Nefazodone action

Atypical Antidepressants. StmcturaHy diverse dmgs such as the tetracyclic mianserin (46) and various bicyclic and tricyclic compounds such as trazodone (47), venlafaxine (48), nefazodone (49), and amfebutamone (50) are atypical antidepressants. The exact mechanism of action is unclear but probably... 

Mirtazapine (Remeron). Mirtazapine is the newest of the atypical antidepressants. It mainly works by blocking the alpha-2 negative feedback receptor and thus increases norepinephrine and serotonin activity. In addition, mirtazapine blocks serotonin-2 and serotonin-3 receptors to produce a specific serotonin action like nefazodone. Mirtazapine is approved for the treatment of depression. Its use in the anxiety disorders is being studied. 

Pharmacoiogy Nefazodone is an antidepressant with a chemical structure unrelated to available antidepressant agents. The mechanism of action is unknown. Nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Pharmacokinetics ... 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

Bromocriptine (Parl el) [Antiparkinsonian Agent/Dopamine Receptor Agonist] Uses Parkin on Dz, hyperprolactinemia, acromegaly, pituitary tumors Action Direct-acting on the striatal dopamine receptors X prolactin secretion Dose Initial, 1.25 mg PO bid titrate to effect, w/ food Caution [B, ] Contra Severe ischemic heart Dz or PVD Disp Tabs, caps SE X BP, Raynaud phenomenon (vasospastic disorder resulting in discoloration of the fmgers/toes), dizziness, N, hallucinations Interactions T Effects W/ erythromycin, fluvoxamine, nefazodone, sympathomimetics, antihypertensives X effects W/ phenothiazines, antipsychotics EMS Monitor BP may cause intolerance to EtOH OD May cause NA, severe hypotension give IV fluids symptomatic and supportive... 

The initial reports from open studies (Artigas et al. 1994 Blier and Bergeron 1995) suggest that the combination is associated with improved efficacy with probable faster onset of action. This rapid response was reported with augmentation of fluoxetine and paroxetine, and more recently with nefazodone (Bakish et al. 1997), but interestingly not with sertraline or low doses of fluvoxamine. These results needed to be confirmed in placebo-controlled studies, and the reports from large studies do indeed find an acceleration of response measured as time to response and possible superiority of action with some antidepressants at the end of treatment (Perez et al. 1997 Tome de la Granja et al. 1997). 

Sharp T, Bramwell SR, Lambert P, et al Effect of short- and long-term administration of lithium on the release of endogenous 5-HT in the hippocampus of the rat in vivo and in vitro. Neuropharmacology 30 977-984, 1991 Sharpley AL, Cowen PJ Effect of the pharmacological treatment on sleep of depressed patients. Biol Psychiatry 37 85-98, 1995 Sharpley AL, Walsh AES, Cowen PJ Nefazodone—a novel antidepressant— may increase REM sleep. Biol Psychiatry 31 1070-1073, 1992 Shaw DM, Harris B, Lloyd AT, et al A comparison of the antidepressant action of citalopram and amitriptyline. Br J Psychiatry 149 515-517, 1986 Shaw PJ, Ince PG A quantitative autoradiographic study of H-3-Kainate binding sites in the normal human spinal-cord, brain stem, motor cortex. Brain Res 641 39-45, 1994... 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

Nefazodone has some unusual pharmacological properties, not only inhibiting serotonin uptake, but also blocking the 5-HT 2a receptor. It may be that the antidepressant effect of serotonin agents is due to mediation of 5-HT transmission in the absence (or even the blockade) of 5-HT2a transmission. As a result of these actions, nefazodone is even more specific in terms of affecting a subtype of serotonin receptor than are the SSRIs or venlafaxine. 

Unlike venlafaxine and the SSRIs, nefazodone in adults is started at 200 mg per day and then requires at least a one time increase to 300 mg per day to achieve an effective dose. Similar to the immediate release formulation of venlafaxine, nefazodone requires twice-a-day administration and may induce a greater response rate with higher doses if the patient fails to respond initially. Thus, like venlafaxine, nefazodone appears to have a dual mechanism of action, although the specific mechanisms involved are different for these two agents. At lower doses, the most potent action of nefazodone is 5-HT 2 blockade, whereas higher concentrations produce greater inhibition of the 5-HT uptake pump ( 254, 255 and 256). 

In the analysis of the comparative adverse effects of the newer generation of antidepressants, dizziness was most common with nefazodone. Indeed, it occurred more often on this drug than with any of the others (1). These results are compatible with its preclinical pharmacology, which differs substantially from the other new antidepressants (i.e., most potent action is blockade of the 5-HT2a receptor). 

Because nefazodone does inhibit the 5-HT uptake pump, it has the same class warning against combined use with an MAOl. Nevertheless, there are several reasons to suspect that there may be less risk of this interaction with nefazodone than other serotonin uptake pump inhibitors. First, trazodone, an analogue of nefazodone, is one of the few antidepressants that can be used in combination with an MOAI with minimal risk of an adverse interaction. Second, the most potent action of nefazodone is 5-HT2a receptor blockade, rather than 5-HT uptake inhibition. Nonetheless, we recommend the conservative approach of avoiding this combination, particularly when using high doses (i.e., > 450 mg per day), at which appreciable serotonin uptake inhibition is produced by nefazodone. 

Other Serotonergic Antidepressants In recent years, new antidepressants with serotonergic actions have also been shown to benefit patients with chronic PTSD, many of whom had been treatment refractory. These drugs include venlafaxine (278), mirtazapine (279), and nefazodone (280). 

The majority of positive studies have found that later generation antidepressants, especially those with strong serotonergic effects, are effective and may have a more rapid onset of action when used for PMDD (27). Thus, studies with SSRIs (e.g., fluoxetine, sertraline), nefazodone, venlafaxine, and clomipramine have all shown promise. In several studies, luteal phase dosing has been as effective or more effective than continuous dosing in women with PMDD. 

Buspirone is rapidly absorbed orally but undergoes extensive first-pass metabolism via hydroxylation and dealkylation reactions to form several active metabolites. The major metabolite is l-(2-pyrimidyl)-piperazine (1-PP), which has K2-adrenoceptor-blocking actions and which enters the central nervous system to reach higher levels than the parent drug. It is not known what role (if any) 1-PP plays in the central actions of buspirone. The elimination half-life of buspirone is 2-4 hours, and liver dysfunction may slow its clearance. Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. 

Nefazodone is the prototypical member of the SARI class of antidepressants. It is a powerful serotonin 2A antagonist with secondary actions as a serotonin and norepinephrine reuptake inhibitor (Figs. 7—14 and 7—15). Nefazodone also blocks alpha 1 receptors, but the clinical consequences of this are generally not important, perhaps because its norepinephrine reuptake inhibition reduces this action in vivo. 

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