These results suggest that the automated analysis system of forced swimming of mice using MicroAct can be used as a high-throughput method to examine antidepressive activity of a compound with objectivity and reliability.
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Chinese herbal products including SHs and HFs are prescribed for patients with sleep disorder and MDD. However, the efficacy and safety of CHPs for sleep disorder and MDD need to be further evaluated.
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Both preclinical and clinical evidence support the usefulness of antidepressants in chronic pain treatment. Monoamine uptake inhibitors influence the neurotransmissions of noradrenaline (NA) and/or serotonin (5-HT); their effect on nociception is thought to take place predominantly within the spinal cord. Antidepressant drugs seem to differ in their properties as analgesics and as thymoleptics. The present work is aimed at correlating the special mechanism of action of antidepressants in diminishing nocicepetion with the pharmacological profile of these drugs in clinical pain treatment. From a preclinical, experimental point of view, it can be expected, that mixed type uptake blockers should be superior to selective NA or 5-HT uptake inhibitors. The analgesic profile of antidepressants was established by a metaanalysis of clinical trials on the effect of these drugs, given alone or in combination with other analgetics, in chronic pain syndromes. 57 Clinical trials were separated into 5 groups according to their scientific quality:  placebo-controlled double-blind studies with high power;  placebo-controlled double-blind studies with low power; [3-4] open controlled studies or studies with historical controls;  case reports. A study was positive if the tested antidepressant was more effective than placebo or the compared drug or seemed beneficial with respect to the interval of its previous absence. The most effective antidepressants in chronic pain treatment only included unselective monoamine reuptake inhibitors in the following rank order: amitriptyline > clomipramine > or = desipramine > or = imipramine > or = doxepin. A statement about the appropriate dosage of these drugs in chronic pain treatment, however, must wait for properly conducted dose finding studies which include the measurement of plasma concentrations.
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To study the regulatory mechanisms of intracellular Mg(2+) concentration ([Mg(2+)](i)) in renal tubular cells as well as in other cell types, we established a mutant strain of mouse renal cortical tubular cells that can grow in culture media with very high extracellular Mg(2+) concentrations ([Mg(2+)](o) > 100 mM: 101Mg-tolerant cells). [Mg(2+)](i) was measured with a fluorescent indicator furaptra (mag-fura 2) in wild-type and 101Mg-tolerant cells. The average level of [Mg(2+)](i) in the 101Mg-tolerant cells was kept lower than that in the wild-type cells either at 51 mM or 1 mM [Mg(2+)](o). When [Mg(2+)](o) was lowered from 51 to 1 mM, the decrease in [Mg(2+)](i) was significantly faster in the 101Mg-tolerant cells than in the wild-type cells. These differences between the 101Mg-tolerant cells and the wild-type cells were abolished in the absence of extracellular Na(+) or in the presence of imipramine, a known inhibitor of Na(+)/Mg(2+) exchange. We conclude that Na(+)-dependent Mg(2+) transport activity is enhanced in the 101Mg-tolerant cells. The enhanced Mg(2+) extrusion may prevent [Mg(2+)](i) increase to higher levels and may be responsible for the Mg(2+) tolerance.
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There at least two reasons to believe antidepressants might help in smoking cessation. Depression may be a symptom of nicotine withdrawal, and smoking cessation sometimes precipitates depression. In some individuals, nicotine may have antidepressant effects that maintain smoking. Antidepressants may substitute for this effect.
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Among study completers, 31 (39%) had AIDS. The response rate to imipramine was 74% and the response rate to placebo was 26%. There was no difference in depression response between patients with more or less severe immunodeficiency, nor was there a difference in medication dose or side effects. Neither type nor duration of treatment influenced CD4 cell count during the course of treatment.
