Effects of serotonin on memory impairments produced by ethanol.

Subjects treated with low or high doses of ethanol demonstrated impaired memory, particularly in tests involving the recall of poorly learned information. Zimelidine, an inhibitor of serotonin reuptake, reversed this ethanol-induced impairment. The serotonin neurotransmitter system may mediate learning and memory in humans and may determine some of the effects of alcohol on higher mental functions.

The mechanisms of action of lithium. I. Effects on serotoninergic and noradrenergic systems in normal subjects.

The effects of 2 weeks of lithium carbonate administration at therapeutic plasma levels were examined in 11 normal volunteers. Serotoninergic function before and after lithium administration was assessed using low-dose intravenous clomipramine hydrochloride challenge, while urinary and plasma metabolites of norepinephrine (NE) were used to assess noradrenergic systems. Long-term lithium administration in normal subjects did not significantly or consistently enhance serotonin-mediated neuroendocrine responses but did increase measures related to neuronal release of NE. No statistically significant effects of lithium on prolactin, corticotropin, or cortisol responses to serotoninergic challenge could be detected. The probability of a type II error was assessed, and a doubling of prolactin level was unlikely to have been missed, although more modest increases (less than 75%) could have been overlooked. After 2 weeks of lithium administration, there were significant increases in 24-hour urinary excretion of NE, normetanephrine, and fractional NE release, compatible with increased neuronal release of NE and a lithium-induced subsensitivity in alpha 2-adrenergic receptor function. These changes were not statistically significant after 1 week of administration, suggesting that increased NE release is characteristic of long- rather than short-term lithium administration. Since previous reports have demonstrated enhanced prolactin responses after short- but not long-term lithium use, the present study points to temporal specificity in lithium's effects on both serotoninergic and noradrenergic function. Lithium's effects on NE release were consistent but small (a 16% increase), while its effects on serotoninergic responses were larger (a 50% increase in prolactin responses) but quite inconsistent, suggesting that neither of these systems is the primary site of action of lithium.

Bupropion in depression. I. Biochemical effects and clinical response.

We studied the biochemical effects of bupropion hydrochloride, a unicyclic antidepressant, in 11 depressed patients. Plasma homovanillic acid level increased significantly in patients who had poor responses to treatment but not in patients who obtained good clinical responses. Although bupropion is characterized preclinically as a weak dopamine reuptake inhibitor without appreciable effects on norepinephrine (NE) reuptake, it reduced whole-body NE turnover without altering plasma NE levels at rest and following orthostatic challenge. There was a trend toward a reduction in cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and homovanillic acid concentrations following bupropion treatment, although these changes did not achieve statistical significance. Reduction in whole-body NE turnover has now been described for six disparate antidepressant treatments. Poor clinical outcome following treatment with bupropion may be related to perturbations in dopaminergic systems.

Monoamine neurotransmitter interactions and the prediction of antidepressant response.

Clinical studies of monoamine neurotransmitter function in depression have concentrated on individual monoamines without focusing on interactions between monoamine systems. Virtually all modern studies have found significant correlations between monoamine metabolite concentrations in cerebrospinal fluid (CSF). These correlations should in part reflect interactions between central monoamine systems. In the present analysis, CSF had been obtained from depressed patients before (n = 40) and after (n = 36) antidepressant treatment. The patients were grouped based on their response to treatment. Absolute concentrations of CSF monoamine metabolites (homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylethyleneglycol) did not differ between the two groups before or after treatment. However, when correlations between metabolites were compared, nonresponders to treatment differed considerably from responders. In responders, as in previously described normal populations, all three metabolites correlated with one another before and after treatment, and treatment-induced changes in metabolite concentrations also correlated with one another. In contrast, metabolites in nonresponders did not correlate with one another before treatment, nor did treatment-induced changes correlate with one another in this group. Furthermore, correlations between treatment-induced changes in metabolites differed significantly between responders and nonresponders, and there was a trend for pretreatment correlations to differ as well. The lack of correlation between monoamine metabolites in nonresponders suggests that interactions between monoamine systems may be disrupted in these individuals. Using CSF metabolite correlations to study neurotransmitter interactions may have clinical relevance and yields information not available from examining neurotransmitters in isolation.

Exaggerated orthostatic responsivity of plasma norepinephrine in depression.

