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It is recommended that children and adolescents on tricyclics receive an ECG at baseline and after each dose increase. Recommendations are made regarding ECG parameters and indications for cardiac consultation.
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The authors present a case report that provides support for a relationship between estrogen and the menstrual cycle on the 1 hand and affective disorders on the other. The patient in this case, a 35-year old woman, suffered from a rapid cycling affective disorder that was severely affected by her menstrual cycle and responded positively to oral contraceptives (OCs). The patient had a 24-year history of numerous manic and depressive episodes, the 1st of which coincided with menarche. She had noted that, 4 days before menses, she would experience symptoms of premenstrual tension syndrome (PMS) and often the onset of an affective episode. Treatment with a series of psychotropic agents had not been effective in controlling the number of episodes. However, the patient reported that there had been an 8-9-month period in the past when she had taken OCs and had fewer symptoms. Thus, the patient was placed on Ortho-Novum as well as imipramine. At the 9-month follow-up, she reported there had been no further episodes of depression or mania. The exact mechanism behind estrogen's psychotropic effect is unclear, although it increases the central availability of norepinephrine and induces changes in dopaminergic, noradrenergic, and serotonergic receptors. Beta-endorphin levels covary with estrogen levels, and estrogen seems to affect every major neurotransmitter system. The fact that estrogen has not consistently been shown to be effective in this regard may only signify the existence of a distinct subclass of affective disorders closely linked to the menstrual cycle. This subclass may have some type of dysfunction within the hypothalamic-pituitary-gonadal axis that contributes to mood swings.
The effects of equimolar doses of imipramine (IP) and three catatoxic steroids, pregnenolone-16alpha-carbonitrile (PCN), spironolactone (SNL) and dexamethasone (DEXA), on hepatic mixed-function oxidases were investigated in female rats. Liver weight and N-demethylation of IP and amitriptyline (AMI) were significantly increased by 3 days of catatoxic steroid pretreatment. Repeated prior administration of IP enhanced N-demethylase activity and 9000g supernate protein, but diminished hepatic weight.
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Based on the results of an open trial with Ro 8-1998 (chemic name: N,N-dimethyl-3-(1-methyl-5H-dibenzo(a,d)cycloheptene-5-ylidene)-propylamine N-oxide hydrochloride) in 11 endogenous depressed outpatients a double-blind trial with imipramine was proposed. Therapeutic efficacy and side effects of Ro 8-1998 and imipramine were compared in a double-blind trial with 30 patients who were newly hospitalized. Most of them suffered from endogenous depression. On days 0, 5, 10, 15 and 20 the patients were examined and the symptoms were documented with the AMP system, the Hamilton scale for depression, a behaviour rating and the "global depression rating Zurich". Ro 8-1998 caused a decrease of systolic blood pressure, an increase of heart frequency and urea. Twelve out of 15 patients showed a decrease of white blood cells. In four patients the number of white blood cells dropped below 4,000. Statistical analyses proved both substances to be potent antidepressants. The therapeutic efficacy of Ro 8-1998 was at least equal to that of imipramine. Further trials with bigger groups of patients are necessary to show whether the trend towards a better antidepressant efficacy of Ro 8-1998 can be reproduced.
Given the evolving nature of anatomical and functional changes in the nervous system that are involved in the development of neuropathic pain, it is possible that the differing time course after injury underlies the inconsistent efficacy of drugs in neuropathic pain patients. In the current study, we evaluated the behavioral effects of two standard drugs used clinically for neuropathic pain, the anticonvulsant gabapentin and antidepressant imipramine, in rats at different times after peripheral nerve injury. Rats that underwent the spared nerve injury procedure responded to an innocuous mechanical stimulus (von Frey filament) 2, 4, and 8 wk after injury. Gabapentin dose-dependently suppressed mechanical sensitivity at all time points tested but the potency of gabapentin was three-fold less 4 wk postinjury (135 mg/kg) compared with 2 and 8 wk postinjury (41 and 44 mg/kg, respectively). In contrast, imipramine lacked significant efficacy at 2 and 8 wk postinjury but slightly attenuated mechanical hypersensitivity at 4 wk postinjury. The results show that drug effects may change over time in the neuropathic state, which should be an important consideration in the evaluation of drugs in preclinical animal pain models and has implications for temporal approaches to therapy in the clinic.
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Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.
