Dysautonomic symptoms and major depression

自律神經失調 (Dysautonomia) 口乾、口渴、口內疼痛、口舌異常感、味覺異常、 缺乏食慾；耳鳴、耳阻塞感等。 姿勢性低血壓，頭暈，眼前發黑，甚至暈倒。 尿失禁、頻尿，性功能障礙 多汗 呼吸困難、心悸，胸悶，胸部壓迫等。 焦躁易怒、集中力及記憶力減弱、不安等等。全 身乏力，失眠等毛病。

Depressed mood Feelings of guilt Suicide attempt Insomnia- early Insomnia- middle Insomnia- late Loss of interest Retardation Anxious behavior Hamilton Depression Rating Scale Worrying Hypochondriasis Somatic anxiety Appetite Libido Lethargy & fatigue Body weight loss Lack of insight

depressed mood feelings of guilt suicide insomnia- early Insomnia- middle Insomnia- late interest and activities retardation agitation psychic anxiety somatic anxiety general somatism genital symptoms hypochondriasis body weight loss insight Psychic anxiety Sleep disturbance Somatic anxiety Depressed mood Component disturbance of a depressed mood HAM-D Hong CJ, Oct 2006

1. Anxious mood worries anticipates worst 2. Tension startles cries easily restless trembling 3. Fears fear of the dark fear of strangers fear of being alone fear of animal 4. Insomnia difficulty falling asleep nightmares 5. Intellectual poor concentration memory impairment 6. Depressed Mood decreased interest in activities anhedonia 7. Muscular complaints muscle aches or pains bruxism 8. Sensory complaints tinnitus blurred vision Hamilton Anxiety Rating Scale

9. Cardiovascular Symptoms tachycardia palpitations chest pain sensory of feeling faint 10. Respiratory Symptoms chest pressure choking sensation shortness of breath 11. Gastrointestinal Symptoms dysphagia nausea or vomiting constipation weight loss 12. Genitourinary Symptoms urinary frequency or urgency dysmenorrhea impotence 13. Autonomic Symptoms dry mouth flushing pallor sweating 14. Behavior at Interview fidgets tremor paces Hamilton Anxiety Rating Scale

Milestones of Psychiatry 1950‘s 1980‘s SchizophreniaDepression clozapinefluoxetine chlorpromazineimipramine Hong CJ, Dec 1999

Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region Lesch KP: Science.1996 a self-report inventory based on the five-factor model of personality

Molecular Psychiatry 2002 July

Changes in Autonomic Reactivity? Human Depression/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation dementia Postpartum depression Animal Helplessness/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation mice Infanticidal mother mice

Inescapable/uncontrollable shock (Seligman & Maier, 1971; Anisman 1979)

Helplessness Training & Escape Test PsyLab 2002/04/04 Video

Fig.2. Five of the 8 C57 male mice remained helpless 10 days after the stress protocol of intermittent conditioning inescapable minor foot-shock. Non-helpless Helpless

Figure 6. GRPR-Deficient Mice Have Enhanced and Resistant Long- Term But Not Short-Term Amygdala-Dependent Fear Memory

Changes in Autonomic Reactivity? Human Depression/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation dementia Postpartum depression Animal Helplessness/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation mice Infanticidal mother mice

Potential antidepressant effect of PX01 was demonstrated in FST and TST

＊ ＊ ＊ Figure 3. The ambulatory distance in 5min locomotion test (n=5 for each group). Mice receiving cysteamine administration have significant reductions in the locomotion activities(p<0.05). InjectionlocomotionTSTFST 20min rest 5 min rest 6 min14min rest 6 min 2007/01/19

Figure 4. The mobility time in 6min tail suspension test. There are no differences between groups receiving vehicle and drugs (control, n=5; cysteamine50mg/kg, n=5, p=0.149; cysteamine100mg/kg, n=4, p=0.816; cysteamine 200mg/kg, n=5, p=0.179; imipramine10mg/kg, n=4, p=0.258). InjectionlocomotionTSTFST 20min rest 5 min rest 6 min14min rest 6 min 2007/01/19

Figure 5. The mobility time in 6min Forced swimming test. There are no differences between groups receiving vehicle and drugs (control, n=5; cysteamine50mg/kg, n=5, p=1.000; cysteamine100mg/kg, n=5, p=0.497; cysteamine 200mg/kg, n=5, p=0.052; imipramine10mg/kg, n=5, p=0.983). InjectionlocomotionTSTFST 20min rest 5 min rest 6 min14min rest 6 min 2007/01/19

Changes in Autonomic Reactivity? Human Depression/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation dementia Postpartum depression Animal Helplessness/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation mice Infanticidal mother mice

Dementia and Autonomic Reactivity Acetylcholine deficiency is an important pathophysiology of dementia Acetylcholine is the key neurotransmitter of parasympathetic nervous system Anticholinergic agents are bad for memory but good for mood

Archive of General Psychiatry Oct 2006

Changes in Autonomic Reactivity? Human Depression/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation dementia Postpartum depression Animal Helplessness/Anxiety Antidepressant treatments Anticholinergics in depression and dementia PS1 mutation mice Infanticidal mother mice

Dominant Inheritance ENU-mutagenized mice displaying waddling behavior were linked to Chr M B6, ♂ waddling BALB Normal BALB, ♀ F1 F2 PsyLab 2006 Dec (video)video (video)video (video)video Rough mapping

Four of five (80%) waddling mother mice did not nurse their pups The only one nursing mother killed all of her five pups at age 2 weeks.

