精神疾病的神经生物学基础.ppt

精神疾病的神经生物学基 础及精神病药物作用机理 abnormal gene INHERITED DISEASE 100% will develop the inherited disease (classical autosomal dominant pattern) 4-1 Stahl S M, Essential Psychopharmacology (2000) abnormal gene product RISK FACTOR 1 an enzyme is too slow ever since birth so it is hard to metabolize neurotransmitters when release is very fast RISK FACTOR 2 some neurons migrated too far during development in utero RISK FACTOR 3 some of the wrong synapses were eliminated in adolescence RISK FACTOR 4 nerves fire too fast when you see your mother 1-3 are inherited genetic “hits” - 4 & 5 are environmental “hits” expressed through abnormal genetic responses RISK FACTOR 5 nerves fire too fast when you take “speed” 4-2 Stahl S M, Essential Psychopharmacology (2000) LIFE EVENTS FILTER personality/coping skills genetic vulnerability factors for depression 4-3 Stahl S M, Essential Psychopharmacology (2000) even if you inherit the gene for Schizophrenia, the chances of whether or not you develop the disease may be affected by outside factors bad childhood divorce virus or toxin schizophrenia 4-4 Stahl S M, Essential Psychopharmacology (2000) MINOR STRESSORS (DNA with predisposition for schizophrenia - highly biologically determined) SCHIZOPHRENIA MODERATE STRESSORS (DNA with predisposition for depression - moderately biologically determined) DEPRESSION MAJOR STRESSORS (“normal” DNA) PTSD 4-5 Stahl S M, Essential Psychopharmacology (2000) good neuronal selection = healthy neuron = defective neuron bad neuronal selection 4-6 Stahl S M, Essential Psychopharmacology (2000) bad migration good migration 4-7 Stahl S M, Essential Psychopharmacology (2000) CORRECT WIRING 4-8 Stahl S M, Essential Psychopharmacology (2000) WRONG WIRING 4-9 Stahl S M, Essential Psychopharmacology (2000) normal development adult degenerative disease 4-10 Stahl S M, Essential Psychopharmacology (2000) undeveloped neuron developmental disease or no stimulation 4-11 Stahl S M, Essential Psychopharmacology (2000) growth factor (protein) 4-12 Stahl S M, Essential Psychopharmacology (2000) growth factor (protein) 4-13 Stahl S M, Essential Psychopharmacology (2000) New neuron is implanted to take over the functions of the dead neuron 4-14 Stahl S M, Essential Psychopharmacology (2000) = calcium Calcium entering neuron at a normal rate Calcium entering neuron too quickly 4-16 glutamate opens ion channel, allowing calcium to enter the cell. 4-18 Stahl S M, Essential Psychopharmacology (2000) too much neurotrans- mission. can lead to panic attacks 4-19 Stahl S M, Essential Psychopharmacology (2000) 4-20 Stahl S M, Essential Psychopharmacology (2000) too much neurotrans- mission. can lead to dendritic death 4-21 Stahl S M, Essential Psychopharmacology (2000) “pruning” out of control A disease may let the normal process of pruning get out of control. The disease can cause the neuron to be “pruned to death.” 4-22 Stahl S M, Essential Psychopharmacology (2000) even more neurotrans- mission. can lead to cell death 4-23 Stahl S M, Essential Psychopharmacology (2000) 4-24 Stahl S M, Essential Psychopharmacology (2000) new neurotransmitter is given a as drug to take over the functions of the dead neuron 4-25 Stahl S M, Essential Psychopharmacology (2000) Finally, the neuron is destroyed by the excess calcium 4-17 Stahl S M, Essential Psychopharmacology (2000) 精神分裂症及相关精神疾病 n精神分裂症 n物质滥用导致的精神障碍 n精神分裂症样障碍 n分裂情感障碍 n妄想性障碍 n短暂精神障碍 n共患精神障碍 n躯体疾病引起的精神障碍 经常合并精神疾病特征性症状的 精神障碍 n躁狂症 n抑郁症 n认知障碍 nAlzheimer病 精神分裂症的五维症状 n阳性症状 n阴性症状 n攻击敌意 n认知改变 n情感改变 阳性症状 n妄想 n幻觉 n社交中的夸大言语 n语言解体（破裂） n行为解体 n激越 阴性症状 n情感迟钝 n情感退缩 n人际关系恶劣 n被动性 n社会性退缩 n抽象思维障碍 n自主性缺乏 n刻板思维 n语言和思想的量和流畅性降低 n快感缺失 n注意力损害 n有目的行为受损 攻击和敌意 可含概于阳性症状内，但特征性地具有 n暴力 n自伤、自杀 n其他形式的伤害 情感症状抑郁和焦虑 n抑郁情感 n焦虑情绪 n罪恶感 n紧张 n忧虑 n坐立不安 认知症状 n思维异常 n语言怪异、不连贯、语词新作 n注意缺损、信息加工过程受损 n学校能力受损 n执行功能受损 schizophrenia positive symptoms negative symptoms anx/dep aggressive symptoms cognitive symptoms 10-1 Stahl S M, Essential Psychopharmacology (2000) positive symptoms psychotic depression