An orthostatic challenge paradigm was used to assess noradrenergic regulation in depressive disorders. Plasma norepinephrine (NE) concentrations and concurrent blood pressure and pulse were measured at rest and after five minutes of standing in groups of bipolar (N = 22) and unipolar (N = 19) depressives and in 12 partially age-matched healthy female volunteers. Supine plasma NE levels were significantly lower in bipolar patients than in either unipolar depressives or normal volunteers. Following the orthostatic challenge, the fractional NE increase in both patient groups--particularly the bipolar group--was greatly exaggerated, exceeding that in the controls by approximately 100%. Nonetheless, the postural cardiovascular changes--elevations of diastolic blood pressure and heart rate--failed to distinguish the three subject groups. Noradrenergic dysregulation in depression thus is characterized by inefficient hyperreactivity to physiologic stress.

Bupropion in depression. II. The role of metabolites in clinical outcome.

We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.

Antidepressants reduce whole-body norepinephrine turnover while enhancing 6-hydroxymelatonin output.

The effects of antidepressant treatment on noradrenergic function were studied in 27 patients with a major affective disorder. Twenty-four-hour urinary excretion of 6-hydroxymelatonin and "whole-body norepinephrine (NE) turnover," ie, 24-hour urinary output of NE and its major metabolites 3-methoxy-4-hydroxyphenylglycol, vanillylmandelic acid, and normetanephrine, were measured before and after treatment with the tricyclic desipramine hydrochloride, the aminoketone bupropion hydrochloride, the nonselective monoamine oxidase (MAO) inhibitor tranylcypromine sulfate, and the specific MAO type A inhibitor clorgiline. 6-Hydroxymelatonin excretion increased following antidepressant treatment, while at the same time whole-body NE turnover was reduced. These findings support the hypothesis that antidepressant therapy increases noradrenergic "efficiency," in that functional output, as measured by 6-hydroxymelatonin, is maintained while total NE production is decreased.

Selective antidepressants and cerebrospinal fluid. Lack of specificity on norepinephrine and serotonin metabolites.

Cerebrospinal fluid concentrations of the norepinephrine metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid, were measured in depressed patients before and after treatment with three putatively specific antidepressants. The expected specificity of action on these three neurotransmitter metabolites was not observed. Desipramine hydrochloride, a norepinephrine uptake inhibitor, reduced 5-HIAA as well as MHPG concentrations; zimeldine hydrochloride, a serotonin uptake inhibitor, reduced MHPG as well as 5-HIAA concentrations; and clorgyline, a selective monoamine oxidase type A inhibitor, which might be predicted to most affect 5-HIAA, dramatically reduced MHPG, moderately reduced homovanillic acid, and only modestly reduced 5-HIAA concentrations.

The effect of short term lithium administration on suppressibility of parathyroid hormone secretion by calcium in vivo.

We performed graded calcium infusions twice in six normal young men, once without medication and a second time after they had received therapeutic doses of lithium carbonate for 5 days. The serum lithium level was 0.73 +/- 0.08 meq/liter (mean +/- SE) at the beginning of the calcium infusion and reached 0.97 +/- 0.13 150 min after receiving a lithium dose (210 min after beginning the test). There was no significant difference in mean basal serum calcium, plasma PTH, or nephrogenous cAMP for the untreated and treated periods. There was also no significant difference in calcium suppressibility of PTH secretion, as reflected by changes in nephrogenous cAMP. Changes in plasma PTH in response to calcium infusion likewise did not differ for the two periods, with the exception of a slightly greater degree of suppression in the unmedicated state (77% vs. 57% on lithium: P less than 0.02, by paired t test) at the last time point of the calcium infusion. The data show that short term administration of therapeutic doses of lithium does not alter the set-point for calcium suppression of PTH secretion in man. Further studies of calcium suppressibility of PTH secretion in subjects receiving long term lithium therapy will be needed to evaluate the pathophysiology of lithium-induced hypercalcemia.

Dexamethasone suppression test in primary depression: significance of family history and psychosis.

The overnight dexamethasone suppression test (DST) was administered to 31 inpatients with endogenous depression. DST results were abnormal in 42% of the group and in 67% of those patients with psychotic depression. Division of the sample into genetic subtypes based on family history criteria of Winokur et al. failed to replicate his group's DST findings. Subjects with sporadic depressive disorder, especially delusional patients, had a higher rate of dexamethasone nonsuppression than the others. Familial pure depressive patients did not show the expected greater frequency of DST abnormality compared to the depression spectrum disorder group.

