[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.

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.

Treatment of mood-congruent psychotic depression with imipramine.

BACKGROUND: Most studies report a poor response of psychotic depressed patients to treatment with a tricyclic antidepressant alone compared to combined treatment with an antipsychotic preparation and compared to non-psychotic depressed patients. However, the issue of optimal treatment of psychotic depressed patients has not been resolved as yet. Previously, we reported a significant difference in response to mirtazapine compared to imipramine in a randomised, double-blind, fixed-blood-level study with in-patients with major depression. In the current study we focus on the treatment response to imipramine in a group of patients with psychotic depression and compare this to patients who manifest no psychotic features. Our aim in presenting these findings was to contribute to the discussion on the optimal treatment of psychotic depressed patients. METHODS: Fifty-two patients with a unipolar major depression (DSM-IIIR), comprising 15 patients with mood-congruent psychotic features and 37 patients with no psychotic features, were commenced on treatment with imipramine after a drug-free and placebo-washout period of 7 days. The dose of imipramine was adjusted for all patients to a predetermined blood level. The Hamilton (HRSD) and Montgomery-Asberg (MADRS) Depression Rating Scales were used to evaluate treatment response. RESULTS: Of the 45 patients who completed the study, nine of the 13 psychotic patients (69.2%) and 14 of the 32 non-psychotic patients (43.8%) responded to treatment. The patients with psychotic features demonstrated a lower mean final HRSD score, together with a greater fall in MADRS score over time, compared to the non-psychotic group. Both these findings remained statistically significant after controlling for a number of possible confounding factors. CONCLUSIONS: These results demonstrate that, in this group of patients with mood-congruent psychotic depression, imipramine used on its own together with strict control of serum drug levels produced a high treatment response rate of 70%. CLINICAL IMPLICATIONS: If replicated, these findings suggest that imipramine with control of blood levels of medication may be a useful first-line treatment for depressed patients with mood-congruent psychotic features. LIMITATIONS: Our sample size was modest. This fact may caution against generalisation of the results.

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.

Lithium and carbamazepine in bipolar disorder.

Lithium is considered first choice in the prevention of prospective episodes in patients with bipolar disorder. However, efficacy is not satisfactory in all patients and side effects sometimes prevent the use of lithium. It is argued that efficacy in clinical practice may be less impressive than anticipated from clinical trials, and alternative treatments are beinu advocated increasingly for that reason, such as the anticonvulsants, carbamazepine and valproate.

Depressed in-patients respond differently to imipramine and mirtazapine.

Tricyclic antidepressants and more recent antidepressants are generally considered to have equivalent efficacy in the treatment of depression. After a previous report of a marked difference in the response to mirtazapine compared to imipramine, we report here an analysis of different symptom clusters. One hundred seven consecutive in-patients with major depression (Diagnostic and Statistical Manual III-R, DSM-III-R) and a Hamilton Rating Scale for Depression (HRS-D) score of 18 points or more were randomly assigned to double-blind treatment. Two and four weeks after predefined blood levels had been obtained, the severity of depression was assessed using the HRS-D. The mean dosages used were 235 mg/day of imipramine and 77 mg/day of mirtazapine, the latter being in excess of the 15-45 mg/day range currently advised. Total HRS-D scores and seven symptom clusters were analyzed in the 85 patients (79%) who were not receiving any co-medication. Imipramine was more effective against the clusters related to core symptoms of depression: "depression and guilt", "retardation", and "melancholia", respectively. Mirtazapine showed a biphasic response with regard to the clusters "sleep" and "anxiety/agitation", respectively, which consisted of a marked response after two weeks of predefined blood level, but with a waning of this effect at four weeks. Imipramine produced a more gradual response on these clusters, which was more pronounced at four weeks than with mirtazapine. Two aspects of the present study could be related to this finding: blood level control resulted in optimal treatment with imipramine but not mirtazapine, and - most importantly - the patients were not receiving any anxiolytic or hypnotic co-medication. These findings suggest that mirtazapine may have anxiolytic and sedative properties and fewer antidepressant properties than imipramine in severely depressed in-patients.

[Two new antidepressants: mirtazapine and venlafaxine]. / Twee nieuwe antidepressiva: mirtazapine en venlafaxine.

Mirtazapine and venlafaxine are two novel antidepressants which are pharmacologically different from other new anti-depressants. Mirtazapine blocks the presynaptic alpha 2-adrenoreceptors and has a benign safety profile. Venlafaxine particularly inhibits the reuptake of serotonin and in higher doses it inhibits the reuptake of norepinephrine as well. Its adverse events profile is similar to that of the selective serotonin reuptake inhibitors (SSRIs). Efficacy studies show that both compounds are effective in depressed outpatients. In depressed inpatients with psychotic features, suicidality or a longlasting episode mirtazapine is not effective and in such patients venlafaxine was not studied.

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.

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.

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.

Self-reported stressors, symptom complaints and psychobiological functioning-II: Psychoneuroendocrine variables.

