Clomipramine Challenge Research Articles

Brain Circulation during Panic Attack: A Transcranial Doppler Study with Clomipramine Challenge.

Introduction. Cerebral blood flow has been well studied in patients with panic disorder, but only few studies analyzed the mechanisms underlying the onset of a panic attack. The aim of the present study was to monitor the cerebral hemodynamics modifications during a panic attack. Materials and Methods. 10 panic disorder patients with recent onset, fully drug naïve, were compared to 13 patients with panic disorder with a previous history of treatment and to 14 controls. A continuous bilateral monitoring of mean flow velocities in right and left middle cerebral arteries was performed by transcranial Doppler. Clomipramine was chosen as challenge. Results. Eight out of 10 patients drug naïve and 6 control subjects out of 13 had a full blown panic attack during the test, whereas none of the patients with a history of treatment panicked. The occurrence of a panic attack was accompanied by a rapid decrease of flow velocities in both right and left middle cerebral arteries. Discussion. The bilateral acute decrease of mean flow velocity during a panic attack suggests the vasoconstriction of the microcirculation of deep brain structures perfused by middle cerebral arteries and involved in the so-called “fear circuitry,” thus suggesting that cerebral homeostatic dysfunctions seem to have a key role in the onset of a panic attack.

Clomipramine-induced serum prolactin as a marker for serotonin and dopamine turnover: results of an open label study

Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.

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.

Disorders of the Autonomic Nervous System in Patients With Brugada Syndrome: A Pilot Study

The aim of this study was to examine autonomic disorders in patients with Brugada syndrome by performing a cardiac sympathetic innervation evaluation, a head-up tilt-test (HUT) and heart rate variability (HRV) analysis. We enrolled 20 patients with Brugada syndrome (mean age 42.5 +/- 8.8 years), 9 with spontaneous and 11 with an induced type 1 electrocardiogram (ECG) in the setting of symptoms and 20 age-matched controls. All subjects underwent a HUT with parallel measurements of plasma catecholamines and cortisol, a (123)I-metaiodobenzylguanidine single photon emission tomography, and HRV evaluation. Ten control subjects participated in the innervation portion of the study. The tilt-test with clomipramine challenge was positive in 15 of 20 (75%) patients (7 spontaneous, 8 induced) and in 1 in controls (P < 0.01). A sympathoadrenal imbalance was shown in positive tests. The pattern of innervation in all groups was heterogenic and similar to controls with a trend towards lower measurements in patients with a spontaneous type 1 ECG and a positive HUT. HRV analysis did not reveal any significant differences during day and night. Four patients (20%) had sustained ventricular arrhythmias during a follow-up of 31.1 +/- 8.6 months, but no correlations with innervation or response to tilting were found. A high susceptibility to vasovagal syncope was observed in patients with Brugada syndrome, which could be disease-related symptoms. Conversely, sympathetic innervation was observed to follow a physiological, heterogenic pattern; however, these factors did not have prognostic value for life-threatening arrhythmias.

Neurocardiogenic Mechanisms of Unexplained Syncope in Idiopathic Dilated Cardiomyopathy

Syncope in patients with advanced heart failure is a sign of poor prognosis. The cause of syncope in patients with dilated cardiomyopathy (DC) is not fully recognized and may remain elusive even after standardized evaluation. The purpose of the present study was to examine the implication of neurally mediated mechanisms in the pathophysiology of syncopal episodes in patients with DC. Twenty-six patients (21 men, 5 women; mean age 59 +/- 2 years, range 38 to 79) with DC and left ventricular ejection fractions <or=40% were included in the study. Thirteen patients with unexplained syncope or presyncope and a control group of 13 patients without unexplained syncope underwent head-up tilt tests with clomipramine challenge. The 2 groups were matched with regard to age, gender, and left ventricular ejection fractions, and there were no major differences in terms of medication. Heart rate variability analysis and plethysmography of forearm flow were performed during the tilt tests. Blood samples were also drawn for catecholamine measurements. In the group with histories of unexplained syncope, the head-up tilt test results were positive in 11 patients (84.6%). Sympathetic and parasympathetic heart rate indexes were markedly stimulated, while catecholamine concentrations and blood flow changes indicated sympathetic withdrawal during tilting. In the control group, the head-up tilt test results were negative in 12 patients (92.3%). In conclusion, neurally mediated mechanisms seem to be implicated in the pathophysiology of syncope in patients with DC and should therefore be considered in the differential diagnosis of syncopal episodes of unexplained origin.