bipolar childhood psychotic illnesses schizo- affective Alzheimers 10-2 Stahl S M, Essential Psychopharmacology (2000) negative symptoms 1 deficit 2 to environmental deprivation 2 to positive symptoms 2 to EPS 2 to depression 10-3 Stahl S M, Essential Psychopharmacology (2000) schizophrenia Alzheimers autism post stroke 10-4 Stahl S M, Essential Psychopharmacology (2000) cognitive symptoms bipolar ADHD/ conduct disorder borderline personality disorder childhood psychosis schizophrenia Alzheimer & dementias 10-5 Stahl S M, Essential Psychopharmacology (2000) aggressive symptoms bipolar treatment resistant psychotic depression organic major depression child schizophrenia/ schizoaffective 10-6 Stahl S M, Essential Psychopharmacology (2000) depression hypothalamus d c Nucleus accumbens Tegmentum b Substantia nigra Basal Ganglia a DOPAMINE PATHWAYS 10-7 Stahl S M, Essential Psychopharmacology (2000) mesolimbic pathway 10-8 Stahl S M, Essential Psychopharmacology (2000) mesolimbic overactivity = positive symptoms of psychosis 10-9 Stahl S M, Essential Psychopharmacology (2000) meso-cortical pathway 10-10 Stahl S M, Essential Psychopharmacology (2000) primary dopamine deficiency D2 receptor blockade secondary dopamine deficiency mesocortical pathway increase in negative symptoms 10-11 Stahl S M, Essential Psychopharmacology (2000) nigrostriatal pathway tubero infundibular pathway poorly innervated toxic or genetic insult dysfunction death poor neuronal migration inadequate synapse selection normal DNA normal DNA abnormal DNA abnormal DNA abnormal gene for schizophrenia 10-17 Stahl S M, Essential Psychopharmacology (2000) abnormal gene product 10-18 Stahl S M, Essential Psychopharmacology (2000) 10-20 Stahl S M, Essential Psychopharmacology (2000) apoptosis/ necrosis 100% 50% 0 15204060 GLU (Glutamate) Glutamine GLUTAMATE IS PRODUCED Glutaminase Glutamate Glutamate Glutamate synthetase Glutamine Glial cell 10-21 Stahl S M, Essential Psychopharmacology (2000) GLUTAMATE IS REMOVED 10-22 Stahl S M, Essential Psychopharmacology (2000) GLUTAMATE RECEPTORS NMDA receptor AMPA receptor kainate receptor metabotropic receptor 10-23 Stahl S M, Essential Psychopharmacology (2000) glycine site zinc site polyamine site Mg site (in the ion channel) PCP site (in the ion channel) 10-24 Stahl S M, Essential Psychopharmacology (2000) normal excitatory neurotransmission 10-25 Stahl S M, Essential Psychopharmacology (2000) SPECTRUM OF EXCITATION BY GLUTAMATE 10-26 Stahl S M, Essential Psychopharmacology (2000) Excess excitation - Mania - Panic Excitotoxicity - Damage to neurons Excitotoxicity - Slow neuro- degeneration Excitotoxicity - Catastrophic neurodegeneration Normal excitation over excitation due to glutamate 10-27 Stahl S M, Essential Psychopharmacology (2000) excess calcium activates enzyme 10-28 Stahl S M, Essential Psychopharmacology (2000) enzyme produces free radical the end is near 10-29 Stahl S M, Essential Psychopharmacology (2000) enzyme produces free radical the end is near 10-29 Stahl S M, Essential Psychopharmacology (2000) free radicals begin destroying the cell 10-30 Stahl S M, Essential Psychopharmacology (2000) finally, free radicals destroy the cell 10-31 Stahl S M, Essential Psychopharmacology (2000) neuroprotection glutamate antagonist blocks excitotoxic neurotransmission glutamate antagonist 10-32 Stahl S M, Essential Psychopharmacology (2000) free radical scavenger 10-33 Stahl S M, Essential Psychopharmacology (2000) Dead Neuron or Loss of Dendrites 10-34 Stahl S M, Essential Psychopharmacology (2000) Genetic Programming of Apoptosis Prenatal Anoxia / Infection / Toxins Positive Symptoms Causing Excitoxicity 抗精神病药物治疗机制 n经典抗精神病药物纯D2受体阻断剂 nSDADA2/5TH2受体阻断剂 n多受体机制药物 nDA稳定剂 D2 pure D2 blocker 11-1 经典抗精神病药物 pure D2 blocker 11-2 Stahl S M, Essential Psychopharmacology (2000) Increase in negative symptoms 11-3 Stahl S M, Essential Psychopharmacology (2000) Mesocortical pathway EPSs 11-4 Stahl S M, Essential Psychopharmacology (2000) Nigrostriatal pathway