Exercise, antidepressant treatment, and BDNF mRNA expression in the aging brain

Principal mental disorders affecting the geriatric population include dementia and depression. A lack of trophic support is thought to contribute to the pathology of these disorders. Physical activity and antidepressant treatment increase the expression of brain-derived neurotrophic factor (BDNF) in the young rat hippocampus. Herein, we investigated the responsiveness of the aging rat hippocampus to antidepressant treatment and voluntary exercise. In situ hybridization revealed that, in young animals, exercise, antidepressant treatment, or their combination elevated BDNF mRNA levels in several hippocampal regions, most notably in the CA3, CA4, and dentate gyrus (DG). This effect was rapid (detectable at 2 days) and sustainable to 20 days. In aged (22-month-old) rats, hippocampal responsiveness to antidepressant treatment and exercise was also rapid and sustainable, but evident mostly in the CA1 and CA2. Daily swimming also revealed that small amounts of activity led to marked elevations in hippocampal BDNF mRNA. The differences in regional patterns of BDNF mRNA elevations between young and aged animals observed with running were maintained with this different exercise modality. Our results indicate that the aged brain is responsive to exercise and antidepressant treatment, and changes in regional response patterns may reflect shifts in hippocampal physiology during the lifespan.     

Exercise, antidepressant medications, and enhanced brain derived neurotrophic factor expression.

Physical activity and antidepressant treatment have each separately been of significant interest for the management of Alzheimer's disease (AD); particularly the behavioral problems associated with this dementing disorder. We have found that combined antidepressant treatment and physical activity have an additive, potentiating effect on BDNF mRNA expression within several areas of the rat hippocampus. During the 20-day experimental period, animals were treated daily with imipramine (15 mg/kg) or tranylcypromine (7.5 mg/kg) by intraperitoneal injection. Exercising rat groups were given access to running wheels for the duration of the experiment. BDNF mRNA levels were assessed in several cell groups of the hippocampus by in situ hybridization, using a [35S] labelled riboprobe complementary to the full-length BDNF sequence, and computer-assisted densitometry. The combination of physical activity and antidepressant treatment for the 20-day period led to a significant potentiation of full-length BDNF mRNA levels within the dentate gyrus and CA 1, CA 3, and CA 4 cellular fields, above the levels obtained with each intervention alone. These results provide impetus for the study of physical exercise as a potential enhancer of treatment response to antidepressants.     

Effect of MPEP treatment on brain-derived neurotrophic factor gene expression

Treatment with most antidepressants induces expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampus (and cerebral cortex). Recent data indicate antidepressant-like activity of group I mGlu receptor (mGluR1 and mGluR5) antagonists in animal tests/models. We now report that chronic treatment with 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGlu5 receptor antagonist, increased hippocampal but reduced cortical BDNF mRNA level (Northern blot). Desipramine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that an antagonist of mGlu5 receptors, like a majority of well-established antidepressants, induces hippocampal BDNF gene expression. A significance of MPEP ability to reduce cortical BDNF needs further study. Nevertheless, this observation further indicates a potential antidepressant activity of the group I mGlu receptor antagonists in human depression.     

Zinc treatment induces cortical brain-derived neurotrophic factor gene expression

Most of antidepressants induce expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampal/cortical neurons. Recent data indicate antidepressant-like activity of zinc in animal models. We now report that chronic treatment with zinc induced an increase in cortical but not hippocampal BDNF mRNA level (Northern blot). Tranylcypromine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that zinc increases the BDNF gene expression, which is the effect shared by most of clinically effective antidepressants.     

Reboxetine: a review of efficacy and tolerability

Clinical data on the efficacy and tolerability of the novel selective noradrenergic reuptake inhibitor reboxetine are reviewed. Reboxetine appears to have almost no pharmacological activity other than potently blocking the reuptake of noradrenaline. Clinical studies show reboxetine to be highly effective for the treatment of major depression. Reboxetine is more effective than placebo and comparable in efficacy to tricyclic antidepressants and selective serotonin reuptake inhibitors. Some studies suggest that reboxetine may have slightly better efficacy than fluoxetine and imipramine. Reboxetine is effective in severely depressed patients as well as elderly depressed persons. Reboxetine is remarkably well tolerated, having very few side effects. Reboxetine appears to cause little sexual dysfunction. The most common side effects are dry mouth and constipation. The drug does not inhibit or induce hepatic cytochrome P450 enzymes and is safe in overdose. Reboxetine may prove to be as effective and better tolerated than any other antidepressant currently available.     

Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment

Increased expression of brain-derived neurotrophic factor (BDNF) appears to be involved in the mechanism of action of antidepressant drugs. It has also been proposed that potentiation of the AMPA receptor (AMPAR) function may be useful in the treatment of depression. Here we looked for the time course of the effect of different doses of two antidepressants, desipramine (DMI) and paroxetine (PAR), which differentially affect monoamine reuptake, on BDNF mRNA expression in hippocampal subfields (CA1, CA3 and dentate gyrus) and levels of AMPAR subunits in total and membrane-enriched extracts from rat hippocampus. Acute antidepressant treatment changed neither BDNF mRNA expression nor AMPAR subunit levels. In chronic treatments, rats were treated daily with the antidepressants for 7–21 days. PAR produced a time- and dose-dependent increase of BDNF expression in the three hippocampal subfields examined. On the contrary, the effect of DMI on BDNF mRNA was neither dose- nor time-dependent. In rats receiving the same chronic antidepressant treatments, PAR produced a dose-dependent increase of GluR1 and GluR2/3 levels in the membrane fraction after a 3-week treatment, and not at earlier times. DMI increased the membrane levels of AMPAR subunits after a 3-week treatment with the lower dose tested. However, a higher dose, 15 mg/kg, did not produce any change in AMPAR subunits and reduced membrane levels of -tubulin and PSD-95, possibly indicating a disorganization of membrane scaffolding proteins. The results suggest that paroxetine, but not desipramine, enhances synaptic plasticity in the hippocampus by increasing BDNF mRNA expression, which determines a later AMPAR subunit trafficking to synaptic membranes.     

Noradrenergic antidepressants increase cortical dopamine: potential use in augmentation strategies

Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) - but not in nucleus accumbens (NAc) - arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) non-significantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α(2)-adrenoceptor antagonist) increased extracellular DA in mPFC (264 ± 28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472 ± 70%). Repeated (×3) reboxetine + mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine + mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine + mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.     

Repeated unpredictable stress and antidepressants differentially regulate expression of the bcl-2 family of apoptotic genes in rat cortical, hippocampal, and limbic brain structures.

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.     

Differential effects of reboxetine and citalopram on hand-motor function in patients suffering from major depression

Rationale Motor dysfunctions might be a more common side effect of serotonergic than noradrenergic antidepressants. However, the effects of antidepressants on motor function in depression have rarely been analyzed systematically. Computerized methods allow the objective registration of drug-induced motor dysfunction and were applied in this study.Objectives To examine the effects of a selective noradrenaline re-uptake inhibitor (NARI) (reboxetine) and a selective serotonin re-uptake inhibitor (SSRI) (citalopram) on hand-motor function in patients with major depression.Methods Different types of hand movements (drawing of circles and handwriting probes) were recorded and analyzed in 16 acutely depressed inpatients receiving citalopram (30–60 mg/day) and 12 acutely depressed inpatients treated with reboxetine (4–8 mg/day), using a digitizing tablet for the analysis of movement dynamics. Both groups were comparable regarding mean age (42–43 years), gender, handedness (preponderance of right-handers) and the mean baseline HAMD score (about 27). Five kinematical parameters reflecting velocity, regularity and degree of automation of hand movements have been computed.Results Reboxetine had significantly more favorable effects on fine motor function (increased velocity of rapid hand movements) in depressed patients than citalopram. These differences became obvious when patients conducted more complex tasks and are not explained by differential antidepressant effects.Conclusions Our findings are in line with the hypothesis that SSRI tend to have small, but more pronounced negative effects on motor function than NARI.     

Reboxetine: the first selective noradrenaline re-uptake inhibitor

Several treatment approaches are available for treatment of depression. However, reboxetine is the first selective noradrenaline re-uptake inhibitor. Whereas formerly only noradrenaline re-uptake inhibitors with a mixed mechanism of action were available. These included action not only at noradrenergic, but also at serotonergic and other neurotransmitter-sites. Thus, reboxetine represents the first of a new class of antidepressant agents with specificity for the noradrenergic system. Reboxetine has been shown to be an effective first-line treatment for patients with all grades of depression, to be effective in the prevention of relapse and recurrence and to offer significant benefits in terms of relieving the impaired social functioning associated with depressive disorders. Reboxetine was significantly superior to the serotonergic compound fluoxetine in improvement of social functioning in both the general depressed population and in those patients who achieved symptomatic remission, indicating a superior quality of remission. Altogether reboxetine was well tolerated during the acute and long-term treatment phase; side-effects such as increased sweating, constipation and dry mouth were the most prominent to be reported. The availability of reboxetine represents a significant addition to the currently available pharmacologic armamentarium for the treatment of depression.     

