Baseline characteristics of major depressive disorder patients in clinical trials in Europe and United States: is there a transatlantic difference?

There is a widely spread belief that different patients are being recruited into antidepressant clinical trials conducted in Europe and the USA which is probably generated by the fact that recruitment strategies vary between the two continents. In order to get an insight into the patients' characteristics in clinical studies on both continents, we compared the baseline characteristics of depressed patients in a database of a cancelled development program of an antidepressant (2220 patients, Intention-to-Treat group). For the evaluation of continental differences, we compared the elements of demographics, previous psychiatric history, DSM-III-R criteria, HAM-D and MADRS total scores and separate items and/or factors and CGI severity scores at baseline. USA patients had statistically significantly higher baseline values on height, weight and BMI. European patients showed statistically significantly higher baseline severity scores on HAM-D, MADRS and CGI. Furthermore, European patients had statistically significantly higher baseline scores on HAM-D factors I ('anxiety/somatization'), VI ('sleep disturbance'), and HAM-D Angst anxiety/agitation factor, whereas USA patients had a statistically significantly higher baseline value on the Bech depression factor and the HAM-D Angst retarded depression factor. European patients appear to have a more severe depressive episode with more anxiety and melancholic features. Some of the statistically significant differences found may be the result of a large sample size and are probably without any clinical relevance when the absolute size of the difference is taken into account. Our opinion is that the differences found in our sample between European and USA populations are much smaller than is generally expected and not of a magnitude that would question the reliability of the results obtained in our global world-wide, antidepressant drug development program. If our findings were reproducible in other antidepressant databases it would indicate that data gathered in Europe and the USA within a global antidepressant drug development can be pooled.

A prospective, randomized study to assess the tolerance and efficacy of intramuscular and subcutaneous administration of recombinant follicle-stimulating hormone (Puregon).

OBJECTIVE: To compare local tolerance and clinical efficacy after i.m. or s.c. injection of recombinant FSH (Puregon; NV Organon, Oss, The Netherlands). DESIGN: An open-label, prospective, randomized, group-comparative, multicenter study. SETTING: Twelve IVF clinics in 10 countries. PATIENT(S): Two hundred eighteen infertile pituitary-suppressed women undergoing IVF-ET were randomized, of whom 195 (i.m., n = 77; s.c., n = 118) received recombinant FSH. INTERVENTION(S): One cycle of controlled ovarian hyperstimulation induced by either i.m. or s.c. injection of recombinant FSH, followed by IVF-ET. MAIN OUTCOME MEASURE(S): Local tolerance symptoms, number of oocytes retrieved, ongoing pregnancy rate. RESULT(S): The incidences after i.m. injection of bruising, pain, redness, swelling, and itching were 37.7%, 31.2%, 13.0%, 7.8%, and 6.5%; after s.c. injection, the corresponding figures were 54.2%, 28.0%, 16.1%, 5.9%, and 3.4%. Only bruising was significantly lower in the i.m. group, which could be attributed to the more visible superficial injection site with s.c. administration. The overall occurrence of local symptoms were 63.6% after i.m. injection and 68.6% after s.c. injection. The mean numbers of oocytes recovered were 9.8 (i.m) and 10.4 (s.c.) and the ongoing pregnancy rates per attempt were 27.1% (i.m.) and 26.1% (s.c.), respectively. CONCLUSION(S): There were no marked differences in local tolerance symptoms and clinical efficacy between i.m. and s.c. administration of recombinant FSH.

Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study.

Of 580 patients randomly assigned to short-term, double-blind treatment with either mirtazapine, amitriptyline or placebo, a total of 217 patients clinically judged to be responders subsequently continued on the same medication for up to 2 years in the long-term treatment study (mirtazapine, n = 74; amitriptyline, n = 86 and placebo, n = 57). The efficacy of mirtazapine in relapse prevention was seen in an analysis of the first 20 weeks data. Significantly fewer patients relapsed during treatment with mirtazapine compared with placebo (p < 0.05), and a significantly longer time to relapse was shown on the survival analysis. There was a significant advantage for amitriptyline compared with placebo in the first 20 weeks, with fewer patients relapsing. There was a significant advantage for mirtazapine compared with amitriptyline at 20 weeks seen on the survival analysis (p < 0.05). The significant advantage for mirtazapine compared with placebo was also seen in the prophylactic phase of treatment after 20 weeks. At the endpoint there were significantly more patients in the placebo group with a return of symptoms and significantly fewer showing sustained response. Amitriptyline was better than placebo with fewer patients suffering a recurrence of symptoms, but there was no difference from placebo in the proportion of patients with sustained response. Mirtazapine was well tolerated with a side-effect profile similar to that of placebo. The only adverse event reported significantly more frequently on mirtazapine than on placebo was weight gain. Objectively measured weight gain was more frequent with amitriptyline (22% of patients) compared with mirtazapine (13% of patients). Amitriptyline was associated with significantly more adverse events than either mirtazapine or placebo, in particular sedative and anticholinergic side effects. The efficacy of mirtazapine in reducing the risk of relapse and the recurrence of depression, which on some measures showed an advantage compared with amitriptyline, coupled with its improved side-effect profile, commends this antidepressant for the long-term treatment of depression.

