情感性精神障碍疾病治疗药物的研究现状

摘要/Abstract

摘要： 情感性精神障碍包括抑郁症（又称单向情感精神障碍）和躁郁症（双相情感精神障碍），是最为常见的精神疾病，其发病率高、复发率高，社会危害严重。目前临床上治疗单向情感精神障碍的主要药物是以氟西汀、度罗西汀为代表的5-羟色胺选择性再摄取抑制剂（serotonin-specific reuptake inhibitors，SSRIs）和5-羟色胺/去甲肾上腺素双重再摄取抑制剂（serotonin/norepinephrine dual reuptake inhibitor，SNRIs）。治疗双相情感精神障碍的药物主要有碳酸锂、丙戊酸钠和卡马西平等。目前，关于这些药物的机制研究主要有以下几方面：①SSRIs上调细胞溶质型磷脂酶A2（cytosolic phospholipase A2，cPLA₂）、细胞外信号调控激酶（extracellular-signal regulated kinases，ERK）及c-Fos和FosB 基因表达增加；②腺苷酸脱氨酶（adenosine deaminase，ADAR2）介导氟西汀对5-HT_2B受体RNA编辑的调节作用；③碳酸锂、丙戊酸钠和卡马西平对cPLA_2a基因表达的长期调节作用及碱化细胞的作用。但现存的理论都不能明确解释药物的作用机制，并且有些研究结果仍存在尚待解决的问题。

关键词: 抑郁症, 5-羟色胺特异性再摄取抑制剂, 碳酸锂, 丙戊酸钠, 卡马西平, 细胞溶质型磷脂酶A₂, 腺苷酸脱氨酶, 细胞碱化

Abstract: Affective disorders including depression (also known as unipolar depression) and bipolar disorder (unipolar depression)，are the most common psychiatric disorders, which have high incidence ratio, high recurrence ratio, and is harmful to the society. Clinically, anti-unipolar depression drugs are mainly serotonin-specific reuptake inhibitors (SSRIs), fluoxetine as represented, and serotonin/norepinephrine dual reuptake inhibitor (SNRIs), duloxetine as represented. And lithium salts (Li⁺), valproate sodium, and carbamazepine are the three classical anti-bipolar drugs. At present, researches concerning these drugs propose following major mechanisms: ①The expression of cytosolic phospholipase A2 (cPLA₂), extracellular-signal regulated kinases (ERK) and c-Fos and FosB is increased by SSRIs; ②Chronic administration of Fluoxetine could induce 5-HT_2B receptor pre-mRNA editing, with the help of adenosine deaminase (ADAR2) activity; ③Lithium carbonate, carbamazepine, valproate sodium could upregulate the mRNA and protein of cPLA_2a and induce alkalinization of cell. But the accurate pharmacological mechanisms of these drugs have not been fully elucidated and are needed to be further investigated.

Key words: depression, serotonin-specific reuptake inhibitors (SSRIs), lithium carbonate, carbamazepine, valproate sodium, cytosolic phospholipase A₂ (cPLA₂), adenosine deaminase (ADAR₂), intracellular alkalinization

中图分类号:

薛占霞, 彭亮. 情感性精神障碍疾病治疗药物的研究现状[J]. 神经药理学报, 2011, 1(3): 55-64.

XUE Zhan-xia, PENG Liang. Research Status of the Drugs Uesed in the Treatment of Affective Disorders Diseases[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(3): 55-64.

