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The potential effectiveness of imipramine hydrochloride (up to 5 mg/kg/d) was investigated in 53 prepubertal children suffering from major depressive disorder. Two complementary strategies were used simultaneously: a five-week, double-blind, placebo-controlled design (N = 38), and a plasma level/clinical response study (N = 30). Fifteen of the 16 children randomly assigned to active drug in the first study also participated in the second. Subjects were assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children and diagnosed according to unmodified Research Diagnostic Criteria. Response rates in the double-blind study were similar in both groups (imipramine, 56%; placebo, 68%). In the plasma level study, total maintenance plasma level (imipramine plus desipramine) was found to positively and linearly predict clinical response of the depressive syndrome (P less than .003). No evidence of a curvilinear relationship was found. Depressive hallucinations during the episode negatively predicted clinical response (P less than .05). Weight-corrected imipramine dosage did not predict either clinical response or plasma level in the individual subject. No predictors of response were found in the placebo group. These results suggest that the mean imipramine dosage was too low, and that future double-blind, placebo-controlled studies of imipramine in prepubertal major depression should include plasma level titration to above 150 ng/mL and an initial placebo washout period.
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The clinical significance of research findings is an important issue that, until recently, was often neglected. Statistical methods are available, however, to evaluate the meaningfulness of pre- to post-treatment change. The clinical significance of the National Institute of Mental Health Treatment of Depression Collaborative Research Program Data was evaluated. A substantial number of clients receiving treatment for depression made reliable improvements and had posttreatment scores that fell within a functional distribution. A small number of clients reliably deteriorated despite undergoing 12 sessions of treatment. No differences in clinical significance rates among treatment groups existed for measures of depressive symptoms. Treatments differed in terms of clinical significance on a measure of general symptom severity. There was substantial agreement among diverse methods of measurement regarding the identification of individuals making clinically significant change.
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Depression is one of the most prevalent mental illnesses, and causes a constant feeling of sadness and lose of interest, which often leads to suicide. Evidence suggests that depression is associated with aberrant MEK/ERK signaling. However, studies on MEK/ERK signaling in depression have only been done in a few brain regions, such as the hippocampus and mesolimbic reward pathways. Recent studies also implicate the involvement of the prefrontal cortex in depression. Thus, we examined the changes in MEK/ERK signaling in subregions of the prefrontal cortex of C57BL/6 mice by immunohistochemistry using phospho-MEK1/2 (Ser 217/221) and ERK1/2 (Thr202/Tyr204) antibodies. Mice were subjected to 21 consecutive days of restraint stress (for 2h daily), and depression-like behavior was evaluated using a sociability test and tail suspension test. The antidepressant, imipramine (20mg/kg) was injected intraperitoneally 30min before restraint stress exposure. Chronic/repeated restraint stress produced depressive-like behavior, such as increased social avoidance in the social interaction test, and enhanced immobility time in the tail suspension test. This depressive behavior was ameliorated by imipramine. The behavioral changes well corresponded to a decrease in MEK/ERK immunoreactivity in the medial orbital (MO) cortex and dorsal endopiriform nuclei (DEn), which was averted by imipramine, but not in cingulate, prelimbic, infralimbic, and motor cortex. These results suggest that MEK/ERK signaling is disrupted in the DEn and MO subregions of the prefrontal cortex in the depressive phenotype, and that blocking a decrease in activated MEK/ERK is inherent to the antidepressant imipramine response.