Blockade of receptors in the nigrostriatal dopamine pathway causes them to up- regulate This up-regulation may lead to tardive dyskinesia 11-5 Stahl S M, Essential Psychopharmacology (2000) Prolactin levels rise 11-6 Stahl S M, Essential Psychopharmacology (2000) Tuberoinfundibular pathway H1 M1 D2 1 conventional antipsychotic drug 11-7 Stahl S M, Essential Psychopharmacology (2000) constipation LAXATIVE blurred vision dry mouthdrowsiness 11-8 Stahl S M, Essential Psychopharmacology (2000) M1 INSERTED = acetylcholine = dopamine 11-9 Stahl S M, Essential Psychopharmacology (2000) = D2 blocker 11-10 Stahl S M, Essential Psychopharmacology (2000) = anticholinergic 11-11 Stahl S M, Essential Psychopharmacology (2000) H1 INSERTED 11-12 Stahl S M, Essential Psychopharmacology (2000) drowsiness weight gain drowsiness decreased blood pressure dizziness 11-13 Stahl S M, Essential Psychopharmacology (2000) 1 INSERTED 1 D2 haloperidol 11-15 5HT2A D2 SDA 11-16 SDA 5HT7 1 2 5HT2A D2 risperidone 11-39 Stahl S M, Essential Psychopharmacology (2000) 5HT-DA Interactions 11-17 Stahl S M, Essential Psychopharmacology (2000) Substantia nigra raphe nucleus brake brake serotonin neuron dopamine neuron Substantia nigra Raphe dopamine 5HT2A receptor serotonin 5HT2A receptor 11-18 Stahl S M, Essential Psychopharmacology (2000) serotonin neuron dopamine neuron Substantia nigra Raphe dopamine 5HT2A receptor serotonin 5HT2A receptor 11-19 Stahl S M, Essential Psychopharmacology (2000) DA neuron 5HT neuron postsynaptic neuron dopamine D2 receptor 5HT2A receptor Nigrostriatal pathway 11-21 Stahl S M, Essential Psychopharmacology (2000) serotonin Nigrostriatal pathway no dopamine release 11-22 Stahl S M, Essential Psychopharmacology (2000) SDA D2 receptor 11-23 Stahl S M, Essential Psychopharmacology (2000) Nigrostriatal pathway 5HT2A receptor Nigrostriatal pathway 11-24 Stahl S M, Essential Psychopharmacology (2000) conventional antipsychotic caudate nucleus 11-25 Stahl S M, Essential Psychopharmacology (2000) serotonin-dopamine antagonist caudate nucleus 11-26 Stahl S M, Essential Psychopharmacology (2000) mesocortical pathway primary dopamine deficiency secondary dopamine deficiency dopamine release serotonin SDA 11-27 Stahl S M, Essential Psychopharmacology (2000) conventional antipsychotic Cortex 11-28 Stahl S M, Essential Psychopharmacology (2000) serotonin-dopamine antagonist Cortex 11-29 Stahl S M, Essential Psychopharmacology (2000) 5HT7 5HT6 5HT3 5HT2C 5HT1A M1 H1 1 2 D1 D3D4 5HT2A D2 clozapine 11-37 多受体机制药物 5HT6 5HT3 5HT2C M1 H1 1 D1 D3D4 5HT2A D2 olanzapine 11-40 Stahl S M, Essential Psychopharmacology (2000) 5HT7 5HT6 H1 1 2 5HT2A D2 quetiapine 11-41 Stahl S M, Essential Psychopharmacology (2000) Are Antipsychotics with Multiple Therapeutic Mechanisms Better than Selective Dopamine 2 Antagonists? 11-35 Stahl S M, Essential Psychopharmacology (2000) multiple mechanisms = side effects chlorpromazine single selective mechanisms = loss of side effects Haloperidol multiple therapeutic mechanisms = improved efficacy clozapine SDA risperidone quetiapine olanzapine DA部分激动剂或DA稳定剂 hypothalamus d c Nucleus accumbens Tegmentum b Substantia nigra Basal Ganglia a DOPAMINE PATHWAYS 10-7 Stahl S M, Essential Psychopharmacology (2000) 精神分裂症的多巴胺假说 高多巴胺通路 低多巴胺通路 阳性症状 阴性症状 多巴胺部分激动的原理 n对于多巴胺功能失调理想的治疗 - 降低中脑边缘通路的多巴胺活性 - 增强中脑皮质通路的多巴胺活性 - 不影响结节漏斗部通路和黑质纹状体 通路 agonist anxiolytic sedative hypnotic muscle relaxant anticonvulsant amnestic dependency partial agonist anxiolytic only antagonist no clinical effect partial inverse agonist promnestic (memory enhancing) anxiogenic inverse agonist promnestic anxiogenic pro-convulsant 8-25 Stahl S M, Essential Psychopharmacology (2000) FULL AGONIST - light is at its brightest 3-15 Stahl S M, Essential Psychopharmacology (2000) PARTIAL AGONIST - light is dimmed but still shining 3-16 Stahl S M, Essential Psychopharmacology (2000) NO AGONIST - light is off 3-17 Stahl S M, Essential Psychopharmacology (2000) PARTIAL AGONIST - light is dimmed but s