Acute noradrenergic effects of desipramine in depression.

As a probe of the noradrenergic system in depression, single oral doses of the tricyclic antidepressant desipramine (100 mg) and placebo were administered to unipolar and bipolar depressed patients and healthy volunteers. Plasma concentrations of norepinephrine (NE) were determined 2-3 hours after dosing, with subjects in supine and upright positions. On the placebo day plasma NE was low in a subset of bipolar patients; both groups of depressives demonstrated an exaggerated increase in plasma NE upon standing. After desipramine dosing, the orthostatic procedure resulted in even greater relative increments in plasma NE in both patient groups, with no change in volunteers. These data are consistent with noradrenergic dysregulation in depression.

Subjective response during continuous infusion of cocaine.

The relationship between the subjective effects induced by IV cocaine injection(s) and cocaine plasma concentrations is complex and difficult to interpret. We designed a study in which bolus loading doses of cocaine followed by 4-hr placebo infusions were compared with the same bolus loading doses of cocaine followed by 4-hr infusions of cocaine calculated to maintain the peak plasma concentrations produced by the bolus. Seven cocaine-using volunteers were successfully studied using a randomized double-blind design, in which self- and observer-rating scales were used to measure drug effects. After the cocaine bolus loading doses, scores for most subjective measures remained elevated when the bolus was followed by a cocaine infusion. In contrast, the subjective responses returned to baseline when the bolus was followed by a placebo infusion. However, self-estimates of the intensity of the cocaine "rush" were not altered by the presence of active cocaine infusions and returned rapidly to baseline.

Cardiovascular responses to cocaine placebo in humans: a preliminary report.

Cardiovascular responses after placebo-cocaine injections were in the same direction as the effect of cocaine iv in 22 male volunteers. Subjects received iv placebo in a room where they had been given repeated doses of iv cocaine. The placebo response consisted of an increase from baseline values of systolic and diastolic blood pressure and pulse rate. The control group, 8 subjects, which was not exposed to a conditioning phase, showed a smaller increase in the pulse rate and systolic blood pressure after the placebo injection. The results, in accordance with animal literature, suggest the existence of cocaine-conditioned effects in humans.

Effects of intravenous cocaine are partially attenuated by haloperidol.

We examined the effect of the dopaminergic blocking agent, haloperidol, on the subjective and physiologic response to cocaine in cocaine-using volunteers. Five subjects received cocaine (40 mg) or placebo administered intravenously 20 min following pretreatment with haloperidol (8 mg) or placebo intramuscularly in a randomized double-blind study design. Haloperidol pretreatment attenuated cocaine-induced increases in systolic and diastolic blood pressure but not heart rate. Pretreatment with haloperidol reduced subject ratings of pleasant sensations but had no effect on drug "rush." Haloperidol (8 mg) has a small and limited effect on the subjective response to cocaine when given 20 min before cocaine.

Cocaine-induced cocaine craving.

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both "wanting" and "craving" for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug "wanting" and drug "craving" were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.

Intravenous cocaine: psychiatric effects, biological mechanisms.

Volunteer addicts were administered iv loading doses of cocaine, followed by 4-hr cocaine infusions that maintained steady-state conditions. The loading doses were followed by the "rush" and "high" subjective effects that users typically experience; cocaine infusions maintained the experience of drug "high", but not "rush". In a subsequent experiment, haloperidol pretreatment did not alter cocaine "rush" but partially attenuated cocaine "high." During cocaine infusions, we also noted suspicious and paranoid behavior, which were blindly rated by nurses. During one of the infusion conditions, the degree of suspiciousness observed was related to the amount of cocaine previously administered. Although cardiovascular responses to cocaine were marked, we found no alterations in plasma catecholamines following cocaine administrations. Baseline homovanillic acid (HVA) levels, however, were related to the degree of suspiciousness observed following cocaine dosing. The potential contributions of dopaminergic systems and physiological sensitization to the development of the psychiatric toxicity of cocaine are discussed.

Suspiciousness induced by four-hour intravenous infusions of cocaine. Preliminary findings.

Cocaine hydrochloride was administered to experienced users as an intravenous (IV) loading dose of 40 to 80 mg, followed by four-hour continuous IV infusions of either cocaine or placebo. Rates of cocaine infusion were individualized to maintain steady-state cocaine concentrations for the duration of the infusion. During the infusions, subjects rated themselves on questions that assessed their suspiciousness and paranoia, and nurse-observers took descriptive notes on the subjects' behavior; these notes were later scored on a scale for guarded, suspicious, and paranoid behavior. Nurses observed and rated moderately suspicious behavior when cocaine IV bolus loading doses were followed by cocaine infusions, but not when loading doses were followed by saline solution infusions; subjects did not rate themselves as suspicious during any of the study conditions. Suspiciousness during low-dose cocaine infusions significantly correlated with the amount of cocaine previously administered to the subjects. Suspiciousness during infusions was not related to plasma cocaine concentrations, preadmission drug use, or psychiatric symptoms and history. Cocaine infusions may be a useful tool to pursue the biology of stimulant psychoses.

The diurnal variation in plasma homovanillic acid level persists but the variation in 3-methoxy-4-hydroxyphenylglycol level is abolished under constant conditions.

Plasma concentrations of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were determined every two hours for two consecutive days in seven depressed patients and seven matched normal controls. On the first day subjects followed their regular ward routine. On the second day they were placed on a regimen in which activity, posture, diet, and wakefulness were held constant. There were significant diurnal variations in both MHPG and HVA concentrations on the baseline day, whereas on the constant routine, a diurnal variation was present only in HVA. We conclude that diurnal variations in plasma MHPG are evoked by changes in physical activity, posture, or other factors controlled on the constant routine, and that a major component of the diurnal variation in plasma HVA concentrations is regulated by a circadian oscillator that is independent of sleep or activity.

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.

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.

Effects of S-adenosyl-methionine on plasma norepinephrine, blood pressure, and heart rate in healthy volunteers.

S-adenosyl-methionine (SAMe) is currently undergoing trials as a possible antidepressant. Because SAMe's mechanism of action is obscure and norepinephrine (NE) is often implicated in affective disorders, we studied the effects of SAMe on this neurotransmitter in volunteers. Plasma NE and 3-methoxy-4-hydroxyphenylglycol (MHPG) in the supine and standing position were studied before and after acute placebo or a single 400 mg dose of SAMe and following seven daily administrations; concomitant measures were heart rate (HR) and blood pressure. Subjects were unable to distinguish acute drug from placebo, and although chronic SAMe administration was open, they reported no behavioral effects. Standing HR and plasma NE were reduced following chronic SAMe. Qualitatively similar changes are obtained following chronic treatment with monoamine oxidase inhibitors (MAOIs). However, unlike MAOIs, chronic SAMe treatment was not associated with changes in plasma MHPG. Exaggerated standing NE is found in depressed patients; SAMe may reduce this abnormal response, providing a clue for its mechanism of action in depression.

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.

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.

Effects of melatonin on performance testing in patients with seasonal affective disorder.

Psychomotor performance and memory were assessed in 6 patients with seasonal affective disorder following one week of daily administration of oral melatonin. No effect was noted on either vigilance or memory testing, but reaction time on a simple visual/tactile task was significantly reduced. Identical testing following a week of placebo administration showed no changes from baseline. Clinical status was monitored by both observer and self ratings; no clinical changes were detected that could account for the performance difference. The reaction time finding is in contrast to a previous report of a reaction time increase following melatonin administration. We discuss the possibility that this discrepancy is due to different dosages of melatonin administered or to the effects of melatonin on circadian rhythms of performance.