Dopamine, depression and Bupropion

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20101027 Speech in Shin Kong Wu Ho-Su Memorial Hospital

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  • 哈囉潘醫師,我最近因為工作關係患了憂鬱症和恐懼症。
    德國的醫生讓我吃一種草藥叫做貫葉連翹(St John's wort),一天吃900mg,基本上沒有副作用。這種藥要連續吃14天才會開始生效,而且不能斷。
    之前他讓我吃 Paroxetinhydrochlorid 吃了一天很有效,第二天開始就沒效了。給你參考。
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  • <number>
    目前的抗憂鬱劑作用機轉主要與神經傳導物相關,情緒、焦慮疾病相關的神經傳導物質:多巴胺、正腎上腺素、血清素。
    不同的神經傳導物質關係精神、行為功能的不同層面:
    多巴胺:與注意力、喜悅感、回饋機制、動機相關
    正腎上腺素:與覺醒狀態相關
    血清素:與強迫思想、強迫行相關
    除此之外,仍有許多中樞神經的傳導物質、神經胜肽及賀爾蒙涉及憂鬱症造成的原因。
    而Wellbutrin主要是針對多巴胺與正腎上腺素在回收作用,且憂鬱症療效也經研究及臨床多年驗證。
    但過去常因使用300mg需要一天二次的不方便性,讓許多患者停留在不足的治療劑量下。
    今年GSK將推出新的XL劑型,以增加服藥的方便性。
  • <number>
    Iproniazid and imipramine stories
  • <number>
    在seizure方面雖然仍需要注意禁忌症的部分,不要使用於癲癇的患者。
    但是若使用於一般族群,Seizure的發生率與其他抗憂鬱劑相當,且劑量高達每天450mg,其發生的機率也僅千分之一。
    與其他的抗憂鬱劑發生的seizure機率0-0.4%並無差異。
  • <number>
    第一個先看的研究為Clayton在2005年發表的文章,是二個以Wellbutrin XL與Escitalopram使用八週的臨床研究分析。
    這裡是以Hospital Anxiety and Depression (HAD) scale來評估,並同時評估在焦慮的次項分數。
    此研究為隨機雙盲安慰劑組控制的研究,Wellbutrin XL劑量在每天300-450mg之間與Escitalopram10-20mg使用於中度至重度憂鬱症的患者。
    第一觀察的指標為性功能的影響並同時觀察焦慮的改善分數。
    結果顯示焦慮的改善分數二組療效相當,並無統計上的差異。
  • <number>
    另一個療效的比較資料是Thase於2006年發表的文章Wellbutrin XL與venlafaxine比較的十二週研究。
    研究結果是以HAM-D評估,結果顯示Wellbutrin XL的憂鬱症緩解率比venlafaxine高,46%比33%,
    顯示Wellbutrin XL較venlafaxine有較高的機會達到憂鬱症緩解。
  • <number>
    另外在同一篇研究中,一個非常重要的結果指出,以生活品質的喜悅與滿意度自評問卷及激勵與活力問卷評估這一群憂鬱症的老年人,
    使用Wellbutrin XL在活力與激勵的分數的改善非常明顯,相較於安慰劑組也具有明顯的統計差異。
    這可能代表這使用Wellbutrin XL與老年憂鬱症患者,可明顯改善它們的活力、激勵與對生活的滿意度。
    且劑量介於1-2顆之間即可。
  • <number>
    由此圖可明顯看出次項分數的改善明顯高於安慰劑組。
    此代表的意思為低活力、喜悅度的憂鬱症患者使用Wellbutrin XL可能獲得更快速且更明顯的改善。
    所以如果醫師看到憂鬱症患者有此類低活力、喜悅度的憂鬱症患者,可優先考慮使用Wellbutrin XL治療他們。
  • <number>
    Wellbutrin XL與escitalopram的比較研究中,先使用一周的150mgWellbutrin XL後再提高到 300-450mg。
    其中Wellbutrin XL較常發生的副作用是口乾、失眠、便秘;而Escitalopram則是倦怠、嗜睡及打呵欠較常見。
    但與安慰劑組並無統計上的差異。
  • <number>
    Wellbutrin XL與venlafaxine的比較研究中,也是先使用一周的150mgWellbutrin XL後再提高到 300-450mg。
    此研究中大部份的副作用皆相當,但Venlafaxine XR的噁心比例明顯較高。
  • <number>
    另一八週研究顯示,使用venlafaxine這一組有比較高的頭暈、失眠、躁動不安與噁心的比例。
    且在停藥過程中,停斷的症狀也是venlafaxine明顯較高21%, Wellbutrin XL則與安慰劑組相當。
    在老年人的部分也呈現一樣的現象,因副作用而停藥的比例,使用Wellbutrin XL為8%,而安慰劑組為10%。
