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PubMed2004

Effects of imipramine, fluvoxamine and depressive mood on autonomic cardiac functioning in major depressive disorder.

OBJECTIVE: Diminished HR variability is considered to be associated with depression and the increased risk of cardiovascular disease. The pharmacological effects of antidepressants and depressive mood itself may contribute to alterations in autonomic cardiac functioning, but a limited amount of data is available. We studied the effects of two different types of antidepressant treatments (imipramine and fluvoxamine), in addition to the effect of depressive mood, on the cardiovascular system in depressed patients. METHODS: Depressed inpatients were studied during a drug-free period and after 4 weeks of adequate treatment with imipramine (n = 17) or fluvoxamine (n = 24). Heart rate variability, blood pressure variability, and a baroreflex sensitivity index during supine rest and orthostatic challenge were analyzed by means of spectral techniques to obtain noninvasive parameters of sympathetic and parasympathetic activity. RESULTS: Both imipramine and fluvoxamine reduced sympathetic and parasympathetic activity, although the effects of imipramine were much more pronounced. Severity of depression was positively related to mean levels of heart rate and blood pressure in the total patient group. There was no convincing evidence that these relationships differed between depressed patients treated with imipramine and those treated with fluvoxamine. CONCLUSION: Our findings suggest that alterations in mean heart rate and blood pressure in depressed patients after antidepressant treatment are the result of a combined effect of pharmacological actions of antidepressants and improvement of depressive mood state. The present study did not confirm the relationship between clinical state and cardiovascular variability or baroreflex sensitivity.

Adult↗
PubMed1993

Interrelationship between blood serotonin levels and affinity of platelet imipramine binding sites in healthy subjects.

Changes in the density of the platelet imipramine binding sites have been reported for a variety of psychiatric conditions. The discrepancy in binding data between different laboratories renders the interpretation of the results difficult. In addition to differences in the way the various laboratories perform their binding assays, another contributing factor might be their mathematical evaluation. The imipramine binding site appears to be associated with the platelet serotonin uptake site, but it is not clear whether blood-serotonin concentrations are involved in its regulation. In order to elucidate serotonin's influence we determined blood serotonin and platelet imipramine binding simultaneously in 13 healthy female subjects. To optimize data evaluation we tested the applicability of the Scatchard analysis and a modification of the Marquardt iterative algorithm. Computer simulation of binding data suggests a superior goodness-of-fit when using the modified Marquardt algorithm. We observed a significant positive correlation between blood serotonin and the apparent dissociation constant (KD) of the imipramine binding site: the affinity decreased at high blood-serotonin concentrations (Pearson's r = 0.88, p < 0.0001). We interpret this phenomenon as serotonin's negative feedback regulation of the platelet imipramine binding site.

Adult↗
PubMed1991

Circadian variation in platelet imipramine binding during the day in healthy subjects.

Platelet tritiated imipramine binding values in healthy controls vary considerably from study to study. A possible contributor to such variation might be a circadian rhythm affecting binding, although previous studies of this have been contradictory. Platelet imipramine binding was examined in 12 healthy, medication-free subjects studied at 8 a. m., 11 a. m., 4 p. m., and 10 p. m. during one day. Imipramine binding was determined on platelet membranes, using 0.8-8 nM 3H-imipramine, and nonspecific binding was defined by 50 microM desipramine. All samples from a given individual were assayed simultaneously. The intra-assay coefficient of variation was 6.3 percent. There was no evidence of significant differences in binding capacity or affinity (Bmax or Kd) at different times of day. Circadian variation was explored using COSINOR analysis (DeMet et al., 1989). There was no evidence of circadian variation in binding using this model, even when only the variable portion of binding was considered for each individual. Intraindividual variation in binding was substantial, with a mean coefficient of variation of 29 percent for Bmax and 38 percent for Kd. The possible basis of this variation is unclear, but may reflect the presence of "occult" binding sites in the membrane, or the effect of endogenous modulators of binding. The interrelationship of Bmax and Kd may also be a factor. It was considered that low-affinity binding did not account for a significant part of the variation in Kd in this assay. The utility of imipramine binding as a biological marker of depression may be limited by such levels of intraindividual variation in binding parameters.

