title: The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.
abstract: 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 and DAT blockade in bipolar depression.
authors.affiliation: Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.|Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.|South London and Maudsley NHS Foundation Trust, Camberwell, London, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Ashok
authors.affiliation: Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.|Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.|South London and Maudsley NHS Foundation Trust, Camberwell, London, UK.
authors.forename: T R
authors.initials: TR
authors.lastname: Marques
authors.affiliation: Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.|Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.|South London and Maudsley NHS Foundation Trust, Camberwell, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Jauhar
authors.affiliation: Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.|Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Nour
authors.affiliation: Department of Psychiatry, University of Oxford and Oxford Health NHS Trust, Warneford Hospital, Oxford, UK.
authors.forename: G M
authors.initials: GM
authors.lastname: Goodwin
authors.affiliation: South London and Maudsley NHS Foundation Trust, Camberwell, London, UK.|Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Young
authors.affiliation: Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith Hospital, Imperial College London, London, UK.|Psychiatric Imaging Group, Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK.|Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK.|South London and Maudsley NHS Foundation Trust, Camberwell, London, UK.
authors.forename: O D
authors.initials: OD
authors.lastname: Howes
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D017448:Receptors, Dopamine D2; D004298:Dopamine