Reduction of cerebral blood flow in older depressed patients.

BACKGROUND: We investigated regional cerebral blood flow in older, drug-free depressed patients and examined factors that might be related to rCBF. METHODS: We studied 39 physically healthy depressed patients over the age of 50 years and 20 psychiatrically healthy control subjects. Regional cerebral blood flow was measured with single photon emission computed tomography, using both xenon 133 (to quantify regional cerebral blood flow) and 99mTc-hexamethylpropylene amine oxime (to make regional comparisons). From magnetic resonance imaging, we derived a semiquantitative measure of areas of white matter hyperintensity and a ventricle-to-brain ratio. RESULTS: Patients exhibited a global reduction in regional cerebral blood flow compared with controls, with the orbital frontal and inferior temporal areas affected bilaterally. Regional cerebral blood flow was also reduced in higher brain slices in the right but not the left hemisphere. Significant predictors of lowered regional cerebral blood flow were being depressed, being male, and having a greater ventricle-to-brain ratio. There appeared to be a subgroup of patients who demonstrated large areas of white matter hyperintensity and low regional cerebral blood flow. CONCLUSIONS: Cerebral blood flow was lower in older, medication-free depressed patients than in age-matched control subjects, involved the orbital frontal and anterior temporal regions, and was more reduced in the right hemisphere.

Neuroendocrine aspects of primary endogenous depression. II. Serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response.

To determine the contribution of serum dexamethasone concentrations and hypothalamic-pituitary-adrenal cortical activity before dexamethasone administration to the dexamethasone suppression test (DST) response, a series of stepwise discriminant function analyses were performed for 40 patients with definite endogenous depression and 40 matched normal control subjects. The 24-hour serum cortisol concentration before dexamethasone administration and the serum dexamethasone concentrations at 8, 16, and 24 hours after administration served as the independent variables, and the DST "escaper"/"suppressor" dichotomy served as the dependent variable. While both types of independent variables significantly influenced the DST response, the major factor that contributed to the discrimination of escapers from suppressors was the 24-hour cortisol concentration before dexamethasone administration. Sixteen hours after dexamethasone administration, when the DST had the highest positive predictive value, serum dexamethasone concentrations significantly influenced DST outcome only when they were below a certain threshold level. At this time, hypothalamic-pituitary-adrenal cortical hyperactivity before dexamethasone administration accounted for approximately two thirds of the incidence of DST nonsuppression.

Neuroendocrine aspects of primary endogenous depression. I. Cortisol secretory dynamics in patients and matched controls.

To examine both predexamethasone and postdexamethasone cortisol measures in depression, we determined circadian serum cortisol patterns, cortisol responses to dexamethasone, and 24-hour urinary free cortisol excretion before and after dexamethasone administration in 40 patients with primary, definite endogenous depression diagnosed by Research Diagnostic Criteria and in 40 individually matched normal control subjects. Fifteen patients (38%) were dexamethasone nonsuppressors; they had significantly higher predexamethasone serum and urine cortisol measures than both their matched controls and the 25 suppressor patients. Both the predexamethasone and postdexamethasone cortisol measures were unimodally distributed across the patients and the controls. Circadian cortisol rhythms of similar magnitude occurred in both groups. The cortisol measures before and after dexamethasone administration were positively correlated to a similar degree in the patients and their controls, suggesting that predexamethasone hypothalamic-pituitary-adrenocortical hyperactivity and postdexamethasone cortisol nonsuppression are not independently determined in endogenous depression.

Neuroendocrine aspects of primary endogenous depression. XI. Serum melatonin measures in patients and matched control subjects.

To ascertain the extent of dysregulation of melatonin secretion in endogenous depression, we measured nocturnal and diurnal serum melatonin concentrations in 38 depressed patients (23 women and 15 men) who had primary, definite endogenous depression according to the Research Diagnostic Criteria and in 38 individually matched normal control subjects. Previous reports have suggested that such patients may have reduced nocturnal melatonin secretion, often in conjunction with increased hypothalamic-pituitary-adrenal cortical axis activity. This has been considered as a possible reflection of reduced noradrenergic activity in depression. Compared with their matched controls, the depressed patients showed a trend toward a significantly elevated average nocturnal melatonin concentration that was accounted for primarily by the 14 premenopausal women--the postmenopausal female and male depressive patients did not differ significantly from their respective controls. The average diurnal melatonin concentration also showed a trend toward being higher in both the female and male depressed patients. The melatonin measures were not consistently related to any of the previously reported hypothalamic-pituitary-adrenal cortical axis measures in these subjects. Our findings thus failed to confirm a "low melatonin syndrome" or an inverse relationship between nocturnal melatonin and nocturnal cortisol concentrations in depression. This discrepancy may be related to methodologic differences among studies; our data are in accord with those findings of the one other reported study in which normal controls were individually matched to patients on variables that were known to influence melatonin secretion. Most of the studies, including ours, have been cross-sectional.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. I. Efficacy in short-term treatment.