Adult↗
PubMed1982

High-affinity 3H-imipramine binding: a new biological marker in depression.

High-affinity binding of the tricyclic antidepressant drug, 3H-imipramine, has been demonstrated in the brain of various species including man. These specific binding sites have many of the characteristics to be expected for the specific site of action of a drug and appear to be associated with the neuronal uptake mechanism for serotonin. Chronic administration of tricyclic antidepressant drugs or the prolonged application of other antidepressant therapies, such as electroshock and sleep-deprivation, resulted in decreases in the density of 3H-imipramine binding sites. Apparently identical 3H-imipramine binding sites have been found in blood platelets from a variety of species including man. Clinical studies have shown that untreated severely depressed patients have a lower density of binding sites in their platelets than control volunteers. Longitudinal studies of these patients indicate that the density of 3H-imipramine binding sites tends not to change during treatment with tricyclic antidepressant drugs and the subsequent recovery from depression. 3H-imipramine binding in brain and platelets is proposed as a new biological marker in depression and as a useful research tool in biochemical and clinical pharmacological studies in affective disorders.

Binding Sites↗
PubMed1993

Hypnosis and self-hypnosis in the management of nocturnal enuresis: a comparative study with imipramine therapy.

Various therapeutic modalities have been used for treating enuresis due to the lack of a single identifiable cause. We carried out a comparative study of imipramine and direct hypnotic suggestions with imagery used for the management of functional nocturnal enuresis. Enuretic children, ranging in age from 5 to 16 years, underwent 3 months of therapy with imipramine (N = 25) or hypnosis (N = 25). After termination of the active treatment, the hypnosis group continued practicing self-hypnosis daily during the follow-up period of another 6 months. Of the patients treated with imipramine, 76% had a positive response (all dry beds); for patients treated with hypnotic strategies, 72% responded positively. At the 9-month follow-up, 68% of patients in the hypnosis group maintained a positive response, whereas only 24% of the imipramine group did. Hypnosis and self-hypnosis strategies were found to be less effective in younger children (5-7 years old) compared to imipramine treatment. The treatment response was not related to the hypnotic responsivity of the patient in either group.

Adolescent↗
PubMed1991

Imipramine in the treatment of depressed Alzheimer's patients: impact on cognition.

A double-blind study evaluated the impact of imipramine on cognitive function in 61 patients with Alzheimer's disease. Twenty-eight patients had coexistent depression and dementia; 33 had dementia only. All were randomly assigned to an 8-week trial of imipramine or placebo. For both depressed and nondepressed subjects, the effect of imipramine on cognition was minimal. A subtle decrement in general cognitive function was evident in those treated with imipramine, as compared with those treated with placebo. No effects were observed on memory. Clinicians are advised that very low doses of imipramine (25 mg/daily) may be tolerated in depressed Alzheimer patients, but that cognitive changes do occur in some patients and should be carefully monitored.

Aged↗
PubMed1992

Platelet imipramine binding is increased in essential thrombocythaemia.

A decrease in platelet serotonin content is well recognized in myeloproliferative disorders, although the basis for this is unclear. The relationship between decreased platelet serotonin and the number of serotonin transport channels in the platelet membrane was explored indirectly by measuring the number of the closely associated imipramine binding sites. Imipramine binding parameters were determined in 12 patients suffering from either essential thrombocythaemia or polycythaemia rubra vera and in 10 healthy controls. The maximal number of imipramine binding sites (Bmax) was increased in both patient groups, significantly so in those suffering from essential thrombocythaemia. This increase contrasts with a decrease in binding in other conditions known to be associated with decreased platelet serotonin. This study thus demonstrates a discrepancy in terms of reduced platelet serotonin content and increased imipramine binding on platelets from patients suffering from essential thrombocythaemia. It is suggested that further investigation of the imipramine binding site in these disorders, in parallel with measures of platelet serotonin content and uptake, is warranted.