Comparing the onset of action of antidepressants: Comparison of different criteria applied to the same data set.

The issue of early onset of action (EOA) of an antidepressant was addressed by several authors. Unfortunately so far there is neither consensus nor convention on the definitions of EOA, or on measures and methods of assessments. There are several quite different approaches to the statistical analysis of the data. Our objective was to compare the results concerning EOA obtained by different statistical techniques applied on a data set which was generated by several independent conclusive double-blind, placebo controlled randomised trials with two antidepressants. The following statistical techniques were used: 1) statistically significant difference for the first time; 2) statistically significant and clinically relevant difference for the first time; 3) pattern analysis; 4) classical survival analysis without 'sustained response'; 5) survival analysis with sustained response. The advantages and drawbacks of different methods are discussed.

Selecting investigators for a placebo controlled clinical trial: The most critical decision point?

We have analysed the trial results obtained in two placebo and imipramine controlled double blind studies with a new psychotropic compound. Statistical analysis as outlined in the protocol showed a rather meagre therapeutic effect of imipramine of 1.53 points difference on HAMD-17 total score in comparison to placebo. In order to increase the discriminative power of the analysis we performed a post hoc analysis selecting centres that were able to detect a difference of at least two centres points between imipramine and placebo on HAMD-17 total score at week 6 (selective centres). All other were called nonselective. The analysis revealed that there were no statistically significant differences between the two types of centres concerning patient characteristics except that the nonselective centres recruited less patients with previous good response to antidepressant treatment. There was also some difference in drop out rates in the active treatment group wich might indicate different treatment strategies in the two groups of centres that participated in this trials.

[Performance of a rescue breathing device with glossopalatinal tube]. / Die Leistungsfähigkeit eines Atemspende-Hilfsmittels mit glossopalatinalem Tubus.

The "Lifeway" is a device for rescue breathing consisting of a mouthpiece for the rescuer, a non-rebreathing valve, a mouth-sealing cap and a glosso-palatinal tube (GPT) reaching into the patient's mouth. 54 patients--22 toothless and 32 with firm teeth--were ventilated mechanically via the original "Lifeway", via a variant with additional side-holes in the GPT, and, for comparison, via anaesthesia mask plus oropharyngeal airway and via endotracheal tube. Ventilation was sufficient: The arterial oxygen saturations, measured by pulse oximetry, and the end-tidal CO2 partial pressures were equal to those during ventilation via mask. Placing the modified "Lifeway" in toothless patients was significantly easier than placing the original and as easy as placing the mask; with the patients having firm teeth there were no significant differences. The incidence of obstructions, as registered by impediments to exhalation and by increases in peak inspiratory pressure, was significantly less frequent with the modified device, since the tongue could be "scooped" to a ventro-caudal direction if necessary. The modified "Lifeway" was as effective as the combination of anaesthesia mask and pharyngeal airway. The problems of the latter are, however, avoided; the use of the device by laymen thus seems feasible.

Factors that influence the outcome of placebo-controlled antidepressant clinical trials.

An important issue in judging the therapeutic potential of a new antidepressant drug is the effect size it generates in placebo-controlled trials which has to be compared with the effect of an active control. As this effect size tends to vary substantially it is not easy to predict the sample size in a clinical trial. We carried out two dose finding placebo- and imipramine-controlled, double-blind, multicenter and multinational trials (northern part of Europe) with a new psychotropic compound (NPC) currently being investigated in Phase II/III as a potential antidepressant in the indication major depressive disorder (MDD). Statistical analysis showed that the effect size of 150 mg per day imipramine was meager (1.04 points difference from placebo after 6 weeks according to total scores on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] based on the Intent-to-Treat group using last observation carried forward [LOCF] approach). To increase the discriminative power of the analysis we selected centers that were able to detect a difference of at least two points between imipramine and placebo on the HAM-D-17 total score at 6 weeks in the LOCF analysis (discriminative centers, DC). The other group of centers will be called non-discriminative centers (NDC). We found that 36 percent of centers were DC and recruited about 45 percent of patients. Further analysis revealed no statistically significant differences between the groups of centers concerning the important baseline characteristics of the patients. Also the pattern of reported adverse events did not differ between DC and NDC. We found a tendency for the DC to select more patients with recurrent illness, in particular with a previous good response to antidepressant therapy. The groups of centers differed in dropout rates for both active treatments (DC 19.3-20.4% vs. NDC 35.1-37.7%) but not for the placebo (DC 38.2% vs. NDC 30.5%) that could suggest that different treatment strategies were employed by different centers regarding the occurrence of adverse events with and without therapeutic effects.

