CBT-I联合药物治疗伴有条件性觉醒失眠症的疗效分析.pdf

第一章 前 言.13 第二章 重庆市大坪医院体检人员睡眠状况及觉醒状态的调查分析.17 2.1 资料和方法.18 2.2 调查结果.19 2.3 讨 论.20 第三章 CBT-I 联合药物治疗伴有条件性觉醒失眠症的疗效分析：临床随机对照实验.24 3.1 CBT-I 联合右美托咪定治疗伴有条件性觉醒失眠症的疗效分析：临床随机对照试验.28 3.1.1 实验材料及场所：.30 3.1.2 方 法.30 3.1.3 结 果.34 3.1.4 讨 论.35 3.2 CBT-I 联合小剂量喹硫平治疗伴有条件性觉醒失眠症的疗效分析：临床随机对照试验.40 3.2.1 方 法.43 3.2.2 结 果.48 3.2.3 讨 论.50 全文总结.56 参考文献.58 文献综述 条件性觉醒失眠症的病因研究与治疗进展.76 参考文献.90 攻读博士学位期间的研究成果.109 致 谢.110第三军医大学博士研究生论文 1 英文缩写一览表 英文缩写 英文全称 中文全称 APA American Psychiatric Association 美国精神病协会 ASA American Sleep Association 美国睡眠协会 CBT-I Cognitive Behavioral Therapy for Insomnia 失眠的认知行为治疗 CA Conditioned arousal 条件性觉醒 CF Conditioned reflex 条件反射 DEX Dexmedetomidine 右美托咪定 DSM-Diagnostic and Statistical Manual of Mental Disorders Version-精神疾病诊断与统计手册-第五版 EEG Electroencephalogram or Electroencephalography 脑电图 EOG Electrooculography 眼动电图 EMG Electromyography 肌电图 ERPs Event-related Potentials 事件相关电位 ESS Epworth Sleep Scale 埃普沃思嗜睡量表 FDA Food and Drug Administration 食品和药品管理局 fMRI functional Magnetic Resonance Imagery(MRI)功能磁共振 GS Good Sleepers 睡眠良好者 HAS Hyperarousal Scale 过度觉醒量表 ICSD International Classification of Sleep Disorders 国际睡眠障碍分类 ISI Insomnia Severity Index 失眠严重程度指数 MSLT The Multiple Sleep Latency Test 多次睡眠潜伏期试验 NREM Non-rapid Eye Movement 非快速眼动睡眠 N1 N1 stage sleep N1 期睡眠 N2 N2 stage sleep N2 期睡眠 N3 N3 stage sleep N3 期睡眠 PSAS Pre-Sleep Arousal Scale 睡前觉醒量表 第三军医大学博士研究生论文 2 PSG Polysomnography 多导睡眠图 PSQI Pittsburgh Sleep Quality Index 匹兹堡睡眠质量指数 PTOB Prescribed Time out of Bed 规定的起床时间 PTTB Prescribed Time to Bed 规定的上床时间 QF Quetiapine Fumarate 富马酸喹硫平 REM Rapid Eye Movement 快速眼动期睡眠 SCT Stimulus Control Therapy 刺激控制疗法 SD Sleep Diaries 睡眠日记 SE Sleep Efficiency 睡眠效率 SL Sleep Latency 睡眠潜伏期 SOL Sleep onset-latency 睡眠起始潜伏期 SQ Sleep Quality 睡眠质量 SRT Sleep Restriction Therapy 睡眠限制疗法 SWS Slow Wave Sleep 慢波睡眠 TST Total Sleep Time 总睡眠时间 WASO Wake after Sleep onset 入睡后觉醒次数 WHO World Health Organization 世界卫生组织 第三军医大学博士研究生论文 3 Efficacy of different drug with cognitive behavioral therapy for treating chronic insomnia related to conditioned arousal:a randomized controlled trial Abstract Research present status in domestic and foreign,purpose and meaning The diagnosis and treatment of chronic insomnia has experienced from the symptoms to the disease process,the widespread view in medical profession is that insomnia is a symptom,rather than individual a disease in the 1980s.Insomnia have been identified as the taxonomy of an illness again along with the development of sleep medicine and the application of polysomnography.Insomnia has been defined by WHO and APA and ASA respectively,and the definition of insomnia by ASA is that the insomnia is a mental disorder caused by somatization and learned resistance for insomnia which complained the function impairment and sleeplessness.Primary insomnia is classified as psychophysiology insomnia,this definition reveals how exciting and maintaining insomnia.On the one hand,Somatization tension reflects the patients subjective feeling,on the other hand also performs on the sympathetic nervous system awaking.Learned resistance sleep association formed before sleep onset,and limited to appear in the bed sleep environment,A conditioned reflex formed between the arousal before sleep onset and sleep environment(bed),that is known as conditional arousal.This is the etiological theory about chronic insomnia referenced widely.Primary chronic insomnia is great harmful,not only increase spending on health and indulge the drug abusing,also cause the work absent,traffic accidents,working malfunction etc,but also increase the risk of anxiety,depression,diabetes,cardiovascular disease.Therefore,treating chronic insomnia