Selective Noradrenaline Reuptake Inhibitor Reboxetine Research Articles

Effect of combined treatment with noradrenaline and serotonin reuptake inhibitors on conditioned freezing

To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment.

Efficacy and Tolerability of Reboxetine Compared with Citalopram

The objective of this study was to compare efficacy and tolerability of the selective noradrenaline reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram, in the treatment of major depressive disorder (MDD). In total, 357 outpatients with MDD were randomized to treatment with reboxetine 8-10 mg or citalopram 20-40 mg per day during 24 weeks. Primary end-point was change from baseline in the Hamilton Depression Rating Scale (HAM-D, 21 items). Sexual function/dysfunction was measured by the Sexual Function scale (SF). Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores: reboxetine with -21.4 and citalopram with -22.1 points (NS). LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine (-19.6 vs. -17.8; P = 0.034). The response rate was 90.3% for reboxetine and 92.7% for citalopram (NS). The most common side effect in the reboxetine group was dry mouth, and in the citalopram group sexual dysfunction. At week 24, anorgasmia was reported by 5.9% of the sexually active women in the reboxetine group vs 39% in the citalopram group. The dropout number was 91 in the reboxetine group, and 54 in the citalopram group. To summarize, both treatments gave a satisfactory antidepressant effect. The side effect profile differed between the groups, with a notably high prevalence of sexual dysfunctions in the citalopram group. The high number of dropouts in the reboxetine group, is considered as a result of the non-titration starting dose of 8 mg reboxetine per day, which gave a high incidence of early side-effects.

Regulation of Editing and Expression of Glutamate α-Amino-Propionic-Acid (AMPA)/Kainate Receptors by Antidepressant Drugs

Several reports have shown that the glutamatergic system is involved in both the pathogenesis of affective and stress-related disorders and in the action of antidepressant drugs. In particular, antidepressant treatment was shown to modulate expression and function of ionotropic glutamate receptors, to inhibit glutamate release and to restore synaptic plasticity impaired by stress. We analyzed the mRNA expression and RNA editing of alpha-amino-propionic-acid (AMPA) and kainate (KA) receptor subunits, in the pre-frontal/frontal cortex (P/FC) and hippocampus (HI) of rats chronically treated with three different drugs: the selective serotonin (5-HT) reuptake inhibitor fluoxetine, the selective noradrenaline (NA) reuptake inhibitor reboxetine and the tricyclic antidepressant desipramine. Our data showed that fluoxetine and desipramine exerted moderate but selective effects on glutamate receptor expression and editing, while reboxetine appeared to be the drug that affects glutamate receptors (GluR) most. The most consistent effect, observed with pronoradrenergic drugs (desipramine and reboxetine), was a decrease of GluR3 expression both in P/FC and HI. Interestingly, in HI, the same drugs also decreased the editing levels of either the flip (desipramine) or flop (reboxetine) form of GluR3. Overall, these results point to specific and regionally discrete changes in the expression and editing level of glutamate receptors and, in particular, to a selective reduction of conductance for GluR3-containing receptors following treatment with antidepressant drugs. These data support the hypothesis that changes in glutamate neurotransmission are involved in the therapeutic effects induced by these drugs.

