The Murray Springs Clovis site, Pleistocene extinction, and the question of extraterrestrial impact.

Some of the evidence for the recent hypothesis of an extraterrestrial impact that caused late Pleistocene megafaunal extinctions [Firestone et al. (2007) Proc Natl Acad Sci USA 104:16016-16021] was based upon samples collected at Murray Springs, a Clovis archaeological site in southeastern Arizona. Here we describe sampling and analyses of magnetic separates from within, above, and below the lower Younger Dryas boundary (LYDB) black mat at Murray Springs, as well as radiation measurements from the LYDB at Murray Springs and two other well-stratified Clovis sites. The main magnetic fraction at Murray Springs is maghemite. Magnetic microspherules have terrestrial origins but also occur as cosmic dust particles. We failed to find iridium or radiation anomalies. The evidence for massive biomass burning at Murray Springs is addressed and found to be lacking. We could not substantiate some of the claims by Firestone and others, but our findings do not preclude a terminal Pleistocene cosmic event.

Schizophrenia: elevated cerebrospinal fluid norepinephrine.

Concentrations of norepinephrine in cerebrospinal fluid are higher in schizophrenic patients, particularly in those with paranoid features, than in normal volunteer subjects of the same age. This observation supports recent reports of elevated concentrations of norepinephrine in specific brain areas adjacent to the cerebral ventricles of paranoid schizophrenic patients. Overflow of the amine from periventricular regions into the cerebrospinal fluid may reflect abnormally high release or diminished enzymatic destruction of norepinephrine in patients with schizophrenia.

Effects of vasopressin on human memory functions.

Arginine vasopressin and a number of its synthetic analogs augment memory functions in experimental animals. One of these analogs, 1-desamino-8-D-arginine vasopressin (DDAVP), influences human learning and memory. Cognitively unimpaired, as well as cognitively impaired adults, treated with DDAVP for a period of several days, learn information more effectively, as measured by the completeness, organization, and consistency (reliability) of recall. DDAVP also appears to reverse partially the retrograde amnesia that follows electroconvulsive treatment.

Treatment of endogenous anxiety with phobic, hysterical, and hypochondriacal symptoms.

Endogenous anxiety (anxiety hysteria, agoraphobia with panic attacks) is characterized by sudden, spontaneous panic attacks accompanied by multiple autonomic symptoms, overwhelming fear, a flight response, and polyphobic behavior. Psychotherapy, behavior therapy, and tranquillizers have been of limited success in treating this syndrome. Fifty-seven patients severely disabled by the syndrome for a mean period of 13 years completed the three-month study. Randomly assigned in a double-blind, placebo-controlled design to imipramine hydrochloride, pheneizine sulfate, or placebo, they were seen in supportive group therapy every two weeks. Patients in the pheneizine and imipramine cells showed significant improvement ovehe persistent trend for pheneizine to be superior to imipramine achieved significance only on the Work and Social Disability Scale and the Sympton Severity and Phobic Avoidance Scale. The implications for classification and theory are discussed.

Dopaminergic effects of carbamazepine. Relationship to clinical response in affective illness.

Carbamazepine, a drug used widely to treat epilepsy and trigeminal neuralgia, has been shown to be effective in the acute and prophylactic treatment of manic-depressive illness. While the time course of its antimanic effects parallels that of classic neuroleptics, indirect clinical evidence, such as lack of parkinsonian side effects and tardive dyskinesia, suggests that carbamazepine does not act by blocking dopamine receptors. To assess the effects of carbamazepine on dopamine mechanisms, we measured the dopamine metabolite homovanillic acid (HVA) in the cerebrospinal fluid of affectively ill patients before and after treatment. Carbamazepine did not alter basal concentrations of HVA, but decreased probenecid-induced accumulations of HVA, paralleling results in animal studies. In 25 patients, lower baseline cerebrospinal fluid HVA levels were related to subsequent better acute antidepressive responses to carbamazepine. While the precise mechanism of carbamazepine's effects on dopaminergic systems remains to be determined, this study provides further evidence that carbamazepine does not have a biochemical profile typical of neuroleptics.