The effects of neferine, an alkaloid of Nelumbo nucifera Gaertner embryos, on immobility in the forced swimming test, which is used to evaluate antidepressants, were investigated in mice. The administration of neferine from 25 to 100 mg/kg i.p. elicited anti-immobility effects in mice. The molecular dose effects of neferine in the forced swimming test were almost equal to those of the typical antidepressants maprotiline and imipramine. The involvement of the 5-HT receptor subtypes was also studied using 5-HT receptor antagonists. Anti-immobility effects of neferine are antagonized by the serotonin1A (5-HT1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). However, the 5-HT1B receptor antagonist, 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl] benzamide dihydrochloride (GR 55562), the 5-HT2 receptor antagonist, 6-methyl-1-(methylethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester (LY 53857), the 5-HT3 receptor antagonist, ondansetron and the 5-HT4 receptor antagonist, 4-amino-5-chloro-2-methoxy-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205,557) did not affect the anti-immobility effects of neferine. The anti-immobility effect of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetaralin (8-OH-DPAT) was also antagonized by WAY 100635. Furthermore, co-administration of subactive doses of neferine (10 mg/kg) and 8-OH-DPAT (0.1 mg/kg) produced synergistic antidepressant-like effects. These results suggest that neferine shows antidepressant-like effects in mice similar to typical antidepressants and that these effects are mediated by the 5-HT1A receptor. Therefore, the central effects of neferine are likely to be linked to serotonergic neurotransmission.
In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N-demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N-demethylation of IMI.
Therapeutic approaches via transcript regulation, allowing a modulation of LOX-1, may be an easier and safer strategy than a blockade of the receptor. Considering the wide distribution of LOX-1 on different tissues, research on the mechanisms of LOX-1 modulation by drugs and natural products applying "omic"-technologies will not only allow a better understanding of the role of LOX-1 in the processes of atherosclerosis, inflammation and longevity but also support the development of specific LOX-1 modulators, avoiding the initiation of molecular mechanisms which lead to adverse events.
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This report describes a middle-aged female who received imipramine for 7 days, developed severe cholestatic jaundice with features similar to primary biliary cirrhosis, and then improved clinically over the next 12 mo. Biochemical and histologic abnormalities persisted over a 14-yr period of follow-up, though subsequent administration of haloperidol may have influenced the long-term course. High levels of circulating immune complexes were also found 14 yr later, which raises questions about the relationship of primary biliary cirrhosis to drug-induced liver injury. A review of the literature on imipramine- and phenothiazine-related hepatic injuries reveals multiple similarities, and this case provides further evidence for a common hepatic reaction to the two drugs.
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To determine the flow-corrected luminal permeability, P(c), of lipophilic drugs measured by the in situ brain perfusion method under circumstances where the traditional Crone-Renkin equation (CRE) method, using diazepam as a flow marker, often fails.
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A kinetic model capable of predicting the effect of the rate of intraportal imipramine infusion in rats on the steady-state concentrations of imipramine and its active metabolite, desipramine, was developed by using kinetic parameters obtained from in vitro studies. A nonlinear relationship was observed between steady-state concentrations of imipramine and desipramine (formed from imipramine) and the intraportal infusion rate of imipramine. Biliary and urinary excretion rates of both compounds were negligible compared with the corresponding infusion rate, and the free fractions of imipramine and desipramine in blood were constant over the concentration range used in this investigation. In vitro studies revealed that imipramine and desipramine 2-hydroxylations were mediated by a high-affinity and low-capacity (saturable) enzyme(s), while N-demethylation of imipramine (which formed desipramine) was mediated by a low-affinity and high-capacity (not saturable) enzyme(s). The adequate prediction of the steady-state concentrations of imipramine and desipramine by the proposed model was possible only after incorporating the mutual competitive inhibition between 2-hydroxylations of imipramine and desipramine, in addition to the incorporation of saturable kinetics of imipramine and desipramine 2-hydroxylations. Furthermore, the steady-state concentrations of desipramine were predicted to also be affected by the formation rate of desipramine, which increased nonlinearly with the increase in the rate of intraportal infusion of imipramine.
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Artificially ventilated anesthetized dogs were given imipramine 7.5 mg/kg/hr i.v. In the first group (n = 6) mechanical cardiac activity was no longer detectable after a cumulative dose of 20.0 +/- 6.6 mg/kg (mean +/- sd). When aortic flow had decreased to 75% of its initial value, in a second group (n = 5) of experiments dopamine 10 micrograms/kg/min and in a third group (n = 5) isoproterenol 1 microgram/kg/min were administered i.v.. The doses of dopamine and isoproterenol were doubled when aortic flow had again decreased to 75% and 100%, respectively, of the original values. Cardiac mechanical activity was not detectable after a cumulative dose of 43.8 +/- 13.3 in the dopamine and 42.5 +/- 8.0 mg imipramine/kg in the isoproterenol group. These values differed significantly from that in the reference group (both 0.01 greater than p greater than 0.001). In the first group plasma imipramine concentrations at the end of the experiments were 3.06 +/- 0.66, in the second 3.36 +/- 0.66 and in the third 3.32 +/- 1.10 mg/1. Desipramine concentrations were 0.078 +/- 0.06, 0.162 +/- 0.076 and 0.383 +/- 0.09 mg/1 respectively. Dopamine induced a hemodynamic profile of low output and high pressure and isoproterenol one of low pressure and high output. It is concluded that dopamine combined with isoproterenol might be effective in counteracting the cardiodepressant action of imipramine.
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Mice were treated with either a sham procedure or focal hippocampal irradiation to disrupt cell proliferation before being confronted with 5 weeks of UCMS. From the third week onward, we administered monoaminergic ADs (imipramine, fluoxetine), the corticotropin-releasing factor 1 (CRF(1)) antagonist SSR125543, or the vasopressin 1b (V(1b)) antagonist SSR149415 daily. The effects of UCMS regimen, AD treatments, and irradiation were assessed by physical measures (coat state, weight), behavioral testing (Splash test, Novelty-Suppressed feeding test, locomotor activity), and hippocampal BrdU labeling.
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Brahmi exhibited significant decrease in duration of immobility in FST and reduced the shock induced decrease in activity in SID models. It didn't show any activity in the TST model.
Adult fowl of both sexes injected with the monoamine oxidase inhibitor pargyline showed elevated circulating prolactin concentrations and reduced growth hormone concentrations. Young cockerels injected with the serotonin agonist quipazine and the antagonist methysergide showed responses consistent with a serotoninergic stimulatory control of prolactin. Injection of the serotonin precursor tryptophan and the serotonin re-uptake blocker imipramine resulted in elevated prolactin and reduced growth hormone levels. The similarities and differences in the control of prolactin and growth hormone in birds and mammals were discussed.
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In recent years, many Ayurvedic formulations are being researched to provide an effective antidepressant and anxiolytic drug in the field of psycho-pharmacology. The present study was planned to evaluate the anti-depressant and anxiolytic activity of Rasayana Ghana Tablet comprising three herbs Guduchi (Tinospora cordifolia Miers), Aamalaki (Emblica officinalis Garten) (RGT) and Gokshura (Tribulus terrestris Linn). Swiss albino mice were divided into four groups of six animals each, comprising of both male and female in each group. Group I received water served as normal control (WC), group II received vehicle and served as vehicle control (VC), group III received Rasayana Ghana tablet and group IV received standard drug diazepam (2 mg/kg) for anxiolytic study in elevated plus maze and standard antidepressant imipramine (5 mg/kg) for anti-depressant activity in behavior despair test. Rasayana Ghana tablet along with ghee and honey as vehicle is found to be having antidepressant and anxiolytic activity in experimental animals. Thus, this formulation can be used in prevention and treatment of depression and anxiety.
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Abnormalities of sphingolipid turnover in the brain during normal aging and age-related neurological disorders were associated with the neurons loss and cognitive malfunction. Calorie restriction (CR) prevented age-related deficits in hippocampal long-term potentiation and improved cognitive function at old age. In the paper we investigated the ceramide and sphingomyelin (SM) levels in the brain regions, which are critical for learning and memory of 3- and 24-month-old rats, as well as the correction of sphingolipid turnover in the brain of old rats, by means of the CR diet and modulators of SM turnover. Using the [methyl-(14)C-choline]SM, the neutral, but not the acid SMase activity has been observed to increase in both the hippocampus and brain cortex of 24-month-old rats with respect to 3-month-old animals. Age-dependent changes of neutral SMase activities were associated with ceramide accumulation and SM level drop in the brain structures studied. Treatment of the rats with the CR diet or N-acetylcysteine (NAC) or α-tocopherol acetate, but not an inhibitor of acid SMase imipramine, reduced the ceramide content and neutral SMase activity in the hippocampus of 24-month-old animals with respect to control rats of the same age. These results suggest that redox-sensitive neutral SMase plays important role in SM turnover dysregulation in both the hippocampus and neocortex at old age and that the CR diet can prevent the age-dependent accumulation of ceramide mainly via neutral SMase targeting.
