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Approximately 20 million patients suffer from major depressive disorder each year, indicating a need for antidepressant agents that are synonymous with effectiveness, tolerability and patient compliance. The authors examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, in the treatment of outpatients meeting DSM-III-R criteria for major depressive disorder. A randomized, double-blind, parallel group, placebo- and imipramine-controlled single center study was conducted in 150 outpatients. Patients were randomized to receive up to 150 mg/day of fluvoxamine as a single bedtime dose, 240 mg/day of imipramine on a twice-daily (BID) schedule, or placebo for six weeks. Efficacy measurements included HAM-D, MADRS, CGI, Raskin-Covi and SCL-56 scales. The HAM-D total score indicated that both active treatment groups showed significantly (p < or = 0.05) greater therapeutic benefit than did placebo. Severely depressed patients (HAM-D > or = 30) responded better to fluvoxamine in five of six measures. Side-effects from fluvoxamine were similar to those reported for other selective serotonin reuptake inhibitors (nausea, somnolence) and were well tolerated. Imipramine was associated with anticholinergic effects such as dry mouth and dizziness. The pharmacokinetic properties of fluvoxamine which allow the drug to be administered as a single daily dose should aid in the maintenance of patient compliance, while offering significant clinical benefit in the improvement of depressive symptoms.
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All articles were manually reviewed and evaluated. Thereafter, each agent or class of medication was categorized by level of evidence.
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The main objective of the present investigation was to determine whether the uptake of [3H]-dopamine in human lymphocytes is mediated through a serotonin transporter. This was examined by studying the effects of various monoamine uptake inhibitors on the uptake of [3H]-dopamine in human lymphocytes. Among the compounds tested, indatraline, imipramine and fluoxetine, selective inhibitors of neuronal serotonin transporter, were the most potent inhibitors of [3H]-dopamine uptake in lymphocytes. The 50% inhibiting concentration (IC50) for these inhibitors was in the range of 3.5-17 nmol/l. Bupropion, GBR 12909, nomifensine and xylamine, selective inhibitors of dopamine and norepinephrine transporters, had low affinity for the dopamine uptake system in human lymphocytes with IC50 values ranging between 1,000 and 40,000 nmol/l. These findings provide supportive evidence for the participation of a serotonin transporter in the uptake of [3H]-dopamine in human lymphocytes. The existence of a high affinity transport system for dopamine and serotonin in human lymphocytes may serve as a readily accessible model to detect changes in the neuronal uptake of dopamine and serotonin in addictive and psychiatric disorders.
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Tianeptine is an antidepressant agent with a novel neurochemical profile. It increases serotonin (5-hydroxytryptamine; 5-HT) uptake in the brain (in contrast with most antidepressant agents) and reduces stress-induced atrophy of neuronal dendrites. Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with most tricyclic antidepressant agents, tianeptine does not appear to be associated with adverse cognitive, psychomotor, sleep, cardiovascular or bodyweight effects and has a low propensity for abuse. Tianeptine has a comparatively favourable pharmacokinetic profile. It is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. While this offers advantages for tianeptine over the tricyclic antidepressant agents in terms of dose titration, treatment changes and potential drug interactions, its rapid elimination makes adherence to dosage schedules more important. Tianeptine differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system, indicating less likelihood of drug-drug interactions; this is of particular interest for elderly patients. Tianeptine, in dosages of 25 to 50 mg/day, has been investigated in patients with major depression, depressed bipolar disorder, dysthymia or adjustment disorder. It has equivalent antidepressant efficacy to several classical antidepressant agents (amitriptyline, clomipramine, imipramine, mianserin) and the SSRIs fluoxetine (in most patients), paroxetine and sertraline. Comparison with maprotiline indicated superior efficacy for tianeptine but dothiepin appeared superior in another study. Extended treatment with tianeptine decreases the incidence of relapse/recurrence of depression. Tianeptine appears to be as effective as fluoxetine, sertraline, amitriptyline, clomipramine and mianserin and more effective than maprotiline in improving associated anxiety in patients with depressive disorders. Depression and anxiety symptoms in alcohol dependant patients also respond well to tianeptine. The adverse effects associated with tianeptine are similar in many respects to those of the SSRIs and minimal in comparison with the tricyclic antidepressants. The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis.
Tricyclic antidepressant plasma levels were measured in patients and healthy subjects after a single dise of desmethylimipramine (DMI) or imipramine (IMI) and after chronic dosing to steady states. Tricyclic plasma levels measured 24 hr after the single oral dose correlated with steady-state plasma levels. In patients receiving DMI there was a correlation (r = 0.97, n = 10) between 24-hr and steady-state DMI levels, while in normal subjects receiving IMI the correlation was r = 0.92 (n = 20) between 24-hr and steady-state total tricyclic levels (IMI plus its metabolite, DMI). These results suggest the possibility that after a test dose of tricyclic antidepressant, a patient may be put on a "therapeutic" dosage regimen without delay.
