docProdopaminergic antidepressants
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Prodopaminergic antidepressants
Prodopaminergic antidepressants Dr David Cousins MRC Clinician Scientist Institute of Neuroscience Newcastle University UK @teamlithium MDD 5HT NA DA MDD 5HT NA DA SSRI NRI MDD 5HT NA DA SSRI NRI MDD 5HT NA DA Healy 2015 Eyding 2010; Papakostos 2008; Wiles 2014 MDD 5HT NA DA TCA/SNRI MDD 5HT NA DA TCA/SNRI SSRI Cipriani 2009; Nutt 2009 MDD 5HT NA DA MDD 5HT NA Dopaminergic systems Mesolimbic pathway Nucleus Accumbens Distribution • Relatively short pathway • Terminates in ventral striatum and limbic circuitry • D2 type receptors (D3DR) Functions • Reward systems & drive Amygdala Ventral Tegmental Area Dysfunction symptoms • Hedonism • Risk taking • Apathy • Emotional aspects • Psychosis ( activity) Mesocortical pathway Prefrontal cortex VTA Distribution • Long, widely distributed pathway • Projects to anterior cingulate and prefrontal cortex areas • D1 type receptors • D2 type receptors include D4DR Functions • Modulates cognitive processes • working memory • attention • executive functions Dysfunction symptoms • Cognitive dysfunction • Concentration • Thought disorder? Nigrostriatal pathway Distribution • Relatively short pathway • Terminates in dorsal striatum (caudate/putamen) • D2 type receptors (D2DR) Striatum Functions • Modulation of movement Substantia Nigra Dysfunction symptoms • Possibly agitation/retardation • Medication side effects here • Soft neurological signs Tuberoinfundibular pathway Distribution • Very short pathway • Arcuate nucleus to hypothalamus • D1 and D2 type receptors Functions • Controls prolactin secretion • dopamine lowers prolaction Hypothalamus Dysfunction symptoms • Little psychological • Numerous physiological effects Pituitary Bartolomeis 2014 MDD 5HT NA DA MDD 5HT NA DA ? 5HT NA DA MDD: 5 of 9 present nearly every day 2/52 • Depressed mood most of the day • Markedly diminished interest or pleasure in all, or almost all, activities most of the day • Significant weight loss (when not dieting) or weight gain, or decrease or increase in appetite • Insomnia or hypersomnia • Psychomotor agitation or retardation • Fatigue or loss of energy • Feelings of worthlessness or excessive or inappropriate guilt • Diminished ability to think or concentrate, or indecisiveness • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation, attempt or plan MDD: 5 of 9 present nearly every day 2/52 • Depressed mood most of the day • Markedly diminished interest or pleasure in all, or almost all, activities most of the day • Significant weight loss (when not dieting) or weight gain, or decrease or increase in appetite • Insomnia or hypersomnia • Psychomotor agitation or retardation • Fatigue or loss of energy • Feelings of worthlessness or excessive or inappropriate guilt • Diminished ability to think or concentrate, or indecisiveness • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation, attempt or plan Nutt 2007 Bupropion – NDRI Anecdotal evidence of reduction in apathy in depression (Corcoran 2004) Study evidence of improvement in reports of loss of energy (Bodkin 1997, Shelton 2001, Tomarken 2004) HAMD cluster analysis shows superiority to placebo on retardation, fatigue and interest (Jamerson 2003) Potential efficacy for SSRI-induced fatigue (Green 1997) Combines with, but interacts with citalopram (Trivedi 2006) Prins 2011 Jang 2013 Amisulpride Dual D2 and D3 antagonism Frontal cortex Higher doses D1 D3 VTA D3 DA D2 Limbic areas Amisulpride Dual D2 and D3 antagonism Frontal cortex Higher doses D1 D3 VTA D3 DA D2 Limbic areas Amisulpride FRONTAL 1. No D2 receptors here Dual D2 and D3 antagonism Frontal cortex Higher doses D1 D3 VTA D3 DA D2 Limbic areas OR 2. Greater affinity at presynaptic D2 receptors LIMBIC Net blockade of DA transmission Amisulpride FRONTAL 1. No D2 receptors here Dual D2 and D3 antagonism Frontal cortex Lower doses: Regional selectivity D3 and presynaptic D2 Affinity D1 D3 VTA D3 DA D2 Limbic areas OR 2. Greater affinity at presynaptic D2 receptors LIMBIC Net blockade of DA transmission Prins 2011
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