[Treatment of vitally endangered anorexia nervosa patients based on guardianship laws]. / Behandlung vital gefährdeter Anorexia-nervosa-Patienten unter Berücksichtigung der Möglichkeiten des Betreuungsrechts.

Anorexia nervosa is a psychiatric disorder occurring primarily in young women. Especially when chronic or the body mass index is less than 12 kg/m(2), it has a mortality of up to 20%. Often these patients are admitted to emergency units and treated internistically. If they accept psychiatric treatment, they are normally transferred to specialized psychosomatic units for further therapy. If patients are not able to accept necessary further therapy to overcome the danger to health and life, the question arises in terms of guardianship law of whether they are able to handle their personal concerns alone. After several vitally endangered anorexia nervosa patients had been admitted to our closed psychiatric ward, we developed a therapeutic concept for this subgroup of patients, taking the possibilities of guardianship law into account. This concept aims at restoring the body weight continuously and finally enable the patients to be transferred to less restrictive psychosomatic units. The chosen treatment is shown with the therapy courses of 25 patients treated according to this concept.

Endocrinological effects of high-dose Hypericum perforatum extract WS 5570 in healthy subjects.

In this single-blind study, the effects of acute oral administration of high-dose Hypericum perforatum extract WS 5570 on the cortisol (COR), adrenocorticotropic hormone (ACTH), growth hormone (GH), and prolactin (PRL) secretions were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or WS 5570 at several dosages (600, 900, and 1,200 mg) at 08.00 h on 4 different days. After insertion of an intravenous catheter, blood samples were drawn 1 h prior to administration of placebo or WS 5570 (600, 900, or 1,200 mg), at the time of administration, and during 5 h thereafter at intervals of 30 min. The serum concentrations of COR, GH, and PRL as well as the plasma levels of ACTH were determined in each blood sample by means of double antibody radioimmunoassay, fluoroimmunoassay, and chemiluminescence immunometric assay methods. The area under the curve value was used as parameter for COR, ACTH, GH, and PRL responses. Repeated-measures Anova revealed a significant stimulatory effect of WS 5570 on the ACTH secretion, whereas COR and PRL secretions were not significantly influenced. Moreover, there was a stimulatory peak of GH release 240 min after challenge with WS 5570 in some but not all volunteers, without reaching statistical significance in comparison with placebo. Mean arterial blood pressure and heart rate remained unchanged after administration of WS 5570. Apparently, WS 5570 at the dosages given in this study inconsistently causes endocrinological effects in healthy subjects by influencing central neurotransmitters.

Influence of mirtazapine on salivary cortisol in depressed patients.

Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic alpha(2)-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1 receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day -1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified.

[Hypericum perforatum extract in treatment of mild to moderate depression. Clinical and pharmacological aspects]. / Hypericum-perforatum-Extrakt bei der Behandlung leichter bis mittelschwerer Depressionen. Klinische und pharmakologische Aspekte.

For many years, hypericum extracts have been used in the treatment of depressive disorders. The therapeutical use of these extracts has been predominantly justified for a long time by the clinical evidence of efficacy and only partly by results of scientific studies. The aim of the present investigation is to perform a meta-analysis of the placebo- and verum-controlled studies carried out till now, to examine the relevance of hyperforin and hypericin for the clinical efficacy of St. John's Wort, to discuss biochemical and pharmacoendocrinological studies investigating the mechanism of action, and to describe side effects and interactions of hypericum extracts. In particular during recent years, methodologically quite sophisticated studies have been performed. The comprehensive evaluation of all studies available suggests a significant superiority of hypericum extracts over placebo, despite the negative results of two recently published American trials, and a therapeutic efficacy comparable to that of synthetic antidepressants in mildly to moderately depressed patients. Furthermore, it has been suggested in preclinical and clinical studies that the content of hyperforin but not of hypericin decisively contributes to the antidepressant efficacy of hypericum extracts. Hyperforin has been demonstrated in biochemical investigations--like synthetic antidepressants--to inhibit the reuptake of the neurotransmitters norepinephrine, serotonin, and dopamine. Hypericum extracts can be regarded as well tolerated, and they extend the variety of pharmacotherapeutical options in the treatment of depression, especially in outpatients. However, interactions in combination treatments are possible by interference with the cytochrom P450 system, thereby changing plasma levels of other medications.

Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study.

In recent years, sedating antidepressants have been increasingly used to treat primary insomnia. Up to now, only one open pilot study with trimipramine and one double-blind placebo-controlled study with doxepin have provided scientific support for this approach in treating primary insomnia. In order to test the hypothesis that sedating antidepressants are useful in the treatment of primary insomnia, the effect of trimipramine on objectively and subjectively measured parameters of sleep was investigated in a double-blind placebo- and lormetazepam-controlled study in a sample of 55 patients with primary insomnia attending outpatient sleep-disorder clinics. Trimipramine was selected since it has shown positive effects on sleep continuity with a lack of REM sleep suppression in studies on depressed patients and in one pilot study on patients with primary insomnia. Trimipramine at an average dose of 100 mg over a period of 4 weeks significantly enhanced sleep efficiency, but not total sleep time (which had been the primary target variable) compared to placebo as measured by polysomnography. Changes in objective sleep parameters were paralleled by changes in subjective sleep parameters. Trimipramine did not suppress REM sleep. Lormetazepam decreased wake time and sleep stage 3 and increased REM sleep compared to placebo. After switching trimipramine to placebo, sleep parameters returned to baseline. There was no evidence of any rebound effect from trimipramine. Side effects from trimipramine were only marginal. This first double-blind placebo-controlled study with trimipramine suggests its efficacy in the treatment of primary insomnia. However, due to the large intra- and interindividual variance in the parameters of interest before and during treatment a larger sample size would have been necessary to strengthen the validity of our findings.

Neuroendocrine effects of Hypericum extract WS 5570 in 12 healthy male volunteers.

In the present study, the effects of acute p.o. administration of placebo at 300 mg and 600 mg of WS 5570 Hypericum perforatum extract on cortisol (COR), growth hormone (GH) and prolactin (PRL) secretion were examined in twelve physically and mentally healthy subjects. WS 5570 is a hyperforin containing extract of St. John's Wort which has been proven effective in mild to moderate depression. After inserting an i.v. catheter, blood samples were drawn one hour prior to the administration of WS 5570 or placebo, at the time of application and up to five hours after application in 30-minute intervals. Plasma concentrations of COR, GH, and PRL were determined in each blood sample by double-antibody RIA methods. No PRL stimulation could be observed after placebo or after WS 5570 (300, 600 mg). A small but statistically significant elevation in GH AUC values occurred after 300 mg of WS 5570. After 600 mg of WS 5570, a clear-cut COR stimulation was observed, occurring from 30 up to 90 minutes after the application. In this period of time (from t = 30 min to t = 90 min), the mean COR concentrations were significantly higher after 600 mg of WS 5570 compared to placebo. 300 mg of WS 5570 did not show any effects on COR secretion. We propose that the Hypericum extract WS 5570 is able to influence central neurotransmitters, thereby causing COR stimulation in a dose-dependent manner.

[Interferon alpha-associated agranulocytosis during clozapine treatment. Case report and status of current knowledge]. / Interferon-alpha-assoziierte Agranulozytose während Clozapin-Behandlung. Kasuistik und Wissensstand.

Little is known about possibilities of chronic hepatitis C treatment with interferon-alpha (IFN-alpha) in psychiatric patients continuously taking antipsychotics. We report on a 28-year-old hepatitis C-positive man with paranoid psychosis. He was successfully treated with clozapine, an atypical antipsychotic drug which is known for the risk of granulocytopenia and agranulocytosis. With doses up to 200 mg/day over 3 years, he showed no remarkable changes in WBC. Because of the chronic hepatitis C with genotype 3a, additional treatment was started with IFN-alpha (s.c., 3 x 6 million IU/week). After 2 months of therapy he developed a severe agranulocytosis. Both clozapine and IFN-alpha were discontinued, and his WBC returned to normal. Results from bone marrow examination were compatible with a toxic reaction possibly caused by either or both medications. We discuss possible problems with IFN-alpha during the treatment of psychiatric patients, interactions with psychiatric medication, and hematotoxic side effects like those from clozapine. We recommend combining IFN-alpha with less "toxic" antipsychotics and weekly checks of WBC.

