Stimulation of growth hormone secretion by desimipramin and chlorimipramin in man.

In twelve healthy male subjects 75 mg desimipramin (DMI) administered intramuscularly and 100 mg DMI given orally led to a prompt rise in serum growth hormone (GH) levels. The maximum level of serum GH was observed 60 min after the i.m. and 150 min after the oral administration of DMI. Chlorimipramin (CI) administered in the same manner and in the same dosages resulted in a significant increase in GH in only six out of twelve subjects. The maximum level was observed 60 min after the i.m. and 150 min after the oral administration of DMI. There was no change in the prolactin (PRL) levels after administration of DMI and CI.

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.

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.

Influence of clenbuterol, a beta-adrenergic agonist, on desipramine induced growth hormone, prolactin and cortisol stimulation.

We report herein the effects of the beta-adrenergic agonist clenbuterol on desipramine (DMI)-induced growth hormone (GH), prolactin (PRL) and cortisol secretion in healthy male subjects. In the first study, nine subjects were treated with either clenbuterol (0.04 mg, p.o.) or placebo. In the second study, 12 subjects received either DMI (50 mg, i.v.) alone or in combination with clenbuterol (0.04 mg, p.o.) given 60 min prior to DMI administration. Clenbuterol alone had no influence on GH, PRL, or cortisol concentrations, compared to placebo. DMI alone caused GH stimulation (mean maximum = 15.7 +/- 3.4 ng/ml), which was significantly lower after combined administration of DMI and clenbuterol (mean maximum = 7.7 +/- 1.6 ng/ml) (p less than or equal to 0.01). DMI-induced PRL and cortisol stimulation was not influenced by clenbuterol pretreatment. These results indicate the inhibiting influence of noradrenergic beta-receptors on GH stimulation.

Comparison of growth hormone stimulation induced by desimipramine, diazepam and metaclazepam in man.

A comparison of the effect on growth hormone (GH) stimulation in men (n = 6) of desimipramine (DMI), a tricyclic antidepressant, and of the benzodiazepine derivatives diazepam and metaclazepam with that of a placebo, showed that only DMI caused a significant (p less than 0.01) GH stimulation. After DMI, all six subjects showed a GH stimulation greater than 7.5 ng/ml, whereas after diazepam or metaclazepam, only three of the six subjects showed GH stimulation greater than 7.5 ng/ml, and the other three showed only a very small change, or no change at all in GH secretion. Higher GH stimulation occurred after diazepam (10 mg i.v.) than after diazepam (10 mg p.o.). No dose-dependent difference in GH stimulation after metaclazepam (10 and 30 mg p.o.) was apparent. No side effects appeared after administration of DMI during the test period (180 min); however, after administration of the benzodiazepine derivatives, sedative effects were clearly noted. DMI thus causes reliable GH stimulation in healthy male subjects, whereas GH stimulation could only be measured in some of the subjects after diazepam and metaclazepam.

Dose-dependent growth hormone, prolactin and cortisol stimulation after i.v. administration of desimipramine in human subjects.

In previous studies it was shown that the tricyclic antidepressant desimipramine (DMI) had different stimulatory effects on growth hormone (GH), prolactin (PRL), ACTH and cortisol secretion in healthy subjects, depending on the mode of administration. The present study examined the effects following i.v. administration of placebo and DMI (5, 15, 25, 50 and 75 mg) on GH, PRL and cortisol secretion in male subjects (n = 6). This primarily noradrenergic and secondarily serotonergic reuptake-inhibiting substance was found to stimulate the secretion of GH, PRL and cortisol in a dose-dependent manner. Compared to placebo, significant increases occurred in GH (p less than 0.05) and in PRL (p less than 0.05) from a dose of DMI 25 mg on, and in cortisol (p less than 0.05) from 15 mg on. The results indicate that, in addition to the dose, the method of administration influenced the effects of DMI on the three hormones.

Dependency of growth hormone (GH) stimulation following releasing hormones on the spontaneous 24-hour GH secretion in healthy male and female subjects.

The purpose of this investigation was to evaluate whether in healthy subjects the GH response following stimulation with releasing hormones is dependent on the spontaneous GH secretion within 24 hr prior to the stimulation test. In 18 male and 9 female healthy subjects (21-59 years) GH was measured every 15 min over 26 hr. Twenty-four hours after the beginning of blood sampling, a GH stimulation test was performed by using a combined releasing hormone test. Sleep was recorded in three consecutive nights. A positive correlation was found between the AUCs of the 24-hr GH secretion and the AUCs of GH stimulation, which could not be explained by an age effect only. This study demonstrates that subjects with comparatively high amounts of GH secreted within 24 hr also show good GH secretory responses when immediately after the 24-hr sampling period a stimulation test is undertaken. Therefore, a low GH response to stimulation cannot be explained by feedback effects of high GH amounts secreted during the 24 hr before the test or by empty pituitary GH storages.

