Safety and tolerability of combined treatment with moclobemide and SSRIs

Cj, Hawley; Sj, Quick; Ratnam, S.; Ha, Pattinson; McPhee, S.A.

doi:10.1097/00004850-199609000-00005

Cited by 30 publications

(12 citation statements)

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“…Unfortunately, previous adjunct drug strategies had limitations, related to mechanism, safety, or pharmacokinetics. Adjunct monoamine oxidase inhibitors are reported effective in TRD (Ebert et al, 1995) but can elicit severe adverse events (Hawley et al, 1996). Adjunct tryptophan is reported effective in TRD (Walinder et al, 1976), but tryptophan's half-life is short, 2 h (Green et al, 1980), and only a fraction of tryptophan is metabolized to 5-HT (Bender, 1983).…”

Section: Introductionmentioning

confidence: 99%

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Jacobsen

Rudder

Roberts

et al. 2016

Neuropsychopharmacol

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Drugs, notably SSRIs, that elevate brain extracellular 5-HT (5-HT Ext ) are antidepressants. Unfortunately, most patients fail to remit. Multipronged clinical evidence suggests that elevating 5-HT Ext beyond the SSRI effect enhances antidepressant efficacy, but previous such drug strategies had prohibitive limitations. In humans, adjunct treatment with the 5-HT precursor 5-hydroxytryptophan (5-HTP) elevates 5-HT Ext beyond the SSRI effect. Small pilot trials suggest that adjunct 5-HTP can confer antidepressant response in treatment-resistant depression (TRD). However, sustained, stable 5-HT Ext elevation is required for antidepressant effect; therefore, the rapid absorption and elimination of standard 5-HTP immediate release (IR) likely curtail 5-HTP IR's antidepressant potential. Slow-release (SR) drug delivery can crucially improve efficacy and safety of rapidly absorbed and eliminated compounds. Here we tested in mice the hypothesis that SR delivery will substantially improve 5-HTP's drug properties, by minimizing adverse effects and securing sustained 5-HT Ext elevation beyond the SSRI effect. We modeled 5-HTP SR with minipumps, 5-HTP IR with injections, and chronic SSRI with dietary fluoxetine. We tested adjunct 5-HTP SR in wild-type mice and in mice with low brain 5-HT owing to expression of a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2. In both lines of mice, adjunct 5-HTP SR synergized with SSRI to elevate 5-HT Ext beyond the SSRI effect. We observed no adverse effect. Adjunct 5-HTP IR could not produce this therapy-like profile, producing transient 5-HT Ext spikes and marked adverse effects. Integrated with a body of clinical data, our mouse data suggest that an adjunct 5-HTP SR drug could safely and effectively elevate 5-HT Ext beyond the SSRI effect and represent a novel treatment for TRD.

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Section: Introductionmentioning

confidence: 99%

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Jacobsen

Rudder

Roberts

et al. 2016

Neuropsychopharmacol

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“…19 Therapeutic doses of moclobemide have been associated with severe toxicity when combined with serotonin reuptake inhibitors. 20 Mirtazapine is a presynaptic a 2 -receptor antagonist. It may theoretically increase synaptic noradrenaline and serotonin concentrations.…”

Section: Antidepressant Drugsmentioning

confidence: 99%

Serotonin syndrome

Thanacoody¹

2007

Adverse Drug Reaction Bulletin

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“…Within 4 weeks 13 patients (53.9%) responded as determined by a significant improvement in HAM-D (125). A few small open trials (usually of 4 to 6 weeks duration) reported response-rates of 55 to 75% after augmentation treatment of tricyclic-or SSRIs-resistant depression with 300 to 800 mg moclobemide (15,106,116). One study of moclobemide (329 ± 125 mg/d) plus a tricyclic (trimipramine: 117 ± 24 mg/d, doxepine 67 ± 24 mg/d or amitriptyline 94 ± 33 mg/d) recorded a response-rate of 70% in 18 hospitalized refractory patients (223).…”

Section: Refractory Depressionmentioning

confidence: 99%

Moclobemide: Therapeutic Use and Clinical Studies

Bonnet¹

2003

CNS Drug Reviews

200

100

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Moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA) and has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively studied in anxiety disorders. Nearly all meta-analyses and most comparative studies indicated that in the acute management of depression this drug is more efficacious than placebo and as efficacious as tricyclic (or some heterocyclic) antidepressants or selective serotonin reuptake inhibitors (SSRIs). There is a growing evidence that moclobemide is not inferior to other antidepressants in the treatment of subtypes of depression, such as dysthymia, endogenous (unipolar and bipolar), reactive, atypical, agitated, and retarded depression as with other antidepressants limited evidence suggests that moclobemide has consistent long-term efficacy. However, more controlled studies addressing this issue are needed. For patients with bipolar depression the risk of developing mania seems to be not higher with moclobemide than with other antidepressants. The effective therapeutic dose range for moclobemide in most acute phase trials was 300 to 600 mg, divided in 2 to 3 doses. While one controlled trial and one long-term open-label study found moclobemide to be efficacious in social phobia, three controlled trials subsequently revealed either no effect or less robust effects with the tendency of higher doses (600 -900 mg /d) to be more efficacious. Two comparative trials demonstrated moclobemide to be as efficacious as fluoxetine or clomipramine in patients suffering from panic disorder. Placebocontrolled trials in this indication are, however, still lacking.A relationship between the plasma concentration of moclobemide and its therapeutic efficacy is not apparent but a positive correlation with adverse events has been found. Dizziness, nausea and insomnia occurred more frequently on moclobemide than on placebo. Due to negligible anticholinergic and antihistaminic actions, moclobemide has been better tolerated than tri-or heterocyclic antidepressants. Gastrointestinal side effects and, espe-97

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Safety and tolerability of combined treatment with moclobemide and SSRIs

Cited by 30 publications

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SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

SSRI Augmentation by 5-Hydroxytryptophan Slow Release: Mouse Pharmacodynamic Proof of Concept

Serotonin syndrome

Moclobemide: Therapeutic Use and Clinical Studies

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