Clinical Trials in Psychiatry: Focusing on Antipsychotic Development

精神醫學的臨床試驗：焦聚於抗精神病藥物的研發

林式穀(Shih-Ku Lin)

思覺失調症相關的認知障礙 ； lurasidone ； brexpiprazole ； cariprazine ； cognitive impairment associated with schizophrenia

台灣精神醫學

30卷2期（2016 / 06 / 01）

91 - 100+ii

英文

臨床試驗是以病人為對象的臨床研究，針對一種疾病或障礙症施行包括藥物、疫苗、飲食選擇、營養補充或醫療儀器的介入是否產生效果，並且觀察其副作用的症狀與程度。本綜說回顧抗精神病藥物發展過程中的臨床試驗。當今精神疾患的治療以藥物為主，但在早期則有許多有趣而奇怪的治療方式。這些包括瘧疾發燒，胰島素引發昏迷與抽搐，pentylenetetrazole和電氣引發抽搐及大腦額葉切除來治療各種精神病。Lithium，chlorpromazine，imipramine，chlordiazepoxide 和 iproniazid 則是在研究者細心的觀察下，意外發現其治療效果，成為現代精神藥理學的磐石。經過數十年的演變，目前新藥要上市都必需通過嚴格規範與嚴謹設計的臨床試驗。在本綜說中，作者將介紹新近上市的lurasidone，brexpiprazole，cariprazine與 blonanserin，它們具有不同的接受器結合與副作用。認知強化劑則利用麩胺酸系統調節劑，磷酸二酯酶抑制劑和尼古丁受體促動劑機轉研發中，用來治療思覺失調症相關的認知障礙。作者也在本綜說中，回顧台灣相關的臨床試驗與臨床藥物研究。未來精準醫療，即在正確診斷的病人，適時給予適切的治療，也適用於精神疾患。臨床試驗則必需建立在生物、心理與社會文化的差異上，才可達到精準醫學的要求。

Clinical trial is referred to an experiment to investigate novel therapies including drug, vaccines, dietary choices, dietary supplements, and medical devices or other intervention to a certain disease or illness, and to assess the contingent side effects. This overview is to focus on the clinical trial in the development of antipsychotic drugs. Pharmacotherapy is the mainstay of treatment for mental disorders in modern medicine, while there were many interesting and strange therapies implemented in the early days. These therapies include malaria-induced fever to treat neurosyphilitic paresis, insulin-induced coma and convulsions to treat schizophrenia, pentylenetetrazole-induced convulsions and electroconvulsive shock therapy to treat schizophrenia and affective psychoses, and prefrontal lobotomy to treat psychosis and personality disorder. Lithium, chlorpromazine, imipramine, chlordiazepoxide, and iproniazid (MAOI) were developed serendipitously by careful clinical researchers and became the founders of modern psychopharmacology. Currently there are strict regulations and paradigms for clinical trial after decades of evolution. Recently approved antipsychotic drugs such as lurasidone, brexpiprazole, cariprazine and blonanserin are introduced. They have different receptor affi nity and carry different side effect profi les. Cognition enhancers are developed using the mechanism of glutamate system modulation, phosphodiesterase inhibition and nicotinic receptor agonism. Inverse agonist in an old concept and a new antipsychotic has been developed using this concept. Also the clinical trials and clinical pharmacological studies in psychiatric fi eld done in Taiwan are reviewed. In the future, precise medicine as getting the right treatment at the right time to the right person is also important for mental disorders. More precise diagnostic categories based on biological, psychological, and socio-cultural variables, which need many kinds of data to reach precision of a clinical trial.