Adult↗
PubMed2000

Imipramine compliance in adolescents.

OBJECTIVE: To investigate side effects, medication compliance, and assumption of medication assignment in adolescents taking imipramine versus placebo in a clinical trial. METHOD: Sixty-three anxious-depressed adolescents in an 8-week double-blind study of imipramine versus placebo, each in combination with cognitive-behavioral therapy for school refusal, were evaluated. Measures of side effects, global improvement, family functioning, medication compliance based on pill counts, and guesses of drug assignment (imipramine versus placebo) were analyzed. RESULTS: Mean side effects ratings were significantly higher for the imipramine group compared with the placebo group (p = .001). Side effects were not associated with noncompliance or with dropping out. Oppositional defiant disorder (ODD) in the adolescents was significantly associated with medication noncompliance (p = .036). On the Family Adaptability and Cohesion Evaluation Scale II (FACES II), low family adaptability (i.e., rigidity), low family cohesion (i.e., disengagement), and extreme family type were significantly associated with greater noncompliance with medications. Accuracy rates for guessing medication assignment (imipramine versus placebo) were 66% for subjects, 62.5% for mothers, and 79.5% for the psychiatrist. Logistic regression demonstrated that side effects (p = .005) and global improvement scores (p = .06) predicted the psychiatrist's guesses of drug assignment. CONCLUSIONS: Side effects were not associated with noncompliance. Nonadherence with taking medications was associated with ODD in the adolescents and problematic family functioning on FACES II. The psychiatrist, who was blind to treatment condition, guessed the subjects' medication assignments with high accuracy. Thus, because of expectancy bias, the data support the use of blind independent evaluators for rating changes in medication trials.

Adolescent↗
PubMed1985

Orthostatic effect of imipramine and doxepin in depressed geriatric outpatients.

Blood pressure measurements were collected from 36 depressed geriatric outpatients (ages 55 to 81 years) enrolled in a double-blind, placebo-controlled study of the efficacy of doxepin and imipramine. Mean systolic postural changes were 25.9 mm Hg for imipramine, significantly higher than the 10.5 mm Hg for doxepin, and 12.4 mm Hg for placebo. The orthostatic drop in the imipramine group was only weakly related to dose and did not correlate with amount of pretreatment orthostatic hypotension or with duration of treatment. The increased orthostatic hypotension occurred early in treatment and at low doses of imipramine. Accordingly, caution is advised in the use of imipramine for the elderly.

Age Factors↗
PubMed2002

Effect of fluoxetine and imipramine on the pharmacokinetics and tolerability of the antipsychotic quetiapine.

The effects of fluoxetine and imipramine on the pharmacokinetics and nonpsychiatric side effect profile of quetiapine fumarate were investigated in 26 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a multicenter, two-period, multiple-dose, open-label, randomized trial. Over a 1- to 2-week period, patients were titrated to a 300-mg twice-daily dose of quetiapine. Patients treated for at least 7 days at the target dose entered a combination therapy period, receiving fluoxetine (60 mg daily) or imipramine (75 mg twice daily) for 8 days. Key assessments included pharmacokinetic analysis of quetiapine, the Udvalg for kliniske undersøgelser (UKU) Side Effect Rating Scale, and safety evaluations (e.g., adverse events, electrocardiograms, laboratory tests, and vital signs). Fluoxetine increased the quetiapine area under the plasma concentration time curve during a 12-hour interval (+12%), maximum plasma concentration during the dosing interval (C(ss)(max); +26%), and minimum plasma concentration at the end of the dosing interval (+8%), although it decreased oral clearance (-11%). The change in C(ss)(max) was statistically although not clinically significant. Imipramine did not affect the pharmacokinetics of quetiapine. Overall, scores on the UKU Side Effect Rating Scale improved during combination therapy with either agent, and no statistically significant deterioration was observed for any item. For safety assessments, the only clinically remarkable event was an imipramine-associated complete left bundle branch block in one patient. No unexpected side effects were reported. In conclusion, combination therapy with quetiapine and fluoxetine or imipramine had a minimal effect on quetiapine pharmacokinetics and was well tolerated.

