Remy von Frenckell

Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients

A multicenter study compared the antidepressant efficacy and the tolerance of two doses of milnacipran (50 mg and 100 mg/day) and amitriptyline (150 mg/day) in three parallel groups of 45 major depressive inpatients defined by Research Diagnostic Criteria. After a wash-out period of 4–7 days on placebo with lorazepam and/or nitrazepam if necessary, patients were randomly assigned to a daily dose of milnacipran 50 mg, milnacipran 100 mg or amitriptyline 150 mg reached on the 5th day and then stable over a 4-week period, with weekly assessments by means of the Montgomery and Asberg depression scale, the Hamilton depression scale, the Clinical Global Impressions (CGI) and the Target Emergent Signs and Symptoms. Results showed significant superiority of both milnacipran 100 mg/day and amitriptyline over milnacipran 50 mg/day at the end of the treatment period. However, amitriptyline induced a nonsignificant trend toward more rapid improvement after 2 weeks of treatment, mainly based on items related to insomnia, supporting more sedative properties of amitriptyline as compared to milnacipran. Anticholinergic side-effects were significantly lower with milnacipran than with amitriptyline, explaining why milnacipran 100 mg exhibited at the end of the treatment period, a nonsignificantly better efficacy index on the CGI. Moreover, in contrast to milnacipran, amitriptyline was responsible for a significant decrease in blood pressure and a significant weight gain.

Dopaminergic function in panic disorder: Comparison with major and minor depression

Several lines of evidence suggest that dopamine might be involved in anxiety states. In this study, we assessed the growth hormone (GH) response to apomorphine (a dopaminergic agonist) 0.5 mg SC in nine drug-free inpatients meeting Research Diagnostic Criteria (RDC) for panic disorder who were age-matched and gender-matched with nine major depressive, and nine minor depressive inpatients. The three groups differed significantly in their mean GH peak response: 5.29 +/- 2.75 ng/ml in major depressives, 26.27 +/- 12.71 ng/ml in minor depressives, and 37.28 +/- 10.58 ng/ml in panics, with a significantly higher response in panic than in either minor or major depressive patients. These results support dopaminergic overactivity in panic disorder as compared with major and minor depression.

Neuroendocrine evaluation of catecholaminergic neurotransmission in mania

Several lines of evidence suggest catecholamine overactivity (noradrenergic and/or dopaminergic) in mania. We studied the growth hormone (GH) response to clonidine (an alpha-adrenergic agonist) and apomorphine (a dopaminergic agonist) in seven inpatients meeting Research Diagnostic Criteria for mania. They had been completely drug free for at least 3 months before the neuroendocrine procedures and were age- and sex-matched to seven major depressive and seven minor depressive inpatients, drug free for at least 2 weeks. GH was assayed every 20 min for 40 min before and 120 min after either clonidine (0.15 mg i.v.) or apomorphine (0.5 mg s.c.), with an interval of at least 2 days between the tests. The three groups differed significantly in the GH peak response: after clonidine (mean +/- SD), 3.2 +/- 2.4 ng/ml in manics, 3.2 +/- 2.4 ng/ml in major depressives, and 13.2 +/- 8.7 ng/ml in minor depressives; after apomorphine, 10.5 +/- 7.4, 3.2 +/- 1.9, and 26.9 +/- 15.8, respectively. While there were significant differences between manics and minor depressives and between major and minor depressives after both clonidine and apomorphine, manics did not significantly differ from major depressives on either test. These results do not provide neuroendocrine support to the catecholaminergic hypothesis of manic disorders.

Controlled comparison of the efficacy and safety of four doses of suriclone, diazepam, and placebo in generalized anxiety disorder

The anxiolytic activity and tolerance of four doses of suriclone (0.1, 0.2, 0.3 and 0.4 mg tid), diazepam (5 mg tid), and placebo were compared in six parallel groups of 54–59 outpatients with generalized anxiety disorder (DSM III-R). After a 1-week placebo run-in period, the patients were treated for 4 weeks, with assessments at baseline and after 1, 2, and 4 weeks by the Hamilton anxiety scale and the Clinical Global Impressions. Results showed better improvement with active drugs as compared to placebo, without significant differences among the four different doses of suriclone and diazepam. The number of adverse events, particularly drowsiness, was significantly higher with diazepam than with suriclone, particularly 0.1 and 0.2 mg tid which did not differ from placebo. These results demonstrate that suriclone at daily doses ranging from 0.1 to 0.4 mg tid is an effective anxiolytic, better tolerated than diazepam.