Worsening of Borderline Symptoms Under Reboxetine Treatment

Back to table of contents Previous article Next article LetterFull AccessWorsening of Borderline Symptoms Under Reboxetine TreatmentIon Anghelescu, M.D., Britta Jänen, M.D., Frank Schindler, M.D., and Claas-Hinrich Lammers, M.D., Ion AnghelescuSearch for more papers by this author, M.D., Britta JänenSearch for more papers by this author, M.D., Frank SchindlerSearch for more papers by this author, M.D., and Claas-Hinrich LammersSearch for more papers by this author, M.D., Department of Psychiatry, University Medicine Berlin, GermanyPublished Online:1 Nov 2005AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Reboxetine, a norepinephrine reuptake inhibitor, is a potent antidepressant for patients with major depressive disorder or dysthymia.1 Borderline patients do not only show symptoms such as self-mutilation, suicidality, dissociative symptoms, aversive tension and instability of mood but also very often depressive symptoms which require a psychopharmacological treatment. Here we report the clinical observation in two patients that the use of reboxetine as an antidepressant in borderline patients does provoke an increase in borderline symptoms such as dissociative symptoms, aversive tension and irritability.Case ReportsMs. A. is a 23-year-old female with the diagnosis of dysthymia who was admitted because of acute suicidality. The diagnoses made over the past few years were borderline personality disorder, cannabis and alcohol abuse, panic disorder with agoraphobia and anorexia nervosa. Her major complaints were affective lability, depersonalisation and concentration difficulties. Self-injuries have occurred for about 7 years, her childhood history was remarkable for sexual abuse by her father. Because of insufficient efficacy and sedation as a side effect the premedication with mirtazapine 30 mg daily was switched to reboxetine, because she refused to take an SSRI. Already with reboxetine 4 mg daily she suffered from severe irritability and aversive tension with increased suicidality and dissociative symptoms, which could also be translated into a visual analogue scale. Three days after discontinuation the symptoms completely remitted.Ms. B. is a 32-year-old female with the diagnosis of a major depressive episode (HDRS-17 of 17 at admission). Her major complaint was sadness and feelings of guilt with insomnia. She was treated with quetiapine (200 mg daily) because of its sedating effects and because of galactorrhea associated with amisulpride intake before. Moreover, she suggested the substitution of venlafaxine, which had caused significant weight gain of about 5 kg in 4 weeks. Therefore, reboxetine was initiated, and increased from 2 to 6 mg daily over 3 days. With this dosage she developed severe affective lability and impulsivity with acute suicidality (HDRS-17: 21). Two days after discontination and switch to 50 mg sertraline she remitted completely from these new symptoms. She then reported—what was denied at the beginning—recurrent states of aversive tension, identity problems and flashback intrusions since the age of 14. This led to the supplementary diagnosis of borderline personality disorder.DiscussionWe report for the first time worsening of borderline symptoms, especially dissociative symptoms and aversive tension, under the treatment with reboxetine in two patients with borderline personality disorder. We interpret this clinical observation as an increased noradrenergic sensitivity with an hyperresponsiveness of the adrenergic system under stimulation. An heightened and dysregulated adrenergic function and a symptom provocation through increase of noradrenergic neurotransmission is a robust finding in patients with post traumatic stress disorder (PTSD).2 Since borderline personality disorder has been conceptualized as a chronic complex PTSD, our clinical observation indicates that noradrenergic hyperresponsitivity is a neurobiological mechanism for borderline symptoms. This observation is supported by the finding of reduction of aversive tension and dissociation by clonidine, an inhibitor of the central noradrenergic system.3References1 Burrows GD, Maguire KP, Norman TR: Antidepressant efficacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review. J Clin Psychiatry 1998; 59(suppl 14):4-7Google Scholar2 Southwick SM, Bremner JD, Rasmusson A, et al: Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry 1999; 46:1192–1204Crossref, Medline, Google Scholar3 Philipsen A, Richter H, Schmahl C, et al: Clonidine in acute aversive inner tension and self-injurious behavior in female patients with Borderline personality disorder. J Clin Psychiatry (in press)Google Scholar FiguresReferencesCited byDetailsCited bySocial Cognitive and Affective Neuroscience, Vol. 4, No. 2Psychopharmacology, Vol. 197, No. 1Medications in the treatment of borderline personality disorder 200618 April 2007 | Current Psychiatry Reports, Vol. 9, No. 1Pharmakologische und psycho- therapeutische Behandlung der Borderline-StörungZeitschrift für Psychiatrie, Psychologie und Psychotherapie, Vol. 54, No. 3 Volume 17Issue 4 November 2005Pages 559-560 Metrics PDF download History Published online 1 November 2005 Published in print 1 November 2005

Resolution of sexual dysfunction during double-blind treatment of major depression with reboxetine or paroxetine

