Neurobiology of Placebo Effect

Year 2013, Volume: 5 Issue: 3, 299 - 312, 01.09.2013

Murat Erdem Süleyman Akarsu Murat Gülsün

https://doi.org/10.5455/cap.20130520

Abstract

Placebo is defined as a substance or method that has no specific effect on the condition being treated. Placebo leads to the state of contentment and shows its effects just like a drug by the pathways in the body. Various changes formed by plasebo on the brain activation, neurotransmitters and hormones have been observed with the development of neuroimaging methods. The effects of dopamine, serotonin, and opioid systems in the formation of the placebo response; the relationship between placebo effect, reward cycle and expectation process and the role of the some specific regions in the brain where pharmacological agents acting on during the placebo response have been shown in several studies. There are similarities between hypnosis and the placebo effects and expectation of improvement is closely related to the suggesting phenomenon in the hypnosis as well as placebo responses. The formation of similar changes in the brain after administration of placebo and hypnosis associated with the expectation models and suggestions attracts attention. Neurochemical pathways in the brain constitute functional impact with many of the common mechanisms. Therefore, all of these mechanisms in the placebo response can take part in relation to each other. Although it is known that many factors may influence, understanding of the effects of placebo and viewing the changes in the brain formed by placebo have an important place for enlightening roles of psychological factors in the onset of diseases and treatment.

Keywords

Placebo effect, neurobiology, anticipation and reward models.

Plasebo Etkinin Nörobiyolojisi

Abstract

Plasebo, tedavi edilen duruma yönelik özgületkisi olmayan madde ya da yöntem olarak tanımlanmıştır. Plasebo, hoşnutluk durumuna yol açmakta, tıpkı bir ilacın etkisi gibi vücuttaki yolaklar aracılığıyla etkisini göstermektedir. Nörogörüntüleme yöntemlerinin gelişmesi ile plasebonun beyin aktivasyonu, nörotransmitterler ve hormonlar üzerinde çeşitli değişiklikler oluşturduğu gözlenmiştir. Plasebo cevabının oluşmasında dopamin, serotonin, opioid sistemlerinin etkisi, plasebo etkisinin beklenti süreci ve ödül döngüsü ile ilişkisi, farmakolojik ajanların etki ettiği beyindeki bazı özgül merkezlerin plasebo cevabı sırasındaki rolü çalışmalarda gösterilmiştir. Plasebo etkisi ile hipnozun etkisi arasında da benzerlikler vardır ve hem plasebo hem de hipnoz yanıtında iyileşme beklentisi telkin fenomeni ile yakından ilişkilidir. Telkin ve beklenti modelleri ile ilişkili olarak hem hipnoz hem de plasebo uygulanımı sonrası beyinde benzer değişiklikler oluşması ilgi çekmektedir. Beyindeki nörokimyasal yolaklar izole olarak değil birçok ortak mekanizmalarla fonksiyonel etki oluşturmaktadır. Bu nedenle plasebo yanıtında tüm bu mekanizmalar birbirleriyle ilişkili olarak görev alabilirler. Her ne kadar birçok faktörün etkisi olduğu göz önünde bulundurulsa da; plasebonun etkisini anlamanın ve beyinde yaptığı değişiklikleri görüntüleyebilmenin, psikolojik faktörlerin hastalıkların oluşumunda ve tedavisindeki rollerini aydınlatmada önemli yeri vardır.

Keywords

Plasebo etkisi, nörobiyoloji, beklenti ve ödül modelleri.