Psychosis in a methadone-substituted patient during interferon-alpha treatment of hepatitis C.

Interferon-alpha (IFN-alpha) is the only effective treatment for chronic hepatitis B and C. Over 2/3 of methadone-substituted patients suffer from chronic hepatitis C but a history of psychiatric disorders or drug addiction is still seen as a contraindication for IFN-alpha because of a possible increased risk of severe psychiatric side effects such as depression, suicide attempts or psychotic episodes. We report on the case of a 33-year-old patient with chronic hepatitis C and a positive psychiatric history (drug abuse, borderline personality and four suicide attempts). After 4 months of therapy with IFN-alpha he developed a psychosis with persecution mania, complex thought disorder, disturbance of sexual identity, sleeplessness, anxiety, depression and increased irritability with suicidal thoughts. Symptoms did not disappear after discontinuation of interferon treatment. To our knowledge, there are no other reports of persistent psychosis with a possible association to interferon treatment. Development of psychosis and other psychiatric side-effects may be an indication of possible neuromodulatory effects of IFN-alpha with long-term treatment. On the other hand, the treatment for hepatitis C was successful. Ideas for safer treatment in methadone patients with psychiatric co-morbidity and chronic hepatitis C are needed.

Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects.

In the present study the effects of acute PO-administration of 15 mg mirtazapine on the growth hormone (GH), prolactin (PRL), and cortisol (COR) secretion were examined in eight physically and mentally healthy male subjects, compared to placebo. Mirtazapine is a new antidepressant agent which does not inhibit the reuptake of norepinephrine or serotonin but is an antagonist of presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors. After insertion of an i.v. catheter, blood samples were drawn 1 h prior to the administration of mirtazapine or placebo, at time of application, and during the time of 4 h after application in periods of 30 min. Plasma concentrations of GH, PRL, and COR were determined in each blood sample by double antibody RIA methods. The area under the curve (AUC) value was used as parameter for the GH, PRL, and COR response. With respect to GH and PRL secretion, mirtazapine did not show any effects in comparison with placebo. However, in all subjects, the COR concentrations were remarkably lower after mirtazapine compared to placebo, the difference being obvious in the mean value graphs 60 min after the application up to the end of the measurement period. The t-test for paired samples revealed a highly significant difference (P < 0.01) in COR-AUC-values between the mirtazapine group (mean COR-AUC: 1558.07 micrograms/100 ml x 240 min) and the placebo group (mean COR-AUC: 2698.86 micrograms/100 ml x 240 min). Further studies have to elucidate the question whether the demonstrated inhibition of COR secretion after application of 15 mg mirtazapine is caused by central or peripheral effects of this substance.

St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy.

In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John's wort were investigated in 147 male and female outpatients suffering from mild or moderate depression according to DSM-IV criteria. Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3 x 1 tablets of either placebo, Hypericum extract WS 5573 (300 mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin). The manufacturing process for the two Hypericum preparations was identical, so that they differed only in their hyperforin content. Efficacy regarding depressive symptoms was assessed on days 0, 7, 14, 28, and 42, using the Hamilton Rating Scale for Depression (HAMD, 17-item version) and the Depression Self-Rating Scale (D-S) according to von Zerssen. In addition, the severity of illness was also rated by the investigators on days 0 and 42 using the Clinical Global Impression (CGI) scale. The last observation of patients withdrawn from the trial prematurely was carried forward. At the end of the treatment period (day 42), the patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 +/- 4.6 points; mean +/- SD), followed by the WS 5573 group (0.5% hyperforin; HAMD reduction 8.5 +/- 6.1 points) and the placebo group (7.9 +/- 5.2 points). As regards the change in the HAMD total score between day 0 and treatment end and its relationship to the hyperforin dose, a significant monotonic trend was demonstrated in the Jonckheere-Terpstra test (p = 0.017). In pairwise comparisons, WS 5572 (5% hyperforin) was superior to placebo in alleviating depressive symptoms according to HAMD reduction (Mann-Whitney U-test: p = 0.004), whereas the clinical effects of WS 5573 (0.5% hyperforin) and placebo were descriptively comparable. These results show that the therapeutic effect of St. John's Wort in mild to moderate depression depends on its hyperforin content.

