkee Hostility Inventory assault score in patients with personality disorder but not in healthy volunteer subjects. This relationship was independent of influences of factors related to depression, global function, or history of alcoholism or drug abuse. CONCLUSIONS: Reduced numbers of platelet 5-HT transporter sites may covary with life history of aggressive behavior in patients with personality disorder. This may represent another abnormality in 5-HT function in individuals with personality disorder and aggressive behavior.

3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity.

Increasing evidence has accumulated for structural brain changes associated with unipolar recurrent major depression. Studies of neuroanatomic structure in early-onset recurrent depression have only recently found evidence for depression-associated structural change. Studies using high-resolution three-dimensional magnetic resonance imaging (MRI) are now available to examine smaller brain structures with precision. Brain changes associated with early-onset major depression have been reported in the hippocampus, amygdala, caudate nucleus, putamen, and frontal cortex, structures that are extensively interconnected. They comprise a neuroanatomic circuit that has been termed the limbic-cortical-striatal-pallidal-thalamic tract. Of these structures, volume loss in the hippocampus is the only consistently observed change to persist past the resolution of the depression. Possible mechanisms for tissue loss include neuronal loss through exposure to repeated episodes of hypercortisolemia; glial cell loss, resulting in increased vulnerability to glutamate neurotoxicity; stress-induced reduction in neurotrophic factors; and stress-induced reduction in neurogenesis. Many depressed patients, particularly those with late-onset depression, have comorbid physical illnesses producing a high rate of hyperintensities in deep white matter and subcortical gray matter and brain damage to key structures involved in the modulation of emotion. Combining MRI studies with functional studies has the potential to localize abnormalities in blood flow, metabolism, and neurotransmitter receptors and provide a better integrated model of depression.

Platelet serotonin markers and depressive symptomatology.

Dysfunction of brain serotonergic symptoms may be a factor in the mood and behavioral disturbances associated with depression. Platelet serotonin measures represent indirect but easily obtainable indices of brain serotonin function. To examine the specificity of relationships between cognitive and vegetative symptom groupings and platelet serotonin measures, we assessed 35 depressed outpatients using the Hamilton Rating Scale for Depression and collected platelets after a minimum 3-week drug-free period. Platelets were also collected from 14 controls. The results showed that depressed patients had lower platelet serotonin (5-HT) uptake site density values than controls and that 5-HT uptake site density values were inversely correlated with the severity of cognitive symptoms of depression. Platelet 5-HT2 receptor density values were higher in depressed patients than controls, and there was a trend toward a direct correlation between the cognitive symptoms of depression and 5-HT2 receptor density values. Neither platelet measure showed any relationship with the severity of the vegetative symptoms of depression.

Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.

BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces. METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.

Memory improvement following induced hyperinsulinemia in Alzheimer's disease.

Dementia of the Alzheimer type (DAT) is accompanied by disruption in glucose regulation and utilization that may contribute to its characteristic memory impairment. Increasing glucose availability by raising plasma glucose improves memory in patients with DAT. Such memory improvement is associated with a secondary elevation in plasma insulin levels, raising the question of whether improvement is due to changes in insulin levels, independent of hyperglycemia. Distributions of insulin receptors in the hippocampus and insulin-mediated increases in glucose utilization in entorhinal cortex provide potential mechanisms for such improvement. We show that raising plasma insulin through intravenous infusion while keeping plasma glucose at a fasting baseline level produces striking memory enhancement for patients with DAT. Previous findings of hyperglycemic memory enhancement were also replicated. Patients with DAT also showed abnormal plasma levels of glucoregulatory hormones and metabolites at baseline and during metabolic manipulations. Our findings suggest that neuroendocrine factors play an important role in the pathophysiology of DAT.

Absence of striatal volume differences between depressed subjects with no comorbid medical illness and matched comparison subjects.

OBJECTIVE: The striatum (caudate and putamen) appears to be important in the pathogenesis of depression. Some studies show smaller than normal striatal structure volumes in depressed subjects. This study compared striatal volumes in depressed and nondepressed women, screened to exclude major cerebrovascular disease risk factors and comorbid medical illness. METHOD: Caudate and putamen volumes were measured from magnetic resonance imaging scans of 24 depressed women and 24 matched nondepressed comparison subjects. RESULTS: Caudate and putamen volumes were not significantly different between depressed and nondepressed groups. CONCLUSIONS: These findings differ from those of previous studies, possibly because of the exclusion of subjects with cerebrovascular risk factors in this study.