References

• Brody H. The lie that heals: the ethics of giving placebos. Ann Intern Med 1982; 97:112-118.
• Benedetti F, Mayberg HS, Wager TD, Stohler CS, Zubieta JK. Neurobiological mechanisms of the placebo effect. J Neurosci 2005; 25:10390-10402.
• Göka E. Plasebo kavramı ve plasebo etkisi. Turk Psikiyatri Derg 2002; 13:58-64.
• Oken BS. Placebo effects: clinical aspects and neurobiology Brain 2008; 131:281228
• Stoessl AJ, de la Fuente-Fernandez R. Willing oneself better on placebo–effective in its own right. Lancet 2004; 364:227-228.
• Colloca L, Benedetti F. Placebos and painkillers: is mind as real as matter? Nat Rev Neurosci 2005; 6:545-551.
• Haour F. Mechanisms of the placebo effect and of conditioning. Neuroimmunomodulation 2005; 12:195-200.
• Klosterhalfen S, Enck P. Psychobiology of the placebo response. Auton Neurosci 2006; 125:94-99.
• Price DD, Craggs J, Verne GN, Perlstein WM, Robinson ME. Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients. Pain 2007; 127:63-72. de la Fuente-Fernandez R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson’s disease. Science 2001; 293:1164-1166.
• Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia – imaging a shared neural network. Science 2002; 295:1737-1740.
• Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placeboinduced changes in fMRI in the anticipation and experience of pain. Science 2004; 303:1162-1167.
• Lieberman MD, Jarcho JM, Berman S, Naliboff BD, Suyenobu BY, Mandelkern M et al. The neural correlates of placebo effects: a disruption account. Neuroimage 2004; 22:447-455
• Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA et al. Placebo effects mediated endogenous opioid activity on m–opioid receptors. J Neurosci 2005; 25:7754-7762.
• Leuchter AF, Cook IA, Witte EA, Morgan M, Abrams M. Changes in brain function of depressed subjects during treatment with placebo. Am J Psychiatry 2002; 159:122—129.
• Mayberg HS, Silva JA, Brannan SK, Tekell JL, Mahurin RK, McGinnis S et al. The functional neuroanatomy of the placebo effect. Am J Psychiatry 2002; 159:728-737. Kaasinen V, Aalto S, Någren K, Rinne JO. Expectation of caffeine induces dopaminergic responses in humans. Eur J Neurosci 2004;19:2352-2356.
• Ader R. Conditioned immunomodulation: research needs and directions. Brain Behav Immun 2002; 17:S51-S57.
• Ader R, Cohen N. Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 1982; 215:1534-1536.
• Smith GR, McDaniel SM. Psychologically mediated effect on the delayed hypersensitivity reaction to tuberculin in humans. Psychosom Med 1983; 45:65-70.
• Giang DW, Goodman AD, Schiffer RB, Mattson DH, Petrie M, Cohen N et al. Conditioning of cyclophosphamide-induced leukopenia in humans. J Neuropsychiatry 1996; 8:194-201.
• Ribeiro SCM, Tandon R, Grunhaus L, Greden JF. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry 1993; 150: 618-1629.
• Beecher HK. The powerful placebo. JAMA 1955; 159:1602-1606.
• Melzack R. Evolution of the neuromatrix theory of pain. The Prithvi Raj Lecture: presented at the third World Congress of World Institute of Pain, Barcelona 2004. Pain Pract 2005; 5:85-94.
• Knudsen L, Petersen GL, Nİrskov KN, Vase L, Finnerup N, Jensen TS, et al. Review of neuroimaging studies related to pain modulation. Scand J Pain 2011; 2:108-120. Fricchione G, Stefano GB. Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries. Med Sci Monit 2005; 11: MS54MS de la Fuente-Fernandéz R, Stoessl AJ. The placebo effect in Parkinson’s disease. Trends Neurosci 2002; 25:299-303.
• Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 2010; 67:857-865.
• Pollo A, Torre E, Lopiano L, Rizzone M, Lanotte M, Cavanna A et al. Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients. Neuroreport 2002; 13:1383-1386.
• Benedetti F, Colloco L, Torre E, Lanotte M, Melcarne A, Pesare M et al. Placeboresponsive Parkinson patients show decreased activity in single neurons of subthalamic nucleus. Nat Neurosci 2004; 7:587-588.
• Irizarry KJL, Licinio J. An explanation for the placebo effect? Science 2005; 307:1411-1412.
• Scott DJ, Stohler CS, Egnatuk CM, Want H, Koeppe RA, Zubieta JK. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007; 55:325-326.