Alcohol and central serotonin metabolism in man.

Animal studies and some of thephenomena associated with alcoholism in humans suggest that some central effects of alcohol may involve serotonergic systems. The CSF metabolites of serotonin and dopamine, 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA) were studied in hospitalized alcoholics. There were no significant differences in HVA levels between groups. The level of 5HIAA of alcoholics in the abstinence phase, 28 to 63 days after their last drink, was significantly lower (21.8 +/- 1.9 ng/mL) than both a nonalcoholic comparison group (31.7 +/- 2.0 ng/mL) and alcoholics in the immediate postintoxication phase, within one to two days after their last drink (32.3 +/- 2.9 ng/mL).

Dopamine beta-hydroxylase in CSF. Relationship to personality measures.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 32 subjects. Those individuals with a low level of DBH in the CSF had significantly elevated profiles on the Minnesota Multiphasic Personality Inventory, suggesting a relationship between the central noradrenergic system and some aspects of personality in man.

Depressed patients have decreased binding of tritiated imipramine to platelet serotonin "transporter".

The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.

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.

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. II. Patient acceptance, side effects, and safety.

In a multicenter placebo-controlled study, the safety, side effects, and patient acceptance of alprazolam for the treatment of panic disorder and agoraphobia were examined. A total of 525 patients meeting DSM-III criteria for agoraphobia with panic attacks or panic disorder were randomly assigned to receive alprazolam or placebo, which they took for eight weeks. The mean daily dose at the end of the study was 5.7 mg of alprazolam or 7.5 capsules of placebo daily. Potentially serious reactions to alprazolam occurred in ten of 263 subjects who received the drug. These included acute intoxication (three), hepatitis (two), mania (two), amnesia (one), aggressive behavior (one), and depression (one). Treatment-related side effects that were worse in patients taking alprazolam than in those taking placebo included sedation, fatigue, ataxia, slurred speech, and amnesia. Sedation was the most frequent but tended to subside with dose reduction or continued administration of the drug. Patient acceptance of alprazolam, as measured by the rate of completion for study participants, was high. Eighty-four percent of patients receiving active drug completed the study compared with 50% receiving placebo.

Carbamazepine and its -10,11-epoxide metabolite in plasma and CSF. Relationship to antidepressant response.

Levels of carbamazepine and its -10,11-epoxide metabolite were measured in plasma and CSF of affectively ill patients treated only with carbamazepine for an average of 33 days at an average dosage of 1,055 mg/day. The CSF levels of carbamazepine were 2.06 micrograms/mL (ie, 31% of plasma levels, which equaled 6.55 micrograms/mL); CSF -10,11-epoxide concentrations averaged 0.91 micrograms/mL in 18 subjects (63% of those found in plasma). Carbamazepine levels in plasma or CSF were not related to degree of antidepressant or antimanic response. In contrast, concentrations of the -10,11-epoxide metabolite were correlated with the degree of antidepressant response. This preliminary study suggests the possibility that the -10,11-epoxide metabolite of carbamazepine may be related to the degree of clinical efficacy in affectively ill patients and may thus possess active psychotropic properties in man in addition to its reported anticonvulsant effects in animals.

CSF dopamine beta-hydroxylase in schizophrenia.

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine, was measured in the CSF of 30 schizophrenic patients and 27 normal controls. The CSF DBH activity in the patients was not significantly different from that in controls. Levels of CSF DBH activity in individual patients were highly constant over time and were not influenced by clinical state or neuroleptic treatment. Low levels of DBH in CSF did significantly relate to good social and sexual functioning, good prognosis, less symptoms between hospitalizations, and excellent clinical response to neuroleptic treatment. We speculate from these data that low brain DBH activity may produce a type of vulnerability to psychotic decompensation and thereby influence the clinical course, although it does not cause schizophrenia, in general. Low CSF DBH activity may delineate a "reactive" subgroup from the heterogenous population of patients with diagnoses of schizophrenia.

CSF somatostatin in affective illness.

