Naloxone-induced behavioral and physiological effects in normal and manic subjects.

Intravenous naloxone hydrochloride (20 mg) was administered to eight normal control subjects and 12 affective disorder patients manifesting manic or hypomanic symptoms. On two consecutive days, in a counterbalanced order, naloxone and placebo were given in a double-blind crossover design. The overall effect of naloxone was to decrease pulse rate and to promote lethargy and inactivation. The normal controls manifested reduced feelings of well-being, and the manic patients noted a subjective sense of slowing. There was a variable response pattern to naloxone in the manic patients in which four of the 12 patients manifested an observable reduction in their manic symptoms and behavior after the naloxone administration. Naloxone seems to have had a nonspecific subduing effect in both normal subjects and patients and may also have had a selectively greater effect in a small subsample of the manics.

The effect of lithium carbonate on affect, mood, and personality of normal subjects.

Data reflecting affect, mood, and personality attributes of 23 normal men were compared after two weeks of placebo administration and two weeks of therapeutic serum lithium levels (mean, 0.91 mEq/liter). The study was a placebo-controlled, split-half crossover, double-blind design. Affect and mood were measured by three self-rating instruments, independent rater observation, and by the subjects' "significant others." Two personality inventories were administered. Substantial affect and mood changes are induced by lithium carbonate. Lethargy, dysphoria, a loss of interest in interacting with others and the environment, and a state of increased mental confusion were reported. No generalized effects were found in the responses to ther personality inventories.

The effect of lithium carbonate on the cognitive functions of normal subjects.

The responses of 24 normal male subjects were compared after weeks of placebo administration and two weeks of lithium carbonate administration (mean serum lithium level, 0.9 mEq/liter) on a series of tasks of intellectual function, aesthetic judgement, and semantic creativity. This was a placebo-controlled, split-half crossover, double-blind design. There were no significant changes on semantic creativity or aesthetic perception measures following lithium carbonate maintenance. There were lithium carbonate-related performance deficits on three of five performance tasks concerned with cognitive and/or motor functions. The deficit is probably due to a lithium carbonate-induced slowing of performance, consistent with our previous report of subjective effects in normal subjects. The implications of slowing on possible behavioral mediating mechanisms by which lithium carbonate exerts its clinical effects are discussed.

Blunted prolactin response. A neuroendocrine abnormality manifested by depressed patients.

Prolactin concentrations of 30 unmedicated psychiatric inpatients and 11 normal controls were measured at baseline and at 30 and 60 minutes after the administration of 10 mg of intramuscular methadone hydrochloride. Methadone raised the prolactin level at 60 minutes to more than twice the mean baseline level for the full subject sample. Patients with depressive disorders had lower mean basal prolactin levels than did the other subjects, and also manifested attenuated prolactin responses to methadone. Eight of 16 depressives had markedly blunted prolactin responses, a finding consistent with other studies reporting deficient responses in depression. These data are consistent with the hypothesis that the pathophysiology of depressive disorders involves dysfunctions in the anterior pituitary itself or in the hypothalamic neurotransmitter and neuromodulator systems (eg, endorphins) that regulate the secretion of prolactin and other neurohormones.

Lithium carbonate and ethanol induced "highs" in normal subjects.

The responses of twenty-three normal male subjects to a standardized dose of 95% ethanol (1.32 ml/kg of body weight) were compared after two weeks of placebo and two weeks of therapeutic serum lithium ion levels (mean 0.91 mEq/liter). The study was a placebo controlled, split-half crossover, double-blind design. Prealcohol and postalcohol responses were assessed by self-rating scales of affect and mood, independent rater observation, perceptual-motor, and cognitive performance tasks. Pretreatment by lithium carbonate neither blocked nor dampened an alcohol-induced subjective "high" in normal subjects. A complex reciprocal interaction may exist between the effects of lithium and alcohol upon other behavioral attributes. Alcohol was seen to reverse aspects of lithium-induced dysphoria and there is a suggestion that lithium may attenuate alcohol-induced cognitive inefficiency.

Central cardiovascular effects of physostigmine in humans.

