Augmentation effect of combination therapy of aripiprazole and antidepressants on forced swimming test in mice.

RATIONALE: A deficiency in brain monoamine systems (serotonin, dopamine, and/or norepinephrine) have long been hypothesized for the pathogenesis of depression. Drugs enhancing neurotransmission of those monoamines have been proven to have antidepressant effects. We hypothesized that aripiprazole, a partial D(2) agonist, could increase the activity of various antidepressants in the mice forced swimming test (FST), an animal model of depression. OBJECTIVES: The scope of this study was to investigate the antidepressant-like effect of aripiprazole, when combined with conventional antidepressants drugs. MATERIALS AND METHODS: This study assessed the effects of co-administration of aripiprazole with selective serotonin reuptake inhibitors (SSRIs; sertraline, paroxetine, and citalopram), selective serotonin-norepinephrine reuptake inhibitors (SNRIs; venlafaxine and minalcipran), selective norepinephrine reuptake inhibitor (NRI; desipramine), and the dual dopamine and norepinephrine reuptake inhibitor (bupropion), using the FST in mice. Subactive doses of aripiprazole and antidepressants sertraline, paroxetine, citalopram, venlafaxine, minalcipran, bupropion (4 and 8 mg/kg), and desipramine (2 and 4 mg/kg) were given i.p. 30 and 45 min, respectively, before the test. RESULTS: Aripiprazole (0.03 and 0.06 mg/kg) combined with inactive doses of antidepressants, increased the activity of all antidepressants with the exception of bupropion and desipramine. CONCLUSION: The augmentation effects of aripiprazole, in the present study, are in agreement with clinical evidence suggesting that aripiprazole may enhance the efficacy of therapeutic effect of SSRIs and SNRIs but not of NRI. These results suggest that augmentation effect of aripiprazole only appears when 5-HT system is activated and might implicate complex regulation between dopamine and 5-HT(1A) and 5-HT(2A) receptors.

Melatonin receptor agonist agomelatine: a new drug for treating unipolar depression.

Agomelatine markedly differs from other classes of antidepressant drugs: its primary molecular targets in vivo are the melatonin MT(1) and MT(2) receptors, where it acts as a potent agonist, and the 5-HT(2C) receptors, where it exerts clear-cut antagonist properties. Agomelatine across a wide range of clinical trials suggests that agomelatine offers an important alternative for the treatment of depression, combining efficacy, even in the most severely depressed patients, with a favorable side-effect profile. It will be of interest to see if agomelatine expands the spectrum of treatment for unipolar depression. It shows efficacy in acute phase and in of maintenance treatment compared to reference antidepressants as paroxetine and venlafaxine.

ASIC1a activation by amitriptyline and FMRF-amide is removed by serine proteases.

Analgesia induced by certain tricyclic antidepressants has been largely used for decades, yet the mechanisms involved are incompletely understood. Starting from previously reported dual effects of amitriptyline on wild-type ENaC (Pena F, et al. J Pharm Pharmacol 54:1393-8: 2002), we extended our study to ASIC1a by performing a series of whole cell and single-channel recordings of proton-activated currents in HEK293 cells. Acid pulses were applied at 2 or 5 min intervals, and amitriptyline (1-500 microM) was applied at a holding pH of 7.4 or 8.4 between pulses. Dose-response plots were fitted with dual Hill type functions, yielding a half-activatory constant of 0.3 microM and a half-inhibitory constant of 382 microM at pH 7.4. At pH 8.4 both constants were shifted to higher values (0.5 and 444 microM, respectively). In whole-cell experiments, FMRF-amide increased the peak amplitude of ASIC1a transients at 0.1 microM and decreased it at 1 and 100 microM. Single-channel recordings were idealized and fitted using an 8-state linear connectivity model comprising four consecutive activation steps. Both amitriptyline (1 microM) and FMRF-amide (0.1 microM) increased the unitary current amplitude, and modified the opening and closing rates of the first gating mode. They also increased the transition rate from the second to the first gating mode, and the rate of final closure. The activatory effect of both compounds vanished after a mild trypsin pretreatment, suggesting the existence of activatory sites for FMRF-amide and amitriptyline in the outer vestibule of ASIC1a, which can be removed by exo- or endogenous serine-proteases.