Following promising preliminary evidence, the benzodiazepine-derivative alprazolam was studied in a large, placebo-controlled, eight-week, flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder. Of 526 patients, 481 completed three weeks of treatment; however, significantly more placebo (102/234) than alprazolam (21/247) recipients subsequently dropped out of the trial, primarily citing ineffectiveness (of placebo) as the reason. Alprazolam was found to be effective and well tolerated. There were significant alprazolam-placebo differences in improvement for (1) spontaneous and situational panic attacks, (2) phobic fears, (3) avoidance behavior, (4) anxiety, and (5) secondary disability, all significant by the end of week 1. At the primary comparison point (week 4), 82% of the patients receiving alprazolam were rated moderately improved or better vs 43% of the placebo group. At that point, 50% of the alprazolam recipients vs 28% of placebo recipients were free of panic attacks.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.

Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

Serum dexamethasone concentrations in endogenous depressives before, during, and after treatment: preliminary observations.

The 1.0-mg Dexamethasone (DEX) Suppression Test (DST) was performed in 10 endogenous depressives prior to treatment, during treatment, and again when the patients were medication- and symptom-free. Five of the 10 patients were DST escapers prior to treatment, and all 10 patients were DST suppressors following treatment. During treatment, 6 patients were DST escapers, 2 of them having been suppressors initially. There were no significant differences in serum DEX concentrations before, during, and after treatment in either the 5 DST escapers or the 5 DST suppressors. These results lend further support to the concept that reduced serum DEX concentrations are not the major factor underlying DST nonsuppression.

Neuroendocrine aspects of primary endogenous depression. X: Serum growth hormone measures in patients and matched control subjects.

To determine the extent of dysregulation of growth hormone (GH) secretion in endogenous depression, we measured nocturnal serum GH concentrations and GH responses to thyrotropin-releasing hormone (TRH, gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared with their controls, the patients showed no difference in basal nocturnal GH concentrations or in GH responses to TRH or LHRH. The GH measures were not significantly related to the other endocrine measures reported previously, including dexamethasone suppression test status. None of the diagnostic schemes for endogenous/melancholic depression which we studied was significantly related to the GH measures in the patients. Of the other subject and symptom variables, the mood depression factor of the Hamilton depression scale and the performance difficulty factor of the Beck depression inventory were moderately negatively correlated with the nocturnal GH measures. These findings suggest that, in contrast to the previously reported hypothalamopituitary-adrenal cortical and thyroid axis abnormalities in our patients, GH secretion was relatively normal. Patients with more severe depressed mood and greater difficulty accomplishing tasks did have moderately lower nocturnal GH values.

Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects.

To ascertain the extent of dysregulation of prolactin (PRL) secretion in endogenous depression, we determined nocturnal serum PRL concentrations and PRL responses to thyrotropin-releasing hormone (TRH), gonadotropin-releasing hormone (LHRH), and dexamethasone administration in 40 Research Diagnostic Criteria (RDC) primary, definite endogenous depressives and 40 individually matched normal control subjects. Compared to their matched controls, the patients showed no difference in basal nocturnal PRL concentrations, a marginally significant 20%-25% increase in the PRL response to TRH, and no differences in post-LHRH or postdexamethasone PRL concentrations. In the patients, there was a weak, negative correlation between age and PRL (r = -0.30), but none of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the PRL measures. The PRL measures also were unrelated to pre- and postdexamethasone cortisol concentrations and to the thyrotropin (TSH) responses to TRH in both groups of subjects. In contrast to the previously reported hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities in these patients, our findings suggest that PRL secretion was relatively normal.

Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression.

Scopolamine (SCOP) (3.0 mu/kg and 6.0 micrograms/kg) and saline were administered intramuscularly at 11:00 PM to eight normal male volunteers in a randomized design, and the effects on the sleep electroencephalogram (EEG) and nocturnal cortisol secretion (via blood sampling every 15 min) were evaluated. Compared to saline, SCOP produced a significant dose-related delay in rapid eye movement (REM) latency. In contrast, neither dose of SCOP significantly affected nocturnal plasma cortisol concentrations. These results suggest that the central cholinergic system that regulates the onset of REM sleep is more sensitive to dysregulation than the cholinergic system that controls the degree of nocturnal cortisol secretion. If central cholinergic overactivity is responsible for both the REM sleep latency and cortisol abnormalities in depressed patients, then our findings with SCOP might help explain why the incidences of these abnormalities are different.

Differential response of rapid eye movement sleep to cholinergic blockade by scopolamine in currently depressed, remitted, and normal control subjects.