Reboxetine: the first selective noradrenaline re-uptake inhibitor

Several treatment approaches are available for treatment of depression. However, reboxetine is the first selective noradrenaline re-uptake inhibitor. Whereas formerly only noradrenaline re-uptake inhibitors with a mixed mechanism of action were available. These included action not only at noradrenergic, but also at serotonergic and other neurotransmitter-sites. Thus, reboxetine represents the first of a new class of antidepressant agents with specificity for the noradrenergic system. Reboxetine has been shown to be an effective first-line treatment for patients with all grades of depression, to be effective in the prevention of relapse and recurrence and to offer significant benefits in terms of relieving the impaired social functioning associated with depressive disorders. Reboxetine was significantly superior to the serotonergic compound fluoxetine in improvement of social functioning in both the general depressed population and in those patients who achieved symptomatic remission, indicating a superior quality of remission. Altogether reboxetine was well tolerated during the acute and long-term treatment phase; side-effects such as increased sweating, constipation and dry mouth were the most prominent to be reported. The availability of reboxetine represents a significant addition to the currently available pharmacologic armamentarium for the treatment of depression.     

Reboxetine and citalopram in panic disorder: a single-blind,cross-over,flexible-dose pilot study

Both noradrenergic and serotonergic systems have been implicated in the pathophysiology of panic disorder. The advent of selective serotonin (5-HT) reuptake inhibitors (SSRIs) (e.g. citalopram) and, more recently, selective noradrenergic (NA) reuptake inhibitors (NRIs) (e.g. reboxetine) has provided potentially important avenues of treatment for the disorder. To date, the comparative efficacy of selective NA and 5-HT reuptake inhibitors for panic disorder remains unresolved. Nineteen patients with panic disorder were randomized in a single-blind, cross-over design to either citalopram or reboxetine for 8 weeks and after a 2-week washout were switched to the other study drug. At week 18, seven of 13 patients (54%) in the intent-to-treat sample responded to reboxetine and nine of 11 patients responded to citalopram (82%). Both citalopram and reboxetine led to significant improvements in panic attack severity with no apparent between-drug differences in efficacy. However, citalopram demonstrated superior efficacy in treating depressive symptoms. One non-responder to citalopram responded to reboxetine and three non-responders to reboxetine responded to citalopram. Although SSRIs are viewed as a first-line treatment for panic disorder, these results suggest that a NA agent such as reboxetine may also have a role. These data also suggest an advantage for citalopram in treating comorbid depressive symptoms, although some patients may respond preferentially to an SSRI and other patients to an NRI.     

Adverse effects from antidepressant treatment: randomised controlled trial of 601 depressed individuals

Rationale

Premature discontinuation of antidepressant drugs is a frequent clinical problem. Adverse effects are common, occur early on in treatment and are reported to be one of the main reasons for discontinuation of antidepressant treatment.

Objectives

To investigate the association between adverse effects occurring in the first 2 weeks of antidepressant treatment and discontinuation by 6 weeks as the outcome. To investigate the time profile of adverse effects induced by the selective serotonin reuptake inhibitor citalopram and the noradrenaline reuptake inhibitor reboxetine over 12 weeks of treatment.

Methods

Six hundred and one depressed individuals were randomly allocated to either citalopram (20 mg daily) or reboxetine (4 mg twice daily). A modified version of the Toronto Side Effects Scale was used to measure 14 physical symptoms at baseline (medication free) and at 2, 6 and 12 weeks after randomisation.

Results

Individuals randomised to reboxetine reported a greater number of adverse effects and were more likely to stop treatment than individuals receiving citalopram. Dizziness (OR 1.83; 95% CI 1.09, 3.09; p?=?0.02) and the total number of adverse effects (OR 1.12; 95% CI 1.00, 1.25; p?=?0.06) reported at 2 weeks were associated with discontinuation from overall antidepressant treatment by 6 weeks. Reports of adverse effects tended to reduce throughout the 12 weeks for both antidepressants.

Conclusions

The majority of adverse effects were not individually associated with discontinuation from antidepressant treatment. Reports of physical symptoms tended to reduce over time. The physical symptoms that did not reduce over time may represent symptoms of depression rather than antidepressant-induced adverse effects.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10–50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.     

Discriminative stimulus properties of antidepressant agents: a review

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.     

Evidence for modulation of facial emotional processing bias during emotional expression decoding by serotonergic and noradrenergic antidepressants: an event-related potential (ERP) study

RATIONALE: Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing such that perceptual bias is shifted away from negative and towards positive emotional material. However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown. OBJECTIVE: The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli. MATERIALS AND METHODS: This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg). RESULTS: Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP). CONCLUSIONS: Citalopram and reboxetine have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli.