[Comparison of the effectiveness of two treatment strategies in inpatients with a depressive disorder. A double-blind study of imipramine followed by lithium addition versus fluvoxamine followed by lithium addition]. / De vergelijking van de effectiviteit van twee behandelingsstrategieën bij opgenomen patiënten met een depressieve stoornis. Een dubbelblind onderzoek met imipramine versusfluvoxamine, gevolgd door lithiumadditie.

BACKGROUND: There is still uncertainty regarding the best treatment optionfor depressed inpatients and the best strategy to follow if patient response is insufficient. AIM: To compare the efficacy of imipramine and fluvoxamine in depressed inpatients who subsequently received lithium supplement in case of poor response. METHOD: After a drug-free period and four days of placebo use, patients were randomised either to imipramine or to fluvoxamine (phase 1); the antidepressant dosage was fixed according to a predetermined plasma level. The efficacy of the antidepressant was evaluated four weeks after the predetermined plasma level had been attained. If patient response was inadequate, the antidepressant was augmented with lithium (phase 2). Patient response to the lithium addition was evaluated three weeks after an adequate lithium level had been attained. RESULTS: The study involved 138 inpatients. At the end of phase 1, imipramine was found to be superior tofluvoxamine according to the Clinical Global Impression of Improvement. Remission was achieved by 6 (23%) patients on imipramine and by 10 (15%) patients on fluvoxamine; this difference was not statistically significant. At the end of phase 2, 41 (9%) patients on imipramine and 27 (40%) patients on fluvoxamine achieved remission, this significant difference demonstrating the superiority of the imipramine strategy. CONCLUSION: Imipramine with subsequent lithium addition is superior to a similar strategy with fluvoxamine.

Urinary excretion of catecholamines and their metabolites in relation to circulating catecholamines. Six-hour infusion of epinephrine and norepinephrine in healthy volunteers.

Some depressed patients have been shown to excrete abnormal amounts of catecholamines and their metabolites in urine. Some studies suggest that hypersecretion of epinephrine by the adrenals and of norepinephrine by the peripheral sympathetic system cause increased excretion of urinary catecholamines and their metabolites in a subgroup of patients. To evaluate the effect of increased catecholamine levels in the peripheral circulation on urinary catecholamine and metabolite levels, we infused healthy volunteers during 6 hours with epinephrine, norepinephrine, or placebo, respectively, in a three-period, double-blind, crossover design. The results indicate that (1) urinary epinephrine and norepinephrine levels were the most sensitive indicators of increased circulating epinephrine and norepinephrine levels, respectively; (2) changes in circulating epinephrine or norepinephrine levels were not readily reflected in changes in urinary vanillylmandelic acid or 3-methoxy-4-hydroxyphenylglycol levels; and (3) increased normetanephrine excretion was not only induced by infusion of norepinephrine but also by epinephrine. This last finding may be due to activation of the sympathetic nervous system by circulating epinephrine. These results may help to explain the mechanism of adrenal epinephrine and sympathetic nervous system norepinephrine hypersecretion observed in subgroups of depressed patients.

Seasonal variations in binding of 3H-paroxetine to blood platelets in healthy volunteers: indications for a gender difference.

Binding of paroxetine to blood platelet membranes was studied longitudinally in 20 healthy volunteers (11 men and 9 women) in order to determine seasonal and gender variations. Blood samples were obtained in September, December, March, and June, and repeated in September. A significant seasonal variation in the maximal number of binding sites (Bmax) was found. Men were found to have significantly lower (Bmax) values than women. Although the pattern of seasonal variation was not identical in men and women, no significant differences were detected. The affinity constant (KD) of paroxetine binding showed a significant seasonal variation. Men were found to have a significantly higher KD (lower affinity) than women. The pattern of seasonal variation was identical in men and women. These data support the evidence indicating a substantial seasonal effect on the serotonergic system, and show that in paroxetine binding studies, groups of subjects should be matched for season and gender.

Cardiovascular, neuroendocrine, and sedative responses to four graded doses of clonidine in a placebo-controlled study.

Effects of four doses of the alpha 2-receptor agonist clonidine (CLO) (0.25, 0.5, 1, and 2 micrograms/kg IV) and placebo were studied in seven healthy men who volunteered in a double-blind randomized design in order to delineate possible presynaptic and postsynaptic components in the mechanism of action of CLO. Blood pressure, heart rate, plasma noradrenaline (NOR), plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma growth hormone (GH), and subjective sedation were monitored for a period of 1 hr following infusion of CLO. NOR and MHPG were also analyzed in urine, collected at 1 and 4 hr after the infusions. Dose-dependent decrements were observed in systolic and diastolic blood pressure and plasma NOR levels, and dose-dependent increases in subjective sedation and plasma GH. CLO did not influence plasma MHPG levels, whereas only urinary MHPG excretion was reduced 4 hr after infusion of 2 micrograms/kg CLO. Because no obvious differences between dose-response relations of plasma NOR (believed to be a presynaptic and peripheral effect), blood pressure (believed to be mainly a central presynaptic and postsynaptic effect), and subjective sedation (believed to be a central and probably postsynaptic effect) were observed, our results do not provide simple parameters to discern the multiple mechanisms of action of CLO. However, at a dose of 0.5 micrograms/kg CLO (a dose lower than that generally used) clear effects on plasma NOR, blood pressure, and sedation, but not on plasma GH (a central postsynaptic effect) or urinary MHPG (a presynaptic effect), were observed. When using CLO as a challenge test in psychiatric disorders, a design with 0.5 micrograms/kg CLO, in addition to the traditional 2 micrograms/kg CLO, may provide more information to characterize discrete abnormalities in the noradrenergic system at the level of the brainstem, the pituitary, or the peripheral sympathetic nervous system.

Relationship between age and incidence of parkinsonism in psychiatric patients treated with haloperidol.

In a retrospective follow-up study of 230 psychotic patients treated with haloperidol, the incidence of parkinsonian side effects was greater in patients under 40 than in patients 40 years of age or older.

Sleeping with and without norepinephrine: effects of metoclopramide and D,L-threo-3,4-dihydroxyphenylserine on sleep in dopamine beta-hydroxylase deficiency.

Sleep characteristics are presented for two female patients (aged 21 and 31 years) with central and peripheral dopamine beta-hydroxylase (DBH) deficiency. This deficiency results in the absence of norepinephrine, epinephrine, and their metabolites in plasma, urine, and cerebrospinal fluid, while concentrations of dopamine are increased. The sleep pattern of these patients was studied when they were untreated, after blockade of central dopamine receptors with metoclopramide, and after restoring norepinephrine production with D,L-threo-3,4-dihydroxyphenylserine (DOPS). When the patients were untreated sleep duration was normal, with tendencies of a decreased amount of rapid eye movement (REM) sleep, presence of alpha-delta sleep, and an increased amount of slow-wave sleep. The amount of REM sleep varied between 18 and 21% of sleep period time. Administration of metoclopramide resulted in a slight reduction of REM sleep to 16-17%, whereas wakefulness after sleep onset increased. During treatment with DOPS, an increase in the amount of REM sleep was observed in both patients to an average amount of 27%. These data indicate that in patients with DBH deficiency norepinephrine is not essential for the development of a normal sleep/wake pattern but may have a facilitatory role in the generation of REM sleep.

Extrapyramidal side effects and oral haloperidol: an analysis of explanatory patient and treatment characteristics.

The incidence of extrapyramidal side effects (EPS) was evaluated in 98 patients treated with haloperidol. The incidence of parkinsonism was higher at higher doses of haloperidol and in younger patients. Prophylactic antiparkinsonian medication was effective in younger but not in older patients. However, these medications were more effective in both young and old patients when given after parkinsonism developed. Akathisia was controlled by the benzodiazepine lorazepam in 14 out of 16 patients, while prophylactic antiparkinsonians were ineffective. The present study points to patient characteristics that may be of significance in the development of EPS due to haloperidol.

Comparison of 2 treatment strategies for depressed inpatients: imipramine and lithium addition or mirtazapine and lithium addition.

BACKGROUND: The purpose of this study was to compare the overall effectiveness of 2 treatment strategies for inpatients with severe major depressive episode (DSM-III-R): (1) mirtazapine (phase 1) and subsequent lithium addition (phase 2) or (2) imipramine (phase 1) and subsequent lithium addition (phase 2). We previously reported the results of phase 1. METHOD: In phase 1, patients were randomly assigned to treatment with either mirtazapine or imipramine, and doses were adjusted to obtain predefined blood drug levels. Nonresponders had lithium added to the double-blind mirtazapine or imipramine medication. The dose was adjusted to obtain a blood lithium level of 0.5-1.0 mmol/L. Treatment effects were evaluated weekly by the Montgomery-Asberg Depression Rating Scale for up to 2 weeks on this blood lithium level. RESULTS: Data for 100 patients were available for comparison of the 2 treatment strategies. 80 patients received no comedication. By the end of phase 2, 24 (48%) of 50 had responded to mirtazapine and 32 (64%) of 50 had responded to imipramine (intent-to-treat analysis). A survival analysis of the total patient group intent-to-treat showed a significant difference in favor of the treatment strategy with imipramine and subsequent lithium addition. CONCLUSION: Efficacy of imipramine and subsequent lithium addition for nonresponders is superior to the same treatment strategy with mirtazapine. This applies to the patient sample studied, which consisted of 100 severely depressed inpatients, 29 of whom were psychotically depressed. More serious side effects of imipramine, however, led to discontinuation of imipramine in 5 patients. No serious side effects were observed during the phase of lithium addition to either imipramine or mirtazapine. We, therefore, prefer to start treatment with imipramine and test for fixed blood drug levels, and, if necessary, add lithium. In the case of prohibitive side effects, patients are switched to a modern antidepressant such as mirtazapine, and, if necessary, lithium is added to this antidepressant.

Patients with congenital dopamine beta-hydroxylase deficiency. A lesson in catecholamine physiology.

We recently described a case of congenital dopamine beta-hydroxylase (DBH) deficiency. The syndrome is characterized by noradrenergic denervation, adrenomedullary failure, but intact baroreflex afferents, cholinergic innervation, and adrenocortical function. Norepinephrine, epinephrine, and their degradation products were undetectable in plasma, urine, and cerebrospinal fluid, whereas dopamine and its degradation products were elevated. Plasma DBH was not detectable. Studies in this novel syndrome showed evidence for the peripheral production of dopamine from sympathetic nerve terminals noradrenergic in nature. Tyrosine hydroxylase is probably induced in this syndrome, since plasma levels of L-DOPA were also elevated. Absence of hemodynamic effects of sympathicolytic agents in the face of an increase in blood pressure after dopamine antagonists suggest that intrasynaptic concentrations of dopamine are in the range of its plasma concentrations. Hypoprolactinemia, reduced REM sleep, increased slow wave sleep and sodium loss, despite low blood pressure, are further evidence for the biological role of dopamine in man.

Effects of alprazolam and lorazepam on catecholaminergic and cardiovascular activity during supine rest, mental load and orthostatic challenge.

Effects of oral alprazolam (0.5 and 1 mg) and lorazepam (2 mg) on sympathetic adrenomedullary activity and sedation were studied during supine rest, mental load (Color Word Test, CWT) and active standing (OCT), in 12 male volunteers in a randomized double-blind placebo-controlled cross-over design. Compared to placebo, alprazolam significantly increased subjective sedation, reduced plasma adrenaline and noradrenaline concentrations and mean blood pressure (MBP) during supine rest, and attenuated plasma adrenaline responses during the CWT and the OCT; these effects during the CWT and OCT appeared to be dose-dependent. In comparison with lorazepam (2 mg), alprazolam (1 mg) showed reduced MBP levels during supine rest, whereas lorazepam showed a higher heart rate level during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (1 mg) and lorazepam regarding subjective sedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and lorazepam induced differential effects on sympathetic adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity may be specific for alprazolam.

Dose-dependent effects of intravenous lorazepam on cardiovascular activity, plasma catecholamines and psychological function during rest and mental stress.

Dose-dependent effects of intravenously administered lorazepam on psychophysiological activity during rest and mental stress were studied in order to examine differential responses to doses which may induce anxiolysis or sedation. In a double-blind randomized cross-over study, nine male volunteers participated in a placebo and a lorazepam session, during which the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.6, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). Heart rate showed a dose-dependent decrease during rest with an ED50 of 0.13 mg lorazepam, while lorazepam had no effect on the cardiovascular and plasma catecholamine response magnitudes to the CWT. Subjective fatigue and reaction time increased significantly after 0.94 mg lorazepam, while at the same dose vigor decreased; state anxiety after the CWT was not influenced by lorazepam. These data show differential effects of lorazepam on cardiovascular, biochemical and psychological function. While heart rate was suppressed at low doses during rest and reaction time and subjective fatigue increased at doses which induced sedation, state anxiety and physiological response patterns to the CWT were not influenced by lorazepam.

Effects of lorazepam on cardiac vagal tone during rest and mental stress: assessment by means of spectral analysis.