Adolescent↗
PubMed1993

The effects of nefazodone, imipramine and placebo, alone and combined with alcohol, in normal subjects.

Nefazodone (200 mg, 400 mg/day) imipramine (150 mg/day) and placebo were administered to 12 normal, healthy volunteer subjects for a period of 8 days each. A measured dose of alcohol was consumed with the drug on day 8. A battery of physiological, psychomotor, cognitive and subjective tests was carried out before drug administration and 2 h after drug administration on days 1, 7, and 8. Nefazodone had little effect on heart rate and blood pressure whereas imipramine increased both heart rate and diastolic blood pressure. Nefazodone 400 mg impaired the critical flicker fusion threshold. Dose-dependent improvements in psychomotor performance (Gibson Spiral Maze) and complex memory performance (learning, pursuit rotor, and visual working memory) were produced by nefazodone while imipramine administration impaired performance on these tasks. Subjective changes in alertness and bodily symptoms were produced by all active compounds. While nefazodone failed to potentiate the sedative-hypnotic (depressant) effects of alcohol, imipramine tended to enhance them for psychomotor performance, memory assessments, and some subjective ratings. Thus, nefazodone, particularly at lower dose levels, causes less disruption of human performance than imipramine. This effect probably reflects the lack of anticholinergic activity of nefazodone. Also, nefazodone failed to potentiate the depressant effects of alcohol, perhaps because of its minimal alpha-blockade.

Adolescent↗
PubMed1995

Antidepressant efficacy in relation to item analysis and severity of depression: a placebo-controlled trial of fluvoxamine versus imipramine.

In this investigation, the antidepressant efficacy of fluvoxamine and imipramine was compared in a randomized, double-blind, placebo-controlled study lasting 4 weeks; 338 depressed patients were recruited at five North American centres. For the efficacy analyses an intent-to-treat sample was defined. The global efficacy of the two drugs was assessed by the Hamilton Depression scale (HAM-D) and Clinical Global Impression (CGI) scores. Antidepressant activity was also assessed using the percentage of responders on the CGI "improvement" scale. In addition the time of onset of antidepressant effect was evaluated by weekly analysis of individual HAM-D items. The intent-to-treat sample was stratified retrospectively according to the severity of the depression (mild, moderate or severe). Regarding global efficacy, compared with placebo, only fluvoxamine significantly improved the HAM-D total scores at Week 4 (p < 0.05). There was a suggestion from individual HAM-D item scores (depressed mood, suicide, psychic anxiety) that fluvoxamine had an earlier effect than imipramine. Overall, compared with placebo, more HAM-D items were improved by fluvoxamine than imipramine. Fluvoxamine but not imipramine was significantly superior to placebo in severely depressed patients as shown by improvements in the HAM-D score (p < 0.01) and the CGI "improvement" score (p < 0.05). Side effect profiles for the active agents were typical for their pharmacological category:imipramine was associated with anticholinergic effects, particularly dry mouth, and fluvoxamine was associated with nausea and vomiting.

Adult↗
PubMed1993

Lack of pharmacokinetic interaction between chloroquine and imipramine.