1. Bai, YM(2012).Pharmacological studies on patients with schizophrenia in Taiwan: a compilation of literature.Taiwanese Journal of Psychiatry,26,6-18.
   連結：
2. Chang, TT,Leng, CH,Wu, JY(2008).Lower side effects of milnacipran than paroxetine in the treatment of major depression disorder among Han Chinese in Taiwan.Chin J Physiol,51,387-393.
   連結：
3. Lopez-Munoz, F,Shen, WW,Alamo, C,Cacabelos, R,Lai, TJ(2014).Serendipitous discovery of first two antidepressants.Taiwaneses Journal of Psychiatry,28,70.
   連結：
4. Lopez-Munoz, F,Shen, WW,Moreno, R(2012).International scientific productivity on second generation antipsychotic drugs in Taiwan: a bibliometric study.Taiwanese Journal of Psychiatry,26,114-129.
   連結：
5. Adams, DH,Kinon, BJ,Baygani, S(2013).A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia.BMC Psychiatry,13,143.
6. Adler, LE,Olincy, A,Waldo, M(1998).Schizophrenia, sensory gating, and nicotinic receptors.Schizophr Bull,24,189-202.
7. Ban, TA(2007).Fifty years chlorpromazine: a historical perspective.Neuropsychiatr Dis Treat,3,495-500.
8. Bruijnzeel, D,Yazdanpanah, M,Suryadevara, U,Tandon, R(2015).Lurasidone in the treatment of schizophrenia: a critical evaluation.Exp Opin Pharmacother,16,1559-1565.
9. Bruzziches, R,Francomano, D,Gareri, P,Lenzi, A,Aversa, A(2013).An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors.Expert Opin Pharmacother,14,1333-1344.
10. Bugarski-Kirola, D,Wang, A,Abi-Saab, D,Blattler, T(2014).A phase II/III trial of bitopertin monotherapy compared with placebo in patients with an acute exacerbation of schizophrenia - results from the CandleLyte study.Eur Neuropsychopharmacol,24,1024-1036.
11. Chan, HY,Lin, WW,Lin, SK(2007).Efficacy and safety of aripiprazole in the acute treatment of schizophrenia in Chinese patients with risperidone as an active control: a randomized trial.J Clin Psychiatry,68,29-36.
12. Chang, YH,Chen, SL,Lee, SY(2015).Low-dose addon memantine treatment may improve cognitive performance and self-reported health conditions in opioid-dependent patients undergoing methadonemaintenance-therapy.Sci Rep,5,9708.
13. Chen, CH,Chiu, CC,Huang, MC(2008).Metformin for metabolic dysregulation in schizophrenic patients treated with olanzapine.Prog Neuropsychopharmacol Biol Psychiatry,32,925-931.
14. Chen, CH,Lee, CS,Lee, MT(2014).Variant GADL1 and response to lithium therapy in bipolar I disorder.N Engl J Med,370,119-128.
15. Chrysant, SG(2013).Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension.Curr Hypertens Rep,15,475-483.
16. Chung, WH,Hung, SI,Hong, HS(2004).Medical genetics: a marker for Stevens-Johnson syndrome.Nature,428,486.
17. Citrome, L(2011).Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic.Int J Clin Pract,65,189-210.
18. Cummings, J,Isaacson, S,Mills, R(2014).Pimavanserin for patients with Parkinson’s disease psychosis: a randomised, placebo-controlled phase 3 trial.Lancet,383,533-540.
19. Dax EC, Freudenberg RK, et al.: Prefrontal leucotomy; a review. Postgrad Med J 1948; 24: 415-26.
20. Deeks, ED,Keating, GM(2010).Blonanserin: a review of its use in the management of schizophrenia.CNS Drugs,24,65-84.
21. Durgam, S,Cutler, AJ,Lu, K(2015).Cariprazine in acute exacerbation of schizophrenia: a fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial.J Clin Psychiatry,76,e1574-e1582.
22. Durgam, S,Earley, W,Lipschitz, A(2016).An 8-week randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of cariprazine in patients with bipolar I depression.Am J Psychiatry,173,271-281.
23. Essayan, DM(2001).Cyclic nucleotide phosphodiesterases.J Allergy Clin Immunol,108,671-680.
24. Feuerbach, D,Pezous, N,Weiss, M(2015).AQW051, a novel, potent and selective alpha7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation.Br J Pharmacol,172,1292-1304.
25. Garay, RP,Bourin, M,de Paillette, E(2016).Potential serotonergic agents for the treatment of schizophrenia.Expert Opin Investig Drugs,25,159-170.
26. Garay, RP,Citrome, L,Samalin, L(2016).Therapeutic improvements expected in the near future for schizophrenia and schizoaffective disorder: an appraisal of phase III clinical trials of schizophrenia-targeted therapies as found in US and EU clinical trial registries.Expert Opin Pharmacother,17,921-936.
27. Garcia, E,Robert, M,Peris, F(2009).The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, doubleblind, placebo-controlled, multicentre study.CNS Drugs,23,615-625.
