Effects Of Various Antidepressants Research Articles

The influence of concomitant antidepressant and antipsychotic medication on antidepressant effect and seizure duration of electroconvulsive therapy.

A significant proportion of patients with a depressive disorder show resistance to pharmacological and psychotherapeutic antidepressant treatments. Electroconvulsive therapy (ECT) is still one of the most effective treatment methods, especially in the acute phase. In everyday clinical practice, this usually accompanies pharmacological treatment. It has been shown that pharmacological treatment following acute ECT treatment reduces the rate of relapses. However, the effect of various antidepressants (ADs) and antipsychotics (APs) on the effect during the course of ECT has rarely been investigated. In this retrospective chart review study, the data of 104 depressive patients treated with ECT were examined. We analyzed the influence of concomitant administration of AD and AP or no psychotropic medication on the effect of ECT using the Montgomery-Åsberg Depression Rating Scale (MADRS). We further analyzed the influence of the ADs Bupropion, Venlafaxine, and Sertraline or no AD and the influence of augmentation with Aripiprazole or Quetiapine or Olanzapine. Psychotropic medication did not have an impact on antidepressant efficacy of ECT as measured with the MADRS scores. In addition, the comparison between the antidepressant or antipsychotic medications themselves did not show any significant difference. However, we found a significantly different seizure duration depending on the antidepressant substance that patients received during ECT (p = .008). ECT treatment itself led to a highly significant reduction of 13.3 points in the MADRS (p <.001). Taken together, our study underlines that concomitant psychotropic medication while doing electroconvulsive therapy does not bare the risk of prolonged seizure duration or does it reduce the effectiveness of ECT. To the best of our knowledge, this study is the first to examine the effect of treatment with antidepressants in combination with antipsychotics while doing ECT. In light of our results, this combination therapy is safe and effective. Bearing in mind the delay in onset of antidepressant action of medication and the importance of antidepressant medication for relapse prevention, this study further supports the recommendation that psychotropic medication should be given in adjunction to ECT.

Retinal markers of therapeutic responses in major depressive disorder: Effects of antidepressants on retinal function

BackgroundOne goal of research into major depressive disorder (MDD) is to develop markers to predict and monitor the response to psychotropic treatments. The retina is endowed with a complex neurotransmission system, composed of the main neurotransmitters involved in the pathophysiology of MDD. The retina is therefore a relevant site of investigation for the identification of reliable and robust markers. However, the effects of antidepressants on the human retina are poorly studied. Here, we seek to study the potential specific effects of various antidepressants on retinal function in MDD patients. MethodsWe assessed retinal function using flash (fERG), pattern (PERG) and multifocal (mfERG) electroretinogram in 19 MDD patients treated using antidepressants at baseline and at weeks 4, 8 and 12. ResultsWe observed reduced b-wave amplitude of photopic fERG 3.0 in patients treated with Selective Serotonin Reuptake Inhibitor (SSRI) in comparison with patients treated with Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) or Tricyclic Antidepressant (TCAD). We also showed that SNRIs were associated both with a decrease in PERG P50 implicit time and an increase in fERG 3.0 b-wave amplitude. TCADs were associated with an increase in fERG flicker 3.0 a- and b-wave amplitude. ConclusionsThis is the first study in real-life conditions to show a specific effect of various antidepressants on retinal function evaluated by electroretinogram. Further investigations should be led to specify the effects of antidepressants on ERG in order to isolate reliable and reproducible markers for predicting and monitoring the response to antidepressants.

Effects of Antidepressant Treatment on Neurotrophic Factors (BDNF and IGF-1) in Patients with Major Depressive Disorder (MDD).

Major depressive disorder (MDD) remains the subject of ongoing research as a multifactorial disease and a serious public health problem. There is a growing body of literature focusing on the role of neurotrophic factors in pathophysiology of MDD. A neurotrophic hypothesis of depression proposes that abnormalities of neurotrophins serum levels lead to neuronal atrophy and decreased neurogenesis, resulting in mood disorders. Consequently, in accordance with recent findings, antidepressant treatment modifies the serum levels of neurotrophins and thus leads to a clinical improvement of MDD. The purpose of this review is to summarize the available data on the effects of various antidepressants on serum levels of neurotrophins such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1). In addition, the authors discuss their role as prognostic factors for treatment response in MDD. A literature search was performed using the PubMed database. Following the inclusion and exclusion criteria, nine original articles and three meta-analyses were selected. The vast majority of studies have confirmed the effect of antidepressants on BDNF levels. Research on IGF-1 is limited and insufficient to describe the correlation between different antidepressant drugs and factor serum levels; however, four studies indicated a decrease in IGF-1 after treatment. Preliminary data suggest BDNF as a promising predictor of treatment response in MDD patients. The role of IGF-1 needs further investigation.