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Tricyclic antidepressants (TCAs) play an important role in the treatment of pediatric psychiatric disorders. Despite widespread clinical use, concerns about their possible cardiovascular risk have arisen following several published reports of sudden death associated with their use in children. Accordingly, available evidence concerning TCA-associated cardiovascular effects in children and adolescents was surveyed.
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Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively).
Association between emotionality and effect of imipramine on immobility time in forced swimming test was investigated in Swiss and Balb/c mice. Mice of both the strains were segregated into normal emotional (mean +/- 1SD), low emotional (> mean + 1SD) and high emotional (< mean - 1SD) based on their performance with respect to each indices of emotionality in novel arena and elevated plus maze. Baseline immobility and effect of imipramine (20 mg/kg, po) on immobility time was evaluated in these emotionally different groups of mice using forced swimming test model. Baseline immobility time of low emotional mice was found to be significantly less (P<0.01) and that of high emotional mice was found to be significantly more (P<0.01) when compared to normal emotional mice of both the strains. Immobility time after imipramine administration was found to be significantly less (P<0.05) with low emotional mice and significantly more (P<0.01) with high emotional mice when compared to normal emotional mice of both the strains.
Hydroxychloroquine (HCQ) and chloroquine (CQ) are well absorbed (0.7-0.8 bioavailability) when given orally. Severe malnutrition (such as kwashiorkor) effects absorption but diahrrea does not. Both HCQ and CQ have prolonged half-lives, between 40 and 50 days, and low blood clearance (e.g. hydroxychloroquine's blood clearance is 96 ml/min). There is great variability of blood concentrations with an eleven-fold range of drug concentrations found after similar doses in RA patients. Protein binding ranges between 30 and 40% with binding to both albumin and alpha, glycoprotein. There is differential binding and metabolism of the (R) and (S) stereoisomers. Both drugs bind strongly to pigmented tissues but also bind to mononuclear cells, muscles, etc. There is stereo-selective excretion of both drugs and 40-50% of the drug is excreted renally. Between 21 and 47% is excreted unchanged. There is a suggestion of concentration response and concentration toxicity relationships with decreased morning stiffness as HCQ concentrations increase and increased EKG abnormalities as CQ concentrations become higher, but further testing is required. Pharmacokinetic interaction studies are limited. Potentially important kinetic interactions have been documented for d-penicillamine and cimetidine but have not been found for aspirin, ranitidine or imipramine.
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Impairments of cellular plasticity appear to underlie the pathophysiology of major depression. Recently, elevated levels of phosphorylated AMPA receptor were implicated in the antidepressant effect of various drugs. Here, we investigated the effects of an antidepressant, Tianeptine, on synaptic function and GluA1 phosphorylation using murine hippocampal slices and in vivo single-unit recordings. Tianeptine, but not imipramine, increased AMPA receptor-mediated neuronal responses both in vitro and in vivo, in a staurosporine-sensitive manner. Paired-pulse ratio was unaltered by Tianeptine, suggesting a postsynaptic site of action. Tianeptine, 10 μM, enhanced the GluA1-dependent initial phase of LTP, whereas 100 μM impaired the latter phases, indicating a critical role of GluA1 subunit phosphorylation in the excitation. Tianeptine rapidly increased the phosphorylation level of Ser(831)-GluA1 and Ser(845)-GluA1. Using H-89 and KN-93, we show that the activation of both PKA and CaMKII is critical in the effect of Tianeptine on AMPA responses. Moreover, the phosphorylation states of Ser(217/221)-MEK and Thr(183)/Tyr(185)-p42MAPK were increased by Tianeptine and specific kinase blockers of the MAPK pathways (PD 98095, SB 203580 and SP600125) prevented the effects of Tianeptine. Overall these data suggest that Tianeptine potentiates several signaling cascades associated with synaptic plasticity and provide further evidence that a major mechanism of action for Tianeptine is to act as an enhancer of glutamate neurotransmission via AMPA receptors.
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Pharmacotherapy provides considerable relief from the symptoms of dysthymia in patients suffering from this chronic affective disorder, with both sertraline and imipramine being more effective than placebo. The greater tolerability of sertraline is an important consideration because of the chronicity of dysthymia, which may require prolonged treatment with antidepressant medication.