Central cholinergic control of pulse rate and blood pressure has seldom been studied in humans. In the current study we contrasted the cardiovascular effects of the centrally acting cholinesterase inhibitor physostigmine, which increases central and peripheral acetylcholine levels, with those of saline placebo and with those of the non-centrally acting cholinesterase inhibitor neostigmine, which only increases peripheral acetylcholine levels. We found that physostigmine, in contrast to neostigmine and saline, caused significant and often profound increases in pulse rate and blood pressure levels in humans. Thus, we conclude that acetylcholine may have a role in central cardiovascular regulation in humans. We also found that administration of physostigmine may cause net increases in pulse of up to 74 beats/minute, systolic blood pressure increases of up to 50 mm Hg, and diastolic increases of up to 45 mm Hg. Such increases could be dangerous in elderly patients with concomitant cerebrovascular or coronary circulation disorders.

Lithium antagonizes ethanol intoxication in alcoholics.

Thirty-five detoxified alcoholics given lithium in a placebo-controlled, double-blind study reported less intoxication, a decrease in the desire to continue drinking, and less cognitive dysfunction when challenged by standardized doses of ethanol. Lithium also appeared to antagonize the ethanol-induced decrement in cognitive and perceptual motor performance. No differential lithium effect was noted when alcoholics were divided by diagnoses of affective disorder versus no affective disorder. The authors suggest that, in addition to mood normalization, lithium's capacity to directly affect ethanol intoxication may help explain its potential therapeutic efficacy in alcoholism, providing further confirmatory evidence that lithium may be useful in the treatment of alcoholism.

Effects of lithium carbonate on memory and other cognitive functions.

The authors studied the effects of lithium carbonate on memory and cognitive function in 16 psychiatric patients, who received lithium for 2 weeks and placebo for 2 weeks in a double-blind cross-over design. At the end of each treatment phase, subjects were administered a battery of memory and cognitive tests. As reported previously, lithium induced slowing of performance on certain of the perceptual motor tests; however, lithium did not cause memory impairment or a change in self-assessment of memory functions.

Effects of physostigmine on pulse, blood pressure, and serum epinephrine levels.

In this study, the infusion of physostigmine in 14 patients with affective disorder who were pretreated with methscopolamine caused significant and often profound increases in the patients' epinephrine levels, pulse rates, and blood pressure. Since physostigmine is being used experimentally in the treatment of elderly subjects who have Alzheimer's disease, these cardiovascular effects may have clinical importance.

Central and peripheral cholinesterase inhibition: effects on anterior pituitary and sympathomimetic function.

Ten physically healthy inpatients of mixed diagnosis received, in a randomized, counterbalanced double-blind paradigm, physostigmine (22 micrograms/kg) and neostigmine (11 micrograms/kg). Infusions were separated by at least 2 days. The differential effects of physostigmine and neostigmine on plasma concentrations of cortisol, prolactin, growth hormone, ACTH, beta-endorphin/beta-lipotropin-like immunoreactivity, dopamine, norepinephrine, and epinephrine are reported. Administration of physostigmine, unlike that of neostigmine, was associated with statistically significant increases in plasma concentrations of cortisol, prolactin, ACTH, beta-endorphin/beta-lipotropin-like immunoreactivity, and epinephrine, presumably via central mechanisms. In a separate study, 15 subjects, mostly depressed inpatients, were pretreated with methscopolamine (0.75 mg) on one day and scopolamine (0.5 mg) on another day, at least 2 days apart, in a randomized, counterbalanced double blind paradigm and subsequently on each day received physostigmine (22 micrograms/kg). Scopolamine significantly attenuated the physostigmine-associated increase in plasma concentrations of cortisol, growth hormone, prolactin, ACTH, and dopamine compared to methscopolamine, and a close-to-significant attenuation of epinephrine as well. These results provide further evidence that physostigmine's effects on plasma concentrations of pituitary hormones and epinephrine occur via central mechanisms and are muscarinically mediated.

Plasma levels of tricyclic antidepressants and clinical efficacy: review of the literature -- part II.