Functional and Micro-Magnetic Resonance Imaging Center DWI_SE_BIO TR=1500 msTE=32 msSlth=1 mmFOV=2 cm NEX=4SW= HzBig delta=15 msMatrix =256*192b=1100 s/mm 2 controlwaddling Lt Entorhinal cortex Lat ventricle

Functional and Micro-Magnetic Resonance Imaging Center DWI_SE_BIO TR=1500 msTE=32 msSlth=1 mmFOV=2 cm NEX=4SW= HzBig delta=15 msMatrix =256*192b=1100 s/mm 2 controlwaddling Lat ventricle

OVER

Dysautonomia 的原因 長期壓力 細菌病毒感染 中風、心肌梗等 更年期荷爾蒙異常 遺傳或基因突變

The prevalence of autonomic symptoms in dementia and their association with physical activity, activities of daily living and quality of life. Dement Geriatr Cogn Disord. 2006;22(3): Epub 2006 Aug 10. Acute dysautonomia following mumps. Neurol India Jun;47(2): Review. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med May-Jun;67 Suppl 1:S Review. Depression in patients with acute myocardial infarction: influence on autonomic nervous system and prognostic role. Results of a five-year follow-up study. Int J Cardiol Jan 31;115(1): Epub 2006 Jun 22. Increased systemic catecholamines in complex regional pain syndrome and relationship to psychological factors: a pilot study. Anesth Analg Nov;99(5): ; table of contents. A functional-structural model to understand cardiac autonomic nervous system (ANS) dysregulation in affective illness and to elucidate the ANS effects of antidepressive treatment. Eur J Med Res Jan 26;9(1): Review.

Dysautonomia in dogs Dysuria11/11 Distended urinary bladder10/10 Mydriasis11/11 Absent pupillary light reflex11/11 Dry mucous membranes10/11 Weight loss8/10 Decreased Schirmer tear test (<15 mm/min)8/10 Decreased anal reflex7/9 Decreased appetite7/10 Vomiting/Regurgitation6/9 Lethargy7/11 Elevated third eyelid5/11 Constipation3/9 Dysphagia3/9 Diarrhea3/9 Weakness2/9 Abdominal pain1/10

Diagnostic Criteria for Major Depression Depressed mood Markedly diminished interest or pleasure More than 5% body weight loss or gain in a month Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy, feeling of worthlessness or guilt Diminished ability to think, concentrate Recurrent thoughts of death # Five of above symptoms appear most of the day, nearly every day for at least 2 weeks and cause a significant change from previous functioning. Diagnostic Criteria for Major Depressive Episode

Montgomery-Asberg Depression Rating Scale (1) apparent sadness (2) reported sadness (3) inner tension (4) reduced sleep (5) reduced appetite (6) concentration difficulties (7) lassitude (8) inability to feel (9) pessimistic thoughts (10) suicidal thoughts

SOMATIC ANXIETY (Tachycardia, palpitations, chest pain, choking feeling, sighing, dyspnea, hyperventilation, dry mouth, difficulty swallowing, flatulence, gastric pain, nausea, vomiting, diarrhoea, constipation, urinary frequency, sweating, giddiness, blurred vision or tinnitus) The ANS controls Cardiovascular system Digestive system Respiratory functions Salivation Perspiration Pupils Micturition Erection

Am J Hum Genet March; 68(3): 753–758. Familial Dysautonomia Is Caused by Mutations of the IKAP Gene Sylvia L. Anderson, 1 Rocco Coli, 1 Ira W. Daly, 1 Elizabeth A. Kichula, 1 Matthew J. Rork, 1 Sabrina A. Volpi, 1 Josef Ekstein, 2 and Berish Y. Rubin 1 1 Department of Biological Sciences, Fordham University, Bronx, NY; and 2 Dor Yeshorim, The Committee for Prevention of Jewish Diseases, Brooklyn, NY/Jerusalem

Orthostatic hypotension - extreme drop in blood pressure with change in posture Breath holding in early years to the point of fainting Episodic vomiting Excessive drooling and sweating A smooth tongue and decrease in sense of taste Inappropriate temperature control with very high to very low temperatures Poor weight gain and growth Decreased reaction to pain or no reaction at all Cold, puffy hands and feet Extremes in blood pressure Corneal abrasions and dry eyes Gastric dysmotility Dysautonomic "crisis" Symptoms in an older child with familial dysautonomia

Autonomic nervous system controls Cardiovascular system Digestive system Respiratory functions Salivation Perspiration Pupils Micturition Erection

Antidepressants in Depression and Anxiety The serotonergic system has been implicated in the alterations in appetite, energy, sleep, mood, libido, and cognitive functioning seen in anxiety and affective disorders.

Mitral valve prolapse and dysautonomia Fatigue Chest pain Palpitations or irregular heart beat Migraine headaches Anxiety Depression Panic attacks Shortness of breath