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Assessment of an elderly depressed patient with an imipramine-induced tremor led to the conclusions that imipramine tremor (1) can be severe and incapacitating, (2) is most pronounced early in the treatment, (3) does not seem to be dose-related, and (4) is readily reversible with a beta-adrenergic blocking agent.
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The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ≥ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ≤ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.
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Recent studies have demonstrated a scrutinized association of diabetes mellitus with depressive symptoms and major depression. Glycogen synthase kinase-3 (GSK-3) is a protein kinase enzyme constitutively active in non-stimulated cells and in multiple signalings. Independent lines of research provide a converging evidence for an involvement of GSK-3 in the regulation of behavior and hyperglycemia. The present study revealed that streptozotocin (STZ)-induced diabetic rats were found to show lengthened duration of immobility in the forced-swimming test (FST) and reduced locomotor and exploratory activities in the open-field test (OFT). Imipramine (15 mg/kg), Paroxetine (10 mg/kg) and lithium carbonate (36.94 mg/kg) for 14 days reduced immobility behavior in FST. Paroxetine and lithium carbonate increased the locomotor and exploratory activities, while imipramine decreased the locomotor activity in the OFT. Imipramine and lithium carbonate reduced the blood glucose level while paroxetine didn't alter it. STZ-induced diabetes increased GSK-3 gene expression which was determined using the reverse transcription-quantitative polymerase chain reaction test, while the three drugs decreased its expression. It can be concluded that lithium carbonate and imipramine can control both hyperglycemia and the associated symptoms of depression at the same time by inhibiting GSK-3 activity. On the other hand, paroxetine may only manage the depressive-like symptoms associated with diabetes through modulating the enzyme GSK-3, without changing blood glucose levels.
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The dexamethasone suppression test (DST) was performed in panic disorder (PD) patients with (n = 32) or without (n = 31) agoraphobia and in normal controls (n = 49). Postdexamethasone serum cortisol levels were significantly higher in agoraphobic PD patients (105.3 +/- 19.3 nmol/L) both when compared to PD patients without agoraphobia (47.3 +/- 7.7 nmol/L; p less than 0.01) and when compared to healthy controls (51.7 +/- 8.3 nmol/L; p less than 0.01). The rate of nonsuppressors (i.e., subjects displaying postdexamethasone cortisol levels greater than 138 nmol/L) was 28% and 3% in agoraphobic and nonagoraphobic PD patients, respectively, and 12% in controls. In patients, the postdexamethasone cortisol levels did not correlate with the number of panic attacks per week, baseline anxiety as measured using the Hamilton Anxiety Scale, depressive symptoms as measured using the Montgomery-Asberg Depression scale, or duration of illness. Data from eight patients in whom a second DST was performed after treatment with imipramine or clomipramine for three months indicate that a marked reduction of the number of anxiety attacks is not necessarily accompanied by a normalization of a pathological DST. In conclusion, it is suggested that the elevated postdexamethasone cortisol levels sometimes observed in agoraphobic PD patients are more closely related to the agoraphobic behavior than to the panic attacks per se.
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Daytime melatonin was measured by radioimmunoassay in 113 depressed outpatients before and after treatment with imipramine, mianserin, phenelzine, and placebo. At baseline, elevation of daytime melatonin values above expected levels suggests nonspecificity of the assay. After 6 weeks of treatment, melatonin levels were somewhat lower in patients on imipramine, mianserin, and placebo and slightly increased in patients treated with phenelzine. Changes in melatonin levels during treatment were significantly different for phenelzine compared with the other treatments. These findings are consistent with alterations in beta-adrenergic functioning or changes in serotonin levels.
It has been suggested that tachykinin NK(2) receptor antagonists may have therapeutic utility in anxiety and/or depressive disorders.