The authors have critically reviewed the literature regarding the relationship between plasma levels of tricyclic antidepressant and their clinical efficacy. When available, drug-drug interactions, pharmacokinetics, and other factors influencing plasma levels of tricyclic antidepressants are discussed. Although many studies are confounded by significant methodological and statistical problems, it appears to these reviews that the available evidence suggests a curvilinear relationship between nortriptyline plasma levels and antidepressant efficacy in tricyclic responsive endogenously depressed inpatients, with maximal therapeutic efficacy achieved with notriptyline plasma levels between 50-175 ng/ml. The evidence for imipramine supports a linear relationship between plasma levels of imipramine plus desmethylimipramine and clinical response in nondelusional endogenously depressed tricyclic responsive inpatients. For amitriptyline, the picture is less clear. However, with the exception of one well-controlled study, the available evidence suppprts some significant relationship between amitriptyline plus nortriptyline plasma levels and antidepressant efficacy in tricyclic respoonsive endogenously depressed patients, but it is not clear as to whether this is a linear relationship or a curvilinear one. For the other antidepressants: protriptyline, desmethylimipramine, doxepin, clomipramine, maprotiline, and butriptyline, a significant relationship (if any) awaits further elucidation. It is important to point out that these plasma level relationships probably do no generalize to other types of depressions (e.g. neurotic, characterological, delusional, acute situationa, etc.) and clearly do not apply to every endogenous tricyclic responsive patient. /owever, it appears that, in general, a clinician will obtain therapeutic efficacy for endogenously depressed patients if these guidelines are followed. The actual therapeutic levels will depend on the assay's sensitivity and specificity and may vary from center to center, illustrates the importance of each center defining its own therapeutic limits, or conversely all centers adoptina a universal reproducible assay methodology for each compound measured. Despite these limitations, these reviewers feel that routine monitoring of plasma levels of the tricyclic antidepressants is a useful method to maximize therapeutic efficacy and prvent undue side effects, as well as to insure good medication compliance.

Prediction of lithium dose: a mathematical alternative to the test-dose method.

A method of estimating the optimal dose of lithium is presented. The charts of 548 patients were reviewed to obtain data regarding the factors thought to affect the lithium dose, and an equation to estimate the dose was derived by stepwise multiple linear regression. The equation was also applied to 390 patients to determine the difference between the estimated and the actual dose; the mean difference was only 19 mg/day and the standard deviation was 325 mg/day. Lithium level, presence of a cyclic antidepressant, age, sex, and weight were found to be important variables for estimation of lithium dose.

Effects of lithium carbonate on methylphenidate-induced mood, behavior, and cognitive processes.

Evidence is presented which suggests that lithium modifies the mood and behavioral alterations resulting from IV methylphenidate. Specifically, lithium significantly reduces the level of arousal-activation, euphoria-grandiosity, and the total score of manic-state ratings following a methylphenidate challenge. In addition, lithium appears to be capable of modifying the growth hormone response to methylphenidate.

The effects of naloxone on methylphenidate-induced mood and behavioral changes: a negative study.

The effects of naloxone on IV methylphenidate-induced mood, behavior, and neurohumoral changes were assessed in eight psychiatric inpatients. While methylphenidate alone produced anticipated changes, the indications for significant naloxone-methylphenidate interactions were minimal. It is speculated that larger doses of naloxone might be required to produce modification of the psychostimulant effects.

Hypothalamic-pituitary-adrenal regulation, neurotransmitters and affective disorders.

Considerable evidence has accumulated indicating that alterations in neurotransmitters may play a role in the etiology of affective disorders on the one hand, and in the regulation of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) on the other. Acetylcholine, norepinephrine, serotonin, GABA, the opioid polypeptides and dopamine have all been implicated in both phenomena. Although some contradictory evidence exists, norepinephrine, opioids, and GABA appear inhibitory, and serotonin and acetylcholine appear excitatory of the LHPA axis. In a correlative study, non-suppression of cortisol by dexamethasone correlated positively and significantly with methylphenidate-induced euphoric and antidepressant responses, and methadone induced growth hormone responses, possibly suggesting catecholamine and opioid receptor hypersensitivity. Although the overall effects of the cholinomimetic, physostigmine, did not correlate with dexamethasone non-suppression, strong positive correlations were found in a subgroup, consisting of affective disorder patients, between non-suppression of cortisol by dexamethasone and the physostigmine response, suggesting cholinergic hypersensitivity in the non-suppressing subjects.