The degree of cholinergic dysregulation of sleep in adult depression was evaluated using scopolamine. On separate sessions, placebo and scopolamine (4.5 micrograms/kg, IM) were administered to 14 patients with unipolar major depression, 16 recovered/remitted patients, and 18 normal controls. Scopolamine increased rapid eye movement (REM) latency (RL), reduced REM activity (RA), REM density (RD), and REM duration, and increased the percentage of stage 4 sleep in all groups. There was a differential effect of scopolamine on RL, RA, and REM duration for the first REM period, and on percentage of stage 4 sleep. Whereas a primary cholinergic hyperactivity could account for the RA and RD responses, the response profile for RL was more compatible with reduced aminergic tone as the proximal cause of the cholinergic hyperactivity. Whether the sleep abnormalities observed in remitted patients reflect an underlying vulnerability for development or recurrence of depression, and/or a scar, remains to be determined.

Alexithymia: examining the development of a psychological concept.

Alexithymia is a clinically derived concept that refers to difficulty patients have with verbal expression of emotions and with fantasy elaborations. Since its recent introduction into the literature, it has been discussed in various contexts and has been considered by some to be a useful concept in integrating data from a variety of disciplines. The authors contend that many of the speculations about alexithymia are based on an inadequately researched data base and that its application in some areas is premature. They recommend careful investigation of any newly introduced psychological concept to avoid either its premature rejection or its reification.

Attitudes toward medication change among chronically impaired psychiatric patients.

As the hazards of long-term use of psychotropic drugs become more apparent, drug holidays and medication discontinuance are increasingly being implemented. Chronically ill patients are often reluctant to cooperate with such treatment recommendations. The authors questioned 52 chronically impaired patients taking neuroleptics about their attitudes toward medication changes and their fantasies about the results of discontinuing their medication. Although they were seemingly compliant, the majority of the patients anticipated severe negative consequences.

Alprazolam plasma concentrations and treatment response in panic disorder and agoraphobia.

OBJECTIVE: The authors' goal was to evaluate the relationship between plasma concentrations of alprazolam and both treatment response and side effects in patients with panic disorder and agoraphobia. METHOD: Ninety-six patients with panic disorder and agoraphobia were treated at three sites in a 6-week, fixed-dose, double-blind, placebo-controlled, dose-response study of 2 mg/day or 6 mg/day of alprazolam. Assessments were made of panic attacks, avoidance behavior, generalized anxiety, and global response. Blood samples were collected throughout the study and analyzed for alprazolam and other benzodiazepines. RESULTS: Patient compliance with the protocol was judged to be good on the basis of plasma concentrations. According to logistic regression analysis, the relationships between plasma alprazolam concentration and response, as reflected by number of panic attacks reported, phobia ratings, physicians' and patients' ratings of global improvement, and the emergence of side effects, were significant. However, there was no significant relationship between plasma alprazolam concentration and the degree of generalized anxiety symptoms. CONCLUSIONS: The authors conclude that plasma concentration of alprazolam is related to treatment response, particularly in panic attacks. The alprazolam concentration associated with treatment response or with emergence of a given side effect varied widely among individuals, highlighting the necessity for individualized dose adjustment to obtain optimal treatment response while minimizing side effects.

Cognition and white matter hyperintensities in older depressed patients.

OBJECTIVE: The authors compared amounts of white matter hyperintensity in late- and early-onset depressed patients and never-depressed older subjects, compared neuropsychological function in these groups, and investigated the association between white matter hyperintensities and cognitive function in depression. METHOD: Sixty currently depressed patients whose first depression occurred after age 50 years, 35 depressed patients over age 50 whose first depression occurred before age 35, and 165 nonpsychiatrically ill subjects over age 50 underwent magnetic resonance imaging (MRI) and neuropsychological evaluation. Areas of white matter hyperintensity were measured from MRI images. RESULTS: The late-onset patients had more white matter hyperintensity than either of the other groups. Compared to the nondepressed subjects, the patients had significantly lower scores in the cognitive domains of nonverbal intelligence, nonverbal memory, constructional ability, executive ability, and information processing speed. The cognitive abnormalities were mostly confined to the late-onset patients, and the presence of a large amount of white matter hyperintensity was associated with significantly poorer executive skills. However, most of the scores were not in the significantly impaired range. CONCLUSIONS: Large amounts of white matter hyperintensity are more frequent in patients with late-onsetdepression than in elderly subjects with early-onset or no depression. Both late- and early-onset elderly depressed patients show mild decrements in some "right hemisphere" cognitive skills; the late-onset subjects also show deterioration in information processing speed and executive functions. Patients with large amounts of white matter hyperintensity have significantly poorer executive function.

Neuropsychological correlates of white-matter lesions in healthy elderly subjects. A threshold effect.

