Abnormal neuroendocrine response to clomipramine in hereditary affective psychosis

Background: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. Methods: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n=15, recurrent depression n=5, according DSM‐IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re‐uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. Results: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed seperately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P=.046). For prolactin, this effect could be found in the male (P=.012) as well as in the female (P=.007) subsample. Conclusions: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Prolactin and cortisol responses to acute intravenous clomipramine challenge in patients with mania, depression and healthy controls: evidence for reduced serotonergic responsivity

Serotonergic dysregulation has been shown to be involved in the pathophysiology of unipolar and bipolar depression. Neuroendocrine challenge tests have been extensively used to investigate serotonin functioning in the brain. Although the role of serotonin has received a great deal of attention using neuroendocrine challenge paradigms, little effort has been made to explore the role of serotonin in mania. We assessed serotonergic neuroendocrine responsivity in patients with depression (n = 22), mania (n = 11) and 15 healthy controls by measuring the prolactin (PRL) and cortisol responses to i.v. clomipramine (CMI) and searched for possible differences among the groups. Blunted PRL responses to CMI in manic and depressed patients compared to healthy controls were found. The response to CMI disclosed similar results for the 2 patient groups. No significant differences were found among the 3 subject groups in the cortisol response to CMI. The blunted PRL responses to CMI in patients with mania and depression suggest that serotonergic functioning in mania and depression is similarly impaired, at least at the level of hypothalamus-hypophysis.     

Neuroendocrine effects of intravenous clomipramine in depressed patients and healthy subjects.

OBJECTIVE: Neuroendocrine challenge paradigms have been used to asses serotonergic systems in depression, but limitations in the specificity of many of these tests have been noted. In this study, the neuroendocrine responses to acute intravenous administration of the serotonin (5-HT) reuptake inhibitor clomipramine were assessed in depressed patients and matched control subjects. METHODS: Thirty hospitalized patients who met DSM-III-R criteria for major depression, and 30 healthy control subjects who were matched for age, sex, and season of year for the time of study, received 12.5 mg of intravenously administered clomipramine. RESULTS: The depressed patients demonstrated significant blunting of prolactin responses to clomipramine, as well as trends toward blunted ACTH and cortisol responses. There was no difference between the patient and control groups in growth hormone responses, plasma clomipramine levels, or self-reports of side effects. CONCLUSIONS: These data support the hypothesis that depressed patients have abnormal neuroendocrine responses to the intravenous administration of the 5-HT reuptake inhibitor clomipramine. Further study is required to delineate the mechanisms responsible for the abnormal response to intravenously administered clomipramine in depression.     

Effects of clomipramine infusion on sleep in depressed patients

Sleep structure of 10 endogenous depressed patients was investigated before and after clomipramine treatment. Clomipramine significantly reduced REM time, increased REM latency and induced dissociation between the tonic and phasic events of REM sleep, without affecting any of the other sleep parameters. The REM suppressing effect was most prominent on the third night after beginning treatment.     

Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment

Clomipramine is a potent serotonin reuptake blocker that decreases the symptoms of obsessive-compulsive disorder (OCD). To investigate whether clomipramine treatment in OCD affects brain serotonergic responsiveness, metachlorophenylpiperazine (mCPP), a selective serotonin agonist, and placebo were given under double-blind conditions to nine patients with OCD before and after treatment with clomipramine. Unlike our previous observations of a marked transient increase in obsessional symptoms and anxiety following 0.5 mg/kg of mCPP, readministration of mCPP after four months of treatment with clomipramine did not significantly increase obsessional symptoms and anxiety. Similarly, the hyperthermic effect of mCPP observed before treatment was eliminated after treatment with clomipramine. These findings are consistent with the development of adaptive subsensitivity to the serotonergic agonist mCPP during clomipramine treatment. A similar alteration in the response to endogenous serotonin may mediate clomipramine's antiobsessional effects.     

Relationship between prolactin responses to ECT and dopaminergic and serotonergic responsivity in depressed patients

The prolactin (PRL) increases in plasma, induced by the electrical stimulus during electroconvulsive therapy (ECT), is a consistent finding that can be studied in order to obtain information about its actions on the brain neurotransmitter systems, the most probable candidates being the serotonergic and the dopaminergic system. Central serotonergic and dopaminergic responsivity may also be assessed using neuroendocrine challenge tests. In this study, we measured the PRL responses during the first ECT of a therapeutic course in 15 male depressive patients, of mean age 49.2 ± 14.5 (range 22 to 68 years), and score in the HDRS of 29 ± 8 (range 18 to 43 points). Before the ECT course, we assessed the central serotonergic and dopaminergic responsivities, by measuring the PRL responses to the administration of the serotonin uptake inhibitor clomipramine (CMI) intravenously, and, two days later, the PRL responses dopamine receptor blocker haloperidol (HAL), administered intramuscularly. The CMI and HAL tests were also performed in 15 healthy male subjects. The PRL responses to CMI of the patients were blunted compared to healthy controls, while the PRL responses to HAL were not significantly different from controls. Searching for correlations among the maximal PRL responses to the three stimuli in the patient's group, we found that the PRL responses to ECT were significantly correlated to the PRL responses to i. m. HAL (r = 0.8205, N = 15, p < 0.001) and not to the PRL responses to i. v. CMI (r = 0.1713, n. s.). It is suggested that the rises in PRL during ECT reflect the responsivity of the hypothalamus-pituitary dopaminergic system, and seem to be the result of a transient decrease in the inhibitory dopaminergic input of the hypothalamus to the pituitary lactotrophs, caused by the electrical stimulus and the subsequent seizure. Received: 5 March 2002 / Accepted: 15 July 2002     

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.     

Noradrenergic responses to clonidine in acute and remitted depressed male patients.

To investigate noradrenergic function in depression, plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma norepinephrine (NE), mean arterial pressure (MAP), and heart rate responses to intravenous clonidine (2 micrograms/kg), an alpha 2-adrenergic agonist, were measured in 27 acutely depressed patients, 18 remitted depressed patients, and 27 normal control subjects; a placebo infusion was administered to a subgroup. Clonidine compared with placebo, over a 150-minute time course, decreased plasma NE, MAP, and heart rate, but not plasma MHPG, in the control subjects. Plasma MHPG, plasma NE, MAP, and heart rate at baseline or in response to clonidine and placebo over 150 minutes did not indicate any group differences. The only significant plasma MHPG response to clonidine in the normal control subjects occurred 60 minutes after the infusion. A significantly diminished plasma MHPG response to clonidine at 60 minutes was found in the acutely depressed group compared with the normal control subjects. These results suggest that peripheral inhibitory noradrenergic responses to clonidine are normal in depressed patients, while plasma MHPG responses to clonidine, which have a limited central contribution, appear to be a weak reflection of central noradrenergic function and appear insufficiently robust for a meaningful evaluation of hypothetical group differences in central inhibitory alpha 2-adrenergic activity in this population.     

Plasma norepinephrine responses to cold challenge in depressed patients and normal controls

Thirty depressed patients were compared with 39 controls for their plasma norepinephrine (NE) levels in relation to a cold challenge (placing a hand in ice cold water for 1 minute). Depressed patients showed significantly higher plasma NE levels than controls. Unipolar, but not bipolar patients, had significantly higher plasma NE levels than age- and sex-matched controls. Unipolar melancholic patients who were nonsuppressors on the dexamethasone suppression test showed a strong trend to have higher plasma NE levels than suppressors. These results are further evidence that the NE system is dysregulated in depression.     

