Otto Benkert

ACTH and multisteroid responses to corticotropin-releasing factor in depressive illness: Relationship to multisteroid responses after ACTH stimulation and dexamethasone suppression ☆

One hundred micrograms of ovine-corticotropin releasing factor (o-CRF) was administered intravenously to eight unmedicated patients with severe endogenous depression. Responses of immunoreactive (ir)-ACTH and the adrenal glucocorticosteroids corticosterone (B), 11-deoxycortisol (S), cortisol (F) and cortisone (E) were measured and compared with those following synthetic corticotropin stimulation and dexamethasone suppression. A comparative evaluation of the three pituitary--adrenal function tests suggests that hypersecretion of ir-ACTH and adrenal corticosteroids (B, S, F, and E) in depression reflects a central dysfunction rather than an altered responsiveness of the pituitary or adrenal glands. The data illustrate that the o-CRF paradigm is a valuable instrument to further support the hypothesis that a limbic--hypothalamic overdrive is the basic mechanism underlying exaggerated adrenocortical output in the endogenous subgroup of depressed patients.

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology – a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist

Abstract The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi-center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000 mg/day; FPX: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956 mg; FPX: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. The difference between the mean BPRS decreases of both treatment groups was 5.6 points (95% CI: 0.55; 10.65) in favour of ASP. According to CGI, 62% of patients in either drug group were treatment responders. ANCOVA analysis showed that reductions of BPRS (ASP: −42%; FPX: −32%) and SAPS (ASP: −78%; FPX: −65%) were more pronounced under ASP. Due to adverse events, significantly fewer ASP patients (6%) were withdrawn from the study (FPX: 18%). Extrapyramidal tolerability was better in the ASP group, as demonstrated by smaller increases in the Simpson-Angus Scale, the AIMS, and the Barnes Akathisia Scale in ANCOVA analyses with dosage as covariate. ASP appears to be as effective as FPX with regard to antipsychotic effects on positive schizophrenic symptomatology, while extrapyramidal tolerability is better. These conclusions have to be drawn cautiously, as dosage effects on outcome parameters cannot be entirely ruled out. The present results question the notion that additional blockade of D1-like receptors may be necessary to achieve sufficient antipsychotic effects or to improve extrapyramidal tolerability.

Decreased benzodiazepine receptor binding in panic disorder measured by IOMAZENIL-SPECT. A preliminary report.

Single photon emission tomography (SPECT) imaging of the central benzodiazepine receptor (BZr) became possible with the newly developed ligand123I-IOMAZENIL. The BZr binding was investigated in ten patients with panic disorder (PP) compared to ten epileptic patients (EP). Panic patients had lower IOMAZENIL uptake rates in the frontal, occipital and temporal cortex than EP, indicating the involvement of the BZr complex in panic disorder.

A randomized, double-blind comparison of a rapidly escalating dose of venlafaxine and imipramine in inpatients with major depression and melancholia

A double-blind, randomized, parallel study in 167 hospitalized patients with major depression and melancholia was conducted to determine if rapidly escalated doses of venlafaxine produced an earlier response, compared with rapidly escalated doses of imipramine. The daily dose of venlafaxine was rapidly increased to 375 mg/day over a five-day period, was maintained at this level for 10 days, and then was reduced to 150 mg/day for the remainder of the study. The imipramine dose was rapidly increased to 200 mg/day over five days and was maintained at this level to the end of the study. The primary efficacy variables were time to response and time to sustained response on the HAM-D and MADRS. No differences in the response rates on the HAM-D or MADRS were observed between treatments. However, among patients who demonstrated a response on the HAM-D, there was a significantly faster onset of response (p = 0.036) and sustained response (p = 0.018) in the venlafaxine group. The median time to response on the HAM-D among responders was 14 days with venlafaxine and 21 days with imipramine. However, no differences between treatments were observed among responders on the MADRS (median time to response: 15 days for venlafaxine, 18 days for imipramine). Study events were reported in 69% of venlafaxine-treated patients and 76% of imipramine-treated patients. In severely depressed patients with melancholia, a faster onset of response was observed with venlafaxine on the HAM-D, but not the MADRS, and maximal tolerated doses of venlafaxine and imipramine were comparable for overall efficacy. These results confirm and extend previous observations and suggest that venlafaxine may have an early onset of action and may produce a rapid response in hospitalized patients with severe depression complicated by melancholia.

Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome.

In a multicenter, double-blind, parallel group trial, the efficacy of risperidone (RIS) was compared with a combination of haloperidol and amitriptyline (HAL/AMI) over 6 weeks in patients with coexisting psychotic and depressive symptoms with either a schizoaffective disorder, depressive type, a major depression with psychotic features, or a nonresidual schizophrenia with major depressive symptoms according to DSM-III-R criteria. A total of 123 patients (62 RIS; 61 HAL/AMI) were included; the mean daily dosage at endpoint was 6.9 mg RIS versus 9 mg HAL combined with 180 mg AMI. Efficacy results for those 98 patients (47 RIS; 51 HAL/AMI) who completed at least 3 weeks of double-blind treatment revealed in both treatment groups large reductions in the Positive and Negative Syndrome Scale-derived Brief Psychiatric Rating Scale (RIS 37%; HAL/AMI 51%) and the Bech-Rafaelsen Melancholia Scale total scores (RIS 51%; HAL/AMI 70%). The reductions in the Brief Psychiatric Rating Scale and the Bech-Rafaelsen Melancholia Scale scores in the total group were significantly larger in the HAL/AMI group than in the RIS group (p < 0.01), mostly because of significant differences in the subgroup of patients suffering from depression with psychotic features, whereas treatment differences in the other diagnostic subgroups were not significant. The incidence of extrapyramidal side effects as assessed by the Extrapyramidal Symptom Rating Scale was slightly higher under RIS (37%) than under HAL/AMI (31%). Adverse events were reported by 66% of RIS and 75% of HAL/AMI patients. The results of this trial suggest that the therapeutic effect of HAL/AMI is superior to RIS in the total group of patients with combined psychotic and depressive symptoms. However, subgroup differences have to be considered.

Clinical subtypes in panic disorder: Their descriptive and prospective validity

In a sample of 97 patients with panic attacks, presence of agoraphobia was associated with a more severe syndrome of panic anxiety both at index assessment and during one-year follow-up but was not associated with increased incidence of major depression. Groups with a history of depression--primary or secondary to the onset of panic--did not differ from the group without depression when severity of anxiety was concerned but were more severely impaired and had a higher incidence of further depressive episodes during follow-up. For future classification of panic disorder, subtypes defined according to associated syndromes of agoraphobia or depression are proposed, since these conditions appear constant through follow-up.

Neuroendocrine response to antipsychotics : Effects of drug type and gender

BACKGROUND To study the influences of drug type and gender on the neuroendocrine response to neuroleptic treatment, we compared the endocrine actions of two neuroleptics with different receptor affinity profiles--a substituted benzamide, amisulpride, a selective D2-like dopamine antagonist; and a thioxanthene, flupenthixol, a mixed D1/D2-like antagonist also blocking serotonin, H1, and D1 receptors--on anterior pituitary hormone secretion in schizophrenic patients (DSM-III-R). METHODS Blood was withdrawn at 15-min intervals to assess basal secretion of prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH). Four hundred micrograms of thyrotropin-releasing hormone (TRH) was injected i.v. to investigate drug effects on TRH-stimulated secretion of prolactin, TSH, and GH. RESULTS Prolactin plasma levels were markedly elevated in both treatment groups. In female, but not in male patients, this elevation was significantly more pronounced under amisulpride than under flupenthixol. The prolactin response to TRH was significantly blunted by amisulpride only in male subjects. While basal TSH secretion was significantly increased by both compounds, TRH-stimulated TSH secretion was elevated only in patients treated with amisulpride. Low basal prolactin levels predicted improvement of negative symptoms in patients treated with amisulpride. CONCLUSIONS Amisulprides more pronounced endocrine effects may be a reflection of its distinguished pharmacology and pharmacokinetics.