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Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive inflammation.
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Patients older than 18 years with persistent monosymptomatic primary nocturnal enuresis were treated with 20 to 40 microg. desmopressin (DDAVP) nightly for 6 months. If the patients remained incontinent on maximal pharmacotherapy or if they became incontinent after cessation of DDAVP we initiated treatment with an enuretic alarm for 6 months. Patients not responsive to DDAVP or the enuresis alarm were given a trial of 50 mg. imipramine nightly. All patients were reassessed for continence 18 months after initiation of the treatment protocol.
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This work describes the development of a simple, sensitive and selective method based on high-performance liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) to determine antipsychotics (olanzapine, quetiapine, clozapine, haloperidol and chlorpromazine) along with antidepressants (mirtazapine, paroxetine, citalopram, sertraline, imipramine, clomipramine and fluoxetine), anticonvulsants (carbamazepine and lamotrigine) and anxiolytics (diazepam and clonazepam) in plasma samples obtained from schizophrenic patients. The samples were prepared by protein precipitation. The target drugs were separated on an XSelect SCH C18 column (100 mm × 2.1 mm × 2.5 µm) within 8.0 min by means of gradient elution. The drugs were then detected on a quadrupole tandem mass spectrometer equipped with an electrospray ionization source, operating in the multiple reactions monitoring mode and in the positive ionization mode. The LC-MS-MS method was linear range from subtherapeutic to toxic concentrations with lower limit of quantification values ranged from 0.2 to 5.0 ng mL(-1), precision with coefficient of variation values lower than 12%, and accuracy ranged from 90 to 108%. The developed method enabled successful analysis of the target drugs in plasma samples obtained from 51 schizophrenic patients. Therapeutic drug monitoring revealed that many of the evaluated schizophrenic patients presented altered plasma concentrations of the analyzed drugs. These altered concentrations resulted from pharmacokinetic interactions among the medications prescribed to treat schizophrenia.
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Two reviewers independently assessed the quality of the eligible trials, and extracted data.
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A growing body of evidence indicates that facilitation of serotonin-2C receptor (5-HT2CR)-mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) is involved in anxiety generation. We investigated here whether BLA 5-HT2CRs exert a differential role in the regulation of defensive behaviours related to generalized anxiety (inhibitory avoidance) and panic (escape) disorders. We also evaluated whether activation of BLA 5-HT2CRs accounts for the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine and fluoxetine. Male Wistar rats were tested in the elevated T-maze after intra-BLA injection of the endogenous agonist 5-HT, the 5-HT2CR agonist MK-212 or the 5-HT2CR antagonist SB-242084. This test allows the measurement of inhibitory avoidance acquisition and escape expression. We also investigated whether intra-BLA administration of SB-242084 interferes with the acute anxiogenic effect caused by imipramine and fluoxetine in the Vogel conflict test, and imipramine in the elevated T-maze. While intra-BLA administration of 5-HT and MK-212 facilitated inhibitory avoidance acquisition, suggesting an anxiogenic effect, SB-242084 had the opposite effect. None of these drugs affected escape performance. Intra-BLA injection of a sub-effective dose of SB-242084 fully blocked the anxiogenic effect caused either by the local microinjection of 5-HT or the systemic administration of imipramine and fluoxetine. Our findings indicate that 5-HT2CRs in BLA are selectively involved in the regulation of defensive behaviours associated with generalized anxiety, but not panic. The results also provide the first direct evidence that activation of BLA 5-HT2CRs accounts for the short-term aversive effect of antidepressants.
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Simple and sensitive method for determination of imipramine and desipramine is reported. The procedure is based on the oxidation of the drugs by ammonium metavanadate. Linear calibration graphs were obtained in the concentration range 0.6-40 microg ml(-1) of imipramine and 0.7-35 microg ml(-1) of desipramine with a relative standard deviation (RSD) less than 0.5%. The method was applied to the determination of the drugs in pharmaceutical preparations and compared favourably with independent official methods.
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The influence of the oral administration of different doses of citalopram (5, 15 and 45 mg/kg), imipramine (15, 30, 45 and 60 mg/kg), nortriptyline (15, 45 and 60 mg/kg) and amineptine (45 mg/kg) on stress-induced analgesia has been studied in anaesthetized rats. None of the administered antidepressants seem to have appreciable analgesic activity when analgesia is tested by the tail-immersion method. Citalopram, imipramine and nortriptyline, but not amineptine, increase the analgesia induced by inescapable footshock delivered continuously for 2 min to rats. Citalopram is the most potent drug. Our results support the suggested importance of 5-HT and noradrenaline terminals, but not those of dopamine, in the mediation of the stress-induced analgesia and seem to support the hypothesis that the analgesic activity of antidepressants is partially related to their modulating effects on the endogenously released opioid peptides involved in the endogenous pain inhibitory systems.