White matter hyperintensities and gray matter lesions in physically healthy depressed subjects.

OBJECTIVE: Previous studies reported that depressed subjects had more white matter hyperintensities on magnetic resonance imaging scans than control subjects, but the subjects had cerebrovascular disease risk factors. This study used subjects with a history of recurrent major depression and matched comparison subjects, screened to exclude cerebrovascular disease risk factors, to determine whether depressed subjects had more white matter hyperintensities and other lesions. METHOD: A semiautomated volumetric computer program was used to compare numbers and volumes of white matter hyperintensities, basal ganglia lesions, and total lesions in 24 women with a history of recurrent major depression and 24 comparison subjects case-matched on age and education and group-matched on height. In addition, images were measured with the use of a validated categorical scale. All subjects were screened to exclude cerebrovascular disease risk factors. RESULTS: There were no significant differences in the total volumes or total numbers of lesions. However, multiple linear regression showed a significant correlation of age and depression with number of lesions; this was accounted for by a greater number of small lesions (diameter < or = 0.4 cm). CONCLUSIONS: These findings suggest that cerebrovascular disease risk factors most likely mediated the relationship between depression and white matter hyperintensities seen in previous studies. However, the independent effect of depression, as well as an age-by-depression interaction, for small lesions suggests a causal role of depression in certain types of white matter pathology irrespective of other cerebrovascular disease risk factors. The volumetric method used in this study may be more sensitive than other methods in determining lesion characteristics and correlations with clinical variables.

CSF excitatory amino acids and severity of illness in Alzheimer's disease.

Researchers have proposed that increased release of excitatory amino acids (EAAs) is involved in the pathogenesis of dementia of the Alzheimer type (DAT), and CSF EAA concentrations have been measured to obtain evidence in support of this hypothesis. However, previous comparisons of CSF EAA concentrations in patients with DAT and in controls have yielded inconsistent results, perhaps because patient samples have been heterogeneous as to dementia severity. To determine whether there are changes in CSF concentrations of EAAs related to severity of illness in patients with DAT, we measured CSF concentrations of glutamate, aspartate, and taurine in 32 subjects with DAT, in whom we also assessed the severity of illness using clinical and neuropsychological measures, and 11 age-matched controls. The results suggested that increased CSF aspartate and glutamate concentrations, as well as decreased taurine concentrations, may occur in some persons with more advanced symptoms of DAT.

Impulsive aggression in personality disorder correlates with platelet 5-HT2A receptor binding.

The purpose of this study was to examine the relationship between platelet 5-HT2A receptor binding and aggressive behavior. 125I-LSD Bmax and Kd values were measured for 22 subjects meeting DMS-III-R criteria for one or more personality disorders and 12 healthy volunteer subjects. Aggression and impulsivity were assessed using the Buss-Durkee Hostility Inventory (BDHI) Assault scale, Life History of Aggression (LHA) scale, and the Barratt-11 Impulsiveness scale (BIS-11). Bmax and Kd values did not differ between personality disordered subjects and healthy volunteers. However, both Bmax and Kd values correlated positively with BDHI Assault scores in personality-disordered subjects but not in healthy volunteer subjects. These results suggest that assaultiveness in personality-disordered subjects may covary with increasing numbers, but decreasing affinity, of platelet 5-HT2A receptor sites labeled by 125I-LSD.

Platelet binding characteristics distinguish placebo responders from nonresponders in depression.

To determine whether there are characteristics distinguishing placebo responders from nonresponders, we studied 37 outpatients meeting DSM-III-R criteria for depression who were enrolled in controlled drug trials and 14 control subjects. Clinical data and blood samples were collected on admission and after a 7- to 10-day placebo washout. All patients experiencing a 40% drop in the Hamilton Rating Scale for Depression (HRSD) at the time of the second evaluation were considered placebo responders. There were no statistically significant differences between the two groups in clinical variables. Platelet markers distinguished the groups: Most notably, placebo nonresponders had the lowest 5-HT uptake site density values, placebo responders had intermediate values, and normal controls had the highest values. Placebo responders and placebo nonresponders had higher 5-HT uptake affinity values. No significant differences were observed among the groups in platelet 5-HT2 receptor site density or affinity values. These results suggest that platelet serotonin characteristics, but not common clinical characteristics, may distinguish depressed patients who do and do not respond to placebo.