The pharmacokinetic interaction between chloroquine (CQ) and imipramine was investigated in six healthy volunteers who received 300 mg of CQ, 50 mg of imipramine, and combined doses of both drugs in a randomized, crossover design. Blood and urine samples were collected at predetermined time intervals and were analyzed for the drugs and their metabolites by high-performance liquid chromatography methods. The results revealed that the plasma concentrations of CQ and its pharmacokinetic parameters were not significantly altered when CQ was coadministered with imipramine (p > 0.1). The plasma concentration-time profiles and the disposition characteristics of imipramine also were not altered after coadministration with CQ. The results suggest that there appears to be no pharmacokinetic interaction between CQ and imipramine given as single oral doses.

Administration, Oral↗
PubMed2004

TDM-based imipramine treatment in neuropathic pain.

Tricyclic antidepressants (TCA) are the best-documented treatment of neuropathic pain. TCAs have a pronounced interindividual pharmacokinetic variability and a narrow therapeutic index. The aim of this study was to characterize the plasma concentration-effect relationship of imipramine in neuropathic pain and to determine the usefulness of therapeutic drug monitoring (TDM) of TCA treatment in a population with noncancer chronic pain. To do this, 83 patients with chronic noncancer neuropathic pain were included. Information on previous use of TCA was collected, and patients were tested for the presence of hyperalgesia. Pain intensity and pain relief were recorded, and the Short Form McGill Pain Questionnaire and Major Depression Inventory were completed before and during a TDM-based imipramine treatment. Imipramine dose was increased in steps of 25 mg/d every second week, and blood samples were taken at every dose. Endpoints were best possible pain relief, unacceptable side effects, or insufficient pain relief despite plasma drug level > 500 nmol/L. Dose range used was 10-300 mg/d. The study showed that imipramine 75 mg/d caused a 36-fold interindividual variation in steady-state plasma drug concentrations. In 46 responders (global pain relief > 25%) the plasma drug concentration at which an individual maximal analgesic effect was obtained ranged from 50 to 1400 nmol/L, but for the majority it was below 400 nmol/L. The concentration-effect relationship was similar for patients with central versus peripheral neuropathic pain and independent of the presence of hyperalgesia. Previous treatment failure with non-TDM TCA treatment was not a predictor of poor response to TDM-based treatment. In conclusion, there is a pronounced interindividual variability in concentration-effect relationship for imipramine treatment in neuropathic pain, but the majority of patients obtain a maximal analgesic effect at drug levels below 400 nmol/L. The concentration-effect relationship is similar for patients with central and peripheral neuropathic pain. Further studies are needed to document if TDM improves pain relief; however, TDM reduces the risk for toxicity.

Adult↗
PubMed2004

Switching from imipramine to sertraline in panic disorder.

BACKGROUND: There are no systematic switching studies of antidepressants in the treatment of panic disorder. The present pilot study examined the usefulness of switching from imipramine to sertraline in 18 patients diagnosed with panic disorder with agoraphobia. METHOD: 15 patients who had had an unsatisfactory outcome in a 24-week, open, weight-adjusted fixed-dose imipramine treatment study and 3 patients who had had a very satisfactory outcome but had subsequently relapsed following imipramine discontinuation were systematically switched to protocolized, 24-week open treatment with sertraline, 50-100 mg/day. Uniform measures of efficacy and side effects were used throughout the study. The net benefit obtained from the switch was assessed using an operationalized outcome grade ranging from 0-2, where 0 = inadequate duration of trial (dropouts) or non-response, 1 = partial response or full responders with side effects necessitating a change in treatment, and 2 = full response without complications. RESULTS: Based on paired t-tests, following the switch from imipramine to sertraline, a significant improvement was seen on phobic and panic symptomatologies, side effects, and overall outcome grade (from 0.67 [+/- 0.77] to 1.17 [+/- 0.92], p < or = 0.05]. Of the 18 patients who were switched to sertraline treatment, 9 (50%) clearly gained from the switch, 6 (33.3%) had an outcome similar to that achieved with imipramine, and 3 (16.7%) had a worse outcome following the switch. Of the 9 patients who failed to respond to or were unable to tolerate treatment with imipraminel (rating of 0), 3 patients (33.3%) achieved full and 2 patients (22.2%) achieved partial response after switching to sertraline. CONCLUSION: The findings in this study suggest that switching between antidepressants with established antipanic efficacy may be an effective strategy in the management of patients with panic disorder who have had an unsatisfactory outcome with the first antidepressant tried.