Correlated cholinomimetic-stimulated beta-endorphin and prolactin release in humans.

Previous studies, both in animals and humans, have demonstrated that the intravenous or intraventricular administration of endogenous opioids and opiates produce dose dependent increases in plasma concentrations of prolactin. Notably, in humans, intravenous infusion of centrally active cholinomimetic drugs, such as physostigmine or arecoline, may produce significant increases in plasma concentrations of prolactin and beta-endorphin immunoreactivity. In three separate studies, conducted collaboratively between the National Institute of Mental Health and the University of California at San Diego, physostigmine and arecoline associated increases in plasma concentrations of beta-endorphin immunoreactivity were highly correlated with increases in plasma prolactin concentrations. These results are of interest because centrally active cholinomimetic drugs have been variously reported either to have no effect, to increase, or to inhibit anterior pituitary prolactin release. We propose that cholinergic stimulation of hypothalamic beta-endorphin may represent an interesting example of peptidergic modulation of primary neurochemical effects on hypothalamic-pituitary hormonal regulation.

Physostigmine effects on serotonin uptake in human blood platelets.

Platelet serotonin (5HT) uptake was measured in 18 subjects administered physostigmine salicylate in a double-blind, placebo crossover design. In comparison to placebo, the drug caused a significant transient depression in mood, as measured by self- and observer-rated depression scores. In addition, physostigmine significantly increased platelet counts while independently decreasing the maximum velocity (Vmax) of platelet serotonin uptake. Physostigmine administration did not significantly affect the affinity constant (Km) for platelet serotonin uptake. The data are interpreted as being consistent with the postulate that platelet serotonin uptake may be decreased in depressed patients via cholinergic mechanisms.

Psychic distress and the immune response.

This minireview surveys recent progress in the field of immunoregulation by the central nervous system. Representative findings from human and animal studies show evidence for significant immunosuppression in states of psychic distress. Mechanisms of immunomodulation are discussed in light of data implicating neuroendocrine, genetic, neuroanatomical, and learning factors. Evidence for reciprocal modulation of immune and nervous systems is considered. A simple hierarchical model proposes traits that are acted on by environment and experience to produce chronic states of mental health vs. psychic distress; these states determine baseline immunocompetence and response to afferent signals during acute immune challenge. Multidisciplinary interest in psychoneuroimmunology has accelerated the rate of inquiry into the mechanistic details of immunoregulation and has generated new appreciation for the pervasive effects of mental status on physiologic homeostasis.

Effects of naloxone-HCl on cortisol levels in patients with affective disorder and normal controls.

Cortisol levels were measured before and after administration of naloxone-HCl in patients with affective disorder (n = 16) and normal control subjects (n = 8). On two consecutive days, 20 mg of naloxone-HCl or placebo was administered i.v. over 15 minutes in a double-blind crossover design. Blood samples were collected at 30, 15, and l minute(s) both before and after infusion. Cortisol rose from a mean baseline level of 14.8 microgram% to a mean peak level of 23.1 microgram% following the naloxone administration. Significant cortisol increases were found in both the 15- and 30-minute samples during the naloxone session. There were no differences between patient and normal subject samples or between diagnostic groups. A subgroup of manic patients who had responded to naloxone with a reduction of their manic behavior also had an attenuated cortisol response to naloxone. This proved to be an artifact secondary to variability in the cortisol response in these patients.

A kinetic analysis and replication of decreased platelet serotonin uptake in depressed patients.

Platelet serotonin uptake was kinetically measured in 32 psychiatric inpatients and 32 age- and sex-matched controls. Patients were categorized into four groups: depressed patients, manic bipolars, other affective disorders, and nonaffective psychiatric disorders. A randomized block factorial analysis of variance indicated that the depressed patients had a significantly lower maximal velocity (Vmax) of serotonin uptake in comparison to matched controls, without a statistically significant difference in Km. No statistically significant difference was found for any of the other diagnostic groups in comparison to controls for Vmax or Km. These results are compared with previous studies of platelet serotonin transport in clinically depressed patients and in physostigmine-induced depression.