• Faria V. Mind really does matter: the neurobiology of placebo-induced anxiety relief in social anxiety disorder (Doctoral thesis). Uppsala, Uppsala University, 2012. de la Fuente-Fernandez R, Schulzer M, Stoessl AJ. Placebo mechanisms and reward circuitry: clues from Parkinson’s disease. Biol Psychiatry 2004; 56:67-71.
• Teixeira MZ, Guedes CHFF, Barreto PV, Martins MA. The placebo effect and homeopathy. Homeopathy 2010; 99:119-129.
• Benedetti F, Lanotte M, Colloca L. When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience 2007; 147:260-271.
• Petrovic P, Dietrich T, Fransson P, Andersson J, Carlsson K. Ingvar M. Placebo in emotional processing-induced expectations of anxiety relief activate a generalized modulatory network. Neuron 2005; 46:957-969. de la Fuente-Ferna´ndez R, Phillips AG, Zamburlini M, Sossi V, Calne DB, Ruth TJ et al. Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 2002; 136:359-363.
• Etkin A, Egner T, Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn Sci 2011; 15:85-93.
• Wager TD, Atlas LY, Leotti LA, Rilling JK. Predicting individual differences in placebo analgesia: contributions of brain activity during anticipation and pain experience. J Neurosci 2011; 31:439-452.
• Lyby PS, Aslaksen PM, Flaten MA. Is fear of pain related to placebo analgesia? J Psychosom Res 2010; 68:369-377.
• Morton DL, Brown CA, Watson A, El-Deredy W, Jones A. Cognitive changes as a result of a single exposure to placebo. Neuropsychologia 2010; 48:1958-1964.
• Furmark T, Appel L, Michelgård A, Wahlstedt K, Åhs F, Zancan S et al. Cerebral blood flow changes after treatment of social phobia with the neurokinin-1 antagonist GR205171 citalopram or placebo. Biol Psychiatry 2005; 58:132-142.
• Peres JFP, Newberg AB, Mercante JP, Simão M, Albuquerque VE, Peres MJP et al. Cerebral blood flow changes during retrieval of traumatic memories before and after psychotherapy: a SPECT study. Psychol Med 2007; 37:1481-1491.
• Fu CHY, Williams SCR, Cleare AJ, Brammer MJ, Walsh ND, Kim J et al. Attenuation of the neural response to sad faces in major depression by antidepressant treatment. Arch Gen Psychiatry 2004; 61:877-889.
• Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP. Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 2005; 112:1479-1485.
• Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 279:400-403.
• Morton DL, Watson A, El-Deredy W, Jones AKP. Reproducibility of placebo analgesia: effect of dispositional optimism. Pain 2009; 146:194-198.
• Wager TD, Scott DJ, Zubieta JK. Placebo effects on human μ-opioid activity during pain. Proc Natl Acad Sci USA 2007; 104:11056-11061.
• Zhang W, Luo J. The transferable placebo effect from pain to emotion: changes in behavior and EEG activity. Psychophysiology 2009; 46:626-634.
• Zhang W, Qin S, Guo J, Luo J. A follow-up fMRI of a transferable placebo anxiolytic effect. Psychophysiology 2011; 48:1119-1128.
• Bremner JD, Southwick SM, Charney DS. The neurobiology of posttraumatic stress disorder: an integration of animal and human research. In Posttraumatic Stress Disorder. A Comprehensive Text (Eds PA Saigh, JDBremner):103-143. Boston, Allyn and Bacon, 1999.
• Grossman A: Opioids and stress in man. J Endocrinol 1988; 119:377-381.
• Maier SF, Davies S, Grau JW, Jackson RL, Morrison DH, Moye T et al. Opiate antagonists and long-term analgesic reaction induced by inescapable shock in rats. J Comp Physiol Psychol 1980; 94:1172-1183.
• Insel TR, Kinsley CH, Mann PE, Bridges RS. Prenatal stress has long-term effects on brain opiate receptors. Brain Res 1990; 511:93-97.
• Sanchez MD, Milanes MV, Pazos A, Diaz A, Laorden ML, Autoradiographic evidence of mu-opioid receptors down-regulation after prenatal stress in offspring rat brain. Brain Res Dev Brain Res 1996; 94:14-21.
• Sanchez MD, Milanes MV, Pazos A, Diaz A, Laorden ML. Autoradiographic evidence of delta-opioid receptor downregulation after prenatal stress in offspring rat brain. Pharmacology 2000; 60:13-18.
• Myers RD. Neuroactive peptides: unique phases in research on mammalian brain over three decades. Peptides 1994; 15:367-381.
• Friedman MJ. What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? J Clin Psychiatry 2000; 61(Suppl 7):44-51.