Abnormal Prolactin Response May Predict Recurrent Depression

Abnormal Prolactin Response May Predict Recurrent Depression

A Longitudinal Study of Serotonergic Function in Depression

Several reports have described abnormal neuroendocrine responses to serotonergic challenge tests in depression, but few have studied depressed patients followed longitudinally. In order to determine whether blunted prolactin responses to clomipramine challenge is a “state” vs. “trait” marker in depression, we applied this challenge paradigm to 20 patients with Major Depression prior to treatment and at three additional time points following response to desipramine: at the completion of acute treatment; at the end of the continuation phase of treatment; and after a minimum of three weeks “washout” following the discontinuation of treatment. The prolactin response to clomipramine challenge was blunted in depressed patients compared with matched healthy control subjects, at each time point over the longitudinal course of their illness and recovery. Challenge test results in depressed patients did not change after response to acute desipramine therapy, at the conclusion of the continuation phase of treatment, or while in a medication-free state of remission. Blunted prolactin response to clomipramine challenge persists in depressed patients after recovery from acute illness, and may reflect an underlying biological vulnerability.

Influence of synaptic serotonin level on [ 18F]altanserin binding to 5HT 2 receptors in man

The feasibility of in vivo serotonin 5HT 2 receptor binding measurement using [ 18F]altanserin as a radioligand has been well established. In this study, the postsynaptic receptor binding potential of this ligand was examined as a possible indicator of synaptic serotonin content after pharmacological challenge. Studies were performed in 11 subjects with a history of recurrent major depression. Six of them received serotonergic antidepressive treatment at the time of the experiment, the other five patients were untreated. Two PET measurements were carried out in each subject within 2 or 3 days. Before one of the measurements, 25 mg of the serotonin re-uptake inhibitor clomipramine were given intravenously, the other measurement was done without pharmacological challenge. The data were analyzed using non-linear least-square regression and Logan's graphical method. In the whole group of subjects, binding potential and distribution volume of altanserin decreased following clomipramine challenge. The decrease was between 14 ( P=0.03) and 23% ( P=0.004). This effect was mainly seen in subjects not on antidepressive medication. Clomipramine challenge probably increased the synaptic serotonin level, which competed with altanserin leading to the lowered binding potential. The paradigm might, thus, be useful to estimate serotonin release in vivo. Pretreatment with serotonergic antidepressants reduces the effect of clomipramine.

Clomipramine challenge studied by [15O]H2O PET: focus on the thalamus

Clomipramine challenge studied by [15O]H2O PET: focus on the thalamus

PET neuroimaging of clomipramine challenge in humans: focus on the thalamus

PET neuroimaging of serotonin responsivity relied previously mainly on fenfluramine, but that drug has been withdrawn from the market. Therefore, we determined whether clomipramine, which stimulates serotonergic mechanisms by inhibiting serotonin reuptake, has reliable effects in the healthy human brain as measured by [ 15O]H 2O PET. The clomipramine challenge markedly reduced the relative rate of blood flow in the selected region of interest, namely the dorsomedial nucleus of the thalamus, a limbic region rich in serotonin uptake sites. These findings show similarities between effects of fenfluramine and clomipramine in the healthy human brain, and support the use of the clomipramine challenge in conjunction with PET for studying cerebral serotonergic mechanisms.