in time,reducing the harm of insomnia,saving the social property are particularly important.Cognitive behavioral therapy is currently as the first-line therapy for chronic insomnia scheme in Europe and the United States and other countries,auxiliary in different sedative hypnotic drugs.The Chinese 第三军医大学博士研究生论文 4 adult insomnia diagnosis and treatment guidelines recommend the insomnia treatments include drug therapy and non-drug therapy,on drug treatment in patients with chronic insomnia should be assisted to psychological behavior treatment at the same time.Because in China to engaging in professional medical resources is relative lack of cognitive behavioral therapy,and patients resistant to mental disease in the heart,and the patient adherence problems on applying cognitive behavior therapy for insomnia purely,the drug treatment is still the mainstream of the therapy for chronic insomnia in domestic.But the traditional benzodiazepines hypnotic drugs will arise daytime sleepiness,hypotonia,cognitive function damage,drug dependence and bounce the adverse reactions such as insomnia,The non-benzodiazepines drugs can also occur drug dependence and transient rebound insomnia,Antidepressant drugs is limited to insomnia patients with mental disorders.The results of the research in the treatment of insomnia with cognitive behavioral therapy combined benzodiazepines drugs and non-benzodiazepines drugs(e.g.,alprazolam,zolpidem)show that the long-term curative effect is matched the simple application of cognitive behavioral therapy.How to enhance the curative effect of cognitive behavioral therapy with applying medication,exerting the synergy of drug and cognitive behavior therapy,minimize the adverse effects of drug treatment,improve the success rate of cognitive behavior therapy is a problem of this study to explore.The theoretical basis of this study The theoretical basis of cognitive behavioral therapy for insomnia is that the conditioned reflex is established and eliminated.The cognitive-behavioral model of insomnia suggests that the formation of chronic insomnia is the accidental factors such as sudden events in life and people in the susceptible factors interact to produce a transient insomnia,and then,patients take inappropriate safe behavior in response to a transient insomnia,such as go to bed early and stay waking in bed,a long time waking in bed and bed form pairs repeatedly,forming the classical conditioning reflex.According to the theory of operant conditioning reflex,the conditioned reflex will abates when the original stimulus vanished,and gives the new stimulus,it will establish a new conditioned reflex.Cognitive behavioral therapy mainly lies in the control of patients awake time in bed,to prevent patient has nothing to do but sleep behavior occurs inside 第三军医大学博士研究生论文 5 the bedroom,let original sleep environment(bed)and the awakening of conditioned reflex gradually eliminate,arise a new conditioned reflex between environment(bed)and sleep.Dexmedetomidine is an auxiliary drug used in anesthesia clinic widely.The conscious sleep induced by dexmedetomidine is similar to sleep occurring naturally changes in respiration,blood pressure,heart rate and basal metabolism rate,etc.As known dexmedetomidine is a specificity of adrenaline 2 receptor agonist,it maybe restrain postsynaptic membrane of epinephrine and norepinephrine released by activating the presynaptic membrane adrenaline 2 autoreceptor and then reduce norepinephrine in the locus coeruleus nuclear activity of neurons,inhibition of cortical arousal levels.This phenomenon is similar to natural sleep that norepinephrine concentrations decrease in the locus coeruleus