How safe are serotonin reuptake inhibitors for depression in patients with coronary heart disease?

Depression occurs frequently in patients with coronary heart disease (CHD), and confers significant risk for additional morbidity and mortality. The cardiac effects of the tricyclic antidepressants (TCAs) have been well characterized. In contrast, the cardiac effects of the selective serotonin reuptake inhibitors (SSRIs) have been less thoroughly investigated. The Medline database from 1986 to 1996 was searched for all reports of cardiac effects of SSRIs, and this literature is summarized. In addition, potential drug interactions, reports of side effects, and efficacy studies in the elderly are reviewed. Finally, recommendations are made considering the risk/benefit ratio.

Amygdala core nuclei volumes are decreased in recurrent major depression.

The amygdala is a key structure in the brain's integration of emotional meaning with perception and experience. Patients with depression have impaired functioning in emotional tasks involving the amygdala, and have abnormal resting amygdala blood flow. To better understand the anatomical basis for these functional changes we measured the volumes of the total amygdala and of the core amygdala nuclei in 20 patients with a history of depression and 20 pair-wise matched controls. Depressed subjects had bilaterally reduced amygdala core nuclei volumes and no significant differences in total amygdala volumes or in whole brain volumes. Since patients with a depression history have bilateral hippocampal volume reduction the volume loss in this closely related structure suggests a shared effect on both structures, potentially glucocorticoid-induced neurotoxicity mediated by the extensive reciprocal glutamatergic connections.

Personality disorder scores improve with effective pharmacotherapy of depression.

INTRODUCTION: We hypothesized that the probability of personality disorder ('PROB') predicted by the Temperament and Character Inventory ('TCI') would decline after successful pharmacotherapy of depression. METHODS: We administered a computerized version of the TCI to 15 patients with DSM-III-R major depression, before and after treatment with serotonergic antidepressants. RESULTS: PROB declined from 58.9% +/- 18.0% to 42.4% +/- 22.8% (P < 0.003), due to a significant increase in the Self-Directedness scale. This change in PROB correlated with improvement in self-rated severity of depression (P < 0.02). CONCLUSION: TCI prediction of personality disorder is susceptible to state effects of depression.

High prevalence of physical illness in a geriatric psychiatric inpatient population.

The prevalence of physical illness was determined in a population of geriatric patients on a unit of psychiatric inpatients. Ninety-two percent of the 95 patients were found to have one or more significant medical problems. The average number of medical conditions was 1.9. The disorders were classified according to affected organ system.

Cost and utility of routine admission laboratory testing for psychiatric inpatients.

We retrospectively evaluated the cost and utility of routine laboratory testing for psychiatric patients admitted to an acute inpatient hospital. Medical records were reviewed for 252 patients accounting for 305 sequential admissions over a recent 3-month period. Of the patient population, 49.6% had one or more coexisting medical illnesses. Overall, 6% of the abnormal laboratory findings resulted in changes in medical management: 49.2% of complete blood counts were abnormal, and 11.6% led to changes in medical management. Of the 20-factor blood chemistry analyses, 86.2% were abnormal, and 4.7% led to changes in medical management. Of the urinalyses, 85.3% were abnormal, and 2.2% led to changes in medical management. Of 277 screening syphilis titers, 5 were positive but only 1 was a potential new finding. The average cost to the facility for laboratory testing was $65 per patient admission, and the average cost per change in medical management resulting from the laboratory studies was $1070.

Platelet paroxetine binding in major depressive disorder with and without comorbid obsessive-compulsive disorder.

Platelet 3H-paroxetine binding measures were compared in three age-matched groups each containing 11 individuals: a group with DSM-III-R major depressive disorder (MDD) and comorbid obsessive-compulsive disorder (OCD), a group with DSM-III-R MDD alone, and a psychiatrically screened normal comparison group. No differences were found between groups in Bmax values. The patients with MDD only were found to have significantly higher Kd values than either the group with comorbid OCD or the normal subjects. No significant correlations were found between binding measures and either depressive or OCD symptoms. Our data suggest that inconsistencies remain in the literature on 3H-imipramine binding in OCD and that a variety of confounding factors may explain them. Duration of illness, for example, may be one such factor as decreases in uptake site number tend to dissipate with longer duration of illness.