Somatostatin is a hypothalamic tetradecapeptide with many actions. We investigated a potential role for somatostatinergic neuron dysfunction in affective disorder by measuring somatostatin in the CSF of 47 patients with affective illness and of 39 normal volunteers. Medication-free depressed patients showed significantly lower levels of CSF somatostatin than normal volunteers (P less than .001) or patients during the improved state (P less than .01). A significant inverse correlation was observed between somatostatin and the duration of sleep on the night of the lumbar puncture. We also observed significant correlations between somatostatin and 5-hydroxyindoleacetic acid and norepinephrine in the CSF. Also noted were the significance of depression-related decreases in CSF somatostatin in relation to information about central somatostatin secretion, reported abnormalities of somatostatin activity, and potential interactions between alterations in somatostatin activity and the pathophysiology of depression.

Carbamazepine diminishes the sensitivity of the plasma arginine vasopressin response to osmotic stimulation.

Carbamazepine, a drug used to treat manic-depressive illness, has been reported to possess antidiuretic properties, but its effects on arginine vasopressin (AVP) secretion are controversial. Consequently, we examined plasma AVP secretion during hypertonic (5%) saline infusion in seven manic-depressive patients while on placebo and after 3-5 weeks of carbamazepine treatment. We also measured carbamazepine's effects on basal levels of the hormone in cerebrospinal fluid. Carbamazepine significantly reduced the sensitivity of the plasma AVP response to osmotic stimulation without affecting the osmotic threshold for AVP secretion. Moreover, carbamazepine did not affect baseline weight, plasma osmolality, plasma sodium, urine output, plasma AVP, or cerebrospinal fluid AVP. Although the functional significance of these findings remain to be fully determined, the fact that carbamazepine significantly reduced AVP secretion without inducing diuresis supports previous suggestions that carbamazepine enhances renal responsivity to available AVP. In addition, since carbamazepine failed to affect the osmotic threshold, the reported cases of carbamazepine-induced inappropriate AVP secretion and water intoxication must be very uncommon and probably represent idiosyncratic responses.

The effect of lithium on the osmoregulation of arginine vasopressin secretion.

The effect of lithium on the plasma arginine vasopressin (AVP) response to the iv infusion of 5% saline was determined in six patients with primary effective disorder. Lithium did not significantly affect baseline weight, plasma osmolality, sodium, or AVP levels. However, lithium significantly increased the mean rate of change or the sensitivity of the plasma AVP response to the osmotic stimulus (from 0.42 +/- 0.17 to 1.08 to 0.24 pg/ml/mosmol/kg; P less than 0.025, by paired t test). This change was associated with a slight but significant increase in the precision of the response, as reflected in the correlation coefficient, but there was no difference in the calculated intercept or osmotic threshold for AVP secretion. This study indicates that patients on lithium do not, as previously suggested, show partial central diabetes insipidus. Rather, AVP secretion seems to be enhanced. Moreover, the mechanism of this enhancement is a specific increase in the sensitivity of the osmoreceptor rather than a lowering of the osmotic threshold for AVP secretion. The effect of lithium cannot be clearly accounted for by any of the physiological variables known to influence the sensitivity of the system and is probably due to an effect of the drug on the level or activity of neuromodulators which influence the function of hypothalamic osmoreceptors.

Current treatments of the anxiety disorders in adults.

The progress in developing effective treatments for the five principal anxiety disorders (ADs) in adults--panic disorder (PD), social phobia (SP), obsessive compulsive disorder (OCD), generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD)--has been rapid in the past 15 years. There are now well-controlled clinical trials documenting effective pharmacological and psychological treatments for all of these disorders, although generally the evidence is better developed for some disorders than for others. Both the pharmacological treatments and the effective psychological treatments for each disorder will be briefly reviewed. The available data for combination treatment will be reviewed and comparisons of the two types of treatment will be made. This review will contain at least brief reviews of what the treatments involve and attempt to describe how well they work. Many studies unfortunately report only the percentage of patients who "improve" without quantifying the clinical significance of those responses. Data underlining clinical response in terms of the percentage of patients who have an "excellent," "marked," or "moderate" response, and the percentage of patients with a "clinically significant" response will be reported whenever available. Other clinically relevant issues such as length of treatment-relapse rates upon discontinuation and side effects will be presented. As such, this article should provide a brief but comprehensive review of the treatment of these disorders in adults.