The effects of serotonin3 receptor blockade on the psychobiological response to intravenous clomipramine in healthy human subjects

Background: The purpose of this study was to determine the role that serotonin (5-HT)3 receptors play in the prolactin and nausea responses to clomipramine challenge.Methods: Twenty healthy subjects were randomly assigned to pretreatment with either the selective 5-HT3 receptor antagonist ondansetron, or placebo, prior to intravenous infusion with clomipramine.Results: Ondansetron pretreatment had no effect on the prolactin response to clomipramine challenge. There was a trend toward decreased nausea with ondansetron pretreatment.Conclusions: These findings are consistent with other data suggesting that 5-HT3 receptors do not play a major role in the prolactin response to 5-HT challenge in human subjects, but may mediate nausea associated with enhanced 5-HT neurotransmission.

Parenteral clomipramine challenge in depressed adolescents: mood and neuroendocrine response

Background: Major depressive disorder (MDD) in the adolescent demonstrates a unique clinical profile, and pathogenic serotonergic dysregulation is hypothesized. Parenteral clomipramine (CMI) is known to distinguish adult MDD from control, but neurochallenge data are lacking in adolescent MDD. Methods: Thirteen drug-free outpatient adolescents who met DSM-III-R criteria for MDD were compared to adolescent controls by acute neuroendocrine and mood response to 12.5 mg of parenteral CMI. Results: Repeated measures analysis revealed significant changes from baseline for sadness ( p < .01) between groups, with normal controls increasing sadness rating after CMI. Prolactin (PRL) maximum change score from baseline was decreased in MDD relative to controls ( p < .05). Gender effects on PRL were evident in controls but not in MDD. Conclusions: The findings of PRL blunting in adolescent MDD mirrors previous work in adults. A unique finding is the induction of sadness in normal adolescent controls after CMI infusion.

Intravenous clomipramine challenge in obsessive-compulsive disorder: predicting response to oral therapy at eight weeks

Background: Challenge with intravenous clomipramine (CMI) is serotonin selective and has been reported to transiently exacerbate symptoms in obsessive-compulsive disorder (OCD) patients, and to predict subsequent response to oral CMI therapy. Methods: We administered CMI (12.5 mg, IV) to medication free OCD patients ( N = 29) and normal controls ( N = 22) to characterize neurohormonal response. A subset of OCD patients (26/29), was then treated with either pulse load IV or oral CMI followed by 8 weeks of oral CMI therapy. Results: In response to CMI challenge, OCD patients exhibit blunted cortisol and exaggerated growth hormone response relative to normal controls. OCD patients differ from controls in “sadness” ratings, with controls exhibiting increased dysphoria in response to CMI. Growth hormone response to CMI challenge predicts treatment response (≥ 25% ↓ YBOCS from baseline) to oral CMI at 8 weeks. Conclusions: Growth hormone abnormalities associated with OCD in response to CMI challenge differentiates nonresponders after 8 weeks of oral CMI treatment from responders.

Clomipramine challenge responses covary with tridimensional personality questionnaire scores in healthy subjects

Cloninger's Unified Biosocial Theory of Personality postulates a relationship between the relative functional activity of central serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, and the strength of three elemental dimensions of personality. These dimensions are Harm Avoidance, Novelty Seeking, and Reward Dependence, respectively. Accordingly, we predicted that neuroendocrine responses to serotonergic challenge would correlate with Harm Avoidance scores, but not with Novelty Seeking or Reward Dependence scores. We examined the relationship between the prolactin and cortisol responses to a 12.5-mg intravenous clomipramine challenge and these personality dimensions as measured by Cloninger's Tridimensional Personality Questionnaire in 32 healthy subjects. The cortisol response correlated only with Harm Avoidance scores, as predicted; however, prolactin response did not correlate with Harm Avoidance scores. Instead, it demonstrated an inverse relationship with Novelty Seeking scores. There was a positive relationship of baseline prolactin with Harm Avoidance in a post hoc analysis. Cortisol response to serotonergic challenge may be a better indicator for responsivity of serotonergic systems as they relate to the personality dimension of Harm Avoidance than is prolactin. Prolactin responses may be overly affected by dopaminergic influences; however, baseline prolactin may still be a valid indicator of serotonergic tone.