The Calgary Depression Rating Scale for Schizophrenia: development and interrater reliability of a German version (CDSS-G)

A German version of the Calgary Depression Rating Scale for Schizophrenia (CDSS-G) approved by the author of the original scale is presented comprising a semi-structured interview for 9 items to sensitively and specifically assess depression in schizophrenia and related disorders. The process of translation is outlined and the finally derived CDSS-G was investigated with respect to interrater reliability in three studies. To keep comparability with the CDSS source version a standard procedure was used. Two trained raters jointly assessed ten schizophrenic patients (study I). In a second study, videotapes with the CDSS-G were presented to clinically inexperienced raters (study II, N = 14/15) to test the agreement on the CDSS-G in this sample. Finally, in a third study clinically experienced researchers participated in a rater training (study III, N = 34). They carried out CDSS ratings on three patients with mild depressive symptoms. The dependence of interrater reliability on depression severity was investigated for all studied patients. Both intraclass correlation coefficients (ICC) and weighted kappa coefficients (kappa(w)) were calculated. The results revealed a high ICC = 0.97 in study I for the total CDSS-G score. Single item ICC values were all above 0.70. The results of study II revealed somewhat lower agreement on CDSS-G items and total scores in psychiatric novices with however acceptable values of kappa(w)>0.50 for the total scores. Study III yielded satisfactory results (0.66<kappa(w)<0.76) for clinically experienced psychiatrists in schizophrenic patients with mild depression. The results demonstrate adequate to excellent interrater reliability of the CDSS-G corroborating the results of the original version in different settings.

Acute antagonism of dopamine D2-like receptors by amisulpride: Effects on hormone secretion in healthy volunteers

Amisulpride is a selective D2-like dopamine receptor antagonist with a high affinity for the cloned D2 and D3 receptors. At low doses it may improve depressive and negative schizophrenic symptoms whereas antipsychotic effects on positive schizophrenic symptomatology require higher dosages. Acute endocrine effects were studied for two doses of amisulpride with regard to the daytime secretion of prolactin, thyroidea stimulating hormone (TSH), growth hormone (GH), luteinizing hormone (LH) and cortisol. Amisulpride was administered i.v. to eight healthy male volunteers in a single-blind trial under a randomized cross-over, placebo-controlled design using doses of 20 mg or 100 mg, or saline. The drug was injected at 09:00 h, and plasma samples were withdrawn from 08:30 h to 16:00 h at intervals of 15 and 30 min, respectively. At both dosages, prolactin was significantly elevated to the eight- to ten-fold of baseline levels. Likewise, a significant 50% elevation of TSH concentrations with a trend to a greater increase under the 100 mg dose was observed. Plasma levels of LH and cortisol were not significantly affected by amisulpride. With regard to GH secretion, there was a trend to a decrease only with the 20 mg dose. These results indicate that the neuroendocrinological side-effect profile of acute amisulpride administration may be similar to conventional neuroleptics, and that there are only minor dose-dependent differential effects on hormone secretion in the dose range investigated.

Mirtazapine orally disintegrating tablets versus venlafaxine extended release: a double-blind, randomized multicenter trial comparing the onset of antidepressant response in patients with major depressive disorder.

This randomized, multicenter, double-blind study was designed to compare specifically the onset of antidepressant action of mirtazapine orally disintegrating tablets (ODT) with venlafaxine extended-release (XR) formulation in outpatients with major depression. Both treatments were administered in a rapidly escalating dosing regimen. Target doses (mirtazapine ODT, 45 mg OD; venlafaxine XR, 225 mg OD) were reached by day 6 of treatment. On the primary efficacy parameter [the average of the change in HAM-D (17-item) total score on days 5, 8, 11, and 15], mirtazapine ODT was significantly superior to venlafaxine XR (P = 0.008). In addition, calculating the HAM-D score without the sleep items resulted in significant reductions in favor of mirtazapine ODT on days 8 (P = 0.006) and 11 (P = 0.037). The proportion of responders (HAM-D decrease of ≥50% from baseline) was higher in the mirtazapine ODT group on all assessment days, being significant on days 8 (P = 0.002), 11 (P = 0.004), and 22 (P = 0.027). More patients in the mirtazapine ODT group achieved remission (HAM-D total score of ≤7) up to day 29, and the difference was statistically significant on day 15 (P = 0.016). Significant differences in favor of mirtazapine ODT were evident in the CGI of change on days 8 (P = 0.019), 11 (P = 0.004), and 15 (P = 0.031), and the CGI of severity on days 8 (P = 0.014) and 11 (P = 0.033). Both treatments were well tolerated. These results indicate that mirtazapine ODT has a faster onset of antidepressant efficacy than venlafaxine XR in patients with major depressive disorder, and that this effect is independent of its sleep-improving properties.