• Schmauss C, Yaksh TL. In vivo studies on spinal opiate receptor systems mediating amtinociciption. II. J Pharmacol Exp Ther 1984; 228:1-12.
• Napier TC, Mitrovic I. Opioid modulation of ventral pallidal inputs. Ann N Y Acad Sci 1999; 877:176-201.
• Schmauss C. Spinal kappa-opioid receptor-mediated antinociception is stimulusspecific. Eur J Pharmacol 1987; 137:197-205.
• Steiner H, Gerfen CR. Role of dynorphin and enkephalin in the regulation of striatal output pathways and behavior. Exp Brain Res 1998; 123:60-76.
• Kalin NH, Sherman JE, Takahashi LK. Antagonism of endogenous CRH systems attenuates stress-induced freezing behavior in rats. Brain Res 1988; 457:130-135.
• Quirarte GL, Galvez R, Roozendaal B, McGaugh JL. Norepinephrine release in the amygdala in response to footshock and opioid peptidergic drugs. Brain Res 1998; 808:134-140.
• Howard JM, Olney JM, Frawley JP, Peterson RE, Smith LH, Davis JH et al. Studies of adrenal function in combat and wounded soldiers; a study in the Korean theatre. Ann Surg 1955; 141:314-320.
• Sher L. The placebo effect on mood and behavior: possible role of opioid and dopamine modulation of the hypothalamic-pituitary-adrenal system. Forsch Komplementärmed Klass Naturheilkd 2003; 10:61-68.
• Bendetti F, Amanzio M. The neurobiology of placebo analgesia: from endogenous opioids to cholecystokinin. Prog Neurobiol 1997; 51:109-125.
• Zubieta JK, Bueller JA, Xu Y, Koeppe RA, Stohler CS. Neurochemical mediation of the placebo effect in humans; in: 59th Annual Convention of the Society of Biological Psychiatry New York. Biol Psychiatry 2004; 55:57S–58S.
• Katz RJ, Lott MH, Arbus P, Crocq L, Herlobsen P, Lingjaerde O et al. Pharmacotherapy of posttraumatic stress disorder with a novel psychotropic. Anxiety 1994-95; 1:169-174.
• Brady K, Pearlstein T, Asnis GM, Baker D, Rothbaum B, Sikes CR. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA 2000; 283:1837-1844.
• Shestatzky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress disorder. Psychiatry Res 1988; 24:149-155.
• Reist C, Kauffmann CD, Haier RJ, Sangdahl C, DeMet EM, Chicz-DeMet A. A controlled trial of desipramine in 18 men with posttraumatic stress disorder. Am J Psychiatry 1989; 146:513-516.
• Zohar J, Amital D, Miodownik C, Kotler M, Bleich A, Lane RM et al. Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder. J Clin Psychopharmacol 2002; 22:190-195.
• Sher L. The role of endogenous opioids in the placebo effect in post-traumatic stress disorder. Forsch Komplementärmed Klass Naturheilkd 2004; 11:354-359.
• Baker SL, Kirsch I. Hypnotic and placebo analgesia: order effects and the placebo label. Contemp Hypn 1993; 10:117-126.
• Glass LB, and Barber TX. A note on hypnotic behavior the definition of the situation and the placebo effect. J Nerv Ment Dis 1961; 132:539-541.
• Kirsch I, Hypnosis and placebos: response expectancy as a mediator of suggestion effects. Anales de Psicología 1999; 15:99-110.
• Maquet P, Faymonville ME, Degueldre C, Delfiore G, Franck G, Luxen A et al. Functional neuroanatomy of hypnotic state. Biol Psychiatry 1999; 45:327-333.
• Derbyshire SW, Whalley MG, Stenger VA, Oakley DA. Cerebral activation during hypnotically induced and imagined pain. Neuroimage 2004; 23:392-401.
• Derbyshire SW, Whalley MG, Oakley DA. Fibromyalgia pain and its modulation by hypnotic and non-hypnotic suggestion: an fMRI analysis. Eur J Pain 2009; 13:5425
• Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 1997; 277:968-971. Wik G, Fischer H, Bragée B, Finer B, Fredrikson M. Functional anatomy of hypnotic analgesia: a PET study of patients with fibromyalgia. Eur J Pain 1999; 3:7-12. Murat Erdem, Doç. Dr., Gülhane Askeri Tıp Fakültesi Psikiyatri A.D, Ankara; Süleyman Akarsu, Dr., Gülhane Askeri Tıp Fakültesi Psikiyatri A.D, Ankara; Murat Gülsün, Doç. Dr., Gülhane Askeri Tıp Fakültesi Psikiyatri A.D, Ankara. Yazışma Adresi/Correspondence: Murat Gülsün, Gülhane Askeri Tıp Fakültesi Psikiyatri A.D, Ankara, Turkey. E-mail: [e-mail] Yazarlar bu makale ile ilgili herhangi bir çıkar çatışması bildirmemişlerdir. The authors reported no conflict of interest related to this article. Çevrimiçi adresi / Available online at: www.cappsy.org/archives/vol5/no3/ Çevrimiçi yayım / Published online 03 Eylül/September 03, 2013; doi:10.5455/cap.20130520