Resolution of Sleepiness and Fatigue in Major Depressive Disorder: A Comparison of Bupropion and the Selective Serotonin Reuptake Inhibitors

Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Biological Psychiatry (Impact Factor: 10.26). 01/2007; 60(12):1350-5. DOI: 10.1016/j.biopsych.2006.06.015
Source: PubMed


The purpose of this study was to examine whether the treatment of major depressive disorder (MDD) with the norepinephrine-dopamine reuptake inhibitor (NDRI) bupropion results in a greater resolution of sleepiness and fatigue than with the selective serotonin reuptake inhibitors (SSRIs).
Six double-blind, randomized clinical trials comparing bupropion (n = 662) with an SSRI (n = 655) for the treatment of MDD were pooled. Hypersomnia scores were defined as the sum of scores of the Hamilton Depression Rating Scale (HDRS) items #22, 23, and 24. Fatigue scores were defined as the score of HDRS item #13.
There was a greater improvement in hypersomnia scores among bupropion-treated than SSRI-treated (p < .0001) or placebo-treated patients (p = .0008). There was also a greater improvement in fatigue scores among bupropion-treated (p < .0001) and SSRI-treated (p = .0005) than placebo-treated patients as well as a greater improvement in fatigue scores among bupropion-treated than SSRI-treated patients (p = .0078). Fewer bupropion-remitters than SSRI-remitters experienced residual hypersomnia (20.5% vs. 32.1%; p = .0014) or residual fatigue (19.5% vs. 30.2%; p = .0020).
Treatment of MDD with the NDRI bupropion resulted in a greater resolution of sleepiness and fatigue than SSRIs treatment. Although preliminary, these results warrant prospectively designed studies examining potential differences between bupropion and the SSRIs on these specific depressive symptoms.

