Excess dopamine negatively affects mental health and psychological stability
the verdict
INSUFFICIENT LEANING
refutedsupported
the weight of evidence
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Retrieved literature indicates that elevated or hyperactive dopamine systems are associated with specific psychiatric symptoms such as psychosis and mania, partially supporting the claim but lacking comprehensive coverage across general mental health and psychological stability.
Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania
The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if con firmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression. Molecular Psychiatry (2017) 22, 666– 679; doi:10.1038/mp.2017.16; published online 14 March 2017 INTRODUCTION Bipolar disorder (BD) is a severe mental illness characterised by recurrent episodes of mania, depression or mixed states.
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106 Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 2007; 12: 331 – 359. 107 Greil W, Haberle A, Haueis P, Grohmann R, Russmann S. Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the Interna- tional AMSP Project between 1994 and 2009. J Affect Disord 2012; 136: 534– 542. 108 Hayes J, Prah P, Nazareth I, King M, Walters K, Petersen I et al. Prescribing trends in bipolar disorder: cohort study in the United Kingdom THIN primary care database 1995-2009. PloS One 2011; 6: e28725.
109 Hooshmand F, Miller S, Dore J, Wang PW, Hill SJ, Portillo N et al. Trends in pharmacotherapy in patients referred to a bipolar specialty clinic, 2000-2011. J Affect Disord 2014; 155:2 8 3– 287. Dopamine hypothesis of bipolar affective disorder AH Ashok et al 678 Molecular Psychiatry (2017), 666 – 679 110 Walpoth-Niederwanger M, Kemmler G, Grunze H, Weiss U, Hortnagl C, Strauss R et al. Treatment patterns in inpatients with bipolar disorder at a psychiatric university hospital over a 9-year period: focus on mood stabilizers. Int Clin Psychopharmacol 2012; 27: 256 – 266. 111 Ketter TA, Miller S, Dell'Osso B, Calabrese JR, Frye MA, Citrome L.
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<h4>Importance</h4>Abnormal reward processing is suggested to underlie the formation of psychotic symptoms, likely driven by elevated ventral striatal (VS) dopamine levels. Functional magnetic resonance imaging studies reveal alterations of VS activity during reward processing in patients with chronic psychosis and first episode of psychosis, as well as individuals at high risk for psychosis, but findings are inconclusive, conflicting, and difficult to subject to meta-analysis without introducing bias because several studies reported that findings were not statistically significant but did not report statistics.<h4>Objective</h4>To assess the differences between patients with schizophrenia spectrum disorders and healthy controls in VS activation during reward processing.<h4>Data sources</h4>Web of Knowledge database (incorporating Web of Science and MEDLINE) until July 2015, including references of eligible articles and reviews.<h4>Study selection</h4>Functional magnetic resonance imaging studies comparing VS activity during monetary reward processing between patients with schizophrenia spectrum disorders or clinical or genetic high-risk state for psychosis and healthy controls.<h4>Data extraction and synthesis</h4>Statistics and thresholds related to the main outcome measures and potential moderators were independently retrieved by 2 investigators. Effect sizes were analyzed using MetaNSUE, a random-effects method that enables the unbiased inclusion of nonstatistically significant unreported effects.<h4>Main outcomes and measures</h4>Effect size of the group differences in VS activity, and correlation between VS activity and negative and positive symptom scores in patients.<h4>Results</h4>The meta-analysis included 23 studies (917 patients) for reward anticipation, 9 studies (358 patients) for reward feedback, and 8 studies (314 patients) for reward prediction error. We found significant bilateral VS hypoactivation during reward anticipation (23 studies, n = 917) i
Ventral Striatal Activation During Reward Processing in Psychosis A Neurofunctional Meta-Analysis Joaquim Radua, MD, BStat, PhD; André Schmidt, PhD; Stefan Borgwardt, MD, PhD; Andreas Heinz, MD, PhD; Florian Schlagenhauf, MD; Philip McGuire, MD, PhD; Paolo Fusar-Poli, MD, PhD IMPORTANCE Abnormal reward processing is suggested to underlie the formation of psychotic symptoms, likely driven by elevated ventral striatal (VS) dopamine levels.
7,8Predictionerrors,thediscrepancybetweentheac- tual inputs and the prediction about it, are mediated via mid- braindopamineneuronsandtheirtargetsintheVS. 9,10Acon-
Our meta- analysisfurthershowedthatleftVSactivationduringreward anticipation was negatively correlated with negative symp- tomsinpatients. TherobustfindingofVShypoactivationduringrewardan- ticipationmaysupportthatpsychosisischaracterizedbyim- paired learning of stimulus-reinforcement associations.
4,65Moreover,achaotic stress-associated striatal dopamine release5,7 may also im- pedeaphasicdopaminereleaseinresponsetocontextuallyrel- evant (eg, reward indicating) cues, leading to decreased dif- ferentiationbetweentheresponsestorelevantandirrelevant stimuli. 65Inthisframework,theVShypoactivationduringre- ward anticipation can be taken as a measure of altered sa- lience processing because it reflects a blunted response to- wardreward-indicatingcomparedwithneutralcues.
69,70Wecould thus speculate that the elevated striatal dopamine level in psychosis 14mightbeassociatedwiththerightVShypoactiva- tionduringpredictionerrorprocessingthatwefound.Inline withthisargumentation,abehavioralmeasureofaberrantsa- lienceattribution(derivedfromthesalienceattributiontask), which is heightened in patients with schizophrenia, 71 was foundtobepositivelycorrelatedwithstriataldopaminesyn- thesiscapacityandnegativelycorrelatedwithfMRIstriatalpre- dictionerrorssignalinhealthcontrols.
16 The authors sug- gested that high striatal dopamine turnover may increase the “noise” in the reward system, thus interfering with the neuronal processing of reward-predicting cues by phasic dopamine release. 16 This, in turn, may lead to negative symptoms, which group in 2 factors, one involving dimin- ished expression of affect and alogia and the second involv- ing avolition including anhedonia and asociality. 74 Our find- ings may also have some translational effects, given that negative psychotic symptoms are refractory to all available treatments.
75 However, this conclusion requires further research given that there is also evidence showing that dopamine function in the VS was inversely correlated with negative symptom severity. 63 Furthermore, the relation between VS activation during reward anticipation and posi- tive symptoms requires further investigation because only 6 studies were available and there was residual heterogeneity among them. This study has some limitations.
We further showed that the VS dysfunction during reward prediction is correlatedwithnegativesymptoms.Morestudiesareneeded to assess whether the abnormality also affects reward feed- backandpredictionerror. ARTICLE INFORMATION Submitted for Publication: June 2, 2015; final revision received August 10, 2015; accepted September 19, 2015. Published Online: November 11, 2015. doi:10.1001/jamapsychiatry.2015.2196.
Schizophr Bull. 2014;40(6):1328-1337. 45. Gibson CA, Bailey BW, Carper MJ, et al. Author contacts for retrieval of data for a meta-analysis on exercise and diet restriction. Int J Technol Assess Health Care. 2006;22(2):267-270. 46. Stroup DF, Berlin JA, Morton SC, et al; Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008-2012. 47. World Health Organization. The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva, Switzerland: World Health Organization; 1992. 48. American Psychiatric Association.
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