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Circadian rhythms of body temperature, plasma cortisol, norepinephrine (NE), thyroid stimulating hormone (TSH), and melatonin were compared in 16 endogenously depressed, 15 recovered (after 3 weeks of anti-depressant treatment), and 16 normal subjects. The depressed patients showed clear circadian rhythm abnormalities, consisting mainly in amplitude reduction. This amplitude reduction was significantly correlated with the patients' Hamilton depression scores. Normal circadian profiles were restored after recovery when amplitude, in particular, was increased. Features of the circadian rhythms observed in remission may be associated with antidepressant drug effects, whereas those observed in depression resemble the circadian rhythms observed in normal subjects living under conditions of temporal isolation and those of blind subjects. Our findings suggest that depression may be related both to a weakening of the coupling processes between internal pacemakers and to an abnormal sensitivity to environmental information.
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The recognition and treatment of psychiatric illness in general practice is a skilled and difficult task and it is estimated that about 30% of psychiatric diagnoses may be missed. Patients whose illness is recognized are more likely to recover at follow-up than those whose illness is missed, demonstrating the importance of adequate training in recognizing psychiatric illness. Many general practitioners find difficulty in using tricyclic antidepressants to treat depression. The usual dose is lower than research evidence accepts as therapeutic and side effects often result in patient refusal to take a full dose. Additionally, the tricyclics are highly toxic in overdose. Many general practitioners in the UK are wary of new treatments because of previous experience of rare side effects leading to withdrawal of some new drugs. However, prescriptions of the selective serotonin reuptake inhibitors (SSRIs) for depression are gradually increasing here and in other countries such as the USA, France and Canada, where the SSRIs as a class account for upwards of 30% of new antidepressant prescriptions. The SSRIs are well suited to general practice; they have a greater therapeutic index than tricyclics, are much safer in overdosage, and have a different range of side effects (mainly nausea) which are better tolerated by patients at therapeutic doses. Furthermore, the SSRIs generally do not require dosage escalation for most patients and evidence indicates that they are effective in the treatment of depression associated with anxiety and insomnia. The safety and efficacy of the new SSRI sertraline has been established in comparative trials versus amitriptyline, imipramine and dothiepin (Reimherr et al., 1990; Cohn et al., 1990; Fontaine, 1991; Langdon, 1991).(ABSTRACT TRUNCATED AT 250 WORDS)
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The electrocardiographic effects of imipramine hydrochloride at therapeutic plasma concentrations were determined in 44 depressed patients during a 6-week clinical outcome study of depression. During each week of the protocol, i.e., 2 weeks of control and 4 weeks of drug treatment, a standard 12-lead ECG, high-speed, high-fidelity ECG tracings, and a 24-hour continuous ECG recording were obtained. PR, QRS, and QTc intervals, T-wave amplitude, heart rate and frequency of ventricular premature depolarizations (VPDs) were measured. The plasma concentration of imipramine and desmethylimipramine was measured three times a week. Imipramine prolonged the PR (p less than 0.001), QRS (p less than 0.001) and QTc (p less than 0.001) intervals, increased the heart rate (p less than 0.001) and lowered T-wave amplitude (p less than 0.05) during the 4 weeks of treatment. No patient developed high-grade atrioventricular block or severe intraventricular conduction abnormalities. In addition, imipramine had a potent antiarrhythmic action in patients who were recovering from depression. Ten of 11 patients who had more than 10 VPDs/hour had 90% or greater arrhythmia suppression during antidepressant treatment with imipramine at plasma concentrations ranging from 100--302 ng/ml.
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The authors evaluated platelet tritiated imipramine binding in 22 outpatients with obsessive-compulsive disorder (OCD) and 22 psychiatrically normal controls matched for age and gender. Mean maximal binding site density (Bmax) and equilibrium dissociation affinity (Kd) values were not significantly different. In OCD patients, Bmax was positively associated with age but was not associated with age of onset, gender, personality disorder, or five measures of illness severity. Eight patients with OCD were subsequently treated with clomipramine up to 300 mg/day for 10 weeks. Among these 8 patients, Bmax values had a 65% mean decrease from baseline, but Bmax values did not change among 7 OCD patients receiving placebo. The results suggest that a reduced density of tritiated imipramine binding sites may not be associated with OCD.
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Addition of low-density lipoprotein (LDL) to cholesterol-deprived human skin fibroblast cultures treated by imipramine at a 20 microM concentration induced a significant intracellular accumulation of unesterified cholesterol. Intracytoplasmic inclusions were already visible by histochemical filipin staining after 2 h of LDL uptake and were progressively mobilized towards the perinuclear region within 24 h. At this concentration of the drug, the rate of proteolytic 125I-LDL hydrolysis was similar in treated and untreated cells. Treated cells maintained in lipoprotein-deficient medium showed no abnormality, indicating the exogenous origin of the accumulated sterol. Further, the drug induced a drastic dose-dependent impairment of LDL-stimulated cholesterol esterification, not related to an inhibition of acyl CoA:cholesterol acyltransferase, and a significant delay in down-regulation of de novo cholesterol synthesis. However, imipramine did not affect 25-hydroxycholesterol-mediated regulation of the two latter processes. These results resemble those observed in Niemann-Pick type C disease and suggest an impaired mobilization of LDL-derived cholesterol in imipramine-treated cells.
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Alprazolam as antidepressants compounds facilitates 5-HT(1A)- and 5-HT(2A)-receptor-mediated neurotransmission in the DPAG, implicating this effect in the mode of action of different classes of antipanic drugs.
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Seizures are uncommon, but serious, adverse effects of antidepressant drugs. A better understanding of drug-related seizure risk, its predictors, and its neurophysiologic basis might help clinicians avoid this adverse event. A better understanding of the factors involved in the determination of seizure risk would be helpful for interpretation of seizure rates reported.
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1. The active uptake of serotonin by platelets of schizophrenic patients and a healthy control group was compared with imipramine binding to these platelets. 2. Significant correlation was observed between the Vmax of serotonin uptake and the imipramine binding. 3. Serotonin uptake by patients was much lower than that of control group.
This paper uses Bayesian hierarchical models to analyse multi-centre clinical trial data where the outcome variable of interest is continuous, but not normally distributed, and where censoring has occurred. The goal of such an analysis is the same as for any subgroup analysis, to provide survival estimates for specific subgroups as well as for the population and to provide estimates of the degree of heterogeneity between subgroups. An analysis of the Collaborative Study of Long-Term Maintenance Drug Therapy in Recurrent Affective Illness, a multi-centre clinical trial funded by the National Institute for Mental Health's Pharmacologic Research Branch, serves to illustrate the proposed methodology. A feature of this data set is that one treatment group was withdrawn from medication at the time of randomization. The paper contains comparison of models, one that accounts for the drug washout period through the use of a changepoint model as well as a comparison of results across several choices of prior parameter values. In addition, the paper considers sensitivity to model choice and priors in a decision theory context.
The influence of mepiprazole (EMD 16,923), a new pyrazol-ylalkyl-piperazine derivative, on the uptake of 3H-norepinephrine (NE), 3H-dopamine (DA), and 3H-serotonin (5-HT) into rat brain synaptosomes from cerebral cortex, corpus striatum, and hypothalamus was investigated in comparison with several psychotropic drugs, including oxypertine, d-amphetamine, imipramine, desipramine, chlorimipramine, amitriptyline, and chlorpromazine in vitro. Mepiprazole was a relatively weak inhibitor of monoamine uptake and exhibited its strongest action on the hypothalamic 5-HT uptake, being almost equipotent with desipramine (IC50 = 0.9 MUM). Furthermore, the influence of the drugs on the retention of 3H-amines previously taken up by whole rat brain synaptosomes was studied. Unlike the tricyclic antidepressants, mepiprazole as well as oxypertine and d-amphetamine markedly increased the efflux of radioactivity during a 20-min incubation at 37 degrees C at low concentrations (10(-6) to 10(-5) M), whereas at 10(-4) M all drugs greatly enhanced the efflux. The ability of mepiprazole to increase 5-HT concentration at the receptor level by a combination of neuronal uptake inhibition and release is discussed in relationship to the central actions of the drug.
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The goal of this study was to evaluate the plausibility and accuracy of commercially available on-site immunoassay urinalysis kits for the screening of compounds of interest within food matrices. In conjunction with this study, a sensitive, robust, and reproducible analytical method, utilizing solid-phase extraction liquid chromatography/quadrupole ion trap/time-of-flight mass spectrometry for confirmation analysis, was developed. The food matrices analyzed were tomato juice, apple juice, milk, beer, white wine, ground beef, powdered milk, and all-purpose flour. Compounds fortified into the food matrices included heroin, phencyclidine, cocaine, benzoylecgonine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine, imipramine, doxepin, nitrazepam, diazepam, oxazepam, temazepam, alprazolam, flunitrazepam, clonazepam, and lorazepam. Standard curves were prepared for each matrix from 10 to 500 ng/ml for each analyzed compound. All liquid chromatography/tandem mass spectrometry samples were fortified with 20 microl of deuterated internal standard at 90 ng/ml. Quality control standards were prepared at 20 and 400 ng/ml, and > 90% were within 2 SD of the mean for each analyte. The test kits were found to produce up to 85% of the expected results based on concentration levels of adulterants (i-Screen in milk). This study shows that lateral-flow immunoassay test kits are plausible as a rapid, accurate, and reliable screening method in the event of adulteration of the food supply.
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Following pre-treatment with verapamil (20 mg/kg) or a saline solution male Sprague Dawley rats were injected with imipramine (15 mg/kg). Two hours later, the animals were sacrificed, trunk blood collected and brain regions dissected out. High performance liquid chromatography (HPLC) was used to quantitate antidepressant drug concentrations in all samples.
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This study assessed the effects of veratrine, a Na(+) channel opener on antidepressant effect of lamotrigine and others antidepressants: two tricyclic antidepressants (TCAs): imipramine, a mixed serotonergic noradrenergic reuptake inhibitor, desipramine, a specific noradrenergic reuptake inhibitor and a SSRI: paroxetine, the most potent selective serotonergic reuptake inhibitor, using an animal model of depression, the forced swimming test. Veratrine (0.125 mg/kg) and lamotrigine (16, 32 mg/kg) or antidepressants (16, 32 mg/kg) were given i.p. 45 and 30 min, respectively, before the test.
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Tricyclic antidepressants such as imipramine interact with a membrane binding site associated with the uptake of serotonin. Ovarian hormones estradiol and progesterone were found to affect the concentration and affinity of imipramine binding sites in the hypothalamus but not the cortex of female rats. In vivo and in vitro, estradiol increased the amount of imipramine binding at physiological concentrations; at high concentrations estradiol decreased imipramine binding. Ovariectomy (OVX) had no effect on imipramine binding, consonant with the biphasic dose-response relationship for estradiol. The effects of progesterone were dependent upon the concentration of estradiol. Effects of physiological concentrations of both estradiol and progesterone on imipramine binding in an isolated membrane preparation suggest that the hormones are affecting this aspect of serotonergic neuronal function by nongenomic mechanisms.
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Human cytochromes P450 (P450s) play a major role in the biotransformation of drugs. The generated metabolites are important for pharmaceutical, medical, and biotechnological applications and can be used for derivatization or toxicological studies. The availability of human drug metabolites is restricted and alternative ways of production are requested. For this, microbial P450s turned out to be a useful tool for the conversion of drugs and related derivatives. Here, we used 10 P450s from the myxobacterium Sorangium cellulosum So ce56, which have been cloned, expressed, and purified. The P450s were investigated concerning the conversion of the antidepressant drugs amitriptyline, clomipramine, imipramine, and promethazine; the antipsychotic drugs carbamazepine, chlorpromazine, and thioridazine, as well as their precursors, iminodibenzyl and phenothiazine. Amitriptyline, chlorpromazine, clomipramine, imipramine, and thioridazine are efficiently converted during the in vitro reaction and were chosen to upscale the production by an Escherichia coli-based whole-cell bioconversion system. Two different approaches, a whole-cell system using M9CA medium and a system using resting cells in buffer, were used for the production of sufficient amounts of metabolites for NMR analysis. Amitriptyline, clomipramine, and imipramine are converted to the corresponding 10-hydroxylated products, whereas the conversion of chlorpromazine and thioridazine leads to a sulfoxidation in position 5. It is shown for the first time that myxobacterial P450s are efficient to produce known human drug metabolites in a milligram scale, revealing their ability to synthesize pharmaceutically important compounds.
The recurrence of an affective disorder in people who initially recover from major depressive disorder was characterized by using the unique longitudinal prospective follow-up data from the National Institute of Mental Health Collaborative Program on the Psychobiology of Depression-Clinical Studies.
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To investigate antidepressant effects and interactions between testosterone and imipramine in socially isolated male and female rats.