Inhibitory effect of phentolamine on diazepam-induced growth hormone secretion and lack of effect of diazepam on prolactin secretion in man.

Phentolamine, a postsynaptic noradrenergic (NA) receptor blocker, inhibits diazepam-induced growth hormone (GH) secretion in man. In order to study the effect of phentolamine on six healthy subjects with a diazepam (10 mg i.v.)-induced GH increase greater than 7.5 ng/ml, it was necessary to test 11 subjects. The six diazepam GH responders showed a significantly higher (p less than 0.01) GH stimulation after diazepam alone than after diazepam plus phentolamine (60 mg i.v.). The inhibitory effect of phentolamine suggests that NA alpha receptors are involved in the diazepam-induced GH increase. Prolactin secretion after administration of diazepam (10 mg i.v.) was only slightly elevated in comparison with placebo (i.v.), suggesting that diazepam does not have an agonistic effect on dopamine (DA) receptors.

Effect of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desimipramine-induced pituitary hormone stimulation in humans--I. Growth hormone.

In this report the effects of various receptor blockers on desimipramine (DMI)-induced growth hormone (GH) secretion in healthy male subjects are presented. Each trial consisted of two administrations: one of DMI i.v. alone and one of DMI i.v. in combination with the respective receptor blocker: methysergide (serotonin (5-HT) receptor blocker), propranolol (beta receptor blocker), phentolamine (alpha-1/alpha-2 receptor blocker), yohimbine (alpha-2 greater than alpha-1 receptor blocker), and prazosin (alpha-1 receptor blocker). DMI-induced GH stimulation was not significantly different after DMI i.v. alone (n = 12) than after three days' pretreatment with 12 mg methysergide p.o. in another group of subjects (n = 12). Following combined administration of DMI and propranolol (15 mg i.v.), GH secretion was significantly increased by 25 mg DMI (p less than 0.05) and 50 mg DMI (incomplete block design, n = 18). GH secretion was significantly lower (p less than 0.01) after DMI in combination with 60 mg phentolamine i.v. compared to that after administration of DMI alone in the same group (n = 12). Following 10 mg yohimbine i.v. in combination with DMI (n = 6), the DMI-induced GH increase was also significantly less (p less than 0.05) than that after DMI alone. The DMI-induced GH increase following DMI plus 1 mg prazosin p.o. (n = 12) was comparable to that after DMI alone. The results indicate that the GH-stimulating effect of DMI is primarily related to the ability of DMI to inhibit noradrenaline (NA) reuptake. Should serotonergic receptors be involved in the DMI-induced GH secretion at all, they transmit a positive stimulus. The alpha-1 receptors are most likely not (or not essentially) involved, whereas alpha-2 receptors affect the DMI-induced secretion positively, and beta receptors have an inhibitory effect.

Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desimipramine-induced pituitary hormone stimulation in humans--II. Prolactin.

In this report the effects of various receptor blockers on desimipramine (DMI)-induced prolactin (PRL) secretion in healthy male subjects are presented. Each trial consisted of two administrations: one of DMI i.v. alone and one of DMI i.v. in combination with the respective receptor blocker: methysergide (serotonin (5-HT) receptor blocker), propranolol (beta receptor blocker), phentolamine (alpha-1/alpha-2 receptor blocker), yohimbine (alpha-2 greater than alpha-1 receptor blocker), and prazosin (alpha-1 receptor blocker). Following administration of methysergide (12 mg p.o., n = 12), a significantly lower (p less than 0.01) DMI-induced PRL secretion compared to DMI alone in another group of subjects (n = 12) was observed. Combined administration with propranolol (15 mg i.v.) significantly enhanced the DMI-induced PRL secretion compared to DMI 50 mg i.v. alone (n = 18, incomplete block design) (p less than 0.01). Neither combined administration with phentolamine (60 mg i.v., n = 12), yohimbine (10 mg i.v., n = 6), nor prazosin (1 mg p.o., n = 12) significantly influenced the DMI-induced PRL secretion compared to DMI alone in the same subjects. The results of the present study, especially the inhibitory effect on DMI-induced PRL secretion of methysergide, indicate that the primarily noradrenaline (NA) and lesser serotonin (5-HT) reuptake inhibiting antidepressant DMI stimulates PRL secretion via 5-HT neurons. Furthermore, the significantly enhanced PRL release following combined administration of DMI and propranolol suggests that a noradrenergic inhibitory effect also may be involved in the transmission of the PRL stimulus.

Effects of receptor blockers (methysergide, propranolol, phentolamine, yohimbine and prazosin) on desimipramine-induced pituitary hormone stimulation in humans--III. Hypothalamo-pituitary-adrenocortical axis.