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The antidepressant efficacy and safety of venlafaxine was shown previously in 6-week, placebo-controlled trials. We evaluated the long-term safety and clinical acceptability of venlafaxine and imipramine in a double-blind, parallel-group, comparative study. Two hundred ninety depressed outpatients were treated with venlafaxine, and an additional 91 received imipramine for as long as clinically necessary, up to 1 year. The total daily dose of each drug could vary from 75 to 225 mg. The Clinical Global Impressions Scale and a therapeutic response rate that was based on Clinical Global Impressions Scale-Improvement and incorporated discontinuation information were used to evaluate efficacy. Safety determinations and patient subjective ratings were used to evaluate safety and clinical acceptability. During the study, the adverse events were generally mild to moderate and most subsided with continued treatment; the most frequent were nausea for venlafaxine and dry mouth for imipramine. The anticholinergic side effect burden was significantly higher in the imipramine group than in the venlafaxine group. Venlafaxine was judged significantly more acceptable than imipramine, on the basis of the subjective ratings by patients. Fewer venlafaxine-treated patients than imipramine-treated patients withdrew because of adverse events and unsatisfactory response. There was a consistent trend in the therapeutic response rates in favor of venlafaxine that reached statistical significance at months 2, 6, and 12. In this long-term study, patient acceptability was greater for venlafaxine than for imipramine, suggesting therapeutic advantages for venlafaxine in the long-term treatment of depression. Additional studies with other active comparators are underway to confirm and extend these encouraging results.
This report deals with a series of experimental approaches carried out in clinical studies to attempt to examine the role of amines in relationship to affective state and the mode of action of thymoleptic agents. Attempts have been made to examine enzymes, amines and other metabolites in biological fluids to assess the role of catecholamines and indoleamines in these disorders. Synthesis inhibitors were employed in studies where antidepressant drug-induced remission was initiated and the effect of two inhibitors was assessed on the clinical state. The results are presented and discussed in regard to the significance of the role of serotonin in depressive states and the action of thymoleptic agents.
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This article reviews the available data on social functioning in depression and provides clinical guidelines and opinion on this important and expanding field.
We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
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One patient died of a massive pulmonary embolism postoperatively. Followup ranged from 6 to 36 months (mean 19.2 +/- 7.0). During the observation period 6 patients died of local recurrence and/or distant metastasis within 8 months. Of the patients 57 are currently evaluable. All patients are continent during the day with an emptying frequency of 2 to 4 times. Nocturnal enuresis was observed in 4 children who responded favorably to imipramine hydrochloride therapy. Upper urinary tract function was maintained or improved in 95% of the patients. No clinical evidence of acidosis was observed, since all patients were kept on prophylactic oral alkalization.
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In this study, the effect of imipramine on morphine antinociception in tolerant and non-tolerant mice in the formalin test, was investigated. Subcutaneous administration of different test doses of morphine (3, 6 and 9 mg/kg) and intraperitoneal injection of test doses of imipramine (10, 20 and 40 mg/kg) induced a dose-dependent antinociception in non-tolerant mice, both in the first and second phases of the formalin test. The combination of morphine (1 mg/kg) with imipramine (10 mg/kg) showed a potentiated response in the second phase of the test. Combination of a single dose of morphine (1.5 mg/kg) with lower doses of imipramine (2, 4 and 8 mg/kg) did not show potentiation. The antinociceptive response of either morphine or morphine plus imipramine was reduced by the opioid receptor antagonist naloxone (2 mg/ kg). In order to induce tolerance, mice were treated subcutaneously with morphine (50 mg/kg) once daily for 3 days. On day 4, the antinociceptive effect of test doses of morphine or imipramine were assessed. Tolerance to the responses of test doses of morphine (3, 6 and 9 mg/kg), but not imipramine (10, 20 and 40 mg/kg) in both phases of the test was observed. Administration of lower dose of imipramine (4 mg/kg) before the test doses of morphine (3, 6 and 9 mg/kg) was not able to alter the expression of morphine tolerance. When imipramine was used during development of tolerance, either on days 1 and 2 or on days 2 and 3, the morphine tolerance in the second phase of the test was reduced. It is concluded that opioid receptor mechanism(s) may mediate the antidepressant-induced antinociception, however, imipramine may be useful in inhibiting morphine tolerance.