Hypothalamic--pituitary--adrenal axis and monoamine transmitter activity in depression: a pilot study of central and peripheral effects of electroconvulsive therapy.

Central and peripheral measures of hypothalamic--pituitary--adrenal (HPA) axis and monoamine neurotransmitter activity were assessed in 8 depressed patients during a medication-free period and again after completion of a course of electroconvulsive therapy (ECT). Seven patients responded fully to ECT. At baseline there was corresponding activation of the HPA and noradrenergic systems, with apparent elevation in cerebrospinal fluid (CSF) concentrations of corticotropin-releasing hormone (CRH) in some patients. Neither CRH nor adrenocorticotropin (ACTH) in CSF changed significantly after ECT, with a mean 10% decline in CSF CRH. Urinary free cortisol (UFC) excretion was high both before and after treatment. Although peripheral noradrenergic hyperreactivity at baseline appeared to normalize with ECT, CSF concentrations of the principal norepinephrine metabolite, 3-methoxy-4-hydroxyphenyl-glycol (MHPG) were unaffected and remained correlated with CSF CRH. In contrast, there were increases in the CSF levels of the main metabolite of serotonin in half the patients.

Reduction of norepinephrine turnover by serotonergic drug in man.

Zimelidine (ZIM), a relatively specific serotonin reuptake inhibitor, was administered to 12 hospitalized healthy young male volunteers. Chronic but not acute ZIM caused a modest (23%) but significant elevation of plasma norepinephrine (NE) measured in the standing but not in the supine position. The 24-hr urinary excretion of NE itself was unchanged on chronic drug, whereas "whole-body" NE turnover was reduced by 1 week of ZIM, as evidenced by lowered excretion rates (both individually and summed with NE) of the metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NM), and vanillylmandelic acid. Lack of effect of ZIM on the NM/MHPG excretion ratio (which is increased by desipramine) indicated that ZIM and its major metabolite, horzimelidine (NZIM) are not acting by NE reuptake blockade. These data are consistent with modulating serotonergic influence on the noradrenergic system. Reduction of NE turnover and increasing the efficiency of the NE neurotransmission may be a common pathway of all clinically effective antidepressant treatments.

Effects of chronic desipramine on plasma norepinephrine concentrations and cardiovascular parameters in elderly depressed women: a preliminary report.

The effect of chronic administration of desipramine, a relatively specific inhibitor of the reuptake of norepinephrine (NE), on heart rate, blood pressure, and concentrations of NE in plasma was examined in elderly depressed women. Plasma NE concentrations rose significantly following administration of desipramine, while there was no significant change in either heart rate or blood pressure. Implications of these findings are discussed with relationship to the selection of appropriate types and doses of antidepressants in the elderly.

Anticholinergic effects and plasma desipramine levels.

Anticholinergic effects of the tricyclic antidepressant desipramine were studied in 12 outpatients. Objective measurements of salivation and pulse rate and subjective ratings of mouth dryness and palpitations were made before and during treatment with desipramine at a final daily dosage of 150 mg. There were significant changes after 3 wk of treatment in all parameters except ratings of palpitation. Subjects with moderate or high plasma desipramine levels had more suppression of salivation than those with low levels. Changes in salivation and pulse did not correlate, nor did they correlate with subjective reports.

Differences in lithium effects in depressed and healthy subjects.

To evaluate the neurotransmitter actions of lithium without the confounding biochemical abnormalities associated with affective disorders, Li was given to 12 hospitalized healthy young men. After a 600-mg loading dose, subjects were placed on "therapeutic" Li doses averaging 1225 +/- 300 mg for 1 wk, reaching steady-state plasma levels of 0.82 +/- 0.17 mEq/l. Cardiovascular function at rest and diastolic blood pressure and pulse on standing were not altered by Li. Average baseline plasma norepinephrine (NE) concentration in the supine position (1.07 +/- 0.50 pmol/ml) did not change after 1 wk of Li dosing (1.16 +/- 0.57 pmol/ml). There was similar variability, without mean change, in plasma NE increments after orthostatic challenge and in plasma 3-methoxy-4-hydroxyphenylglycol concentrations before and during Li dosing. Urine volume was stable throughout the week of drug dosing, during which daily NE excretion was constant. In contrast to earlier data obtained in patients with depression receiving Li, there were no Li-related decrements in average whole-body NE or dopamine turnover. Mean daily urinary excretion rates of serotonin and its major metabolite 5-hydroxyindoleacetic acid did not change throughout the study. Our and other studies suggest that Li has a corrective action in patients with depression and hypothesized neurotransmitter abnormalities, but Li does not affect individuals without affective disorders.