Role of BDNF-mTORC1 Signaling Pathway in Female Depression.

Depression is a common psychological and mental disorder, characterized by low mood, slow thinking and low will, and even suicidal tendencies in severe cases. It imposes a huge mental and economic burden on patients and their families, and its prevention and treatment have become an urgent public health problem. It is worth noting that there is a significant gender difference in the incidence of depression. Studies have shown that females are far more likely to suffer from depression than males, confirming a close relationship between estrogen and the onset of depression. Moreover, recent studies suggest that the brain-derived neurotrophic factor- (BDNF-) mammalian target of rapamycin complex-1 (mTORC1) signaling pathway is a crucial target pathway for improving depression and mediates the rapid antidepressant-like effects of various antidepressants. However, it is not clear whether the BDNF-mTORC1 signaling pathway mediates the regulation of female depression and how to regulate female depression. Hence, we focused on the modulation of estrogen-BDNF-mTORC1 signaling in depression and its possible mechanisms in recent years.

Compound action potential inhibition produced by various antidepressants in the frog sciatic nerve

Although an inhibition of action potential conduction in nerve fibers possibly contributes to at least a part of antinociception produced by analgesics and the adjuvants, it has not been fully examined yet how the conduction inhibition differs in extent among their drugs. We investigated the effects of various antidepressants used as analgesic adjuvants on compound action potentials (CAPs) recorded from the frog sciatic nerve by using the air-gap method. The results were compared with those of the other adjuvants that were reported previously. Antidepressants, duloxetine (serotonin and noradrenaline reuptake inhibitor, SNRI), fluoxetine (selective serotonin reuptake inhibitor, SSRI), amitriptyline (tricyclic tertiary amine), desipramine (tricyclic secondary amine) and maprotiline (tetracyclic secondary amine), reduced the peak amplitude of the CAP with half-maximal inhibitory concentration (IC50) values of 0.23, 1.5, 0.26, 1.6 and 0.95mM, respectively. Trazodone (non-SNRI, -SSRI, -tricyclic and -tetracyclic antidepressant) at 1.0mM reduced CAP amplitude by about 50%. The duloxetine and amitriptyline values were comparable to those of lamotrigine and carbamazepine (antiepileptics), dexmedetomidine (α2-adrenoceptor agonist) and ropivacaine, levobupivacaine and pramoxine (local anesthetics). The fluoxetine, desipramine, maprotiline and trazodone values were similar to those of oxymetazoline (α2-adrenoceptor agonist) and lidocaine, cocaine, procaine and prilocaine (local anesthetics). The antidepressants’ IC50 values were much larger than that of tetracaine (local anesthetic). In conclusion, the six antidepressants inhibited CAPs with efficacies comparable to some antiepileptics, α2-adrenoceptor agonists and local anesthetics. It was suggested that antidepressants inhibit nerve conduction with efficacies comparable to those of the other adjuvants.

A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder

BackgroundMajor depressive disorder is a common condition that often includes cognitive dysfunction. A systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder.MethodsMEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model.ResultsThe database search retrieved 11337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P=.009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes.ConclusionsThis study highlighted the large variability in measures used to assess cognitive functioning. The findings on the Digit Symbol Substitution Test indicate differential effects of various antidepressants on improving cognitive function in patients with major depressive disorder.

Influence of Pharmacotherapy on Cognitive Functions in Depression: A Review of the Literature.

In addition to irregularities relating to the emotional sphere, the cognitive impairment in depression is a part of the clinical picture of this affective disorder. Some of the cognitive deficits may be associated with the severity of psychopathological symptoms of depression, while others are more established and can also occur during periods of remission. The participation in cognitive functioning of people with depression have a number of factors: the severity of symptoms, concurrent anxiety disorders, gender, age, education, duration of the disease, and number of previous episodes, as well as general somatic health or medication used. The pharmacological treatment may have varying impact on the different areas of cognition. Research on pharmacotherapy for depression and its impact on cognitive functioning continue and are very popular among clinicians and researchers. The relationship between antidepressants and cognitive abilities is always modulated by the type of depressive disorder, neurobiological factors, and demographic variables. This article presents a review of the studies relating to assessment of the effects of various antidepressants on cognitive abilities among patients with depression.