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Moclobemide is an effective antidepressant and is better tolerated than imipramine.
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[3H]Imipramine binding sites are located on serotonergic nerve terminals and on blood platelets. Previous studies on our laboratories have indicated temperature-sensitive conformational changes in [3H]imipramine binding sites in hippocampal and cerebral cortex membranes. We now report that similar changes are observed in both membrane-bound and digitonin-solubilized [3H]imipramine binding sites of human blood platelets. This may indicate integrity of the solubilized binding site.
In a double blind trial in 88 patients, 71 of whom were included in the fin al evaluation, viloxazine (Vivalan ICI) showed an effectiveness corresponding to imipramine. Both antidepressives show properties for lysis of depression and improvement of mood, the target symptom is vitally depressive disturbance of mood. There was clear improvement of depression, anxieties, restlessness, loss of initiative and activity as well as pain syndromes in psychosomatic disorders. In cases of psychomotor inhibition viloxazine was superior to the older drug. Effectiveness of viloxazine commenced rapidly as demonstrated by control assessment after 10-14 days. Results improved further in a second equally long treatment period. Tolerance of viloxazine was superior to imipramine.
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The literature dealing with the convulsant effects of the antidepressant drugs of the non-monoamine oxidase inhibitor variety is reviews. It is concluded that most of these drugs do lower the seizure threshold and may precipitate seizures even at normal therapeutic doses. The pathophysiology of antidepressant-induced seizures is discussed, and attention is drawn to biochemical differences in those antideprssants that have the least epileptogenic potential or may even be anticonvulsant. The clinical difficulties regarding administration of antidepressant drugs to epileptic patients are mentioned, and some practical advice is offered.
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The electroencephalographic (EEG) and cardiovascular effects of milnaciplan hydrochloride (TN-912) were compared with those of imipramine (IMP) and maprotiline (MPT) in rats, guinea pigs and dogs. In conscious rats with chronic electrode implants, TN-912 (10-100 mg/kg, p.o.) had little effect on either the EEG activity or the EEG arousal response to auditory stimulation (2000 Hz). Both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) tended to increase the drowsy EEG pattern period in the cortical and hippocampal EEG and inhibited the EEG arousal response to auditory stimulation. In conscious rats with a chronic arterial catheter, TN-912 (100 mg/kg, p.o.) slightly elevated the mean blood pressure (MBP) and decreased the heart rate (HR), while both IMP (10-100 mg/kg, p.o.) and MPT (10-100 mg/kg, p.o.) dose-dependently increased MBP and HR. In anesthetized dogs, i.v. injection of TN-912 (1-10 mg/kg), IMP (0.3-10 mg/kg) and MPT (1-20 mg/kg) produced a dose-dependent fall in MBP. IMP and MPT but not TN-912 dose-dependently increased HR. TN-912 did not show typical effects on femoral blood flow. TN-912 (30 mg/kg) had little effect on lead II electrocardiogram (ECG), while IMP and MPT markedly increased height of the T-wave on ECG. In the in vitro study with the isolated guinea pig atrium, TN-912 caused a slight positive inotropic and negative chronotropic effect, while both IMP and MPT showed marked negative inotropic and chronotropic actions. These results suggest that TN-912 has less EEG effect and cardiac toxicity, indicating that TN-912 may be safe in clinical use.
After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores.
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A dynamic 23Na nuclear magnetic resonance (NMR) technique was applied to the exchange system of Na+ ions present inside and outside large unilamellar vesicles at an equivalent concentration. Addition of melittin to phosphatidylcholine vesicles did not induce any detectable Na+ transport across the membrane but subsequent addition of a trace of chlorpromazine or imipramine did induce Na+ transport. Because the formation of a drug-melittin adduct in a solution was detected by 1H NMR, the activation of melittin channels was assumed to originate from the direct interaction of the drug and melittin.