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    • "by low doses of tetrabenazine that deplete accumbens DA and reduce DA-related signal transduction in rats. These findings are consistent with clinical studies reporting that patients treated with bupropion show improvements in effort-related motivational symptoms (Papakostas et al., 2006; Pae et al., 2007) and that clinically relevant doses of bupropion occupy DA transporters in vivo (Learned-Coughlin et al., 2003). Furthermore, in the current studies, bupropion increased lever pressing in low responders, bringing them up to the same level as high responders ; this finding is particularly important in view of the recent report indicating that poor performers on this task show lower levels of DA-related signal transduction [ie, pDARPP-32(Thr34) expression] in accumbens core compared with high responders (Randall et al., 2012). "
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    ABSTRACT: Depression and related disorders are characterized by deficits in behavioral activation, exertion of effort, and other psychomotor/motivational dysfunctions. Depressed patients show alterations in effort-related decision making and a bias towards selection of low effort activities. It has been suggested that animal tests of effort-related decision making could be useful as models of motivational dysfunctions seen in psychopathology. Because clinical studies have suggested that inhibition of catecholamine uptake may be a useful strategy for treatment of effort-related motivational symptoms, the present research assessed the ability of bupropion to increase work output in rats responding on a test of effort-related decision-making (ie, a progressive ratio/chow feeding choice task). With this task, rats can choose between working for a preferred food (high-carbohydrate pellets) by lever pressing on a progressive ratio schedule vs obtaining a less preferred laboratory chow that is freely available in the chamber. Bupropion (10.0-40.0 mg/kg intraperitoneal) significantly increased all measures of progressive ratio lever pressing, but decreased chow intake. These effects were greatest in animals with low baseline levels of work output on the progressive ratio schedule. Because accumbens dopamine is implicated in effort-related processes, the effects of bupropion on markers of accumbens dopamine transmission were examined. Bupropion elevated extracellular dopamine levels in accumbens core as measured by microdialysis and increased phosphorylated dopamine and cyclic-AMP related phosphoprotein 32 kDaltons (pDARPP-32) immunoreactivity in a manner consistent with D1 and D2 receptor stimulation. The ability of bupropion to increase exertion of effort in instrumental behavior may have implications for the pathophysiology and treatment of effort-related motivational symptoms in humans. © The Author 2015. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 10/2014; 18(2). DOI:10.1093/ijnp/pyu017 · 4.01 Impact Factor
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    • "In view of the known antidepressant actions of bupropion in humans, the results of experiment 3 serve to validate the hypothesis that tests of effort-related choice behavior can be used to assess some of the motivational effects of antidepressants and other types of drugs. Clinical data indicate that catecholamine uptake inhibitors are moderately efficacious for treating psychomotor retardation and fatigue symptoms of depression (Fabre et al. 1983; Rampello et al. 1991; Pae et al. 2007; Cooper et al. 2014), and can be more effective than 5-HT uptake blockers for treating motivational dysfunction in depressed people (Papakostas et al. 2006; Cooper et al. 2014). Moreover, amphetamine was shown to increase selection of the high effort alternative in an automated decision-making task in humans (Wardle et al. 2011). "
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    ABSTRACT: Rationale Depressed people show effort-related motivational symptoms, such as anergia, retardation, lassitude, and fatigue. Animal tests can model these motivational symptoms, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine produces depressive symptoms in humans and, at low doses, preferentially depletes dopamine. Objectives The current studies investigated the effects of tetrabenazine on effort-based decision making using the T-maze barrier task. Methods Rats were tested in a T-maze in which the choice arms of the maze contain different reinforcement densities, and under some conditions, a vertical barrier was placed in the high-density arm to provide an effort-related challenge. The first experiment assessed the effects of tetrabenazine under different maze conditions: a barrier in the arm with 4 food pellets and 2 pellets in the no barrier arm (4-2 barrier), 4 pellets in one arm and 2 pellets in the other with no barrier in either arm (no barrier), and 4 pellets in the barrier arm with no pellets in the other (4-0 barrier). Results Tetrabenazine (0.25-0.75 mg/kg IP) decreased selection of the high cost/high reward arm when the barrier was present, but had no effect on choice under the no barrier and 4-0 barrier conditions. The effects of tetrabenazine on barrier climbing in the 4-2 condition were reversed by the adenosine A2A antagonist MSX-3 and the catecholamine uptake inhibitor and antidepressant bupropion. Conclusions These studies have implications for the development of animal models of the motivational symptoms of depression and other disorders.
    Psychopharmacology 10/2014; 232(7). DOI:10.1007/s00213-014-3766-0 · 3.88 Impact Factor
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    • "Thus, one can hypothesise that bupropion is especially suited for those subgroups of depressed patients characterised by unstable vigilance regulation, and that EEG vigilance regulation might predict differential treatment response to bupropion compared with other antidepressants. Accordingly, bupropion has been suggested for treatment of depression with ADHD comorbidity (Bond et al., 2012) and depression with sleepiness (Papakostas et al., 2006). "
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    ABSTRACT: According to the recently proposed vigilance model of affective disorders (vigilance in the sense of "brain arousal"), manic behaviour is partly interpreted as an autoregulatory attempt to stabilise vigilance by creating a stimulating environment, and the sensation avoidance and withdrawal in Major Depressive Disorder (MDD) is seen as an autoregulatory reaction to tonically increased vigilance. Indeed, using a newly developed EEG-based algorithm, hyperstable vigilance was found in MDD, and the contrary, with rapid drops to sleep stages, in mania. Furthermore, destabilising vigilance (e.g. by sleep deprivation) triggers (hypo)mania and improves depression, whereas stabilising vigilance, e.g. by prolonged sleep, improves mania. ADHD and mania have common symptoms, and the unstable vigilance might be a common pathophysiology. There is even evidence that psychostimulants might ameliorate both ADHD and mania. Hyperactivity of the noradrenergic system could explain both the high vigilance level in MDD and, as recently argued, anhedonia and behavioural inhibition. Interestingly, antidepressants and electroconvulsions decrease the firing rate of neurons in the noradrenergic locus coeruleus, whereas many antimanic drugs have opposite effects.
    Neuroscience & Biobehavioral Reviews 07/2014; 44:45-57. DOI:10.1016/j.neubiorev.2012.10.008 · 8.80 Impact Factor
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