Paroxetine prevented the down-regulation of astrocytic L-Glu transporters in neuroinflammation

The extracellular L-glutamate (L-Glu) concentration is elevated in neuroinflammation, thereby causing excitotoxicity. One of the mechanisms is down-regulation of astrocyte L-Glu transporters. Some antidepressants have anti-inflammatory effects. We therefore investigated effects of various antidepressants on the down-regulation of astrocyte L-Glu transporters in the in vitro neuroinflammation model. Among these antidepressants, only paroxetine was effective. We previously demonstrated that the down-regulation of astrocyte L-Glu transporters was caused by L-Glu released from activated microglia. We here clarified that only paroxetine inhibited L-Glu release from microglia. This is the novel action of paroxetine, which may bring advantages on the therapy of neuroinflammation.

Clinical application of antidepressants in the treatment of insomnia symptoms

Insomnia is one of the common complaints among all clinical departments. In recent years, some studies have demonstrated that insomnia symptoms can be improved or treated by some antidepressants. Based on literature search both at home and abroad, this paper summarized the effect of various antidepressants with different pharmacological properties on sleep, and the progress of clinical application of antidepressants in treating insomnia according to the classification of antidepressant drugs. doi：10.3969/j.issn.1672-6731.2013.11.012

Antidepressants in the Treatment for Chronic Low Back Pain: Questioning the Validity of Meta‐Analyses

To contrast the analgesic effect of duloxetine with antidepressants reported in other published randomized clinical trials (RCTs) and review articles in patients with chronic low back pain (CLBP). In this narrative review, the results of 13 RCTs and 5 systematic reviews examining the analgesic effect of various antidepressants in CLBP were contrasted with those of 3 placebo-controlled duloxetine RCTs. Treatment effects based on the Brief Pain Inventory (BPI) average score in the duloxetine RCTs were assessed in all completers (by study and overall) and in last-observation-carried-forward (LOCF) analyses (extracted from study reports). 30%- and 50%-reduction response rates were compared between duloxetine and placebo. Eleven different antidepressants were examined in 13 individual RCTs. Sample sizes, treatment durations, and analysis methods varied across studies. Reviews each included 5 to 9 of the RCTs and came to different conclusions regarding the analgesic effect of antidepressants: 2 found no evidence while 3 reported some evidence. The completer analysis showed greater improvements in BPI average scores with duloxetine vs. placebo (significant in 2 studies). Overall, the least square mean (standard error) difference between treatments was - 0.7 (0.15) (P < 0.0001). Overall response rates were significantly larger with duloxetine than with placebo. Due to the diversity of previous studies and the pooling methods used, the conclusions regarding the analgesic effect of antidepressants in CLBP drawn from systematic reviews must be interpreted with caution. Appropriately designed and powered studies similar to recently published duloxetine studies are recommended to demonstrate the analgesic effect of antidepressants.

The Predominant Protective Effect of Tianeptine Over Other Antidepressants in Models of Neuronal Apoptosis: The Effect Blocked by Inhibitors of MAPK/ERK1/2 and PI3-K/Akt Pathways

Tianeptine (Tian) possesses neuroprotective potential, however, little is known about the effect of this drug in models of neuronal apoptosis. In the present study, we aimed (1) to compare the neuroprotective capacities of some antidepressants (ADs) in the models of staurosporine (St)- and doxorubicin (Dox)-evoked cell death, activating the intracellular and the extracellular apoptotic pathway, respectively; (2) to identify the Tian-modulated steps underlying its neuroprotective action; (3) to test the effect of various ADs against Dox-evoked cell damage in glia cells. Primary neuronal and glia cell cultures and retinoic acid-differentiated human neuroblastoma SH-SY5Y (RA-SH-SY5Y) cells were co-treated with imipramine, fluoxetine, citalopram, reboxetine, mirtazapine or Tian and St or Dox. The data showed the predominant neuroprotective effect of Tian over other tested ADs against St- and Dox-induced cell damage in primary neurons and in RA-SH-SY5Y cells. This effect was shown to be caspase-3-independent but connected with attenuation of DNA fragmentation. Moreover, neuroprotection elicited by Tian was blocked by pharmacological inhibitors of MAPK/ERK1/2 and PI3-K/Akt signaling pathways as well by inhibitor of necroptosis, necrostatin-1. Interestingly, the protective effects of all tested ADs were demonstrated in primary glia cells against the Dox-evoked cell damage. The obtained data suggests the glial cells as a common target for protective action of various ADs whereas in relation to neuronal cells only Tian possesses such properties, at least against St- and Dox-induced cell damage. Moreover, this neuroprotective effect of Tian is caspase-3-independent and engages the regulation of survival pathways (MAPK/ERK1/2 and PI3-K/Akt).Electronic supplementary materialThe online version of this article (doi:10.1007/s12640-013-9430-3) contains supplementary material, which is available to authorized users.