nuclear and brain in REM sleep.In REM sleep hippocampal cells tend to reproduce in the spatial distribution,and according to the learning and memory activation of neurons in order for the first time distribution model,which involved in memory consolidation and strengthened and enhanced the establishment of a conditioned reflex.This is what we choose dexmedetomidine inducing sleep to improve the success rate of cognitive behavioral therapy for insomnia.Quetiapine is the antidepressant drug widely used in treatment of mental disorders,but it is not allowed to used in the treatment of chronic insomnia.Quetiapine has obvious sedative effects by antagoned H1 and 5-HT2A receptor,and improve the symptoms of anxiety and depression obviously.Chronic insomnia patients with conditional arousal always have the wrong ideas and worry,anxiety disorder,applying quetiapine to treat for insomnia in result of quetiapine myebe remission anxiety and depression symptoms.It will improve the success rate of cognitive behavioral therapy for insomnia.Methods and results Cross-sectional survey methods is applied in this study,the people surveyed were 426 medical examination personnel in chongqing Daping hospitals from January 2013 to December 2013,and the questionnaire to the prevalence of chronic insomnia survey tool include personal general situation questionnaire,Pittsburgh sleep quality index and 第三军医大学博士研究生论文 6 Hyperarousal Scale.The result of the statistical analysis of the questionnaire shows that the prevalence rate of insomnia with conditional arousal was 18.93%in Chongqing,and women are more than men obviously,the male to female ratio is 1:1.65;The result of hyperarousal Scale indicated that the arousal level of sleep disorder group is more than good sleepers.The scores of hyperarousal scale and Pittsburgh sleep quality index were positively correlated(r=0.424,P0.01),but total sleep time(r=0.334,P0.01)and sleep efficiency(r=0.255,P0.01)showed a negative correlation.The method of clinical randomized controlled trial was applied to study efficacy of dexmedetomidine inducing sleep with cognitive behavioral therapy for treating chronic insomnia related to conditioned arousal.Screening 46 cases of chronic insomnia patients accord with conditional arousal symtoms criterion,which were divided into pure cognitive behaviour therapy groups(CBT-I)and cognitive behavior therapy combine dexmedetomidine inducing sleep group(CBT-I+DEX)randomly according to the random digit grouping method.Applied the Pre-Sleep Arousal Scale,Hyperarousal Scale,Pittsburgh sleep quality index,Epworth Sleep Scale,Insomnia Severity Index to assessment sleep,and completed the objective detection of Polysomnography at before treatment,4 weeks and 8 weeks after treatment,and the patients must complete sleep diary all the daily.The result of statistical analysis shows that it is 8 patients exit treatment in pure CBT-I group,and the treatment success rate was 65.2%,but CBT-I+DEX group was 2 patients quit,the treatment success rate was 91.3%,results compared between two groups have significant difference.The results of two groups patients in the sleep onset latency and sleep efficiency have improved significantly after treatment than before,and the results of CBT-I+DEX group in Wake after Sleep Onset,REM sleep time,N3 sleep stage were improved obviously than CBT-I.On the total sleep time,there is no significant difference between before and after the treatment,the total sleep time of CBT-I group was decreased than before treatment.The N3 stage of sleep and total sleep time was different significant between CBT-I+DEX group and CBT-I group at the treatment of 4 weeks.The results of experiment