参考文献

1          Joan Kaufman，Andres Martin，Robert A King，et al. Are child-，adolescent-，and adult-onset depression one and the same disorder? [J]. Biol Psychiatry， 2001，49(12): 980-1001
2          Charles B.Nemeroff. The burden of severe depression: a review of diagnostic challenges and treatment alternatives [J].，2007，41(3-4): 189-206 J Psychiatr Res
3          Chad E.Beyer，Thomas I.F.H.Cremers. Do selective serotonin reuptake inhibitors acutely increase frontal cortex levels of serotonin? [J]. Eur J Pharmacol，，580(3): 350-354 2008
4          Papakostas George I，Cooper-Kazaz Rena，Appelhof Bente C，et al. Simultaneous initiation (coinitiation) of pharmacotherapy with triiodothyronine and a selective serotonin reuptake inhibitor for major depressive disorder: a quantitative synthesis of double-blind studies [J].，2009，24(1): 19-25 Int Clin Psychopharmacol
5          Lyndal Bond，John W.Toumbourou，Lyndal Thomas，et al. Individual，family，school，and community risk and protective factors for depressive symptoms in adolescents: a comparison of risk profiles for substance use and depressive symptoms [J]. Prev Sci，，6(2): 73-88 2005
6          Susan E.Ramsley. Unipolar or bipolar depression? Improving diagnostic confidence with the adult patient [J].，2007，19(4): 172-178 J Am Acad Nurse Pract
7          Paul J Goodnick. Anticonvulsants in the treatment of bipolar mania [J]. Expert Opin Pharmacother，2006，7(4): 401–410
8          LiBaoman B，Zhang Shiquen，Zhang Hongyan，et al. Fluoxetine-mediated 5-HT_2B receptor stimulation in astrocytes causes EGF receptor transactivation and ERK phosphorylation [J]. Psychopharmacology (Berl)，，201(3): 443-458 2008
9          Li Baoman，Zhang Shiquen，Li Min，et al. Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT_2B-induced，transactivation-mediated ERK_1/2 phosphorylation [J]. Psychopharmacology (Berl)，，207(1): 1-12 2009
10      Li B，Zhang S，Li M，et al. Serotonin increases ERK_1/2 phosphorylation in astrocytes by stimulation of 5-HT_2B and 5-HT_2C receptors [J]. Neurochem Int， 2010，57(4): 432-439 inhiquenaoman
11      Ong WY，Farooqui T，Farooqui AA. Involvement of cytosolic phospholipase A(2)，calcium independent phospholipase A(2) and plasmalogen selective phospholipase A(2) in neurodegenerative and neuropsychiatric conditions [J].，2010，17(25): 2746-2763 Curr Med Chem
12      Mikhail Strokin，Marina Sergeeva，Georg Reiser. Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A₂ and is differently regulated by cyclic AMP and Ca²⁺ [J].，2003，139(5): 1014-1022 Br J Pharmacol
13      Rao JS，Ertley RN，Lee HJ，et al. Chronic fluoxetine upregulates activity，protein and mRNA levels of cytosolic phospholipase A₂ in rat frontal cortex [J].，2006，(6): 13-20 Pharmacogenomics J
14      Meyer Jeffrey H，Goulding Verdell S，Wilson Alan A，et al. Bupropion occupancy of the dopamine transporter is low during clinical treatment [J]. Psychopharmacology (Berl)，，163(1): 102-105 2002
15      Natalie L Rasgon，Heather A Kenna，Cheri Geist，et al. Cerebral metabolic patterns in untreated postmenopausal women with major depressive disorder [J]. Psychiatry Res，，164(1): 77-80 2008
16      Tim A Kimbrell，Terence A Ketter，Mark S George，et al. Regional cerebral glucose utilization in patients with a range of severities of unipolar depression [J]. Biol Psychiatry，，51(3): 237-252 2002
17      Nobler MS，Pelton GH，Sackeim HA. Cerebral blood flow and metabolism in late-life depression and dementia [J].，1999，12(3): 118-127 J Geriatr Psychiatry Neurol