The selective noradrenaline re-uptake inhibitor reboxetine may have advantages over the selective serotonin re-uptake inhibitors fluoxetine and citalopram, in effects on sexual function and satisfaction. The effects of reboxetine and paroxetine on sexual function were compared by examining data from the UK centres in an international double-blind flexible-dose parallel-group multi-centre randomized controlled trial of acute treatment of patients with DSM-IV major depression. Patients were randomly assigned to receive reboxetine (4 mg b.d.) or paroxetine (20 mg mane) using a double-dummy technique to preserve the blind. The dosage could be increased at day 28 (to reboxetine 4 mg mane, 6 mg nocte; or paroxetine 20 mg b.d.). Antidepressant efficacy was assessed by the 21-item Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impression Scale for Severity (CGI-S) at all study visits, and the Clinical Global Impression of Improvement (CGI-I) at each visit after randomization. Sexual function and satisfaction was assessed by visual analogue scale (VAS) items of the Rush Sexual Inventory completed at baseline and days 28 and 56. There were no significant differences between groups in demographic or clinical features at baseline. There was a gradual reduction in severity of depressive symptoms (reboxetine, 14.3; paroxetine, 12.0: observed case analysis), with no significant differences between groups. There were significant differences (p 0.05), with advantages for reboxetine, at Week 4 and Week 8 on the VAS item assessing ability to become sexually excited, and non-significant trends with advantages for reboxetine, in frequency of sexual thoughts at Week 4 (p 0.05) and Week 8 (p 0.08); and in desire to initiate sexual activity at Week 4 (p 0.09). Exclusion of patients who had ever experienced sexual dysfunction with any medication prior to participation in this study (n 10) reduced the statistical significance of the findings, although there were still numerical advantages for reboxetine. Sexual function and satisfaction in depressed patients improves during double-blind acute treatment with reboxetine or paroxetine, but this improvement is greater and more rapid with reboxetine.

Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing behavior following treatment for 3 days, but increases in both swimming and climbing behaviors were measured following treatment for 14 days. Treatment with the high dose of moclobemide for 3 days decreased immobility and increased swimming, whereas treatment for 14 days significantly increased both active behaviors (swimming and climbing). Antidepressants from three different classes produce different effects on active behaviors in the FST. The effects of antidepressants were augmented following chronic administration for 14 days, especially when given at low doses. This suggests that modifications of the FST can be used to examine the onset of action of antidepressant agents produced by long-term administration.

Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with positron emission tomography

Racemic and enantiomerically pure (( S, S) and ( R, R)) 2-[α-(2-(2-[ 18F]fluoroethoxy)phenoxy)benzyl]morpholine ([ 18F]FRB) and its tetradeuterated form [ 18F]FRB-D 4, analogs of the highly selective norepinephrine reuptake inhibitor reboxetine (2-[α-(2-ethoxyphenoxy)benzyl]morpholine, RB), have been synthesized for studies of norepinephrine transporter (NET) system with positron emission tomography (PET). The [ 18F]fluorinated precursor, ( S, S)/( R, R)- N- tert-butyloxycarbonyl-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)- N-Boc-desethylRB), was prepared by the N-protection of ( S, S)/( R, R)-2-[α-(2-hydroxyphenoxy)benzyl]morpholine (( S, S)/( R, R)-desethylRB) with a tert-butyloxycarbonyl (Boc) group followed by enantiomeric resolution with chiral HPLC to provide both ( S, S) and ( R, R) enantiomers with >99% enantiomeric purity. These compounds were then used for radiosynthesis to prepare enantiomerically pure [ 18F]FRB and [ 18F]FRB-D 4 via the following three-step procedure: (1) formation of 1-bromo-2-[ 18F]fluoroethane ([ 18F]BFE or [ 18F]BFE-D 4) by nucleophilic displacement of 2-bromoethyl triflate (or D 4 analog) with no-carrier added [ 18F]F − in THF; (2) reaction of [ 18F]BFE (or [ 18F]BFE-D 4) with N-Boc-desethylRB in DMF in the presence of excess base; and (3) deprotection with trifluoroacetic acid. The racemates, ( S, S) and ( R, R) enantiomers of [ 18F]FRB and [ 18F]FRB-D 4 were obtained in 11–27% (decay corrected to the end of bombardment, EOB) in 120-min synthesis time with a radiochemical purity of >98% and specific activities of 21–48 GBq/μmol (EOB). The results of the whole-body biodistribution studies with ( S, S)-[ 18F]FRB-D 4 were similar to those with ( S, S)-[ 18F]FRB but showed relatively faster blood clearance and no significant in vivo defluorination. Positron emission tomography studies in baboon brain also showed that ( S, S)-[ 18F]FRB-D 4 may be a potentially useful ligand for imaging NET with PET.