Electroconvulsive shock alters the rat overt rhythms of motor activity and temperature without altering the circadian pacemaker

The hypothetical relationship between circadian rhythms alterations and depression has prompted studies that examine the resultant effects of various antidepressants. Electroconvulsive therapy (ECT) exerts significant antidepressant effects that have been modelled in the laboratory via the use of electroconvulsive shock (ECS) in rats. However, data on the effects of ECT or ECS vis-à-vis the circadian rhythms remain scarce. Thus, we report here the effects of acute and chronic ECS administration on the temperature and motor activity circadian rhythms of rats. The motor activity and core body temperature of rats were continuously recorded to determine the circadian rhythms. We carried out three experiments. In the first, we analyzed the effects of acute ECS on both the phase and period when applied at different times of the subjective day. In the second and third experiments ECS was nearly daily applied to rats for 3 weeks: respectively, under dim red light, which allows a robust free-running circadian rhythm; and under light–dark cycles of 22h (T22), a setting that implies dissociation in the circadian system. Acute ECS does not modify the phase or the period of circadian rhythms. Chronic administration of ECS produces an increase in motor activity and temperature, a decrease in the amplitude of circadian rhythms, although the period of the free-running rhythm remains unaffected. In conclusion, while chronic ECS does alter the overt rhythms of motor activity and temperature, it does not modify the functioning of the circadian pacemaker.

In vivo Effect of Antidepressants on [3H]paroxetine Binding to Serotonin Transporters in Rat Brain

Amine transporters are major target for development of various pharmacological agents to treat behavioral disorders. Serotonin transporters (SERT) have been implicated in the etiology of depression and drugs acting on SERT can be effective in treating depression. The aim of the present study was to study the in vivo effect of various antidepressants on [(3)H]paroxetine binding to SERT in regions of rat brain. Rats were treated with tricyclic antidepressant (TCAs) such as amitriptyline (AMI), serotonin/norepinephrine reuptake inhibitor (SNRIs) such as clomipramine (CMI), and selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) and citalopram (CIT) (10 mg/kg body wt.) for 30 days. Density of SERT was measured in cortex and hippocampus using [(3)H]paroxetine (0.03-1.0 nM) in presence and absence of 10 muM fluoxetine as displacer. It was observed that the density of cortical SERT was significantly decreased with CMI (68%, P < 0.0001), FLX (67%, P < 0.0001), CIT (54%, P < 0.0001), and AMI (52%, P < 0.0001) treatment, when compared to the density of 120.7 +/- 4.0 fmol/mg protein in control rats, without altering the affinity (Kd) of [(3)H]paroxetine to the transporters. The density of SERT in hippocampus was also significantly decreased with FLX (65%, P < 0.0001), CMI (54%, P < 0.0001), CIT (52%, P < 0.0001) and AMI (46%, P < 0.0001) treatment, when compared to the density of 74.0 +/- 2.6 fmol/mg protein in control rats, without altering the affinity of [(3)H]paroxetine to the transporters. Displacement study showed high affinity for CMI > CIT > FLX. The results suggest that chronic antidepressant treatment significantly down-regulates both cortical and hippocampal SERT in rat brain and SSRIs have high affinity for SERT than TCAs.