The present study examined resting endocrinological functioning and endocrine responsivity to new challenges as a function of self-reported stress load and symptomatology. Following a baseline period, four groups of male subjects (low-load/low-symptoms; low-load/high-symptoms; high-load/low-symptoms; high-load/high-symptoms) were exposed to stressful films, followed by a rest period. Blood samples were drawn after each film and after the rest condition, and urinary samples were collected during two nights preceding the experimental session. Neuroendocrine variables measured in plasma included adrenaline, noradrenaline, ACTH, cortisol, growth hormone, prolactin, and testosterone. The urinary samples were assayed for noradrenaline and adrenaline (in relation to creatinin). High-symptom subjects had significantly higher plasma levels of noradrenaline and overnight urinary adrenaline levels, whereas their cortisol levels tended to be lower as compared to the low-symptom group. The plasma noradrenaline/cortisol ratio was higher among the high-symptom subjects. However, upon controlling for neuroticism and life style factors (smoking and alcohol consumption), all but the effects on cortisol failed to meet significance criteria. Higher stress load was associated with higher plasma adrenaline responses during the laboratory session, irrespective of neuroticism or life-style measures. These results therefore suggest that in addition to measuring exposure to real-life stressors, it is also necessary to measure outcomes, such as symptoms, and to be aware of the effects of neuroticism and life-style when attempting to understand which specific psychosocial factors effect psychoendocrinological functioning.

Benzodiazepines for depression? A review of the literature.

The English language literature on the use of benzodiazepines: in depressive disorders was reviewed. We selected double-blind random assignment studies in which benzodiazepines; were compared with reference drugs and/or placebo. Comparative studies with classical (non-triazolo) benzodiazepines in major depression show that these agents do not alleviate the core symptoms of depression, although they do have an effect on sleep and anxiety. Classical benzodiazepines show some efficacy in minor depression, but this conclusion could be related to efficacy in patients suffering from anxiety disorders rather than depression. Triazolo-benzodiazepines, mainly alprazolam, have been found to be effective in mild to moderate depression, although they turned out to be inferior to tricyclic antidepressants (TCAs) in patients with endogenous or melancholic depression. Furthermore it is questionable whether triazolo-benzodiazepines cause amelioration of the core symptoms of depression. With regard to combination therapy benzodiazepines may contribute to antidepressant response in the first weeks, because of a faster onset of effect than TCAs and/or because of effects on different symptoms. Beyond the first weeks of treatment combination therapy does not seem superior to monotherapy with TCAs.

[Addition of lithium to medication in depressive patient resistant to treatment with tricyclic antidepressive agents]. / Toevoeging van lithium aan de medicatie bij depressies die resistent zijn tegen behandeling met tricyclische antidepressiva.

Two women, aged 51 and 65 years, with tricyclic-resistant depression (DSM-III-R) were treated with lithium addition. This is a valuable therapeutic alternative. Interactions and side effects should be closely monitored. Treatment response is possible in a short period of time (1 week), but recovery after lithium addition may also take a few weeks. It is not yet clear which patients will respond to lithium addition and in what way, and which will not. It is advisable to use lithium addition with adequate plasma lithium levels.

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.

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)

Cardiovascular variability after clonidine challenge: assessment of dose-dependent temporal effects by means of spectral analysis.

Effects of four intravenous (i.v.) doses (0.25, 0.5, 1, and 2 micrograms/kg) of the alpha 2-adrenoceptor agonist clonidine (CLO) were studied in 7 normotensive male volunteers in a placebo-controlled double-blind randomized design to evaluate the role of alpha 2-adrenoceptors in spontaneous short-term cardiovascular fluctuations. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP; Finapres device), stroke volume (SV) and total peripheral resistance (TPR) were monitored for 1 h after infusion of CLO while the subjects rested in a semirecumbent position. For HR, SBP, and DBP, power spectra and variation coefficients were calculated for consecutive time segments of 2.5 min. Power 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). Per time-segment, baroreflex sensitivity (BRS) was estimated as the gain (or modulus) in MFB between systolic pressure values and R-R interval times. Decreases in mean levels of SBP and DBP were observed within 15 min after infusion of > or = 0.5 micrograms/kg CLO. HR first showed a slight increase 15 min after infusion of 0.5, 1, and 2 micrograms/kg CLO, but decreased subsequently as in all doses, including placebo. SV and TPR decreased after a dose of 2 micrograms/kg CLO. LFB and MFB power of HR were reduced after 2 micrograms/kg CLO, but only during the first 30 min after infusion; during this period, respiratory depth was also diminished, indicating that these effects may reflect a reduction in sympathetic outflow as well as a reduction in vagal outflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Psychological, cardiovascular, and endocrine changes during 6 hours of continuous infusion of epinephrine or norepinephrine in healthy volunteers.

Psychological, cardiovascular, endocrine, and metabolic reactions to a sustained infusion of epinephrine (E) and norepinephrine (NE) were studied in 10 healthy male volunteers in a placebo-controlled randomized design. The subjects participated each in three sessions during which they received 6-hr infusion of either E (82 pmol/kg/min), NE (178 pmol/kg/min), or placebo (PLA) (saline, 5.4 ml/hr). Heart rate and intra-arterial blood pressure were recorded continuously. Blood samples for assay of catecholamines, cortisol, prolactin, growth hormone, insulin, triglycerides, and glucose were obtained at regular intervals. Changes in subjective mood were assessed with the Profile of Mood States (POMS) and the State-Trait Anxiety Inventory (STAI). During infusion of E, arterial plasma epinephrine levels increased 10-fold, which induced significant increases in heart rate, plasma insulin, and glucose levels, and decreases in mean arterial pressure (MAP) and diastolic pressure (DAP). NE infusion caused a 5-fold arterial plasma norepinephrine increase and induced a significant decrease in heart rate and increases in MAP, DAP, and glucose levels. The effects were present shortly after initiation of the infusions, remained fairly constant during the 6-hr infusion period and disappeared within 1 hr after the infusions had been stopped. Changes in subjective mood were not observed during the infusions, nor after the infusions had been stopped. Infusion of E or NE also had no significant effect on systolic blood pressure, plasma prolactin, growth hormone, cortisol, and triglycerides. Our results show that moderate cardiovascular and metabolic effects can be caused by sustained increases in circulating catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)