The effects of antidepressants on the cerebrospinal fluid homovanillic acid/5-hydroxyindoleacetic acid ratio.

Dopamine and serotonin systems are morphologically interconnected in the midbrain. Several studies have also demonstrated a functional relationship between these two monoamine systems. Concentrations of their metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA), consistently correlate with one another in human cerebrospinal fluid. Previous studies of the effects of antidepressants on the dopamine and serotonin systems have focused on the two systems in isolation without considering the interactions between the two. One way of taking this interaction into account may be to form a ratio of dopamine and serotonin measures. The present study measured HVA and 5HIAA in cerebrospinal fluid of 31 patients with depression and 12 patients with Alzheimer's disease before and after treatment with a variety of antidepressant drugs. The ratio of HVA/5HIAA was able to discriminate much more powerfully between effects of different drugs than HVA or 5HIAA examined separately.

Psychoses associated with bupropion treatment.

The authors describe the development of acute psychoses in four patients treated with bupropion, a unicyclic aminoketone antidepressant. In two of the cases the psychoses seemed to be affected by dose. The mechanism responsible for the psychotic reactions is unclear, although it may involve perturbation of dopaminergic systems. On the basis of their experience, the authors offer recommendations regarding the clinical use of bupropion.

Antidepressants. A comparative review of the clinical pharmacology and therapeutic use of the 'newer' versus the 'older' drugs.

Supplementing but not supplanting the original series of tricyclic and monoamine oxidase (MAO) inhibitor compounds, a new generation of antidepressant medications has been developed and marketed throughout the past decade. Constituting a more diverse group of drugs than the standard agents, the newer drugs in general have more selective acute biochemical actions (reuptake blockade of a single neurotransmitter, inhibition of 1 subtype of MAO), enabling more precise targeting of symptoms and avoiding common antidepressant-associated side effects, especially anticholinergic and cardiovascular effects. Moreover, a number of recent additions to this group, such as bupropion and ademetionine (S-adenosyl-methionine), incorporate novel mechanisms of action, challenging previous concepts of how antidepressants work, and offering opportunities for research into the pathophysiology of mood disorders. Caution in prescribing the newer antidepressants must be applied, however, as recent experience, e.g. with nomifensine, suggests that unforeseen toxicities may not appear until a medication has been in use for several years.

Pharmacokinetics of psychotropic drugs in special populations.

Patients treated for psychiatric illness may have a variety of characteristics that alter the pharmacokinetic profiles of psychotropic drugs. Genetic background, age, health status, and personal habits can change the body's ability to absorb, distribute, and metabolize medications. Most psychotropic drugs, with the exception of lithium, are eliminated via biotransformation in the liver rather than renal excretion, and a number of studies have demonstrated distinct phenotypes for hepatic metabolism involving the cytochrome P450 system. "Slow" metabolizers are likely to develop higher plasma concentrations of several different classes of psychotropic drugs, including tricyclic antidepressants. Advancing age reduces renal function but has little effect on hepatic metabolism. Volume of distribution may also be increased in elderly patients because of their greater percentage of adipose tissue. Ethnic background can significantly influence both drug metabolism and the pharmacodynamics of a variety of drugs. Thus, the physician should carefully consider patient characteristics when prescribing psychotropic medications and should engage in therapeutic drug monitoring when there is any doubt about the plasma drug levels that a given dosing regimen will achieve.

Amitriptyline overdose: clinical effects on tricyclic antidepressant plasma levels.

Tricyclic antidepressant (TCA) plasma levels after amitriptyline overdose were reviewed in a retrospective study. Amount of drug taken correlated with total TCA levels. Plasma concentrations were higher in blacks than whites, but no association could be found between TCA levels and age or sex of patients. History of routine use of amitriptyline at the time of overdose did not predict TCA levels, but the one fatality could be shown on the basis of previous steady-state levels to be a slow metabolizer. Serious overdoses as documented by high plasma TCA levels were seen in all major diagnostic groups.