Is co-administration of bupropion with SSRIs and SNRIs in forced swimming test in mice, predictive of efficacy in resistant depression?

UNLABELLED: The monoamine hypothesis based on the deficiency of one or several monoamines is commonly evoked to explain the physiopathology of depression. This hypothesis initially based on noradrenalin and serotonin deficiency has been extended to dopamine. The animal models of depression also suggest an implication of dopamine in the physiopathology of depression. The forced swimming test is an animal model used to predict the antidepressant activity of drugs. OBJECTIVES: The scope of this study was to investigate the antidepressant-like effect of a dopamine re-uptake inhibitor, bupropion, when combined with conventional antidepressants drugs SSRIs (selective serotonin re-uptake inhibitors), SNRI (selective serotonin-noradrenalin re-uptake inhibitors) and a NRI (selective noradrenalin inhibitor). METHODS: This study assessed the effects of co-administration of bupropion with SSRIs: sertraline, paroxetine, citalopram, fluvoxamine, SNRIs: venlafaxine and milnacipran and NRI: desipramine, using an animal model of depression, the forced swimming test in mice. Subactive doses of bupropion (4 and 8mg/kg) and antidepressants: sertraline (2mg/kg), paroxetine, citalopram, fluvoxamine, venlafaxine, milnacipran and desipramine (4mg/kg) were given i.p. 45 and 30min, respectively, before the test. RESULTS: Bupropion (4 and 8mg/kg) combined with inactive doses of antidepressants, decreased immobility time in the mice FST except with sertraline and desipramine. In conclusion, the antidepressant-enhancing effects of bupropion, in the present study, are in agreement with preliminary clinical evidence suggesting that bupropion may enhance the efficacy of therapeutic effect of SSRIs and SNRIs but not the therapeutic effect of NRI. These results suggest that bupropion enhances only the serotonergic system.

Antidepressant-like effect of lamotrigine is reversed by veratrine: a possible role of sodium channels in bipolar depression.

UNLABELLED: Lamotrigine has been found to be efficacious in the acute management of bipolar depression and long-term management of bipolar disorder, especially in delaying depressive recurrence, either as monotherapy or as adjunctive therapy. Lamotrigine is also an antiepileptic drug, and is efficient in the treatment of focal epilepsies. It is thought to act by inhibition of glutamate release through blockade of voltage-sensitivity sodium channels and stabilization of the neuronal membrane. OBJECTIVES: The scope of this study was to determinate if sodium channels are important for lamotrigine and other antidepressant to exert their antidepressant-like function. METHODS: This study assessed the effects of veratrine, a Na(+) channel opener on antidepressant effect of lamotrigine and others antidepressants: two tricyclic antidepressants (TCAs): imipramine, a mixed serotonergic noradrenergic reuptake inhibitor, desipramine, a specific noradrenergic reuptake inhibitor and a SSRI: paroxetine, the most potent selective serotonergic reuptake inhibitor, using an animal model of depression, the forced swimming test. Veratrine (0.125 mg/kg) and lamotrigine (16, 32 mg/kg) or antidepressants (16, 32 mg/kg) were given i.p. 45 and 30 min, respectively, before the test. RESULTS: We observed that when combined with veratrine the antidepressant-like effect of lamotrigine was reversed, but the antidepressant-like effect of the imipramine, desipramine and paroxetine was not changed, indicating that the mechanism of action of lamotrigine is different from that of antidepressants.

The role of mood stabilisers in the treatment of the depressive facet of bipolar disorders.

It was previously shown that available mood stabilisers are used to treat bipolar depression. As part of the natural course of illness, patients with bipolar disorder often suffer from episodes of depression more frequently and for longer durations than mania. A major challenge in the treatment of bipolar depression is the tendency for antidepressant medications, particularly tricyclic antidepressants, to precipitate episodes of mania, or to increase cycle frequency or symptom intensity. Thus, exploring the utility of mood stabilisers as monotherapy for bipolar depression is important. The aim of this review it to collate data involving the effects of some mood stabilisers like lithium, carbamazepine, valproate and lamotrigine in depressive aspects of bipolar disorder, but as well using an animal model of depression, to understand their mechanism of action.