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Daily administration of thyrotropin-releasing hormone (TRH) (20 mg/kg) for 10 days in 2 equally divided doses increased 5-hydroxytryptamine and/or 5-hydroxyindoleacetic acid levels in certain brain areas. Chronic imipramine treatment (10 mg/kg) for 10 days significantly decreased the levels of brain 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. When TRH was administered concurrently with imipramine (10 mg/kg), this neuropeptide significantly potentiated the effects of imipramine on lowering of endogenous levels of 5-hydroxytryptamine (striatum, hypothalamus) and 5-hydroxyindoleacetic acid (striatum, midbrain, pons-medulla). Our data provide a possible neurochemical basis for the reported potentiation of tricyclic antidepressant action by TRH.
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Reduction of tertiary amine N-oxides by the mitochondrial fraction of rat liver was investigated. NADPH was required as a cofactor. The rate of reaction was faster with the NADPH-generating system than with NADPH. Isocitrate in the NADPH-generating system revealed the maximum stimulation. A little less activity was observed when NADH was used as a cofactor instead of NADPH. The reductase activity was markedly inhibited under aerobic conditions. The rates of mitochondrial tertiary amine N-oxide reduction expressed in nanomoles per milligram of protein per minute were: N,N-dimethylaniline N-oxide, 4.3; tiaramide N-oxide, 0.47; and imipramine N-oxide, 0.14. The activity for N,N-dimethylaniline N-oxide was comparable to the microsomal activity, but the activity for imipramine N-oxide was much less than that in microsomes. Isocitrate and alpha-ketoglutarate were found to stimulate mitochondrial tertiary amine N-oxide reduction more efficiently than other Krebs cycle intermediates. Oxalacetate, on the other hand, was the least effective intermediate. ATP together with NADPH and NADP stimulated the reaction efficiently, probably due to the energy-dependent intramitochondrial transhydrogenation. Antimycin, rotenone and cyanide had little or no effect on isocitrate-dependent N-oxide reduction, whereas an inhibitory effect was observed on succinate-supported N-oxide reductase. N-oxide reductase activity in mitochondria was partially suppressed under an atmosphere of carbon monoxide, althouth no increase of the activity was observed by phenobarbital pretreatment, nor inhibition by 2,4-dichloro-6-phenylphenoxyethylamine. Experiments with digitonin-treated mitochondria demonstrated that mitochondrial N-oxide reductase was bound to mitochondrial inner membrane or its matrix.
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Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin2 (5-HT2)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical beta-adrenergic and 5-HT2 binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT2-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT2 binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT2-mediated behavior was coincident with the blockade of down-regulation of beta-adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT2 and beta-adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.
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The basic compound N-N-N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3- propanediamine (HIPDM) accumulates in human and rabbit lungs, where it forms a slowly effluxable pool. In isolated perfused rat lung, HIPDM is taken up by a saturable, energy-independent mechanism, which is competitively inhibited by imipramine, chlorpromazine and propranolol. To ascertain whether beta-adrenergic receptors are involved in the binding process of HIPDM to lung tissue, the ability of unlabelled HIPDM to displace the beta-adrenergic receptor ligand [125I]iodocyanopindolol (ICYP) from rabbit lung beta-receptors was examined. Lung microsomal membrane fractions (75 micrograms ml-1) were incubated at 37 degrees C for 3 h with 68 pM ICYP (with or without 1 microM of (+/-)-propranolol) in the presence of HIPDM (10(-10)-10(-3) M). Bound and free radioactivity were separated through glass-fibre filters and the retained radioactivity was counted in a gamma-spectrometer. HIPDM competed with ICYP for beta-adrenoceptors (13% displacement at 10(-5) M. 50% at 5 x 10(-5) M, and 90% at 2 x 10(-4) M). The inhibition curve of ICYP binding by HIPDM was similar to that observed for (-)-noradrenaline. Although the results of the in vitro studies cannot be extrapolated to in vivo conditions, they suggest that beta-adrenergic receptors may be involved in the observed lung uptake of the basic amine HIPDM.