Relationship between myocardial norepinephrine content and left ventricular function--an endomyocardial biopsy study.

To analyze the relationships between left ventricular function, catecholamine concentrations in plasma and myocardium, and morphological alterations, 20 patients were studied. Fifteen patients had idiopathic dilated cardiomyopathy, and 5 had normal left ventricular function. All patients underwent right ventricular endomyocardial biopsy to determine muscle fibre thickness, percent volume fraction of interstitium, and myocardial catecholamine content. Blood was sampled to measure plasma catecholamine concentrations, and left ventricular cineangiography was performed to determine global ejection fraction. In a simple correlation analysis a significant correlation was found between left ventricular ejection fraction and myocardial norepinephrine content (r = 0.80, P less than 0.001). Left ventricular ejection fraction was negatively correlated with plasma epinephrine concentration (r- = 0.53, P less than 0.02), and with muscle fibre thickness (r = -0.50, P less than 0.03). Myocardial norepinephrine concentration was negatively correlated with plasma epinephrine (r = -0.62, P less than 0.01). Multiple linear regression analysis revealed a strong correlation between myocardial norepinephrine depletion and left ventricular dysfunction, which was independent of all other variables. These data suggest that myocardial norepinephrine depletion determined from right ventricular endomyocardial biopsies strongly correlates with left ventricular dysfunction in idiopathic dilated cardiomyopathy, and seems to be independent of the degree of muscle fibre hypertrophy, volume fraction of interstitium, and of the increased sympathetic tone.

[Myocardial noradrenaline content: a factor not considered up to now for the prognosis of patients with dilated cardiomyopathy]. / Myokardialer Noradrenalingehalt: ein bisher nicht berücksichtigter Faktor für die Prognose von Patienten mit dilatativer Kardiomyopathie.

To evaluate the prognosis of patients with idiopathic dilated cardiomyopathy (EF less than 50%) in 55 patients the myocardial catecholamine concentration, plasma catecholamine concentration, and left ventricular ejection fraction were determined. The follow-up time ranged from 7 to 47 months. At the time of follow-up 10 of the 55 patients (group A) had died and three had undergone hearttransplantation. Group A patients had a significant lower EF (27 +/- 10 vs 36 +/- 9%, p less than 0.03), a lower myocardial norepinephrine (254 +/- 168 vs 579 +/- 416 pg/mg, p less than 0.007), higher plasma norepinephrine (640 +/- 333 vs 372 +/- 254 pg/ml, p less than 0.008) and plasma epinephrine (391 +/- 340 vs 116 +/- 81 pg/ml, p less than 0.006) in comparison to patients, who were still alive and not transplanted (group B). Survival was significantly lower in patients with an EF less than 30%, a plasma norepinephrine concentration greater than 350 pg/ml, a plasma epinephrine concentration greater than 125 pg/ml, and a myocardial norepinephrine content less than 400 pg/mg. Cox regression analysis revealed that the ratio of plasma vs myocardial norepinephrine was the best prognostic indicator for patients with an EF less than 30% and this ratio plus the plasma norepinephrine concentration were the best prognostic indicators for the whole group of patients. These data suggest that myocardial norepinephrine content is an important prognostic factor in patients with idiopathic dilated cardiomyopathy.

Meta-analysis of randomized, double-blind, placebo-controlled, efficacy and safety studies of mirtazapine versus amitriptyline in major depression.

A meta-analysis was performed on efficacy and safety data from 4 randomized, double-blind, 6-week, single-center studies comparing mirtazapine (n = 194; 5-35 mg/day) with amitriptyline (n = 193, 40-280 mg/day) and placebo (n = 193) in outpatients with a DSM-III diagnosis of major depressive episode. On all the main efficacy variables both active drugs consistently produced significantly greater improvements and significantly greater percentages of responders or remitters than placebo. The meta-analysis of adverse events shows that mirtazapine was better tolerated than amitriptyline, particularly with respect to anticholinergic and cardiac adverse events. There were no differences between mirtazapine and placebo regarding the incidence of serotonergic adverse events. In conclusion, the results of this meta-analysis demonstrate that mirtazapine is as effective as amitriptyline but has a better tolerability profile.