    顯示使用Wellbutrin XL因副作用而停藥的比例與安慰劑組相當。
  • <number>
    在使用SSRIs使用時常抱怨的嗜睡副作用,再使用Wellbutrin發生的機會是少的。
    因此可在使用時,讓患者不會因嗜睡的副作用而影響白天的活力。
  • <number>
    在體重的部分Wellbutrin也不像其他抗憂鬱在長期使用後會有體重逐漸上升的困擾,而是呈現較不影響體重的特色。
    但是在研究中也發現,若患者的BMI較高者,使用Wellbutrin會有體重下降的趨勢。
    尤其越高者越明顯。
  • <number>
    在性功能方面,Wellbutrin較不影響性功能的問題是大家所公認的。
    在Wellbutrin XL也不例外。與escitalopram的二個比較研究的整合分析顯示,在第一週使用escitalopram的患者即產生明顯較高比例的患者有此方面的問題。
    且比例高達30%並統計顯示較安慰劑組與Wellbutrin XL明顯高。
    而Wellbutrin XL為15%,雖然高於安慰劑組但並未達統計上差異。
  • <number>
    同樣的與Venlafaxine的比較研究中,不管在性功能的那一個面向,都與使用Wellbutrin XL的患者呈現統計上的差異。
    即使用Venlafaxine的患者,將明顯影響患者對性的喜悅度、慾望、性高潮等等。
  • <number>
    新劑型的Wellbutrin XL,除了同時具有Wellbutrin較無副作用的特色外,一天一次的方便性也明顯提高患者的服藥遵囑性。
    根據2007年的一個迴歸分析研究報告,使用Wellbutrin XL的患者回診領藥的比例明顯高於使用SR的患者比例。
    此現象意味著一天一次的使用確實可提升患者服藥的意願。
  • <number>
    80% with chronic or recurrent depression; mean citalopram dose 41.8 mg/day; remission also QIDS-SR < 5.
  • Dopamine, depression and Bupropion

    1. 1. Dopamine , Depression and Bupropion Dr. BillyPan Taipei Wanfang Medical Center Psychiatry Department http://www.wretch.cc/blog/billypan101
    2. 2. HPA axis CMAJ. 2009 February 3; 180(3): 305– 313. The hypothalamic–pituitary–adrenal axis. This system is activated by stress directly at the level of the hypothalamus or indirectly at the level of the amygdala. Chronic stress increases the level of corticotropin- releasing factor and cortisol and decreases expression of corticotropin-releasing factor type 1 receptors and glucocorticoid receptors. Stress-and depression-associated changes at the level of the hippocampus in particular are thought to underlie the structural changes seen in this brain region, which in turn may contribute to chronic disinhibition of the hypothalamic– pituitary– adrenal axis.
    3. 3. HPA axis and Neurotransmitter  Acute Stress  HPA axis  corticotropin-releasing factor  amygdala, hippocampus, ect.  These neurons may also contribute to activation of the serotonin and norepinephrine systems.  Reciprocal connections between the norepinephrine system and the hypothalamus create a feed-forward cascade in which stress progressively activates corticotropin-releasing factor and norepinephrine signalling.  Activation of this system is thought to increase vigilance and fear. Pharmacol Biochem Behav 2002;73:147-58.