Chronic Reboxetine Desensitizes Terminal but not Somatodendritic α2-Adrenoceptors Controlling Noradrenaline Release in the Rat Dorsal Hippocampus

The slow onset of antidepressant drugs' effects is thought to reflect the time required for the development of adaptive changes such as desensitization of presynaptic autoreceptors controlling the release of neurotransmitters. Using in vivo microdialysis in conscious rats, we studied the effect of a continuous infusion of the selective noradrenaline (NA) reuptake inhibitor reboxetine on extracellular concentrations of NA. Doses of 10 mg/kg/day reboxetine through subcutaneous osmotic pumps for 2 days increased extracellular NA by 272% in the dorsal hippocampus (DH) of rats. NA rose significantly more in rats given reboxetine for 7 (469%) and 14 (437%) days. Intraperitoneal injection of 30 microg/kg clonidine, an alpha2-adrenoceptor agonist, reduced the release of NA to 49% of basal levels in rats given vehicle or reboxetine for 2 days, but this effect was markedly less in rats given reboxetine for 7 and 14 days. Likewise, the effect of intrahippocampal infusion of clonidine (0.05 and 0.2 microM) on extracellular NA was significantly attenuated in rats given reboxetine for 7 and 14 days, whereas the injection of 0.6 nmol clonidine into the locus coeruleus caused similar reductions of extracellular NA in the DH and prefrontal cortex (PFC) of rats infused with vehicle (DH -64%; PFC -42%) and reboxetine (DH -45%; PFC -28%) for 14 days. The results indicate that chronic treatment markedly enhances the effect of reboxetine on extracellular NA in the DH and suggest that this effect may be due to the desensitization of hippocampal alpha2-adrenoceptors.

Chronic Dose effects of Reboxetine on Motor Skill Acquisition and Cortical Excitability

Background: Enhancement of cortical excitability is thought to be potentially beneficial for synaptic plasticity as, e.g., associated with motor skill acquisition. The selective norepinephrine re-uptake inhibitor reboxetine (RBX) might therefore be able to facilitate functional recovery after brain lesions. Considering patient administration in the future we studied the effects of a chronic dose regimen on motor skill acquisition and cortical excitability. Methods: The study was randomized, double blind and placebo-controlled. 12 healthy subjects received 4mg RBX twice a day for 4 full days preceded by 2mg RBX twice a day for 2 days. Each subject served as its own control. There were at least 16 days between the verum and the placebo session. Measurement of cortical excitability by means of paired pulse transcranial magnetic stimulation (ppTMS) was conducted before and after the motor skill acquisition task for each session. The task was to lift two fingers of the right hand at once while the hand positioned sprawled out on the table. The movements were self-paced and subjects had to perform as many moves as possible in 60 seconds. Between 7 blocks of self-paced movements 6 blocks with 60 single trials at a fixed interstimulus interval were presented. Two equally difficult versions of the task using different finger combinations were established in order to avoid carryover effects in performance. The finger movements were recorded with a three-dimensional ultrasound movement analysis system (Zebris). Results: All subjects had a substantial gain in performance over the self-paced blocks. Average increase in number of correct moves was 87% (from 27.8 to 51.9). There was no significant difference either between the versions of the task or between placebo vs. verum. Also, there was no significant difference between first and second session, indicating that there was no carryover effect in performance. ppTMS revealed no significant differences in cortical excitability between groups. Conclusion: The newly developed skill acquisition task yields a robust single session gain of performance. As the two versions of the task do not interact, it is suitable to be used in cross-over designs. In contrast to studies using single doses of RBX, motor cortex excitability seems to be unaffected in a chronic dose steady-state. This could explain why motor behavior was not modulated by the study medication.

Association between Norepinephrine Transporter Gene Polymorphism and Major Depression

Noradrenergic and serotonergic abnormalities have long been implicated in patients with major depression. The novel selective norepinephrine reuptake inhibitor reboxetine has been shown to be at least as effective as imipramine, desipramine and fluoxetine in the treatment of major depression. It is suggested that the dysfunction of the norepinephrine transporter (NET) may be related to major depression. Although the transcriptional activity related to the NET gene expression is little known, it may be a good candidate gene for major depression. Therefore, we investigated whether the T-182C polymorphism of the NET gene is associated with major depression in a Korean sample of 112 major depression patients compared with 136 healthy controls. We found a significantly lower frequency in TT genotype in patients with major depression than in normal controls when the genotypes of T-182C polymorphism were classified into two groups: TT group versus TC + CC group (p = 0.019). This result suggests that the T-182C polymorphism in the NET gene might be associated with major depression.