Dose-dependent effects of intravenously administered lorazepam on haemodynamic fluctuations were studied by means of spectral analysis, in order to elucidate sympathetic and parasympathetic components in cardiovascular control during situations of rest and mental stress after benzodiazepine administration. In a double-blind randomized cross-over study, nine male volunteers participated in two sessions: a placebo and lorazepam session. During these sessions, the subjects repeatedly performed a 10-min version of the Stroop Color Word Test (CWT), with 10 min of rest between the CWTs. Lorazepam was administered before each rest period in increasing doses of 0.0, 0.06, 0.13, 0.25 and 0.5 mg (total cumulative dose: 0.94 mg). During the placebo session the subjects received five placebo injections. For five of the nine subjects the lorazepam session was their first session. Heat rate (HR), blood pressure (BP) and respiration were recorded continuously. Power spectra were calculated per 2.5-min periods for HR, systolic (SBP) and diastolic BP (DBP). Spectral density was assessed for three frequency bands: low (LFB: 0.02-0.06 Hz), mid (MFB: 0.07-0.14 Hz) and high (HFB: 0.15-0.40 Hz). During the consecutive periods of rest, lorazepam induced a dose-dependent decrease in HR, and a dose-dependent increase in LFB, MFB and HFB power of HR, but lorazepam had no effect on BP. The effects were significant after 0.44 mg lorazepam for HR and HFB power, and after 0.94 mg lorazepam for the HR fluctuations in the LFB and MFB. Lorazepam did not influence the cardiovascular responses to the CWT.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients.

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-levels study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of > or = 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of > or = 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied.

Diagnosis at the first episode to differentiate antidepressant treatment responses in patients with mood and anxiety disorders.

RATIONALE: Co-morbidity of mood and anxiety disorders is often ignored in pharmacotreatment outcome studies and this complicates the interpretation of treatment response. The clinical trials are usually based on single categories from the Diagnostic and Statistical Manual of Mental Disorders (DSM). OBJECTIVES: The present study is a first attempt to differentiate the responses to antidepressants using a design that differs from that used in previous clinical trials. To avoid bias due to co-morbidity, we included patients with any DSM-III-R diagnosis of mood or anxiety disorder for which antidepressant treatment was indicated. We also explored the role of the diagnosis at the first episode in the efficacy of the different antidepressants. METHODS: A total of 92 outpatients with a mood and/or anxiety disorder were randomly assigned to treatment with imipramine or fluvoxamine in a 6-week study. The diagnosis at the first episode--or primary diagnosis--was available for 78 patients, 40 with a primary depression and 38 with a primary anxiety disorder. RESULTS: Analyses using the MIXED procedure for repeated measures showed no general differences between treatment with imipramine and treatment with fluvoxamine. When the primary diagnoses were taken into consideration, differentiation occurred. Patients with primary depression showed better responses to imipramine than to fluvoxamine. The assumption that patients with primary anxiety disorder would respond better to fluvoxamine than imipramine was observed for only the Clinical Global Impression. CONCLUSIONS: The results suggest that the nature of the first illness episode may be more valuable than the DSM categories of mood or anxiety disorders, which may lend support to the concept of primary versus secondary depression for purposes of differentiating treatment responses. Given the exploratory nature of the study, however, replication of our finding is needed.

Spectral analysis of hemodynamics during infusions of epinephrine and norepinephrine in men.

Spectral analysis of fluctuations in heart rate (HR) and arterial blood pressure (BP) during a 6-h infusion of epinephrine (15 ng.kg-1.min-1) or norepinephrine (30 ng.kg-1.min-1) in 10 normotensive males was used to analyze effects of peripheral sympathetic nervous system activity and adrenal medullary discharge on cardiovascular variability. Power spectra were calculated for each 5-min period for HR, systolic BP, and diastolic BP to yield power values for three frequency bands: low (0.02-0.06 Hz), mid (0.07-0.14 Hz), and high (0.15-0.40 Hz). Infusion of epinephrine and norepinephrine induced plasma concentrations of epinephrine and norepinephrine, respectively, within the high physiological range. Spectral analysis showed that low-frequency fluctuations of BP during infusions of epinephrine and midfrequency fluctuations of BP during infusion of norepinephrine changed in opposite directions. These fluctuations may represent different components of short-term cardiovascular control mechanisms during situations that mimic increased sympathoadrenal activity. No changes were observed in HR fluctuations or high-frequency fluctuations of BP after either catecholamine. Our data imply that changes in concentrations of circulating catecholamines cannot be unequivocally labeled as indexes of an altered sympathoadrenal involvement in short-term cardiovascular control.

Trait anxiety and the effect of a single high dose of diazepam in unipolar depression.