    4. 4. HPA axis and Neurotransmitter  Chronic Stress  Excessive glutamate activation of NMDA type glutamate receptor  decrease brain derived neurotrophic factor (BDNF)  degeneration of glial cell  brain atrophy CMAJ. 2009 February 3; 180(3): 305– 313.
    5. 5. Brain structural and functional abnormalities in mood disorders Brain Struct Funct (2008) 213:93–118
    6. 6. Brain structural and functional abnormalities in mood disorders CMAJ. 2009 February 3; 180(3): 305–313.
    7. 7. HPA axis and Neurotransmitter  Stress  Amygdala   increse dopamine in Prefrontal Cortext and Ventral Straitum   altering striatal levels of BDNF.  Acute irritable  Chronic anhedonia Pharmacol Biochem Behav 2002;73:147-58.
    8. 8. Prefrontal Cortext and Ventral Straitum
    9. 9. Dopamine and Serotonin Pathway
    10. 10. Depressive s/s
    11. 11. Dopamine and Substance Abuse
    12. 12. Monoamine neurotransmitter regulation of mood and behavior Stahl SM. Essential Psychopharmacology. 2000. Foote SL, Aston-Jones GS. Psychopharmacology. 1995: 335-345 Nutt DJ et al., J Psychopharmacol 2007, in press [Epub ahead of print,18 Oct 2006] Shelton AJ, Tomarken RC, Psychiatric Services 2000; 52 (11):1469–1478 Stahl SM J Clin Psychiatry 2003;64:1145-1146 Dopamine attention motivation pleasure reward Noradrenaline alertness energy Serotonin obsessions compulsions anxiety mood interest
    13. 13. The Dopamine Pathway
    14. 14. The Serotonin Pathway
    15. 15. NDRI
    16. 16. From the study of smoke cessation
    17. 17. Antidepressants - History  1958 Monoamine oxidase inhibitors (MAOIs)  1958 Tricyclics (TCA’s)  1982 Trazodone (Deseryl)  1988 Fluoxetine (Prozac)  1989 Bupropion (Wellbutrin IR) Tid  1994 Nefazodone (Serzone)  1994 Venlafaxine (Effexor)  1996 Mirtazapine (Remeron)  1996 Bupropion (Wellbutrin SR) Bid  2003 Bupriopion (Wellbutrin XL) Qd
    18. 18. Wellbutrin, Failed in 1986…  Wellbutrin was withdrawal from market due to significant incidence of seizure.  Risk of seizure was found to highly dose–dependent.  Wellbutrin was reintrodued in 1989 for limit maximum dose of 450mg. (originally recommended dosage was 400-600mg)
    19. 19. Wellbutrin seizure incidence  Wellbutrin® XL is associated with a dose-related risk of seizure but risk is relatively low- overall incidence in clinical trials (up to 450mg/day) is > 0.1%1 and is similar to other newer antidepressants (0-0.4%)2  Incidence of first seizure in the general population is estimated to be 0.07 to 0.09%2  Wellbutrin® XL is contraindicated in patients with a current seizure disorder or any history of seizures1 1. Wellbutrin XL Prescription Information. 2. Montgomery SM Int J Clin Pract 2005;59(12):1435-1440.