The clinical significance of white-matter lesions (WMLs) detected by computed tomography and magnetic resonance imaging in healthy elderly subjects has been controversial, with some studies reporting associated deficits in cognition and others failing to document cognitive disturbance. In our sample of 100 healthy elderly individuals, almost half (n = 46) had no WMLs, approximately one fourth had minimal (less than or equal to 1 cm2; n = 27) or moderate (greater than 1 cm2 but less than or equal to 10 cm2; n = 21) WML areas, and six subjects had large WML areas (greater than 10 cm2). Substantial disturbances in basic attention and selected frontal lobe skills were detected in the six subjects with the large WML areas. These findings suggest that a "threshold" of WML area must be present before cognitive deficits are observed. Surprisingly, no significant relationships between duration of hypertension or cholesterol levels and WMLs were detected, suggesting that factors other than vascular disturbances are involved in the origin of at least some WMLs.

Frontal lobe degeneration: clinical, neuropsychological, and SPECT characteristics.

The clinical, neuropsychological, and cerebral blood flow characteristics of eight patients with frontal lobe degeneration (FLD) were studied. Social withdrawal and behavioral disinhibition were the earliest and most common clinical presentations, and psychiatric symptoms typically preceded the onset of dementia by several years. Neuropsychological testing showed selective impairment of frontal and memory tasks with relative sparing of attention, language, and visuospatial skills. Single-photon emission computerized tomography demonstrated frontal and temporal hypoperfusion with relative sparing of parietal and occipital blood flow. Previous studies suggest that the neuropathologic findings in patients with FLD are varied; some demonstrate frontal gliosis, neuronal loss, and Pick bodies while others show only gliosis and neuronal loss.

Neuroendocrine aspects of primary endogenous depression VIII. Pituitary-gonadal axis activity in male patients and matched control subjects.

To determine the extent of hypothalamo-pituitary-gonadal (HPG) axis dysfunction in endogenous depressed men, we measured nocturnal and diurnal serum luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and estradiol (E2) concentrations, and their responses to gonadotropin releasing hormone (LHRH) and dexamethasone administration, in 16 Research Diagnostic Criteria primary, definite endogenous male depressives and 16 individually matched male normal controls. Compared to their controls, the patients showed no differences in basal nocturnal or diurnal gonadotropin or gonadal steroid hormone concentrations, and no differences in hormone concentrations either post-LHRH or post-dexamethasone. Age was negatively correlated with baseline serum T in the patients but not in the controls, and it was modestly positively correlated with baseline serum LH in both groups of subjects. In the patients, the presence of DSM-III melancholia was modestly negatively correlated with baseline and post-LHRH concentrations of both LH and FSH and was positively correlated with baseline serum T, but it bore no relation to serum E2. None of the other subject characteristics or specific dimensions of depressive symptomatology were significantly related to the HPG axis measures. The HPG axis measures also were unrelated to pre- and post-dexamethasone cortisol concentrations in both groups of subjects. The results of this study suggest that, in contrast to the hypothalamo-pituitary-adrenal cortical and thyroid axis abnormalities frequently found in endogenous depressives, HPG axis function in male depressives is relatively normal.

Neuroendocrine aspects of primary endogenous depression--IV. Pituitary-thyroid axis activity in patients and matched control subjects.

In order to ascertain the extent of hypothalamo--pituitary--thyroid (HPT) axis dysfunction in endogenous depression, we determined nocturnal serum thyrotropin (TSH) concentrations, TSH responses to thyrotropin releasing hormone (TRH) administration, and serum triiodothyronine (T3) and thyroxine (T4) concentrations in 40 Research Diagnostic Criteria primary, definite endogenous depressives and 40 individually matched normal control subjects. We also examined the relationships of the HPT measures to pre- and post-dexamethasone (DEX) serum and urine cortisol measures and, in the patients, to subject characteristics, the diagnosis of endogenous/melancholic depression by different systems, and the overall severity and specific dimensions of depressive symptomatology. Compared to their matched controls, the patients showed significant reductions in nocturnal serum TSH and serum T3 concentrations. Neither the TSH responses to TRH nor serum T4 concentrations were significantly different between the two groups of subjects. In the patients, none of the subject characteristics, diagnostic schemes for endogenous/melancholic depression or specific aspects of depressive symptomatology were significantly related to HPT activity. The measures of HPT activity were unrelated to measures of hypothalamo--pituitary--adrenal cortical (HPA) axis activity in both groups of subjects.

Situational depression and the dexamethasone suppression test.

Neither baseline integrated 24 hr cortisol concentrations nor cortisol escape from dexamethasone suppression were able to distinguish a group of endogenously depressed patients who experienced precipitating events prior to their depression (situational) from a group of endogenously depressed patients with no discernible precipitating events (non-situational). Symptom severity, features of psychosis, and family history also were similar between the two groups. These results highlight the inadequacy of using the presence or absence of precipitating events for subtyping endogenous depression.