18      Zhang Shiquen，Li Baoman，Lovatt Ditte，et al. 5-HT_2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional 'serotonin-specific reuptake inhibitors [J]. Neuron Glia Biol， 2010，6(2): 113-125
19      Joel Bockaert，Sylvie Claeysen，Carine Bécamel，et al. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure，signaling，and roles in synaptic modulation [J]. Cell Tissue Res，，326(2): 553-572 2006
20      Porter RH，Benwell KR，Lamb H，et al. Functional characterization of agonists at recombinant human 5-HT_2A，5-HT_2B and 5-HT_2C receptors in CHO-K1 cells [J]. Br J Pharmacol, 1999, 128(1): 13-20
21      Chen Ye，Peng Liang，Zhang Xiaohu，et al. Further evidence that fluoxetine interacts with a 5-HT_2C receptor in glial cells [J]. Brain Res Bull，，38(2): 153-159 1995
22      Zhang JJ，Okutani F，Inoue S，et al. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway leading to cyclic AMP response element-binding protein phosphorylation is required for the long-term facilitation process of aversive olfactory learning in young rats [J]. Neuroscience， 2003，121(1): 9-16
23      Gilles Mercier，Anna Maria Lennon ，Benjamin Renouf ，et al. MAP kinase activation by fluoxetine and its relation to gene expression in cultured rat astrocytes [J]. J Mol Neurosci， 2004，24(2): 207-216
24      Gruda MC，Kovary K，Metz R，et al. Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity [J]. Oncogene，，9(9): 2537-2547 1994
25      Peng Liang，Li Baoman，Du Ting，et al. Astrocytic transactivation by alpha_2A-adrenergic and 5-HT_2B serotonergic signaling [J]. Neurochem Int，，57(4): 421-431 2010
26      Milde-Langosch K. The Fos family of transcription factors and their role in tumourigenesis [J].，2005，41(16): 2449-2461 Eur J Cancer
27      Antonia S.New，Monte S.Buchsbaum，Erin A.Hazlett，et al. Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression [J]. Psychopharmacology (Berl)，，176(3-4): 451-458 2004
28      Bohm SK，Grady EF，Bunnett NW. Regulatory mechanisms that modulate signalling by G-protein-coupled receptors [J]. Biochem J，1997，322 ( Pt 1): 1-18
29      Pan Ling，Eugenia V. Gurevich，Vsevolod V. Gurevich. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor [J]. J Biol Chem，2003，278(13): 11623-11632
30      Roth BL，Willins DL，Kroeze WK. G protein-coupled receptor (GPCR) trafficking in the central nervous system: relevance for drugs of abuse [J]. Drug Alcohol Depend，1998，51(1-2): 73-85
31      Marion Hogg，Simona Paro，Liam P Keegan，et al. RNA editing by mammalian ADARs [J].，2011，73: 87-120 Adv Genet
32      Wulf Paschen，John C. Hedreen，Christopher A.Ross. RNA editing of the glutamate receptor subunits GluR2 and GluR6 in human brain tissue [J]. J Neurochem，1994，63(5): 1596-1602
33      Colleen M.Burns，Hsin Chu，Susan M. Rueter，et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing [J]. Nature，1997，387(6630): 303-308
34      Michael T.Englander，Stephanie C.Dulawa，Punita Bhansali，et al. How stress and fluoxetine modulate serotonin 2C receptor pre-mRNA editing [J]. J Neurosci， 2005，25(3): 648-651
35      Li Baoman，Zhang Shiquen，Zhang Hongyan，et al. Fluoxetine affects GluK2 editing，glutamate-evoked Ca²⁺ influx and extracellular signal-regulated kinase phosphorylation in mouse astrocytes [J].，2011，36(5): 322-338 J Psychiatry Neurosci
36      Michael C.J.Chang，Eric Grange，Olivier Rabin，et al. Lithium decreases turnover of arachidonate in several brain phospholipids [J]. Neurosci Lett， 1996，220(3): 171-174
37      Michael C.J.Chang ，Miguel A.Contreras ，Thad A.Rosenberger ，et al. Chronic valproate treatment decreases the in vivo turnover of arachidonic acid in brain phospholipids: a possible common effect of mood stabilizers [J]. J Neurochem， 2001，77(3): 796-803