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The development of drug candidates must take into account that many compounds have off-target activity against voltage-gated ion channels (VGIC) which may prevent their progression to market. Of particular concern are hERG and hNa(V)1.5. Screening against these ion channels is necessary but expensive, partially due to maintenance of constantly cultured cell lines. Here, we show that frozen HEK-293 cells can be maintained indefinitely, reducing variability in cell performance, time and expense of cell culture.
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We assessed multiple domains of psychosocial functioning using interviewer-rated and self-report measures within the context of a 12-week acute treatment trial of sertraline and imipramine for patients with chronic depression (double depression and chronic major depression). We also compared the psychosocial functioning data of this sample before and after treatment with normative data available from published community samples.
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The whole cell recording technique was used to explore the depressant effect of the tricyclic antidepressant imipramine (IP) on calcium currents of neurons in cultures of murine dorsal root ganglia. The maximal whole cell current (ICa) mediated by the L-type calcium channel declined to 54% of control within 3 min of superfusing neurons with a solution containing 30 microM IP. In contrast, the T-type calcium current was unchanged. The IP-induced reduction of ICa was not associated with a change of the current-voltage relations of ICa. The depressant effect of IP on ICa was greatly reduced if neurons were pretreated with pertussis toxin or dialyzed with an intracellular solution containing guanosine 5'-O-2-thiodiphosphate. In contrast, superfusion of neurons with 5 mM 8-bromo-cyclic-AMP did not alter the effect of IP upon ICa. These data suggest that the selective suppressant effect of IP on the L-type calcium channel involves either an interaction with that region of the channel complex coupled to guanosine nucleotide-binding proteins or with guanosine nucleotide-binding proteins themselves.
Ten cases are presented--two in detail--in which clonazepam was used successfully in patients with treatment-resistant panic disorder with or without agoraphobia. Seven of 10 patients who had been resistant to standard pharmacological treatments of panic attacks and agoraphobia achieved cessation of their attacks while three had mild to moderate symptom persistence. These data underscore other reports of clonazepam's usefulness in the treatment of panic disorder. Clinical use of clonazepam is discussed.
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Morphine is an analgesic drug used for the treatment of acute and chronic pain syndromes for cancer patients. Glucuronidation is a major pathway of the elimination of morphine in humans. Morphine is metabolized to 3-glucuronide (no analgesic effect) and 6-glucuronide (more potently analgesic than morphine) mainly by UGT2B7. In the present study, we investigated the inhibitory effects of a variety of drugs on the morphine glucuronosyltransferase activities in human liver microsomes. Twenty-one drugs including anticancer drugs, immunosuppressants, analgesics, anticonvulsants, antidepressants, antipsychotic drugs were selected in this study, because they are frequently co-administered with morphine. We found that 10 out of 21 drugs, tamoxifen, tacrolimus, diclofenac, carbamazepine, imipramine, clomipramine, amitriptyline, diazepam, lorazepam and oxazepam extensively inhibited the morphine 3- and 6-glucuronosyltransferase activities. Although some of the drugs are not substrates of UGT2B7, they would be potent inhibitors of UGT2B7. If patients receive morphine and these drugs simultaneously, the drug-drug interaction may change the levels of morphine and these glucuronides, resulting in altered analgesic efficacy and the risk of side effects. The results presented here will assist clinicians in choosing the proper drugs and/or dosages, and enable them to anticipate potential drug-drug interactions.
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Sodium channel blockers such as lidocaine, lamotrigine, and carbamazepine can be effective in the treatment of neuropathic pain. Though not approved for neuropathic pain indications, tricyclic antidepressants are often considered first-line treatment for conditions such as post-herpetic neuralgia and diabetic neuropathy. Several tricyclic antidepressants have been shown to block peripheral nerve sodium channels, which may contribute to their antihyperalgesic efficacy. In this study, we compared the sodium channel-blocking potency of a number of antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. All compounds tested inhibited Na(V)1.7 in a state- and use-dependent manner, with affinities for the inactivated state ranging from 0.24 micromol/L for amitriptyline to 11.6 micromol/L for zimelidine. The tricyclic antidepressants were more potent blockers of Na(V)1.7. Moreover, IC(50)s for block of the inactivated state for amitriptyline, nortriptyline, imipramine, desipramine, and maprotiline were in the range of therapeutic plasma concentrations for both the treatment of depression as well as neuropathic pain. By contrast, fluoxetine, paroxetine, mianserine, and zimelidine had IC(50)s for Na(V)1.7 outside their therapeutic concentration ranges and generally were not efficacious against post-herpetic neuralgia or diabetic neuropathy. These results suggest that block of peripheral nerve sodium channels may contribute to the antihyperalgesic efficacy of certain antidepressants.