Buspirone and lorazepam in the treatment of generalized anxiety disorder in outpatients.

In this double-blind, placebo-controlled 10-week trial, the anxiolytic properties of the nonbenzodiazepine buspirone were compared with the benzodiazepine lorazepam and placebo in 125 outpatients with generalized anxiety disorder according to DSM-III. After a 3- to 7-day wash-out period, patients were allocated at random to receive orally 3 x 5 mg buspirone (n=58), 3 x 1 mg lorazepam (n=57), or placebo (n=10) over a 4-week period. The study also comprised a 2-week taper period and a 4-week placebo-control period to assess the stability of clinical improvement. The patient's clinical state was estimated on entry and at weekly intervals by general practitioners using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression (CGI) assessment and by a self-rating scale (State Trait Anxiety Inventory X2=STAI-X2). Lorazepam treatment resulted in descriptively, but not significantly, greater improvement on the Hamilton Rating Scale for Anxiety during the whole treatment (week 0-4) and taper period (week 5, 6) than did buspirone. After treatment with active drugs had been discontinued, the 4-week placebo control period showed buspirone-treated patients to display a stability of clinical improvement, while the symptoms of lorazepam-treated patients worsened at week 7-10. Both buspirone and lorazepam were more efficacious in reducing anxiety symptoms than placebo during the treatment and taper period; however, in contrast to the active drugs (buspirone, lorazepam), patients of the placebo group showed further clinical improvement during the control period, especially in the HAM-A score, so differences between placebo and active drugs became smaller at the end of the study.

Clinical significance of hyperforin for the efficacy of Hypericum extracts on depressive disorders of different severities.

In a randomized, double-blind, placebo-controlled, multicenter study, the clinical efficacy and safety of two different extracts of St. John's wort were investigated in 147 male and female out-patients suffering from mild or moderate depression according to DSM-IV criteria. Fifty-six (38.1%) of them had an initial total score ≥ 22 points on the Hamilton Rating Scale for Depression (HAMD, 17-item version). Following a placebo run-in period of three to seven days, the patients were randomized to one of three treatment groups: During the 42-day treatment period, they received 3×1 tablet of either placebo, Hypericum extract WS 5573 (300mg, with a content of 0.5% hyperforin), or Hypericum extract WS 5572 (300 mg, with a content of 5% hyperforin). The manufacturing process for both Hypericum preparations was identical, they only differed with regard to their content of hyperforin. Efficacy regarding depressive symptoms was assessed on days 0, 7,14,28, and 42. The last observation of patients withdrawn from the trial prematurely was carried forward. At the end of the treatment period (day 42), the patients receiving WS 5572 (5% hyperforin) exhibited the largest HAMD reduction versus day 0 (10.3 ± 4.6 points; mean ± SD), followed by the WS 5573 group (0.5% hyperforin; HAMD reduction 8.5 ± 6.1 points) and the placebo group (7.9 ± 5.2 points). The monotonie trend was significant (Jonckheere-Terpstra test; p = 0.017). In patients with an initial HAMD total score ≥ 22, the HAMD reduction was even by 16.5% larger than in the total study group receiving WS 5572. More severely depressed patients treated with WS 5573, however, showed a 22.4% lower reduction of the HAMD total score than the entire WS 5573 treatment group. In patients with HAMD ≥ 22, WS 5572 showed a 53.8% larger HAMD reduction than placebo, whereas WS 5573 was not relevantly different from the placebo level. The mean HAMD reductions, treatment end versus baseline, for the more severely depressed patients were 12.0 (3.7) points, 6.6 (7.7) points and 7.8 (5.4) points [mean (SD)] for WS 5S72, WS 5573 and placebo, respectively. The results of a responder analysis support these findings. The data point to a dose-response relationship between the antidepressant efficacy of Hypericum extract and its hyperforin content. The extract with a higher content of hyperforin was particularly effective in patients who were more severely depressed.

Circadian profiles of melatonin in melancholic depressed patients and healthy subjects in relation to cortisol secretion and sleep.