38      Richard P. Bazinet ，Jaqadeesh S. Rao，Lisa Chang，et al. Chronic carbamazepine decreases the incorporation rate and turnover of arachidonic acid but not docosahexaenoic acid in brain phospholipids of the unanesthetized rat: relevance to bipolar disorder [J]. Biol Psychiatry， 2006，59(5): 401-407
39      Weerasinghe GR，Rapoport SI，Bosetti F. The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A2 or lipoxygenase/cytochrome P450 pathways [J]. Brain Res Bull，2004，63(6): 485-489
40      Sandra Ghelardoni，York A Tomita，Jane M Bell，et al. Chronic carbamazepine selectively downregulates cytosolic phospholipase A₂ expression and cyclooxygenase activity in rat brain [J]. Biol Psychiatry， 2004，56(4): 248-254
41      Richard P. Bazinet，Jagadeesh S. Rao，Lisa Chang，et al. Chronic valproate does not alter the kinetics of docosahexaenoic acid within brain phospholipids of the unanesthetized rat [J]. Psychopharmacology (Berl)，，182(1): 180-185 2005
42      Li Baoman，Gu Li，Zhang Hongyan，et al. Up-regulation of cPLA(2) gene expression in astrocytes by all three conventional anti-bipolar drugs is drug-specific and enzyme-specific [J].，2007，194(3): 333-345 Psychopharmacology (Berl)
43      Harwood AJ. Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited [J]. Mol Psychiatry，2005，10(1): 117–126
44      John R. Atack. Inositol monophosphatase inhibitors––lithium mimetics? [J]. Med Res Rev，1997，17(2): 215–224
45      Dietrich van Calker, Robert H Belmaker. The high affinity inositol transport system––implications for the pathophysiology and treatment of bipolar disorder [J]. Bipolar Disord，2000，2(2): 102–107
46      Inoue Kiyoshi，Shimada Shoichi，Minami Yuki，et al. Cellular localization of Na⁺/MYO-inositol co-transporter mRNA in the rat brain [J]. Neuroreport，，7(6): 1195-1198 1996
47      H. Moo. Kwon，Atsushi Yamauchi，Shinichi Uchida，et al. Cloning of the cDNa for a Na⁺/myo-inositol cotransporter，a hypertonicity stress protein [J]. J Biol Chem，，267(9): 6297-6301 1992
48      Beate Lubrich，Olivia Spleiss，Peter-J Gebicke-Haerter，et al. Differential expression，activity and regulation of the sodium/myo-inositol cotransporter in astrocyte cultures from different regions of the rat brain [J]. Neuropharmacology，，39(4): 680-690 2000
49      Marc Uldry，Mark Ibberson，Jean-Daniel Horisberger，et al. Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain [J]. Embo J， 2001，20(16): 4467-4477
50      Sproule B. Lithium in bipolar disorder: can drug concentrations predict therapeutic effect? [J]. Clin Pharmacokinet，2002，41(9): 639-660
51      Song Dan，Du Ting，Li Baoman，et al. Astrocytic alkalinization by therapeutically relevant lithium concentrations: implications for myo-inositol depletion [J].，2008，200(2): 187-195 Psychopharmacology (Berl)
52      Jair C Soares，Fernando Boada，Steve Spencer，et al. Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T [J]. Biol Psychiatry， 2001，49(5): 437-443
53      Constance Moore，Christina M. Demopulos，Michael E. Henry，et al. Brain-to-serum lithium ratio and age: an in vivo magnetic resonance spectroscopy study [J]. Am J Psychiatry， 2002，159(7): 1240-1242
54      Wraae O，Hillman H，Round E. The uptake of low concentrations of lithium ions into rat cerebral cortex slices and its dependence on cations [J]. J Neurochem，1976，26: 835-843
55      Alan G Mallinger ，Ellen Frank ，Michael E Thase，et al. Low rate of membrane lithium transport during treatment correlates with outcome of maintenance pharmacotherapy in bipolar disorder [J]. Neuropsychopharmacology， 1997，16(5): 325-332