Effects of various antidepressants on serum thyroid hormone levels in patients with major depressive disorder

A total of 62 patients with major depressive disorder were analyzed in the study. Patients were evaluated for 11 weeks in an open label design to investigate the differential effects of reboxetine, sertraline and venlafaxine on thyroid hormones. Serum thyrotrophin (TSH), thyroxine (T4) and free (f)T4 levels were measured before and after treatment. All groups showed significant improvement in HAM-D scores. TSH level significantly reduced and T4 level significantly increased in the reboxetine group, however TSH level significantly increased and T4 level significantly reduced in the sertraline group. Percent changes of TSH ( p = 0.007) and T4 ( p = 0.001) were significantly different between the reboxetine and sertraline groups. In the sertraline group, baseline TSH levels were correlated with response to treatment as determined by the change in HAM-D scores ( p = 0.03, r = 0.648). There was a significant association between the percent changes in TSH values and the reduction in HAM-D scores in the reboxetine group ( p = 0.03, r = − 0.434). In the whole study group, female patients had lower values of basal T4 compared with men ( p = 0.043), however percent changes of T4 did not differ between genders. In the treatment-responders significant increase in the reboxetine group and significant decrease in the sertraline group regarding the T4 values were found . We observed that various antidepressants had different effects on thyroid hormone levels and this could be attributed to the different mechanisms of actions of these antidepressants .

Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model

Growing evidence indicates immunoregulatory effects of various antidepressants. Through the interaction of the nervous and immune systems, the norepinephrine-serotonin system was shown to modulate inflammatory CNS diseases. Thus, we examined the norepinephrine-serotonin reuptake inhibitor venlafaxine in an astroglia-microglia co-culture model which allows mimicking of an inflammatory milieu by increasing the cultured microglial fraction. Astrocytic membrane resting potential and intercellular coupling, two markers becoming severely impaired under inflammation, were assessed with the patch-clamp technique. We measured IL-6, IL-10, IFN-gamma and TGF-beta concentrations and analysed phenotypic changes of microglia. We found (i) a reversal of the inflammation-induced depolarization effect on the membrane resting potential, (ii) an augmentation of TGF-beta release with a concomitant reduction in the secretion of pro-inflammatory IL-6 and IFN-gamma, and (iii) a significant change of microglial phenotype from activated to resting morphology. Our data clearly indicate anti-inflammatory properties of venlafaxine which might be a result of monoamine-mediated immunomodulation.

Time course of hypothalamic-pituitary-adrenocortical axis activity during treatment with reboxetine and mirtazapine in depressed patients

In healthy subjects, cortisol and ACTH secretion are acutely stimulated by reboxetine and inhibited by mirtazapine. However, it was not investigated so far whether reboxetine and mirtazapine may also differ in their impact on hypothalamic-pituitary-adrenocortical (HPA) axis activity in depressed patients and whether these effects are related to clinical outcome. In the present study, we investigated the impact of 5-week treatment with reboxetine or mirtazapine on the combined dexamethasone suppression/corticotropin releasing hormone (DEX/CRH) test results in depressed patients. Forty drug-free patients suffering from a major depressive episode (Diagnostic and Statistical Manual of Mental Disorders-IV criteria) were treated with either reboxetine (8 mg/day; n=20) or mirtazapine (45 mg/day; n=20) for 5 weeks. Before, after 1 and 5 weeks of therapy, the DEX/CRH test was performed and cortisol and ACTH concentrations were measured. During reboxetine treatment, a gradual and significant reduction in HPA axis activity as measured by the DEX/CRH test was seen, which was most pronounced after 5 weeks of treatment. In contrast, mirtazapine significantly reduced the cortisol and ACTH concentrations during the DEX/CRH test within 1 week. However, after 5 weeks of mirtazapine treatment, the cortisol and ACTH responses to the DEX/CRH test partially increased again both in responders and nonresponders. This is the first study demonstrating differential effects of various antidepressants on the time course of serial DEX/CRH test results in depressed patients.

Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs.

