Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major depression (MD) is underdiagnosed and undertreated in patients with temporal lobe epilepsy (TLE). Side effects of some antidepressants, like increased risk of seizures and drug-drug interactions with anticonvulsants, contribute to undertreatment of MD in patients with TLE. We analyzed post hoc the data from 2 years of treatment of inpatients with MD and TLE. Seventy-five patients received standard treatment with citalopram, mirtazapine, or reboxetine, respectively, at recommended dosage. Examinations were done with the Hamilton Rating Scale for Depression at admission and after 4 and 20-30 weeks. Plasma levels of anticonvulsants were examined at admission and discharge. Seizures were documented. The antidepressive treatment was efficacious in all antidepressant groups. No case of serious adverse event or drug interaction occurred. There was no increase in frequency or severity of seizures. At endpoint the dropout rate for mirtazapine was significantly higher than that for reboxetine or citalopram. Reboxetine showed a trend to be more efficacious than citalopram but not mirtazapine at Week 4.
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PMID:Antidepressive treatment in patients with temporal lobe epilepsy and major depression: a prospective study with three different antidepressants. 1469 1

Reboxetine is the first commercially available norepinephrine reuptake inhibitor developed specifically as a first line therapy for major depressive disorder. In vitro and in vivo pharmacological studies indicated that reboxetine methanesulphonate has high affinity and selectivity for the human norepinephrine transporter over the serotonin and dopamine transporters. Pharmacological specificity is further demonstrated by the absence of affinity for 45 transmitter receptors and CNS targets. Pharmacokinetic studies demonstrated that reboxetine is suitable for twice daily administration (8-10 mg/day) and that it exhibits minimal drug-drug interactions. The starting dose of reboxetine should be reduced in the elderly, in patients with renal or hepatic impairment, or in patients receiving potent CYP3A inhibitors. A total of 20 phase II/III clinical studies comprising placebo-controlled, active comparator-controlled and open-label uncontrolled studies in both short-term and long-term treatment of major depression have been conducted. In the treatment of major depression, reboxetine was superior to placebo in 5 of 12 short- or long-term placebo-controlled studies and was comparable in efficacy to active comparators in 3 out of 3 active-controlled studies. Unlike conventional tricyclic antidepressants (TCAs), reboxetine had only minimal sedative and cardiovascular liabilities, probably due to increased pharmacological specificity of reboxetine as compared with TCAs. Unlike serotonin reuptake inhibitors, this selective and specific norepinephrine reuptake inhibitor demonstrated a distinct side-effect profile with diminishing sexual dysfunction and GI side effects. The availability of this agent has afforded patients suffering from major depressive disorder a new class of agents to combat the debilitating consequence of this psychiatric disease. The demonstrated pharmacological specificity of this compound has provided the psychopharmacology community with a tool to elucidate the role of norepinephrine in brain functions. Testing this agent in different animal models has enabled the exploration of the role of modulation of norepinephrine tone in the therapy of CNS disorders beyond depression.
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PMID:The selective norepinephrine reuptake inhibitor antidepressant reboxetine: pharmacological and clinical profile. 1497 12

Reboxetine, 2-[alpha-(2-ethoxyphenoxy)benzyl]morpholine, is a highly selective norepinephrine transporter (NET) blocker that has been used for the treatment of depression. Its methyl analogue, 2-[alpha-(2-methoxyphenoxy)benzyl]morpholine (MRB), has been radiolabeled with C-11 for studies of the NET system with positron emission tomography (PET). The normethyl precursor, 2-[alpha-(2-hydroxyphenoxy)benzyl]morpholine (desethylreboxetine), was synthesized in 6% overall yield via a multi-step regio- and stereo-specific synthesis, starting from a mono-O-protected catechol. The resulting racemic mixture of desethylreboxetine was resolved by chiral HPLC to provide the (2S,3S) and (2R,3R) enantiomers in >98% enantiomeric excess. These enantiomers were then used as precursors for radiosynthesis to prepare enantiomerically pure individual 11C-labeled MRB enantiomers for comparative PET studies in baboons. Selective C-11 methylation at the phenolic oxygen with [11C]CH3I was achieved in the presence of excess base. After HPLC purification, racemic ((2S,3S)/(2R,3R)) or enantiomerically pure ((2S,3S) or (2R,3R)) [11C]MRB was obtained in 61-74% decay-corrected radiochemical yields from [11C]CH3I in a synthesis time of 40 min with a radiochemical purity of >96% and a specific activity of 1.7-2.3 Ci/micromol (63-85 GBq/micromol) corrected from the end of bombardment (EOB).
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PMID:Synthesis, enantiomeric resolution, and selective C-11 methylation of a highly selective radioligand for imaging the norepinephrine transporter with positron emission tomography. 1523 45

Depression occurs frequently in post-stroke patients and appears to be associated with an impairment in their rehabilitation and functional recovery. Although selective serotonin reuptake inhibitors (SSRI) are often used in post-stroke depression (PSD), it has been observed that only a subset of patients is responsive to this treatment. Other patients respond to tricyclic antidepressants or MAO inhibitors, which, however, may not have a favorable profile of safety and tolerability in post-stroke patients. In this double-blinded, placebo-controlled study, we evaluated the efficacy and tolerability of the noradrenaline reuptake inhibitor, reboxetine, in a subset of PSD patients classified as affected by "retarded" depression. Reboxetine (4 mg, twice daily, for 16 weeks) was administered to patients that developed depression after a single ischaemic or hemorrhagic stroke. We assessed the severity of depressive symptoms by the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS). HDRS and BDI scores (mean+/-S.D.) at baseline were, respectively, 24+/-1.31 and 19.87+/-1.46 in the placebo group, 24.06+/-1.52 and 20.56+/-2.16 in the reboxetine group. After 16 weeks, HDRS and BDI mean scores were respectively 22.73+/-2.4 and 18.4+/-3.33 in the placebo group, 9.26+/-2.15 and 8.06+/-3.43 in the reboxetine group [p<0.01 versus the respective baseline (paired t-test); (#)p<0.01 versus retarded depressed patients treated with placebo (one-way analysis of variance (ANOVA) applied to the difference from baseline, associated with Dunnett's t-test to isolate the differences)]. Reboxetine showed a good efficacy, safety and tolerability in PSD patients affected by "retarded" depression. We conclude that reboxetine is well tolerated and may be a useful therapeutic option in PSD patients with "retarded" depression.
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PMID:An evaluation of efficacy and safety of reboxetine in elderly patients affected by "retarded" post-stroke depression. A random, placebo-controlled study. 1581 61

At this large and varied meeting on neuropharmacotherapy, progress was reported on the newer more selective antipsychotics. The selective D(2) dopamine receptor partial agonist, aripiprazole (Otsuka Pharmaceutical Co Ltd) was recently proved effective over the medium term. The atypical antipsychotics generally, such as clozapine, have a good side effect profile and better patient compliance, even in Parkinson's disease (PD). Reboxetine (Pharmacia & Upjohn AB), having a far greater selectivity for norepinephrine reuptake inhibition than for serotonin or dopamine reuptake, is of particular value in treating depression. Paroxetine (Novo Nordisk A/S), a selective serotonin reuptake inhibitor (SSRI), has just completed a multicenter clinical trial, being effective in about 50% of cases of post-traumatic stress disorder. A meta-analysis of trials of other uptake inhibitors showed that ability to block serotonin (rather than norepinephrine) uptake correlated well with efficacy. Bipolar and other disorders were hoped to benefit from more selective agents in the future, the potential for which has been revealed through basic neurobiology, with, for example, only non-alpha7 nicotinic receptor subunits being expressed by those interneurons mediating nicotinic responses. An open label, 30-day study of a pyrrolopyrimidine, the corticotrophin releasing factor (CRF) type 1 receptor inhibitor, NBI-30775 (Neurocrine Biosciences Inc/Janssen Pharmaceutica NV) produced good antidepressant effects, but has had to be abandoned as a product due to indications of potential liver damage. Similarly, although glial-derived neurotrophic factor (GDNF) had proved ineffective in a 1999 trial for PD, due to failure to access the striatum, there was however much evidence to suggest that small molecule agonists of the TRK-B receptor should be effective. Of these, quinones such as L-783281 (Merck Research Laboratories) appear to activate all TRK subtypes by a common intracellular, rather than receptormediated action, which may limit their usefulness. Although such agents would have many potential applications, it is likely that highly selective receptor activation will be needed.
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PMID:CINP 2000 - Collegium Internationale Neuro-Psychopharmacologicum 22nd Congress. 1604 59

Reboxetine is used as a selective noradrenaline reuptake inhibitor for the treatment of major depressive disorders. It is effective in the treatment of severe depression and safer to use than traditional tricyclic antidepressants. In this study, a novel, simple, and rapid stability-indicating high-performance liquid chromatography (HPLC) method for reboxetine methansulfonate was successfully developed and validated for the assay of tablets. The method was used to quantify reboxetine in tablets; it employed a C18 column (150 x 4.6 mm id) with an isocratic mobile phase consisting of methanol-phosphate buffer (pH 7, 0.02 M; 55 + 45, v/v) at a flow rate of 1.0 mL/min. Reboxetine was detected by an ultraviolet detector at 277 nm. The retention time of reboxetine was about 4.5 min. The developed HPLC method was validated with respect to linearity, precision, sensitivity, accuracy, and selectivity. The method was linear over the concentration range 1-50 microg/mL (r = 0.9999). The limits of detection and the quantitation of reboxetine were 0.1 and 0.3 microg/mL, respectively. The relative standard deviation values for intraday and interday precision were 0.78-1.01 and 1.08-1.37%, respectively. Selectivity was validated by subjecting a stock solution of reboxetine to neutral, acid, and alkali hydrolysis, as well as oxidation, dry heat treatment, and photodegradation. The peaks of the degradation products did not interfere with the peak of reboxetine. The results indicated that the proposed method could be used in a stability assay. The proposed method was successfully applied to the determination of reboxetine in tablets. Excipients present in the tablets did not interfere with the analysis.
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PMID:A selective high-performance liquid chromatography method for the determination of reboxetine in bulk drug and tablets. 1722 1

Motor retardation is a relevant aspect of depression. Kinematic analysis of movements can be applied to explore which type of motor dysfunction is associated with depression and to examine motor side effects of antidepressants. Using this tool, we aimed to investigate fine motor performance in patients suffering from depression and to compare a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin reuptake inhibitor (SSRI) (citalopram) regarding motor side effects after 4 weeks of treatment. In the first study (I), we examined 37 depressed patients and 37 healthy subjects using a digitizing graphic tablet and kinematic analysis of handwriting and rapid drawing movements. Both groups were comparable regarding age, gender distribution, handedness (preponderance of right-handers) and educational level. In the second study (ll), we examined different types of hand movements in 16 depressed patients receiving citalopram (flexible dosage) and 12 depressed patients treated with reboxetine (varying dosage) using the afore-mentioned methods. Both groups were comparable regarding age, gender, handedness and the baseline Hamilton Depression Rating Scale total score. I: Depressed patients performed drawing with significantly less regular velocity than controls (p < 0.001), but normal velocity. Handwriting of depressed patients was abnormally slow (p = 0.04). II: Reboxetine led to a significant improvement of repetitive drawing movements in depression. In contrast, citalopram had no pronounced effects on hand movements in depressed patients. I: Irregular patterns of velocity peaks in depressed patients point to basal ganglia dysfunction and/or deficient activity of the sensorimotor cortex and the supplementary motor area as possible substrates of hand-motor disturbances in depression. II: Computer-aided analysis of hand movements is a sensitive tool for the registration of differential pharmaceutical effects on hand-motor function in depression.
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PMID:Hand-motor dysfunction in depression: characteristics and pharmacological effects. 1751 73

We used functional magnetic resonance imaging to investigate the effects of short-term treatment with reboxetine, a selective noradrenaline reuptake inhibitor, on emotional facial processing in healthy volunteers. Reboxetine was associated with a reduced amygdala response to fearful faces and increased activation to happy v. neutral facial expressions in the right fusiform gyrus, relative to placebo treatment and in the absence of changes in mood. Our results show that reboxetine modulates the neural substrates of emotional processing, highlighting a mechanism by which drug treatment could normalise negative bias in depression and anxiety.
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PMID:Short-term antidepressant treatment and facial processing. Functional magnetic resonance imaging study. 1754 Nov 15

Drugs which inhibit the re-uptake of monoamines in the brain are effective in the treatment of depression; however, the neuropsychological mechanisms which lead to the resolution of depressive symptomatology are unclear. Behavioral studies in healthy volunteers suggest that acute administration of the selective norepinephrine reuptake inhibitor reboxetine modulates emotional processing. The current study therefore explored the neural basis of this effect. A single dose of reboxetine (4 mg) or placebo was administered to 24 healthy volunteers in a double-blind between-group design. Neural responses during categorisation and recognition of self-referent personality trait words were assessed using event-related functional Magnetic Resonance Imaging (fMRI). Reboxetine had no effect on neuronal response during self-referent categorisation of positive or negative personality trait words. However, in a subsequent memory test, reboxetine reduced neuronal activation in a fronto-parietal network during correct recognition of positive target words vs. matched distractors. This was combined with increased speed to recognize positive vs. negative words compared to control subjects and suggests facilitated memory for positive self-referent material. These results support the hypothesis that antidepressants have early effects on the neural processing of emotional material which may be important in their therapeutic actions.
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PMID:Single dose antidepressant administration modulates the neural processing of self-referent personality trait words. 1762 17

Apoptosis has been proposed as a contributing cellular mechanism to the structural alterations that have been observed in stress-related mood disorders. Antidepressants, on the other hand, are hypothesized to exert trophic and/or neuroprotective actions. The present study examined the regulation of the major antiapoptotic (Bcl-2, Bcl-xl) and proapoptotic (Bax) genes by repeated unpredictable stress (an animal model of depression) and antidepressant treatments (ADT). In adult rats, exposure to unpredictable stress reduced Bcl-2 mRNA levels in the central nucleus of the amygdala (CeA), cingulate (Cg), and frontal (Fr) cortices. Bcl-xl mRNA was significantly decreased in hippocampal subfields. In contrast, chronic administration of clinically effective antidepressants from four different classes, ie fluoxetine, reboxetine, tranylcypromine, and electroconvulsive seizures (ECS) upregulated Bcl-2 mRNA expression in the Cg, Fr, and CeA. Reboxetine, tranylcypromine, and ECS selectively increased Bcl-xl, but not Bcl-2 mRNA expression in the hippocampus. Chemical ADT but not ECS, robustly enhanced Bcl-2 expression in the medial amygdaloid nucleus and ventromedial hypothalamus. Fluoxetine did not influence Bcl-xl expression in the hippocampus, but it was the only ADT that decreased Bax expression in this region. In the CeA, again in direct contrast to the stress effects, exposure to all classes of ADTs significantly increased Bcl-2 mRNA. The selective regulation of Bcl-xl and Bax in hippocampal subfields and of Bcl-2 in the Cg cortex, amygdala, and hypothalamus suggests that these cellular adaptations contribute to the long-term neural plastic adaptations to stress and ADTs in cortical, hypothalamic, and limbic brain structures.
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PMID:Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures. 1770 Jun 47


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