Primary care physicians must initiate a discussion of overactive bladder and urinary incontinence with their patients who are at risk. A stepwise approach to evaluation and diagnosis and the use of systematic evaluation and treatment algorithms suitable to the primary care setting will improve identification and effective management of the incontinent patient.
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Depression is associated with vascular disease, such as myocardial infarction and stroke. Pharmacological treatments may contribute to this association. On the other hand, Mg(2+) deficiency is also known to be a risk factor for the same category of diseases. In the present study, we examined the effect of imipramine on Mg(2+) homeostasis in vascular smooth muscle, especially via melastatin-type transient receptor potential (TRPM)-like Mg(2+) -permeable channels. The intracellular free Mg(2+) concentration ([Mg(2+) ](i) ) was measured using (31) P-nuclear magnetic resonance (NMR) in porcine carotid arteries that express both TRPM6 and TRPM7, the latter being predominant. pH(i) and intracellular phosphorus compounds were simultaneously monitored. To rule out Na(+) -dependent Mg(2+) transport, and to facilitate the activity of Mg(2+) -permeable channels, experiments were carried out in the absence of Na(+) and Ca(2+) . Changing the extracellular Mg(2+) concentration to 0 and 6 mM significantly decreased and increased [Mg(2+) ](i) , respectively, in a time-dependent manner. Imipramine statistically significantly attenuated both of the bi-directional [Mg(2+) ](i) changes under the Na(+) - and Ca(2+) -free conditions. This inhibitory effect was comparable in influx, and much more potent in efflux to that of 2-aminoethoxydiphenyl borate, a well-known blocker of TRPM7, a channel that plays a major role in cellular Mg(2+) homeostasis. Neither [ATP](i) nor pH(i) correlated with changes in [Mg(2+) ](i) . The results indicate that imipramine suppresses Mg(2+) -permeable channels presumably through a direct effect on the channel domain. This inhibitory effect appears to contribute, at least partially, to the link between antidepressants and the risk of vascular diseases.
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The present study was designed to get further insight into the mode of antidepressant action of extracts prepared from St. John's wort (SJW) and relevant active constituents. Down-regulation of central beta-adrenergic receptors (beta-AR's) has been widely considered a common biochemical marker of antidepressant efficacy. Although previous studies have reported a beta-AR down-regulation for SJW extracts, in vivo studies that compare the effects of SJW extracts with those of relevant active constituents on beta-AR density have not been done yet. We used quantitative radioligand receptor-binding-studies to examine in rats the effects of short-term (2 wks) and long-term (8 wks) administration of different SJW extracts and constituents on beta-AR binding in rat frontal cortex. The effects were compared to those of the standard antidepressants imipramine and fluoxetine. [125I]CYP binding to beta-AR was found to be decreased after short as well as after long-term treatment with imipramine (36%, 40%). Short-term treatment with fluoxetine decreased the number of beta-adrenergic receptors (17%) while long-term treatment with fluoxetine elicited an increase (14%) in beta-AR-binding. This effect was comparable to that of the lipophilic CO2 extract which decreased beta-AR-binding (13%) after two weeks and slightly increased the number of beta-AR's after 8 weeks (9%). Short-term treatment with the methanolic SJW extract decreased beta-AR-binding (14%), no effects for this extract were observed after 8 weeks. Treatment with hypericin led to a significant down-regulation (13%) of beta-AR's in the frontal cortex after 8-weeks, but not after 2 weeks, while hyperforin (used as trimethoxybenzoate, TMB), and hyperoside were ineffective in both treatment paradigms. Compared to the SJW extracts and single compounds the effect of imipramine on beta-AR-binding was more pronounced in both treatment paradigms.