    20. 20. Efficacy of Wellbutrin® XL vs. Escitalopram (lexapro) HAD = Hospital Anxiety and Depression Scale *P<0.05 vs placebo. Bupropion XL Escitalopram Placebo 0 –10 –4 –8 –6 –12 –2 Meanchangefrom baselineatweek8 n = 263 n = 266 n = 256 –5.2 –4.5 –3.6 n = 263 n = 266 n = 256 0 –10 –4 –8 –6 –12 –2 Meanchangefrom baselineatweek8 HAD Anxiety Subscale ScoreHAD Total Score –11.1–10.5 –8.1 * ** * Clayton et al J Clin Psychiatry, 2006
    21. 21. Efficacy of Wellbutrin® XL vs. venlafaxine XL Response and remission rates from the US clinical trial Venlafaxine XR * Statistically significant: odds ratio 1.75, 95% CI 1.04, 2.93 # Includes doses above the maximum recommended dose in South Korea Response = ≥50% reduction in HAMD-17 total score Remission = HAMD-17 total score ≤7 Thase ME et al. J Clin Psychopharmacol 2006: 26:482-488 0 10 20 30 40 50 60 Response Remission Bupropion XL (150-450mg/day#) (75-225mg/day) * Remissionrate(%)
    22. 22. Wellbutrin XL improves low energy and motivation 0 5 10 15 20 25 MEItotalscore meanchangefrombaseline Placebo (n = 180) 17 24* *p = 0.001 vs placebo MEI = Motivation and Energy Inventory Chrzanowski W et al., Eur Neuropsychopharmacol 2006; 16 (Suppl 4): S315. Wellbutrin XL 150-300mg/day (n = 188)
    23. 23. Wellbutrin XL improves depressive in energy, interest and pleasure Improvementinsymptomsof energy,interestandpleasure (IDS-subset# ) Placebo Wellbutrin XL 0 2 4 6 8 5.3 6.7 * Some patients in this analysis received doses of Wellbutrin that are above the licensed dose * p=0.007 significant improvement vs placebo #patient rated subscale Jefferson JW et al., J Clin Psychiatry 2006;67:865-873
    24. 24. Comparison of adverse events (%) for Wellbutrin® XL vs the SSRI escitalopram   Wellbutrin XR 150-450mg/day (n=276) Escitalopram 10-20mg/day (n=281) Placebo (n=273) Dry mouth 22% 13% 11% Fatigue 4% 14% 6% Insomnia 14% 10% 8% Constipation 9% 3% 6% Somnolence 3% 8% 5% Decreased appetite 5% 6% 4% Nasopharyngitis 5% 5% 3% Irritability 5% 1% 4% Yawning <1% 5% 1% Clayton AH et al.,J Clin Psychiatry 2006;67(5):736-46 Some patients in this analysis received doses of Wellbutrin that are above the licensed dose
    25. 25. Comparison of adverse events (%) for Wellbutrin® XL vs the SNRI venlafaxine   Wellbutrin XL 150-450mg/day (n=168) Venlafaxine XR 75-225mg/day (n=174) Dry mouth 24% 29% Nausea 15% 26% Nasopharyngitis 10% 5% Diarrhoea 5% 10% Decreased appetite 4% 9% Somnolence 1% 7% Sedation 1% 6% Yawning 0% 7% Thase ME et al., J Clin Psychopharmacol 2006;26:482-88 Some patients in this analysis received doses of bupropion that are above the maximum licensed dose for Taiwan
    26. 26. Wellbutrin XL has similar rates of discontinuation symptoms to placebo GSK data on file Discontinuation symptoms during taper and follow-up periods % of patients 0 1 2 3 4 5 Nausea Irritability Insomnia Dizziness Headache Placebo Wellbutrin XL Venlafaxine XL Overall rates of discontinuation symptoms similar to placebo (Venlafaxine XR: 21%; Wellbutrin XL: 12%; Placebo: 12%)
    27. 27. Somnolence vs SSRIs Thase ME et al., J Clin Psychiatry 2005; 66(8):974-81 5 12 * 3† Incidenceofsomnolenceas anAE(%) Placebo Pooled SSRIs Bupropion (n=524) (n=758) (n=748) *p<0.001 significantly higher incidence vs placebo †p<0.001 significantly lower incidence vs pooled SSRIs 0 2 4 6 8 10 12 14 Some patients in this analysis received doses of Wellbutrin that are above the maximum licensed dose for South Korea