In this report the effects of various receptor blockers on the desimipramine (DMI)-induced cortisol (ACTH) secretion in healthy male subjects are presented. Each trial consisted of two administrations: one of DMI i.v. alone and one of DMI i.v. in combination with the respective receptor blocker, i.e. methysergide (serotonin (5-HT) receptor blocker), propranolol (beta receptor blocker), phentolamine (alpha-1/alpha-2 receptor blocker), yohimbine (alpha-2 greater than alpha-1 receptor blocker), and prazosin (alpha-1 receptor blocker). In addition, the effect of prazosin on DMI-induced ACTH stimulation was examined. DMI-induced cortisol stimulation was not significantly different after DMI alone (n = 12) from that after three days pretreatment with methysergide (12 mg p.o.) in another group of subjects (n = 12). Neither the combination of DMI plus propranolol (15 mg i.v. n = 18, incomplete block design) nor that of DMI plus phentolamine (60 mg i.v. n = 12) had a significant influence on DMI-induced cortisol secretion. Following combined administration with yohimbine (10 mg i.v.), cortisol secretion was higher compared to that after DMI alone in the same group (n = 6). DMI-induced cortisol secretion was significantly lower (p less than 0.01) following combined administration with prazosin (1 mg p.o. n = 12), as was DMI-induced ACTH secretion (p less than 0.05) in these subjects. The findings of these trials, especially those of the prazosin trial, indicate that DMI-induced stimulation of cortisol and ACTH secretion is attributable to the noradrenaline (NA) reuptake inhibiting effect of DMI, and that the stimulus is transmitted with the aid of noradrenergic alpha-1 receptors. Alpha-2 receptors possibly exert a negative influence on this effect.

Comparison of growth hormone and prolactin stimulation induced by chlorimipramine and desimipramine in man in connection with chlorimipramine metabolism.

In order to compare the effects of chlorimipramine (CI) and desimipramine (DMI) on growth hormone (GH) and on prolactin (PRL) secretion equal doses of 25 mg CI or DMI were administered i.v. to 12 healthy subjects each. In this dose, DMI, which primarily inhibits norepinephrine (NE) uptake, induced a significantly higher GH stimulation, compared to CI, whereas CI, which primarily inhibits serotonin (5-HT) uptake induced a significantly higher PRL stimulation, compared to DMI. Following DMI administration, an increase in GH (greater than 7.5 ng/ml) was found in all subjects, after CI in only about 50% of the subjects. The varying interindividual GH secretions after CI are discussed on the basis of the different plasma levels of CI and of its metabolite desmethyl-chlorimipramine (DCI), which is a NE uptake-inhibitor.

Effects of psychotropic drugs (desimipramine, chlorimipramine, sulpiride and diazepam) on the human HPA axis.

The effects of acute administration of different psychotropic drugs on the human hypothalamic pituitary adrenal (HPA) axis were examined in six groups consisting of six healthy male subjects each, compared to placebo. Desimipramine (DMI) (50 mg IV) significantly stimulated ACTH secretion. DMI (25 and 50 mg IV) and chlorimipramine (CI) (25 mg IV) significantly stimulated cortisol, whereas neither sulpiride (100 mg IV) nor diazepam (10 mg IV) significantly affected secretion of cortisol, as compared to placebo. Since DMI primarily inhibits norepinephrine (NE) uptake and CI primarily that of serotonin (5-HT), whereas sulpiride is a dopamine(DA)-receptor blocker and diazepam a GABA-agonistic benzodiazepine derivative, NE and 5-HT uptake-inhibiting antidepressants seem to influence the HPA axis via the central nervous system.

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.

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.

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.

The lack of effect of bupropion HCL (Wellbatrin) on the secretion of growth hormone and prolactin in humans.

The effect of bupropion HCL (Wellbatrin), a new anti-depressant, on the secretion of GH and PRL in healthy male subjects and male hyperprolactinaemic patients was studied. The study was a randomised double-blind test in which 6 subjects and 6 patients who had been treated with neuroleptics were each, in accordance with the random plan, treated once with placebo and once with 200 mg bupropion p.o.. After administration of the test substance, blood was drawn to measure bupropion, GH and PRL up to 240 minutes thereafter. Neither in the healthy men nor in the patients could a specific effect of bupropion on the secretion of GH be shown in comparison to placebo although bupropion in all subjects and patients was well reabsorbed. As opposed to the results of Stern et al. (5), no change in the secretion of PRL was measured in either the healthy subjects or the hyperprolactinaemic patients. In addition, no change in the TRH-induced stimulation of PRL could be measured. The results of the present study offer no positive contribution towards an explanation of the mechanism of bupropion.

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.

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.