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We reviewed literature regarding the use of TCAs and SSRIs in depressed patients with comorbid anxiety.
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Unsatisfactory clinical efficacy and a variety of adverse effects of current antidepressant drugs have incited search for better therapy. Zinc, an antagonist of the glutamate/N-methyl-D-aspartate (NMDA) receptor, exhibits antidepressant-like activity in rodent tests/models of depression. Similarly to antidepressants, zinc induces brain derived neurotrophic factor (BDNF) gene expression and increases level of synaptic pool of zinc in the hippocampus. Clinical observations demonstrated serum hypozincemia in depression, which was normalized by effective antidepressant treatment. Moreover, our preliminary clinical study demonstrated the benefit of zinc supplementation in antidepressant therapy. All the data indicate the important role of zinc homeostasis in psychopathology and therapy of depression and potential clinical antidepressant activity of this ion.
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The authors review the main pharmacological factors playing a role in the kinetics of tricyclic antidepressant plasma levels. The current data concerning the relationship between tricyclic plasma levels and their clinical responses indicate that there is a therapeutic window at 50-150 ng/ml for the secondary derivatives (nortriptyline and desipramine). The lower limit of efficiency for the primary derivatives (imipramine and amitriptyline) is estimated at 200 ng/ml. The boundaries and prospects of the clinical use of antidepressant plasma levels are discussed in their various methodological aspects.
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Congenic mouse strain AKR.CBA-D13Mit76 carries the 59-70 cM fragment of chromosome 13 transferred from genome of cataleptic CBA/Lac strain to genome of AKR/J none-cataleptic strain. This fragment contains the major gene of predisposition to pinch-induced catalepsy. We investigated contribution of the fragment to regulation of sensitivity of catalepsy, sexual motivation and social investigation to classical tricyclic antidepressant imipramine. The sexual motivation was higher in AKR.CBA-D13Mit76 than in AKR mice. Chronic imipramine treatment (25 mg/kg) reduced it in AKR.CBA-D13Mit76 mice and had no effect on weakly expressed sexual motivation of AKR males. No significant effects of genotype or chronic imipramine treatment on characteristics of social interest were observed. Imipramine failed to alter catalepsy expression in AKR.CBA-DI3Mit76 mice. Possible molecular genetic mechanisms underlying difference in behavioral responses to antidepressant administration are discussed.
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Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naïve DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naïve animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.
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1. The carrier-mediated uptake of labelled 5-hydroxytryptamine (3H-5-HT) in rabbit platelets (defined as the difference between uptake observed in the absence and presence of 10 mumol l-1 imipramine) was studied after inhibition of monoamine oxidase and after a 1:13 dilution of the platelet-rich plasma (PRP) with Tris-containing buffer. 2. Irrespective of whether the rabbits were pretreated with reserpine or not, initial rates of 3H-5-HT uptake were maintained for at least 15 s. 3. Analysis of the saturation kinetics of 3H-5-HT uptake using Hill's equation yielded Km, Vmax and nH values of 130 nmol l-1, 116 pmol 10(8) platelets-1 min-1 and 1.40, respectively. Pretreatment of the animals with reserpine did not affect any of these kinetic parameters, but depleted more than 99% of the platelets' 5-HT stores. 4. The nH value remained greater than unity when the duration of incubation with 3H-5-HT was extended from 15 to 30 s and when the uptake of 3H-5-HT was inhibited by the presence of imipramine (10-40 nmol l-1). However, it was reduced to unity (with a consequential increase in Km) when 300 nmol l-1 ketanserin was present. This concentration of ketanserin did not affect 3H-5-HT uptake at substrate concentrations far below Km. 5. Imipramine inhibited 3H-5-HT uptake by increasing the Km for 3H-5-HT without changing Vmax. The Ki for this interaction was 18 nmol l-1.(ABSTRACT TRUNCATED AT 250 WORDS)