statistical show that dexmedetomidine induced sleep can obviously decrease somatic arousal degree of insomnia with conditional arousal,and increase REM sleep time,consolidate memories,第三军医大学博士研究生论文 7 improve the success rate of cognitive behavioral therapy for insomnia.The method of clinical randomized controlled trial was applied to study efficacy of small dose quetiapine combine with cognitive behavioral therapy for treating chronic insomnia related to conditioned arousal.Screening 46 cases of chronic insomnia patients who were inpatients in Daping hospital sleep center from February 2013 to November 2014 accord with conditional arousal symtoms criterion,which were divided into cognitive behaviour therapy groups combine quetiapine(25mg)(CBT-I+Q)and cognitive behavior therapy group(CBT-I)randomly according to the random digit grouping method.Applied the Pre-Sleep Arousal Scale,Hyperarousal Scale,Pittsburgh sleep quality index,Epworth Sleep Scale,Insomnia Severity Index to assessment sleep,and completed the objective detection of Polysomnography at before treatment,4 weeks and 8 weeks after treatment,and the patients must complete sleep diary all the daily.The results of Polysomnography and sleep diary indicated that sleep latency,sleep efficiency were obviously improved in both groups,and the targets reacting the arousal level in patients with awakening times and sleep latency,quetiapine group is superior than placebo control group;On the sleep structure,obviously increase the N3 stage of sleep,prompt quetiapine can increase the depth of the patients with sleep.It is worth mentioning that total sleep time of two groups of patients have no obvious increase,but sleep efficiency and sleep quality improve notably.The waking and sleep scale statistical results suggest that small dose quetiapine group drop quickly than controll group on sleep severity index scores in the first four weeks of treatment.The score of Pre-Sleep Arousal Scale decreased more than controll group on somatic arousal,but as the drug gradually retreated,curative effect is steady state.The two groups patients have no obvious difference on adverse reactions.Thus,in the early stages of the cognitive behavioral therapy,application of small doses of quetiapine maybe help relieve the discomfort of sleep restriction to bring patients,enhance the curative effect of cognitive behavior therapy for insomnia.Although dexmedetomidine inducing sleep combine with cognitive behavior therapy have a synergistic effect,small dose quetiapine combine with cognitive behavior therapy for insomnia with conditioned arousal also have positive results,but the current 第三军医大学博士研究生论文 8 diagnosis about conditional arousal is lack of unified standards,quetiapine at present have not yet received the FDA approved in the treatment of chronic insomnia,which limits dexmedetomidine and quetiapine in the clinical application.Because of the small sample sizes it will affect the reliability of the experimental results of this study,in the future,it needs the large sample、multicenter、doubie blind and randomized controlled clinical trials to test and verify.Keyword:conditioned arousal,cognitive behavior therapy for insomnia,chronic insomnia,dexmedetomidine,quetiapine 第三军医大学博士研究生论文 9 CBT-I 联合药物治疗伴有条件性觉醒失眠症的疗效分析 摘 要 国内外研究现状、目的和意义 慢性失眠症的诊断与治疗经历了从症状到疾病的过程，在 20 世纪 80 年代，医学界普遍的看法是“失眠是一个症状，而不是单独的一种疾病”。随着多导睡眠脑电图的应用和睡眠医学的发展，失眠再次被确定为疾病分类学中的一种疾病。世界卫生组织、美国精神病学协会和美国睡眠医学协会对失眠分别给出了大同小异的定义，其中美国睡眠医学协会分类系统将原发性失眠定义为“由躯体化紧张和习得性阻睡联想引起的以失眠和觉醒状态下的功能受损为主诉的一种精神障碍”，归类为“心理生理性失眠”，这一定义揭示了失眠是如何被激发和维持的病因机制。躯体化紧张一方面反映了患者的主观感受，另一方面也表现在交感神经系统紧张唤醒上，诸如心率增快、易出汗、易激动等；习得性阻睡联想是在入睡前形成的唤醒形式，一般限于出现在有床的睡眠环境，即入睡前的唤醒与睡眠环境(床)反复配对而形成了条件反射，又称为条件性觉醒。这是