Recovery of left ventricular function after myocardial infarction can be predicted immediately after thrombolysis by semiquantitative intracoronary thallium and technetium pyrophosphate scintigraphy.

The accuracy with which intracoronary thallium and technetium pyrophosphate scintigraphy during intracoronary thrombolysis predicts myocardial salvage was studied in 58 patients with acute myocardial infarction by comparing the acute scintigraphic findings with subsequent left ventricular function. Scintigrams obtained before and immediately after thrombolysis were interpreted by three independent observers using a scoring system. Regional wall motion in the infarct area was determined from left ventricular (LV) cine angiograms using the center-line method. Patients with mild hypokinesis (hypokinesis less than or equal to -2 SD from normal) could be distinguished from those with severe hypokinesis (hypokinesis greater than -2 SD) using the prethrombolysis thallium score with an accuracy of 83%. Accuracy using the post-thrombolysis score was 76%. When the post-thrombolysis thallium and technetium pyrophosphate scores were combined, differentiation was possible in 91% of all patients studied, and in 100% of patients with anterior myocardial infarction. Thus, analysis of combined thallium and technetium pyrophosphate scintigraphy accurately predicts recovery of LV function after thrombolysis and may be helpful in deciding whether acute percutaneous transluminal coronary angioplasty or bypass surgery should be performed after thrombolysis.

[Morphologic findings in dilated cardiomyopathy and their relation to hemodynamics and catecholamine concentrations in the plasma and myocardium]. / Morphologische Befunde bei der dilatativen Kardiomyopathie und ihre Beziehung zur Hämodynamik und zu den Katecholaminkonzentrationen im Plasma und Myokard.

In 72 patients with dilated cardiomyopathy the degree of morphological alterations were studied by transvenous endomyocardial biopsy. These findings were correlated to the clinical status, left ventricular ejection fraction, and to the catecholamine concentrations in plasma and myocardium. Muscle fiber diameter was negatively correlated to ejection fraction (r = -0.3, p = 0.02) and to the volume fraction of mitochondria (r = -0.32, p = 0.001). Between plasma norepinephrine concentration and ejection fraction a significant negative correlation was found (r = -0.37, p = 0.001). In contrast, myocardial norepinephrine concentration was positively correlated to ejection fraction (r = 0.25, p = 0.04). Between myocardial norepinephrine concentration and muscle fiber diameter a negative correlation was found (r = -0.46, p = 0.004). Patients with an EF of less than 30% and an EF of greater than 45% could be differentiated with an accuracy of 79%, when muscle fiber diameter, plasma norepinephrine concentration, and the density of capillary vessels were entered into a multi-variant analysis. In conclusion, dilated cardiomyopathy is associated with morphological alterations and alterations in plasma and myocardial catecholamine concentrations. Patients with highly reduced ventricular function could be best identified by the combined assessment of plasma catecholamine concentration, muscle fiber diameter, and density of capillary vessels.

[Clinical recognition of early forms of malignant melanoma]. / Untersuchungen zur klinischen Erkennbarkeit der Frühformen des malignen Melanoms.

The clinical diagnosis of malignant melanoma (MM) is based on the subjective evaluation of objective measurable parameters (criteria). The accuracy of melanoma diagnosis by dermatologists is only 75%. Particularly difficult is the diagnosis of precursors or early stages of MM. Therefore, we have studied on the one hand the intra- and interindividual reproducibility of the clinical diagnosis of pigmented lesions, and on the other hand the clinico-histopathological correlation. In addition, we have conducted a preliminary investigation designed to evaluate whether image analysis (objective and reproducible) could be used as an auxiliary instrument to differentiate between benign and malignant melanocytic lesions. In the clinical study, the intraindividual reproducibility of the combination of criteria was 69%. The interindividual reproducibility of single criteria even exhibited a range of up to 36%. Histologically "atypical/dysplastic" melanocytic lesions were considered to require excision as frequently as histologically regular melanocytic lesions. Using image analysis (single threshold segmentation, standard deviation of intensity distribution, ratio of area to circumference, Fourier analysis), we could show that it may be possible to differentiate between benign and malignant melanocytic lesions. Therefore, image analysis may be very helpful in determining the dignity of melanocytic lesions.