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An equation is derived from a mathematical model (proposed by Furchgott) which, under certain circumstances, estimates the pKI (-log dissociation constant) of a competitive inhibitor of agonist uptake by utilizing the sensitization of isolated tissues, to the substrate-agonist, by uptake inhibition. The method is theoretically more sound and appears to be improved by the use of potency-ratios of the substrate-agonist and an agonist which is not a substrate for the uptake process since this allows for the detection and correction of receptor and toxic effects of uptake inhibitors. The pKI values of cocaine, desmethylimipramine and imipramine for the neuronal uptake of norepinephrine were estimated by this method in guinea-pig tracheae and left atria. Also, the pKI values for 17 beta-oestradiol, corticosterone, clonidine and metanephrine for the extraneuronal uptake of isoproterenol were estimated in guinea-pig tracheae (and cat left atria for 17 beta-oestradiol). All estimates were consistent with literature pKI values obtained biochemically with radiolabelled substrates.
5-Hydroxytryptamine (5-HT) showed a biphasic effect on the dissociation rate of [3H]imipramine from human platelet membranes: At low concentrations (EC50, approximately 2.5 microM), 5-HT stimulated the rate, as expected for mutually exclusive binding of 5-HT and imipramine; at higher concentrations (EC50, approximately 40 microM), 5-HT reduced this stimulated rate, a result consistent with 5-HT binding at a site that is physically distinct from both the imipramine binding site and the 5-HT transport recognition site of the 5-HT carrier. This modulatory effect could be mimicked by tryptamine, was saturable and independent of Na+ concentration, and could also be demonstrated for detergent-solubilized carriers. Monophasic association kinetics for [3H]imipramine binding were found. Heat stability experiments showed biphasic thermal inactivation curves. These results are consistent with [3H]imipramine binding to two classes of binding sites at the 5-HT carrier on human platelet membranes, with affinities three- to fivefold different. 5-HT can convert the lower-affinity state into the higher-affinity state.
In this article we report on the reliable production of several features of panic attacks following subcutaneous administration of sodium lactate to nonhuman primates. Unrestrained monkeys were evaluated by an observer without knowledge of the subjects' treatment with either sodium lactate or a dextrose control solution. The lactate produced temporally circumscribed episodes of agitation, wariness, and motor responses, normally elicited under stressful or threatening conditions. In an initial pharmacological intervention, we found that pretreatment with imipramine blocked the response to lactate. The further development of this model offers promise for the systematic examination of etiological factors in susceptibility to lactate induction of panic attacks, the physiological basis of the response, and new modes of treatment of panic disorder.
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Alkalinizing agents reverse cardiotoxicity of a variety of sodium channel blockers, including tricyclic antidepressants, but their mechanisms of action are poorly understood.
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Reboxetine is a selective norepinephrine reuptake inhibitor shown to be an effective agent in the treatment of major depressive illness. In clinical trials, reboxetine was effective in decreasing mean total scores of the Hamilton Rating Scale for Depression in adult populations. Improvements were similar between reboxetine and desipramine and imipramine, as well as fluoxetine. Reboxetine is relatively well tolerated, with insomnia, sweating, constipation, and dry mouth being commonly reported adverse events. Hypotension and urinary hesitancy occur at lower rates than with the tricyclics, and compared with fluoxetine, reboxetine is associated with lower rates of nausea, somnolence, and diarrhea. Dosage adjustments may be appropriate in elderly patients and those with renal and hepatic impairment.
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The clouding behavior of tricyclic antidepressant drug imipramine hydrochloride (IMP) in aqueous solution has been studied in presence of surfactants. A pH increase in the presence as well as in the absence of surfactants decreased the CP. Drug molecules become neutral at high pH and therefore head-head repulsion decreases which lead to CP decrease. Addition of non-ionic and cationic surfactants increased the CP whereas anionic surfactants showed a peaked profile. Effect of CTAB/TX-100 at different fixed drug concentrations showed that at all surfactant concentrations the CP value was higher for higher drug concentrations. However, variation of pH produced opposite effect: CP at all CTAB/TX-100 concentrations decreased with increasing pH. All results are interpreted in terms of increase in hydrophobicity or hydrophilicity of micelles on addition of surfactants.
Effects of neuroleptics and tricyclic antidepressants on voltage-gated ion channels were investigated in the neuroblastoma cell line N1E-115 using the whole cell variation of patch electrode voltage-clamp techniques. Imipramine, chlorpromazine and haloperidol in micromolar concentrations blocked sodium, calcium and potassium channel currents in a reversible and concentration-dependent manner. The order of potency was chlorpromazine greater than imipramine greater than haloperidol. These direct blocking actions on neuronal ion channels might play a role in clinical effects of these drugs.