The other face of depression, reduced positive affect: The role of catecholamines in causation and cure
University of Bristol, Bristol, England, United Kingdom Journal of Psychopharmacology
(Impact Factor: 3.59).
08/2007; 21(5):461-71. DOI: 10.1177/0269881106069938
Despite significant advances in pharmacologic therapy of depression over the past two decades, a substantial proportion of patients fail to respond or experience only partial response to serotonin re-uptake inhibitor antidepressants, resulting in chronic functional impairment. There appears to be a pattern of symptoms that are inadequately addressed by serotonergic antidepressants - loss of pleasure, loss of interest, fatigue and loss of energy. These symptoms are key to the maintenance of drive and motivation. Although these symptoms are variously defined, they are consistent with the concept of ;decreased positive affect'. Positive affect subsumes a broad range of positive mood states, including feelings of happiness (joy), interest, energy, enthusiasm, alertness and self-confidence. Although preliminary, there is evidence to suggest that antidepressants that enhance noradrenergic and dopaminergic activity may afford a therapeutic advantage over serotonergic antidepressants in the treatment of symptoms associated with a reduction in positive affect. Dopaminergic and noradrenergic agents, including the dual acting norepinephrine and dopamine re-uptake inhibitors, have demonstrated antidepressant activity in the absence of serotonergic function, showing similar efficacy to both tricyclic and serotonin re-uptake inhibitor antidepressants. Moreover, the norepinephrine and dopamine re-uptake inhibitor bupropion has been shown to significantly improve symptoms of energy, pleasure and interest in patients with depression with predominant baseline symptoms of decreased pleasure, interest and energy. Focusing treatment on the predominant or driving symptomatology for an individual patient with major depression could potentially improve rates of response and remission.
Available from: Hendrikus Hendriksen
- "Here it is hypothesized that in atypical depression, the dopamine transporters and receptors are down regulated due to increased tonic dopamine levels, thereby decreasing capacity of the system to regulate dopaminergic signaling. Dopaminergic pathways are involved in reward and hedonic processes, thereby hypothetically affecting paradoxical anhedonic symptoms in depression (Nestler and Carlezon, 2006; Dunlop and Nemeroff, 2007; Nutt et al., 2007; Guiard et al., 2009). There is a large body of evidence that atypical depression is associated with increased immune activity, reflected by increased proinflammatory cytokine concentrations that affect brain monoamine functioning, not only of dopamine, but also of norepinephrine and 5-HT (van Heesch et al., 2013a, 2013b, 2014; Penninx et al., 2013). "
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ABSTRACT: First line antidepressants are the so-called SSRI's (selective serotonin reuptake inhibitors), e.g. fluvoxamine, fluoxetine, sertraline, paroxetine and escitalopram. Unfortunately, these drugs mostly do not provide full symptom relief and have a slow onset of action. Therefore also other antidepressants are being prescribed that inhibit the reuptake of norepinephrine (e.g. reboxetine, desipramine) or the reuptake of both serotonin (5-HT) and norepinephrine (e.g. venlafaxine, duloxetine, milnacipran). Nevertheless, many patients encounter residual symptoms such as impaired pleasure, impaired motivation, and lack of energy. It is hypothesized that an impaired brain reward system may underlie these residual symptoms. In agreement, there is some evidence that reuptake inhibitors of both norepinephrine and dopamine (e.g. methylphenidate, bupropion, nomifensine) affect these residual symptoms. In the pipeline are new drugs that block all three monoamine transporters for the reuptake of 5-HT, norepinephrine and dopamine, the so-called triple reuptake inhibitors (TRI). The working mechanisms of the above-mentioned antidepressants are discussed, and it is speculated whether depressed patients with different symptoms, sometimes even opposite ones due to atypical or melancholic features, can be matched with the different drug treatments available. In other words, is personalized medicine for major depression an option in the near future?
Copyright © 2015. Published by Elsevier B.V.
- "It is of interest then that SRIs (by releasing 5-HT) adversely affect the neural processing of rewarding and aversive stimuli (Alén et al., 2013), possibly resulting in down-regulation of the reward system (Lane, 2014). Clinically, SRIs are less effective in managing the anhedonic symptoms of depression (Nutt et al., 2007; Lane, 2014) and in fact provoke cognitive and emotional blunting (Sansone and Sansone, 2010). These SRI-associated effects have been ascribed to 5-HT 2C -mediated suppression of frontal DA function (Barnhart et al., 2004; Wongpakaran et al., 2007; McCabe et al., 2010; Sansone and Sansone, 2010) (Figure 2). "
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Antidepressants are at best 50–55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology.DesignThe relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS.ResultsAltered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems.Conclusions
This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to “design-out” a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd.
Available from: Hans Ågren
- "For example, the noradrenaline and dopamine reuptake inhibitor, bupropion, has been shown to significantly improve symptoms of energy, pleasure and interest in patients with depression with predominant baseline symptoms of decreased pleasure, interest and energy. Thus, there is a pattern of symptoms inadequately addressed by serotonergic antidepressants, suggesting treatments that enhance noradrenergic or dopaminergic activity may be more appropriate to certain types of TRD, such as depression with comorbid anxiety disorders or patients with predominant symptoms of fatigue (Nutt et al., 2007). It is also becoming apparent that inflammatory processes can contribute to the pathogenesis of MDD. "
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