P.2.075 Neuroendocrine responsivity to clomipramine challenge test in neuroleptic naive psychotic patients before and after treatment with haloperidol

P.2.075 Neuroendocrine responsivity to clomipramine challenge test in neuroleptic naive psychotic patients before and after treatment with haloperidol

90-116 - Abnormal neuroendocrine responses to clomipramine challenge test in major depression

90-116 - Abnormal neuroendocrine responses to clomipramine challenge test in major depression

76-3 - Neuroendocrine responsivity to clomipramine challenge in elderly: Correlations with clinical evaluation of the serotonin function

76-3 - Neuroendocrine responsivity to clomipramine challenge in elderly: Correlations with clinical evaluation of the serotonin function

The Clomipramine Challenge Test in Major Cases of Depression and Schizophrenia

The neuroendocrine challenge test is a useful way of examining the functional integrity of the monoamine pathways that control the secretion of pituitary hormones. The 5-HT uptake inhibitor clomipramine has a considirable use as a 5-HT challenge test. Serotonergic systems in the brain are often disturbed in depressed patients and the role of serotonin in schizophrenia is still unclear. Serotonin is an effective stimulator of prolactine and cortisol release. In this study, we investigated the activity of serotonergic system in depressive and schizophrenic patients via serum plolactin and cortisol levels stimulated by the clomipramine challenge test. While the prolactin /DeltaEmax responses of the depressed and schizophrenia patients to clomipromine tended to be significantly different, the difference between responses of cortisol /DeltaEmax was not statistically significant. We believe that this study gives quite reliable results relating to the serotonergic system; even though the total number of cases was small, the placebo and clomipramine test results of each patient were compared. This study has two important results 1) The cortisol and prolactin responses to clomipramine are more predictive in depression than schizophrenia cases 2) Depressives give more active responses to serotonergic stimulations.

Neuroendocrine responsivity to clomipramine challenge test in neuroleptic naive psychotic patients before and after treatment with haloperidol

The prolactin, cortisol and growth hormone (GH) responses to intravenous administration of 25 mg clomipramine (CMI) were studied in young male psychotic patients who had never received neuroleptics and suffered from schizophrenia (13 patients), delusional disorder (three patients) or schizoaffective disorder (one patient). The test was repeated after 1 month in 16 patients who were hospitalized and treated with haloperidol in doses appropriate for best clinical response (range: 7.5–40 mg daily). Symptomatology was assessed by the Brief Psychiatric Rating Scale (BPRS). There was no association of the side effects caused by the administration of CMI (nausea and emesis) to the GH responses. The side effects appeared significantly less in the after treatment trials. Treatment with haloperidol did not influence the response patterns of the three hormones. An indication that high haloperidol doses may inhibit the prolactin response to CMI was obtained when the data were compared between low (7.5–10 mg/day, mean 9.7) and high (15–40 mg/day, mean 22.0) dose subgroups. Significant positive correlations were found between the prolactin and cortisol responses to CMI in the drug-free state, and the scores in the positive symptoms subscale of the BPRS. The degree of improvement did not correlate to any of the hormonal data.

The effects of age, gender, and season on serotonergic function in healthy subjects

1. 1. Several factors, including age, gender, and season of the year, have been reported to affect physiologic indices of central serotonergic function, although some of these findings have not been consistent across groups of subjects and types of serotonergic measures. 2. 2. The authors investigated the role that each of these variables might play in the neuroendocrine response to acute intravenous challenge with the serotonin reuptake inhibitor clomipramine (CMI) in healthy volunteers. 3. 3. Thirty seven healthy subjects (17 women and 20 men), with an age range of 19 to 50 years, received 12.5 mg of CMI intravenously under standardized conditions. 4. 4. The maximum change from baseline in plasma prolactin concentrations (“delta-max”) was significantly related to age, after controlling for gender and season. 5. 5. In contrast, neither gender nor season was significantly related to prolactin delta-max, after controlling for the other two variables. 6. 6. Although the age range and sample size are relatively limited, the results from this study suggest that age, but not gender or season, may influence serotonergic function, as measured by the prolactin response to CMI challenge.