Alcohol detoxification and withdrawal seizures: clinical support for a kindling hypothesis.

There has been speculation that a kindling model may have applicability to alcohol withdrawal syndromes and seizures, suggesting that repeated alcohol withdrawals may lead to increased severity of subsequent withdrawals. We evaluated historical and clinical variables of a group of male alcoholics with (n = 25) and without (n = 25) alcohol withdrawal seizures. We found that the number of detoxifications appeared to be an important variable in the predisposition to withdrawal seizures. The withdrawal seizure group had 12 of 25 (48%) patients with 5 or more previous detoxifications, compared to only 3 of 25 (12%) of the control group. A relationship between alcohol use history and withdrawal seizures was not supported by the data. These findings support the concept that previous alcohol withdrawals may "kindle" more serious subsequent withdrawal symptomatology, ultimately culminating in withdrawal seizures.

CSF diazepam-binding inhibitor concentrations in panic disorder.

Diazepam-binding inhibitor (DBI) is a neuropeptide that has been detected in the brain and cerebrospinal fluid (CSF). Previous studies have suggested the possible role of DBI as a potential endogenous anxiogenic ligand modulating GABAergic transmission at the benzodiazepine-GABA receptor complex. The measurement of DBI immunoreactivity (DBI-IR) in CSF of panic-disorder patients and normal controls was undertaken to assess whether there were differences in the CSF concentration of this peptide to assess possible relationships with other monoamines and peptides. Lumbar CSF was obtained from 18 panic patients (4 men, 14 women) and 9 controls (5 men, 4 women). As a group, no significant differences were found between panic patients' CSF concentration of DBI-IR (1.12 +/- 0.27 pmol/mL) and normal volunteers (1.23 +/- 0.27 pmol/mL). No gender differences were demonstrated. However, we did find a positive correlation between CSF levels of DBI and CSF corticotropin releasing hormone (CRH) in our panic patients.

Dopamine-beta-hydroxylase in the cerebrospinal fluid: relationship to disulfiram-induced psychosis.

Cerebrospinal fluid (CSF) dopamine-beta-hydroxylase (DBH) activity in 32 male alcoholics was measured using a modification of the radioenzymatic method of Molinoff et al. In most, the CSF was obtained before treatment with disulfiram, while in others it was obtained while they were on the drug (250 or 500 mg). As expected, treatment with this reversible DBH inhibitor had no effect on the activity of the enzyme measured in our in vitro assay. However, low pretreatment DBH activity was found to correlate with adverse reactions to disulfiram. Mean DBH activity of four individuals who went on to become psychotic on disulfiram was 0.13 +/- 0.02 nmole/ml per hr (mean +/- SEM). An additional four individuals who developed dysphoric but nonpsychotic reactions had a mean DBH of 0.23 +/- 0.03. Both these values were significantly lower than the mean DBH activity of the remaining 24 individuals treated with disulfiram who had no adverse side effects, 0.53 +/- 0.06 p less than 0.02 and p less than 0.05, respectively, 2-tailed t-test.

Cerebrospinal fluid homovanillic acid in male alcoholics: effects of disulfiram.

It is well know that if an individual maintained on disulfiram (Antabuse) ingests alcohol, excess acetaldehyde is formed, resulting in a toxic reaction. In addition to this toxic interaction with alcohol (the basis of its use as a deterrent), there are both behavioral and biochemical observations to suggest that disulfiram alone has a direct effect on the CNS. The possibility that some of disulfiram's effects are related to alterations in biogenic amine metabolism led to the present study of cerebrospinal fluid amine metabolites in a group of male alcoholics. In this group, disulfiram treatment was associated with a significant reduction in homovanillic acid, the major metabolite of dopamine, while no change was noted in 5-hydroxyindoleacetic acid, the major metabolite of serotonin. Prior to disulfiram, patients with withdrawal symptoms had significantly lower homovanillic acid than those without such symptoms.