Adult↗
PubMed1983

A double-blind controlled clinical trial comparing fluvoxamine with imipramine.

1 The effects of fluvoxamine to a maximum of 300 mg daily were compared with those of imipramine to a maximum of 200 mg daily, in 151 patients with primary major depression. 2 Four weeks of treatment with fluvoxamine resulted in 67.2% improvement (+/- s.d. 21.6) on the Hamilton Rating Scale for Depression (26 items). Treatment with imipramine showed 62.1% improvement (+/- s.d. 29.5) on this scale. 3 Fluvoxamine had no untoward effects on the cardiovascular system, while imipramine produced systematic increases in the postural fall in blood pressure. Dry mouth, nausea, daytime somnolence and tremor were seen with fluvoxamine treatment, while imipramine was associated with dry mouth, daytime somnolence, dizziness and tremor. 4 We conclude that fluvoxamine seems to have the same general antidepressant efficacy as imipramine. It was not associated with any safety problems and was generally well tolerated.

Antidepressive Agents↗
PubMed1994

A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline.

The pain relieving properties of imipramine (100 mg orally), tramadol (150 mg orally), and anpirtoline (60 mg orally) were compared in 16 healthy subjects in a cross-over, double-blind, randomized, and placebo-controlled study. Anpirtoline exhibits analgesia which is possibly mediated via serotoninergic pathways, whereas tramadol exerts its effects at opioid receptors. The pain-relieving effect of the tricyclic antidepressant imipramine may involve both serotoninergic and opioid mechanisms. Chemo-somatosensory event-related potentials (CSSERP) were recorded after painful stimulation of the nasal mucosa with carbon dioxide. Subjects rated the perceived intensity of the stimuli by means of a visual analogue scale. In addition, acoustically evoked responses were recorded, the spontaneous EEG was analyzed in the frequency domain, the subjects' vigilance was assessed in a tracking task, and side effects of the drugs were monitored. Anpirtoline and tramadol produced a decrease of both CSSERP amplitudes and subjective estimates of pain, the effects of the former compound being greater. In contrast, after administration of imipramine no change of CSSERP amplitudes could be detected, whereas the subjective estimate of pain intensity decreased significantly. This was accompanied by a significant decrease of arousal indicating that pain relief produced by acute administration of imipramine was primarily related to its sedation action. The analgesic properties of anpirtoline were demonstrated in man. Tramadol was characterized as a week opioid analgesic. In contrast, imipramine appeared to produce its pain-relieving effects predominantly by non-specific actions. It is hypothesized that different analgesics may change ERP sources in a drug-specific manner.

Administration, Oral↗
PubMedDate not supplied

The mechanism of imipramine in enuresis nocturna.

1. To evaluate the mechanism of action of imipramine in enuresis nocturna, we compared the effects of imipramine with those of scopolamine butylbromide in fourteen children suffering from this condition. A double-blind, cross-over design was used. 2. Imipramine, 10--20 mg, was superior to scopolamine butylbromide (10--20 mg), in eleven of the fourteen subjects (P less than 0.01), and the latter drug was no better than the placebo. 3. As scopolamine butylbromide does not cross the blood-brain barrier, it is concluded that peripheral antimuscarinic effects are not important in the beneficial effects of imipramine in enuresis nocturna. 4. The therapeutic effects of imipramine in depression frequently take 3 to 4 weeks to develop. Such a delay was not seen in our enuretic patients. Thus the mechanism of the drug in the two conditions is probably different.

Butylscopolammonium Bromide↗