Circadian secretion of melatonin was measured in melancholic depressed patients (n = 9) and age- and sex-matched healthy control patients (n = 9). The mean age of the depressed patients was 29 years, i.e. younger than in most earlier studies, and a drug-free interval of 3 weeks preceded the investigations. Melatonin secretion was similar in depressed patients and healthy subjects with no significant differences at any of the time points, thus not confirming earlier studies in which depressed patients were found to have lower melatonin levels than control patients. The discrepancy between our result and earlier studies may be explained by different patient characteristics such as age, duration of illness, previous treatment, and alcohol intake. It is conceivable that a diminution of nocturnal melatonin secretion in depressed patients might only occur during the long-term course of the depressive illness and/or its pharmacological treatment.

Pramipexole as adjunct to haloperidol in schizophrenia. Safety and efficacy.

Pramipexole, a presynaptic dopamine D2/D3 autoreceptor agonist, has been given to haloperidol-treated patients with schizophrenia (n = 15) in an effort to ameliorate residual positive and negative symptoms that have not been satisfactorily influenced by haloperidol alone. Total scores of the positive and negative symptom scale (PANSS) decreased by more than 20% in 9 of 15 patients (reduction of total score: 22-62%). Serious adverse events did not occur. Three of the 15 patients dropped out due to worsening of schizophrenia. Insomnia, as the most frequent side effect, occurred in 4 patients. No clinically relevant electrocardiographic and laboratory changes were reported. This study supports the safety of the treatment of schizophrenia with pramipexole and haloperidol as a combination therapy. However, further clinical studies are required to support these preliminary findings.

[Predictive factors for therapeutic success in depressive syndrome]. / Prädiktive Faktoren für den Therapieerfolg beim depressiven Syndrom.

In this retrospektive investigation on 659 depressive outpatients, predictors of antidepressant drug response were evaluated. In accordance with the literature, neither demographic variables nor duration of the current episode, severity of depressive symptoms or scores of rating scales showed any clinically relevant relation to outcome. The prognostic value of recovery within the first 2 weeks seems to be the only reliable predictor. In all, 75% of patients without a significant reduction (less than 20%) of the score in the Hamilton Psychiatric Rating Scale for Depression after 2 weeks of treatment will not fulfill response criteria after 6 weeks. For clinical practice these results imply the necessity of reviewing the applied drug regimen early, i.e. about 2 weeks after beginning, to check for compliance with treatment or an individual problem of resorption or metabolism in order to amend the regimen by increasing dosage and/or adding sleep deprivation, lithium, thyroxine or psychotherapy.

Lateralization of the Bereitschaftspotential to the left hemisphere in patients with major depression.

Fourteen patients with major depression and 18 healthy subjects performed a Bereitschaftspotential (BP) paradigm, which required them to clench the right fist at self-paced intervals. The BP was calculated as the integrated negative amplitude from BP onset to movement onset. The latter was defined by recording the electromyogram (EMG) from the right forearm. To evaluate lateralization, the integrated BPs at C3, C4, P3, and P4 were analyzed. In depressives, a significant asymmetry of the BP to the left was found, whereas in normals the BP was nearly symmetrically distributed around the midline. Three patients were retested when clinically improved. At that time the asymmetry to the left hemisphere had nearly vanished. This asymmetry to the left hemisphere is interpreted as a cortical deactivation of the right cerebral hemisphere and seems to be a state marker of depression.

Profiles of spontaneous 24-hour and stimulated growth hormone secretion in male patients with endogenous depression.

Abnormalities of both the spontaneous and the stimulated release of growth hormone (GH) have been described in patients with endogenous depression. In this study, six unmedicated male patients with endogenous depression (ICD 296.1/3) were compared with six age-matched healthy men. Levels of GH were determined at 15-minute intervals over 26 hours. A combined releasing hormone test was performed during the last 2 hours of blood sampling. The 24-hour profile of GH secretion was significantly lower in the depressed patients than in the healthy control subjects due to a significantly diminished sleep-related GH secretion. GH stimulation following releasing hormones was lower in the depressed patients than in healthy subjects. Hypersecretion of GH before the stimulation test might therefore not explain the blunted GH response to stimulation that has been observed in depressive patients.