56      Philip B.Dunham，Scott J.Kelley，Paul J.Logue，et al. Na⁺-inhibitory sites of the Na⁺/H⁺ exchanger are Li⁺ substrate sites [J].，2005，289(2): C277-282 Am J Physiol Cell Physiol
57      Yuji Furutani，Takeshi Murata，Hideki Kandori. Sodium or lithium ion-binding-induced structural changes in the K-ring of V-ATPase from Enterococcus hirae revealed by ATR-FTIR spectroscopy [J].，2011，133(9):2860-2863 J Am Chem Soc
58      Mitchell Chesler. Regulation and modulation of pH in the brain [J]. Physiol Rev，2003，83(4): 1183-1221
59      Leif Hertz，Ye Chen，Maria Spatz . Involvement of non-neuronal brain cells in AVP-mediated regulation of water space at the cellular，organ，and whole-body level [J]. J Neurosci Res， 2000，62(4): 480-490
60      Christine R. Rose，Stephen G. Waxman，Bruce R. Ransom . Effects of glucose deprivation，chemical hypoxia，and simulated ischemia on Na⁺ homeostasis in rat spinal cord astrocytes [J]. J Neurosci， 1998，18(10): 3554-3562
61      Davis BA，Hogan EM，Boron WF. Activation of Na⁺-H⁺ exchange by intracellular lithium in barnacle muscle fibers [J]. Am J Physiol，1992，263(1 Pt 1): C246-C256
62      Kobayashi Y，Pang T，Iwamoto T，et al. Lithium activates mammalian Na⁺/H⁺ exchangers: isoform specificity and inhibition by genistein [J]. Pflugers Arch， 2000，439(4): 455-462
63      Jose A.Bitran，William Z.Potter，Husseini K.Manji，et al. Chronic Li⁺ attenuates agonist- and phorbol ester-mediated Na⁺/H⁺ antiporter activity in HL-60 cells [J]. Eur J Pharmacol， 1990，188(4-5): 193-202
64      Emily R. Slepkov，Jan K.Rainey，Brian D.Sykes，et al. Structural and functional analysis of the Na⁺/H⁺ exchanger [J].，2007，401(3): 623-633 Biochem J
65      Chen Shuai，Carol Mackintosh. Differential regulation of NHE1 phosphorylation and glucose uptake by inhibitors of the ERK pathway and p90RSK in 3T3-L1 adipocytes [J].，2009，21(12): 1984-1993 Cell Signal
66      Wolfgang Walz，Leif Hertz. Acute and chronic effects of lithium in therapeutically relevant concentrations on potassium uptake into astrocytes [J]. Psychopharmacology (Berl)，1982，78(4): 309-313
67      Chuang De-Maw，Wang Zhifei，Chiu Chi-Tso. GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in Neuronal Cultures and Animal Models of Ischemic Stroke [J].，2011，4: 15 Front Mol Neurosci
68      Xia Yan，Wang ChengZ，Liu Jie，et al. Lithium protection of phencyclidine-induced neurotoxicity in developing brain: the role of phosphatidylinositol-3 kinase/Akt and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways [J].，2008，326(3): 838-848 J Pharmacol Exp Ther
69      Eric E Morgan，Margaret P Chandler，Martin E Young，et al. Dissociation between gene and protein expression of metabolic enzymes in a rodent model of heart failure [J]. Eur J Heart Fail，，8(7): 687-693 2006
70      Youn-Bae Kim，Byung Ho Yang，Zhang Gen Piao，et al. Expression of Na⁺/HCO3^- cotransporter and its role in pH regulation in mouse parotid acinar cells [J]. Biochem Biophys Res Commun，2003，304(4): 593-598
71      Hae Jeong Park，Ira Rajbhandari，Han Soo Yang，et al. Neuronal expression of sodium/bicarbonate cotransporter NBCn1(SLC4A7) and its response to chronic metabolic acidosis [J]. Am J Physiol Cell Physiol，2003，298(5): C1018-C1028
Marina Wolfson ，Yuli Bersudsky ，Evgeny Zinger ，et al. Chronic treatment of human astrocytoma cells with lithium，carbamazepine or valproic acid decreases inositol uptake at high inositol concentrations but increases it at low inositol concentrations [J]. Brain Res， 2000，855(1): 158-161

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