Treatment with an i.v. calcium overload blocker (flunarizine) in acute stroke

Summary In an open pilot study 55 patients suffering from acute stroke were treated with Flunarizine, a calcium overload blocker, in addition to standard therapy including diet, physiotherapy, adequate management of accompanying disorders, and hemodilution. The initial high-dose i.v. treatment (2 x 25 mg Flunarizine/day) and the subsequent oral regimen were well-tolerated. The main side effect was slight transient weariness. No adverse effects regarding blood pressure, heart rate, enzymes, blood analysis, renal function and, especially, no extrapyramidal motor symptoms or depression were detected. Flunarizine may be regarded as a relatively safe drug in acute stroke. The probable beneficial effect on the patient's recovery will be evaluated in a multicenter double-blind study.     

A randomized, double-blind, placebo-controlled pilot study of i.v. immune globulins in combination with i.v. methylprednisolone in the treatment of relapses in patients with MS

BACKGROUND: Some patients with multiple sclerosis (MS) do not show a clear improvement of acute relapses after treatment with intravenous methylprednisolone (IVMP). We compared the efficacy of the combination of intravenous immunoglobulins (IVIg) and IVMP with the standard treatment of IVMP alone in promoting recovery from moderate to severe acute relapses in MS. METHODS: Patients with clinically definite MS having a relapse with at least a one point increase in Kurtzke's expanded disability status scale (EDSS) in comparison to the preattack EDSS were randomized to IVMP-IVIg or IVMP-placebo treatment. The primary outcome criterion was the EDSS grade at four weeks. A preplanned interim analysis was performed after inclusion of 19 consecutive MS patients to evaluate the sample size necessary for a larger trial. FINDINGS: Both groups had improved one point on the EDSS four weeks after start of treatment (P = 0.81) and one of the stopping rules of the interim analysis was fulfilled. There were also no differences in secondary outcomes: EDSS at eight and 12 weeks, time to improve > or = 1 EDSS points, difference in Scripps score and ambulation index. Five patients in the IVMP-IVIg group and two in the IVMP group had a new relapse in the six month follow-up. INTERPRETATION: Our study could not show superiority of IVMP-IVIg in the treatment of moderate to severe acute relapses in MS.     

Is there a relationship between response to total sleep deprivation and efficacy of clomipramine treatment in depressed patients?

Total sleep deprivation (TSD) and tricyclic medication are successful treatment modalities for patients with a major depressive disorder. Recent studies have suggested a positive relationship between TSD response and succeeding tricyclic treatment, even on a very specific level, thus supporting the assumption of two distinct biochemical subtypes of depression. The present study tested this hypothesis by treating 10 inpatients with a major depressive disorder first with TSD and succeedingly with clomipramine. Contrary to expectation, a negative relationship between clinical response to the two treatment modalities was found.     

Electroencephalographic studies with i.v. methaqualone in man.

Methaqualone injected i.v. has been reported to be a safe short-acting anaesthetic agent and a muscle relaxant in man. It has been employed in a variety of operative procedures and to modify convulsions in the management of tetanus and in electroconvulsive therapy. Safety, usefulness and the marked central effects of the drug led us to study its central effects by EEG in man. Discrepancies between clinical and EEG signs were thus seen. EEG patterns resembled those after barbiturates and the effect was dose dependent. Differences between methaqualone and barbiturates are discussed. The EEG patterns were potentiated by thioridazine and antagonised by imipramine.     

Neuroendocrine response to trihexyphenidyl in depressed patients.

The effect of a single dose (10 mg P.O.) of trihexyphenidyl (THP) on plasma cortisol, growth hormone (GH), and immunoreactive beta-endorphin (ir-beta-EP) was studied in seven major depressed patients and seven controls. GH secretion was suppressed (34-41%) by THP in both groups. THP did not affect cortisol secretion in depressed patients and controls. An increase (18%; p less than 0.05) in plasma ir-beta-EP levels was detected in the healthy subjects only. The results of this study do not support the hypothesized altered responsiveness to anticholinergic provocation in major depression. The inhibitory activity of THP on GH secretion indicates the involvement of the cholinergic system in the regulation of GH release in humans.     

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin

Objective – To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. Materials and methods – Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. Results – Seventy‐four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. Conclusions – VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.