Pooling two controlled comparisons of milnacipran (F2207) and amitriptyline in endogenous inpatients. A new approach in dose ranging studies.

Milnacipran is a new potential antidepressant selected for its equipotent inhibition of noradrenaline and serotonin uptake and its lack of effect at any postsynaptic receptor. We recently compared milnacipran 100 and 50 mg/d and amitriptyline 150 mg/d in three parallel randomized groups of major depressive inpatients and found a statistically significant superiority of milnacipran 100 mg/d and amitriptyline over milnacipran 50 mg/d after 4 weeks of treatment. Later on we found similar improvement with milnacipran 200 mg and amitriptyline 150 mg but better tolerance with milnacipran. In order to compare the therapeutic activity of the three doses of milnacipran (50 mg/d, 100 mg/d, and 200 mg/d) we used the responses to amitriptyline as a reference against which to compare the 3 doses of the new drug using analysis of variance on the adjusted data. This approach reveals milnacipran 200 mg is more effective than milnacipran 50 and 100 mg and is the only dose which shows efficacy at least equivalent to that of amitriptyline 150 mg. The dose/efficacy relationship was linear.

Controlled Comparison of Buspirone and Oxazepam in Generalized Anxiety

The anxiolytic activity, the tolerance, and the withdrawal symptoms of buspirone and oxazepam were compared in two groups of 14 and 12 outpatients, respectively, suffering from generalized anxiety in a double-blind study with random allocation of patients. The 6-week active period was preceded and followed by 1 and 2 weeks on placebo, respectively. Clinical assessments were performed before and after the predrug placebo period and every 2 weeks thereafter and included Hamilton anxiety and depression scales and AMDP anxiety subscale. The initial daily dose was 15 mg buspirone or 45 mg oxazepam in 3 intakes and the mean final daily doses were 22.2 and 55.8 mg, respectively. Results showed a slower anxiolytic activity of buspirone compared to oxazepam with less improvement after 2 weeks of treatment. The rebound anxiety following abrupt discontinuation of the drug and the level of side effects did not significantly differ between the two compounds.

Relationship between alpha2-adrenergic function and suicidal behavior in depressed patients

The current main neurochemical theories of the biological correlates of suicidal behavior involve serotonergic and, to a lesser extent, dopaminergic systems. Few data are available about the possible implication of the noradrenergic function. In the present study, we assessed the growth hormone response to clonidine, a selective alpha 2-adrenergic agonist, in 15 DSM-III-R major depressive inpatients with a history of suicide attempts, compared with 15 age- and gender-matched major depressive inpatients without a history of suicidal behavior. Mean (+/- SD) growth hormone peak responses to clonidine were significantly lower in the group of suicide attempters than in the control group: 2.93 +/- 3.01 ng/ml vs. 8.28 +/- 8.15 ng/ml. Therefore, these results suggest that a blunted growth hormone response to clonidine could be a biological correlate of suicidal behavior.

Memory disturbances and dexamethasone suppression test in major depression

Assessed the relationships between hypothalamo-pituitary-adrenal (HPA) activity and memory performance using 16 inpatients (mean age 45.9 yrs) with major depressive syndrome and a memory profile developed by A. Rey (1966). Within 2 wks following hospital admission, HPA assessments (both basal and post dexamethasone suppression test [DST] cortisol levels) and the memory profile were administered. Results suggest that HPA assessments including both basal and post-DST cortisol levels are better correlated with memory processes than isolated post-DST levels.

Prediction of cortisol response to dexamethasone from age and basal cortisol in normal volunteers: A negative study

The dexamethasone suppression test (1 mg at 23 h and 4 P.M. blood collection) was performed in 22 normal subjects. In contrast to a previous study using 0.5 mg dexamethasone and a 8–9 A.M. post-dexamethasone blood sample, age and basal cortisol level did not significantly predict postdexamethasone cortisol levels.

Diagnostic performance of basal free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) ratio in endogenous depression: Comparison with the dexamethasone suppression test

We assessed the 8:00 AM ratio of free cortisol/18-hydroxy-11-deoxycorticosterone (18-OH-DOC) in 56 endogenous depressive inpatients and in 22 normal volunteers. A ratio higher than 40 was associated with a diagnostic sensitivity for endogenous depression of 75%, a specificity of 95.5%, and a diagnostic confidence of 97.7%. These diagnostic results were at least equivalent to the Dexamethasone Suppression Test (DST) using a cortisol cut-off limit of 5 micrograms/dl. This may thus represent a simpler procedure than the DST in the diagnostic analysis of endogenous depression.