In this cross-sectional study we explored in 101 depressive in-patients (DSM III-R) the association between level of trait anxiety and variables that have been investigated previously to discern primary and secondary depression, respectively. Besides, we explored the influence of trait anxiety level on difference in treatment response to either imipramine or mirtazapine. Trait anxiety was measured interviewing a close relative of the patient using a questionnaire related to aspects of psychic anxiety and to aspects of somatic anxiety. The interviewer focussed on fluctuating anxiety symptoms without persistent mood disturbance during the patient's normal lifelong functioning before developing a depressed mood. We found no relation between trait anxiety level and treatment response to either imipramine or mirtazapine. The most important finding of this study is the significant differential response to the diazepam test: depressive patients with high trait anxiety showed, predominantly, a disappearance of depressive symptoms without sedation and depressive patients with low trait anxiety showed, predominantly, sedation without disappearance of depressive symptoms. The opposite response to the diazepam test in patients with a different history of trait anxiety in spite of similar depressive symptomatology suggests differences in underlying pathophysiologic mechanisms.

A procedure to measure the specific activities of dopamine and its metabolites in rat striatum, based on HPLC, electrochemical detection and liquid scintillation counting.

A procedure to determine the specific activities (s.a.) of the putative neurotransmitter dopamine (DA) and its metabolites in rat striatum is described. For this purpose 200 mu Ci L-[3,5-3H]tyrosine was injected via a jugular vein cannula into freely moving rats. Contents and radioactivity of striatal tyrosine, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) were determined by means of HPLC, electrochemical detection (ECD) and liquid scintillation counting. In the phase system applied DA, DOPAC, 3-MT and HVA can be separated in a single run after direct injection of striatal supernatants. The selectivity of the phase system was sufficient to analyse the supernatant of two rat striata over a 150 X 4.6 mm column, even when DA turnover was strongly stimulated. Tyrosine levels and radioactivity were measured by re-analysis of the front peak with divergent mobile phase parameters. In order to demonstrate the applicability of the present procedure, the s.a. of DA and its metabolites, as found 20 min after [3H]tyrosine administration, and the effect of haloperidol thereupon, are presented.

Effects of morphine on dopamine metabolism in rat striatum and limbic structures in relation to the activity of dopaminergic neurones.

Administration of morphine results in efflux of dopamine provided that the nerve impulse flow of the dopaminergic neurones is impaired. In the present study we investigated whether the morphine-induced increase in dopamine metabolite levels is related to impulse flow in a similar way. Pretreatment with gamma-butyrolactone to impair nerve impulse flow, abolished the effect of morphine on the concentrations of dihydroxyphenylacetic acid and homovanillic acid. Pretreatment with apomorphine had a similar effect, as well as combined pretreatment with gamma-butyrolactone and apomorphine. Since gamma-butyrolactone and apomorphine both reduce nerve impulse flow, but gamma-butyrolactone increases while apomorphine decreases dopamine biosynthesis, it would appear that the antagonism of morphine-induced increases in dopamine metabolites is due to the common property of impulse flow reduction. It was also shown, however, that pretreatment with alpha-methyl-paratyrosine, which inhibits dopamine biosynthesis, resulted in antagonism of morphine's effect on dopamine metabolite levels. It is concluded, therefore, that morphine-induced dopamine efflux is observed under conditions when no effect on dopamine metabolism is observed, and vice versa. Three effects of morphine on dopaminergic neurones can be distinguished: an increase in impulse flow in nigrostriatal dopaminergic neurones, increased dopamine biosynthesis and catabolism, and efflux of dopamine. The first effect probably is effected in the cell body areas, while the latter two effects may be produced at the level of the nerve terminals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of diet on urinary excretion of unconjugated catecholamines and some of their metabolites in healthy control subjects and depressed patients.

The effect of a low-monoamine diet on the 24-h urinary excretion of unconjugated catecholamines and some of their metabolites was investigated. Total (unconjugated and conjugated) 3-methoxy-4-hydroxy-phenylglycol excretion was 15% to 20% lower under the low-monoamine diet, both when calculated per 24 h and per creatinine excretion. No effect on the concentrations of unconjugated urinary catecholamines, unconjugated vanillylmandelic acid, or total normetanephrine was observed. It is concluded that, for diagnosis of neural crest tumors, no dietary restrictions are necessary, provided analytical methods such as presented are used. When 24-h urines are analysed for MHPG, however, as in psychiatric studies, dietary effects must be taken into account, especially when small differences in excretion are expected.