G protein-activated inwardly rectifying K+ channels (GIRK, also known as Kir3) are activated by various G protein-coupled receptors. GIRK channels play an important role in the inhibitory regulation of neuronal excitability in most brain regions and the heart rate. Modulation of GIRK channel activity may affect many brain functions. Here, we report the inhibitory effects of various antidepressants: imipramine, desipramine, amitriptyline, nortriptyline, clomipramine, maprotiline, and citalopram, on GIRK channels. In Xenopus oocytes injected with mRNAs for GIRK1/GIRK2, GIRK2 or GIRK1/GIRK4 subunits, the various antidepressants tested, except fluvoxamine, zimelidine, and bupropion, reversibly reduced inward currents through the basal GIRK activity at micromolar concentrations. The inhibitions were concentration-dependent with various degrees of potency and effectiveness, but voltage- and time-independent. In contrast, Kir1.1 and Kir2.1 channels in other Kir channel subfamilies were insensitive to all of the drugs. Furthermore, GIRK current responses activated by the cloned A1 adenosine receptor were similarly inhibited by the tricyclic antidepressant desipramine. The inhibitory effects of desipramine were not observed when desipramine was applied intracellularly, and were not affected by extracellular pH, which changed the proportion of the uncharged to protonated desipramine, suggesting its action from the extracellular side. The GIRK currents induced by ethanol were also attenuated in the presence of desipramine. Our results suggest that inhibition of GIRK channels by the tricyclic antidepressants and maprotiline may contribute to some of the therapeutic effects and adverse side effects, especially seizures and atrial arrhythmias in overdose, observed in clinical practice.

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors.

Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine beta-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh(-/-) mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh(+/-) mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh(-/-) mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using L-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh(-/-) mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh(-/-) mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs.

Antidepressants preferentially enhance habituation to novelty in the olfactory bulbectomized rat.

The mechanisms whereby antidepressant drugs exert their therapeutic effects remain unknown. Responses to stressful stimuli are currently thought to contribute to the onset and course of affective disorders. It has been postulated that antidepressants might act by ameliorating response patterns to challenging life events, such as processes of reactivity and/or habituation. Using the olfactory bulbectomy (OBX) rat model, this study examined the effects of various antidepressants on measures of reactivity and habituation in behavioral tests assessing responses to novel stimuli. Sham-operated and OBX rats received 21 daily injections of fluoxetine (10 mg/kg), amitriptyline (10 mg/kg), desipramine (10 mg/kg), buspirone (3 mg/kg), or vehicle. Forty-eight hours after the last injection, animals were tested in the open field, elevated plus maze, and startle apparatus. For each test, time series data were collected and fit with exponential random effects models, in which estimated parameters assessed behavioral reactivity and habituation. Relative to sham controls, OBX rats displayed increased total locomotor activity in the open field and exhibited increased open arm behavior in the elevated plus maze. Through comparison with zinc sulfate-treated anosmic controls, these OBX-induced increases were attributed to both an augmentation of initial reactivity due to anosmia and an attenuation of the average rate of habituation. Chronic antidepressant treatment did not reduce the anosmia-related initial reactivity levels of OBX rats to that of sham controls. Rather, the antidepressants evoked their restorative effects by increasing the rate of habituation. These findings suggest that antidepressants restore normal responding by permitting more effective adaptation to novel stimuli.

Anxiolytic-Like Effects of Antidepressants After Acute Administration in a Four-Plate Test in Mice

HASCOËT, M., M. BOURIN, M. C. COLOMBEL, A. FIOCCO AND G. B. BAKER. Anxiolytic-like effects of antidepressants after acute administration in a four-plate test in mice. PHARMACOL BIOCHEM BEHAV 65(1) 339–344, 2000.—The four-plate test (FPT) is an animal model of anxiety based on stress caused by unconditioned fear. An increase of spontaneous punished behavior was used as a measure to determine the anxiolytic effects of various antidepressants (ADs). In the present study, ADs with different mechanisms of action, including tricyclics, selective serotonin reuptake inhibitors (SSRIs), a monoamine oxidase inhibitor (MAOI), and atypicals, were studied in the FPT to evaluate their anxiolytic-like effects following acute administration. The number of punished crossings was dramatically increased by the SSRIs citalopram, fluvoxamine, and paroxetine, but not fluoxetine. The mixed 5-HT/NE reuptake inhibitors, milnacipran and venlafaxine, also demonstrated strong antipunishment effects. The specific NE reuptake inhibitors, desipramine and maprotiline, and the atypical AD trazodone, enhanced freezing behavior, suggesting anxiogenic-like behavior. It was concluded that, in the FPT, a model based on spontaneous response, where animals are exposed to an aversive environment from which they can only escape by being motionless, this kind of behavior might be related to anticipatory anxiety. In this situation, ADs acting preferentially on 5-HT transmission possessed clear anxiolytic like effects. The balance between the two transmitters, 5-HT and NE, seemed to be a crucial factor.