Antagonism of the stress-induced increase in cortical norepinephrine output by the selective norepinephrine reuptake inhibitor reboxetine

We have previously shown that long-term treatment of rats with antidepressant drugs that affect the activity of noradrenergic and serotonergic neurons by different mechanisms, inhibits the increase in cortical norepinephrine output induced by stress. With the use of microdialysis, we have now evaluated the effects of reboxetine, an antidepressant drug that selectively inhibits norepinephrine reuptake, on the increase in cortical norepinephrine output elicited in rats by exposure to foot-shock stress or by the acute administration of N-methyl-β-carboline-3-carboxamide (FG 7142) (20 mg/kg, i.p.). Foot-shock stress and FG 7142 each induced a marked increase in the cortical extracellular concentration of norepinephrine (+200 and +90%, respectively) in control rats. Long-term treatment with reboxetine (10 mg/kg, i.p., once a day for 21 days) reduced the effect of foot-shock stress and completely antagonized the effect of FG 7142 on cortical norepinephrine output. Our results suggest that changes in the activity of noradrenergic neurons in the cortex might be relevant to the anxiolytic and antidepressant effects of reboxetine.

Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder

Lack of sexual dysfunction with the selective noradrenaline reuptake inhibitor reboxetine during treatment for major depressive disorder

Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects

In this single-blind study the effects of acute oral administration of the selective noradrenaline reuptake inhibitor reboxetine on the cortisol (COR), ACTH, growth hormone (GH) and prolactin (PRL) secretion were examined in 12 healthy male volunteers. In a randomized order, the subjects received placebo or reboxetine (4 mg) at 0800 h on two different days. After insertion of an intravenous catheter, blood samples were drawn 1 hour prior to the administration of placebo or reboxetine, at time of administration, and during the time of 5 hours thereafter at periods of 30 minutes. Serum concentrations of COR, GH, and PRL as well as plasma levels of ACTH were determined in each blood sample by means of double antibody RIA, fluoroimmunoassay and chemiluminescence immunometric assay methods. The area under the curve (AUC) value was used as parameter for the COR, ACTH, GH, and PRL response. Using t-tests for paired samples, statistical analysis revealed significant stimulatory effects of reboxetine on COR, ACTH, GH, and PRL secretion, compared to placebo (mean AUC values±S.E.M. (a) reboxetine: COR 127893.20±8125.75 nmol/l×min; ACTH 2385.68±387.19 pmol/l×min; GH 56026.59±15594.87 pmol/l×min; PRL 113961.60±10280.44 pmol/l×min; (b) placebo: COR 83672.19±5225.20 nmol/l×min; ACTH 1449.83±190.67 pmol/l×min; GH 9308.16±3402.75 pmol/l×min; PRL 64663.28±7283.62 pmol/l×min). Mean arterial blood pressure and heart rate were significantly increased by reboxetine, too. Our results suggest that besides COR, ACTH and GH secretion, the release of PRL is also under the control of the noradrenergic systems in man.

Influence of Reboxetine on Salivary MHPG Concentration and Cognitive Symptoms Among Patients with Alcohol-Related Korsakoff's Syndrome

This study is based on the hypothesis of a paraventricular cerebral noradrenaline deficit in alcoholic Korsakoff's syndrome. In a randomized open study the effects of a 4-week treatment with the selective noradrenaline reuptake inhibitor reboxetine on (1) the salivary concentration of the noradrenaline metabolite MHPG and (2) changes in cognitive performance measured by the Mini Mental Status Test were examined. The study group consisted of 105 patients diagnosed with alcohol-related Korsakoff's syndrome (ICD-10: F10.6). Korsakoff's patients showed a reduced concentration of salivary MHPG compared to healthy controls; this reduction did not correlate with the results of the Mini Mental Status Test. An increase in salivary MHPG was found together with an improvement in the Mini Mental Status Test both in the verum group treated with reboxetine and in the control group upon completion of the 4-week study. However, a subgroup with a shorter duration of disease (<1 year) was found to profit significantly from reboxetine treatment, as shown by improvements in cognitive performance.

Noradrenaline Reuptake Inhibition Enhances the Antipsychotic-like Effect of Raclopride and Potentiates D2-blockage–induced Dopamine Release in the Medial Prefrontal Cortex of the Rat

We have previously observed that addition of an α2-adrenoceptor antagonist to a selective dopamine (DA) D2 receptor antagonist enhances the antipsychotic-like effect of the D2 blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as α2-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D2 receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D2-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.

Enhancement of human cortico-motoneuronal excitability by the selective norepinephrine reuptake inhibitor reboxetine

It has been proposed that norepinephrine plays a critical role in the modulation of cortical excitability, which in turn is thought to influence functional recovery from brain lesions. The purpose of the present experiments was to determine if it is possible to modulate cortical excitability with the selective norepinephrine reuptake inhibitor reboxetine in intact humans. Recruitment curve and intracortical facilitation, assessed by transcranial magnetic stimulation, were increased after oral intake of 8 and 4 mg reboxetine, in the absence of changes in motor threshold, intracortical inhibition, M-response, F-wave or H-reflex. These results demonstrate that reboxetine enhances cortical excitability and raise the possibility that it could act as a plasticity enhancing substance potentially useful in combination with neurorehabilitative strategies geared to enhance neurorehabilitation.

Successful treatment of reboxetine-induced urinary hesitancy with tamsulosin

Urinary hesitancy can be an uncomfortable side effect during antidepressant treatment. Clinicians often use the selective α 1A -adrenoceptor antagonist, tamsulosin, to treat urinary hesitancy associated with prostate enlargement. We report here a series of case studies in which tamsulosin has been successfully used in the management of urinary hesitancy during therapy with the selective noradrenaline reuptake inhibitor reboxetine for major depressive disorder (MDD). Eight male adults (aged 43–64 years; DSM-IV diagnosis of MDD) who were receiving treatment with reboxetine (4–8 mg/day) were considered candidates for concomitant tamsulosin (0.4 mg/day) therapy. Tamsulosin was administered either as prophylaxis ( n=4) or as treatment ( n=4) for emergent urinary hesitancy. All patients experienced relief of urinary hesitancy within 20 min of tamsulosin therapy and this effect was sustained. Concomitant treatment with tamsulosin should be considered for those patients in whom urinary hesitancy may lead to withdrawal from reboxetine therapy.

Efficacy of Noradrenergic-Selective Agents in the Treatment of Neuropsychiatric Diseases

In recent years, a number of antidepressants with varying degrees of selectivity for the noradrenergic neurotransmitter system have become available. However, these agents represent a pharmacologically heterogeneous group and differ in terms of their precise side-effect profile and, possibly, their clinical efficacy. Bupropion, which is thought to act on both the dopamine and norepinephrine (NE) systems, has not been widely used as an antidepressant and has more recently been licensed as adjunctive therapy for smoking cessation. The serotonin-NE reuptake inhibitors venlafaxine and nefazodone, the noradrenergic and specific serotonergic antidepressant mirtazapine, and the selective NE reuptake inhibitor reboxetine (the only truly NE-selective agent available) have all demonstrated efficacy in the treatment of depressive disorders. Evidence is now emerging for their use in the treatment of anxiety and panic disorders. There is some suggestion of a role for noradrenergic agents in other disorders, including attention-deficit/hyperactivity disorder and social phobia. The full range of disorders for which noradrenergic agents can be used remains to be seen and further research in this area is necessary.

Effect of reboxetine treatment on brain cAMP- and calcium/calmodulin-dependent protein kinases

Previous studies showed that the type II Ca 2+/calmodulin- and cAMP-dependent protein kinases (CaMKII and PKA) are affected by long-term antidepressant treatment in presynaptic and somatodendritic compartments, respectively. This study describes the long-term effects of the selective noradrenaline reuptake inhibitor reboxetine on PKA and CaMKII, in both the microtubule and subsynaptosomal fractions of rat brain. Unlike other antidepressants, chronic reboxetine induced in the cerebrocortical soluble and microtubule fractions a decrease in the [ 32P]cAMP binding to the type II PKA regulatory subunit. No change in the cAMP-dependent endogenous phosphorylation of the protein substrate, microtubule-associated protein 2 was observed. In the hippocampal subsynaptosomal fractions (synaptic vesicles and synaptosomal membranes) reboxetine induced a robust increase in the activity but not in the expression of CaMKII. An increase in the calcium/calmodulin-dependent phosphorylation of presynaptic substrates was also detected. These findings showed that reboxetine modulates post-receptor signal transduction systems in rat brain.

Reboxetine in a patient with seasonal bulimia resistant to SSRIs and light therapy

There is a phenomenological similarity between seasonal affective disorder and bulimia nervosa, as sufferers from both show increased appetite and carbohydrate craving and probably share a common dysfunction in brain serotonergic systems. Serotonergic compounds and bright light therapy have proven to be an effective treatment for both disorders. We describe the case of a woman who suffered from seasonal affective disorder and nonpurging bulimia nervosa for 16 years and was resistant to treatment regimens with selective serotonin re-uptake inhibitors and bright light therapy. She was successfully treated with the selective noradrenaline re-uptake inhibitor reboxetine. The authors want to encourage clinicians to make attempts to treat seasonal and non-seasonal bulimia with selective noradrenergic compounds.