    28. 28. Somnolence vs SSRIs
    29. 29.  Mean change in body weight at study endpoint for patients receiving Wellbutrin SR as a function of baseline body mass index (BMI) Patients who had responded to 8 weeks of open-label treatment with bupropion (SR) followed by 44 weeks of double-blind treatment with bupropion (150mg SR bid) or placebo Adapted from Croft H et al., Clin Ther 2002;24;662-672 -0.1 -0.6 -1.4 -2.4 -3 -2.5 -2 -1.5 -1 -0.5 0 BMI <22 BMI 22-26 BMI ≥27 BMI ≥30 Meanchangeinbodyweight(kg)Weight change during treatment
    30. 30. Orgasm dysfunction vs. SSRI Escitalopram 0 10 20 30 40 Patients(%) Week 2 4 6 8 30% 15% 9% † † † † * 1 Clayton AH et al., J Clin Psychiatry 2006;67:736-746. Bupropion XL (n=263) Escitalopram (n=266) Placebo (n=256) *p < 0.01 Escitalopram vs bupropion XL and placebo †p < 0.001 Escitalopram vs bupropion XL and placebo No statistical difference between bupropion XL and placebo
    31. 31. Minimal sexual side-effects compared with the SNRI venlafaxine XL Thase ME et al. J Clin Psychopharmacol 2006; 26, 482-488. *p≤0.011 vs venlafaxine XR -1 * * * * * 0 1 Pleasure Desire/ Frequency Desire/ Interest Arousal Orgasm Bupropion XL (n=160) Venlafaxine XR (n=164) Adjustedmeanchangefrombaseline CSFQ Subscale Mean Change Scores (Average of Weeks 5-12) Improvement Some patients in this analysis received doses of Wellbutrin® XL that are above the licensed dose
    32. 32. Better Adherence with XL Formulation American Journal of Therapeutics 2007; 14: 241–246 Refill adherence over the study period %CohortRemaining *p<.0001 bupropion XL versus bupropion SR ++p<.0005 bupropion XL versus bupropion SR +p<.005 bupropion XL versus bupropion SR Number of Refills for index Product
    33. 33. Seasonal affective disorder
    34. 34. Smoking Cessation
    35. 35. Smoking Cessation
    36. 36. Weight Reduction
    37. 37. Weight Reduction
    38. 38. Improving Cognitive Function N=541, Neurocognition Index was measured on a computerized battery of tests, CNS Vital Signs (CNSVS)
    39. 39. For Bipolar Depression Am J Psychiatry. 2006 Feb;163(2):232-9.
    40. 40. For Bipolar Depression BRITISH JOURNAL OF P SYCHIATRY ( 2 0 0 6 ) , 1 8 9, 1 2 4 ^ 131.
    41. 41. How Effective is an SSRI in Real World Practice?  ~1/3 met criteria for remission (HAM-D ≤ 7)  ~ 1/2 met criteria for response (≥ 50% decrease in depressive severity) (Trivedi et al, Am J Psychiatry, 2006)
    42. 42. In STAR*D Level 2 Switch: Beat CBT
    43. 43. In STAR*D Level 2 augmentation: : lead to 46% remission
    44. 44. Augumention with escitalopram  12 weeks, Rates of response 62% and remission 50%  Only 6% patient discontinued treatment due to side effect. J Psychiatr Pract. 2008 September ; 14(5): 271–280.
    45. 45. AUGMENTATION IN LATE-LIFE DEPRESSION Am J Psychiatry 164:6, June 2007
    46. 46. XL : Better Compliance and Sleep
    47. 47. Wellbutrin XL  For depressive symptoms involving dopamine, such as anhedonia, fatigue, concentration, interesting  Seasonal affective disorder  Smoking cessation  Weight reduction  Bipolar depression  Less Sexual dysfunction  Augmentation  Switching  Better Compliance
    48. 48. Thank you for your attention !

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