28. Gau, SS,Huang, YS,Soong, WT(2007).A randomized, double-blind, placebo-controlled clinical trial on once-daily atomoxetine in Taiwanese children and adolescents with attention-deficit/hyperactivity disorder.J Child Adolesc Psychopharmacol,17,447-460.
29. Goff, DC,Cather, C,Freudenreich, O(2009).A placebo-controlled study of sildenafil effects on cognition in schizophrenia.Psychopharmacology,202,411-417.
30. Grunder, G(2010).Cariprazine, an orally active D2/D3 receptor antagonist, for the potential treatment of schizophrenia, bipolar mania and depression.Curr Opin Investig Drugs,11,823-832.
31. Hacksell, U,Burstein, ES,McFarland, K,Mills, RG,Williams, H(2014).On the discovery and development of pimavanserin: a novel drug candidate for Parkinson’s psychosis.Neurochem Res,39,2008-2017.
32. Hong, CJ,Chen, JY,Chiu, HJ,Sim, CB(1997).A double-blind comparative study of clozapine versus chlorpromazine on Chinese patients with treatment-refractory schizophrenia.Int Clin Psychopharmacol,12,123-130.
33. Huttunen, M(1995).The evolution of the serotonin-dopamine antagonist concept.J Clin Psychopharmacol,15(1 Suppl 1),4S-10S.
34. Hwang, TJ,Lee, SM,Sun, HJ(2003).Amisulpride versus risperidone in the treatment of schizophrenic patients: a double-blind pilot study in Taiwan.J Formos Med Assoc,102,30-36.
35. Hwang, TJ,Lin, SK,Lin, HN(2001).Efficacy and safety of zotepine for the treatment of Taiwanese schizophrenic patients: a double-blind comparison with haloperidol.J Formos Med Assoc,100,811-816.
36. Hwu, HG(1995).Therapeutic effect of buspiron and loraze-pam in generalized anxiety disorder patients.Taiwanese Journal of Psychiatry,9,310-318.
37. Keefe, RS,Meltzer, HA,Dgetluck, N(2015).Randomized, double-blind, placebo-controlled study of encenicline, an alpha7 nicotinic acetylcholine receptor agonist, as a treatment for cognitive impairment in schizophrenia.Neuropsychopharmacology,40,3053-3060.
38. Kinon, BJ,Millen, BA,Zhang, L,McKinzie, DL(2015).Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia.Biol Psychiatry,78,754-762.
39. Kitchen, H,Rofail, D,Heron, L,Sacco, P(2012).Cognitive impairment associated with schizophrenia: a review of the humanistic burden.Adv Ther,29,148-162.
40. Kopeloff N, Cheney CO: Studies in focal infection: its presence and elimination in the functional psychoses. Am J Psychiatry 1922; 79: 139-56.
41. Lane, HY,Chang, YC,Liu, YC,Chiu, CC,Tsai, GE(2005).Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, doubleblind, placebo-controlled study.Arch Gen Psychiatry,62,1196-1204.
42. Lane, HY,Lin, CH,Huang, YJ(2010).A randomized, double-blind, placebo-controlled comparison study of sarcosine (N-methylglycine) and D-serine add-on treatment for schizophrenia.Int J Neuropsychopharmacol,13,451-460.
43. Lee, SY,Chen, SL,Chang, YH(2015).Low-dose memantine attenuated methadone dose in opioid-dependent patients: a 12-week double-blind randomized controlled trial.Sci Rep,5,10140.
44. Lee, SY,Chen, SL,Chang, YH(2015).A placebo-controlled trial of dextromethorphan as an adjunct in opioid-dependent patients undergoing methadone maintenance treatment.Int J Neuropsychopharmacol,18,pyv008.
45. Li, P,Zheng, H,Zhao, J(2016).Discovery of potent and selective inhibitors of phosphodiesterase 1 for the treatment of cognitive impairment associated with neurodegenerative and neuropsychiatric diseases.J Med Chem,59,1149-1164.
46. Lieberman, JA,Davis, RE,Correll, CU(2015).ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial.Biol Psychiatry,15,pii: S0006.
47. Lin, SK,Chen, CH,Pan, CH(2008).Venlafaxine for acute heroin detoxification: a double-blind, randomized, control trial.J Clin Psychopharmacol,28,189-194.
48. Lin, SK,Pan, CH,Chen, CH(2014).A double-blind, placebo controlled trial of dextromethorphan combined with clonidine in the treatment of heroin withdrawal.J Clin Psychopharmacol,34,508-512.
49. Lin, SK,Strang, J,Su, LW,Tsai, CJ,Hu, WH(1997).Doubleblind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal.Drug Alcohol Depend,48,127-133.
50. Lopez-Munoz, F,Alamo, C,Cuenca, E(2005).History of the discovery and clinical introduction of chlorpromazine.Ann Clin Psychiatry,17,113-135.
51. Maeda, K,Lerdrup, L,Sugino, H(2014).Brexpiprazole II: antipsychotic-like and procognitive effects of a novel serotonin-dopamine activity modulator.J Pharmacol Exp Ther,350,605-614.
52. Malan-Muller, S,Kilian, S,van den Heuvel, LL(2016).A systematic review of genetic variants associated with metabolic syndrome in patients with schizophrenia.Schizophr Res,170,1-17.
53. McKeage, K(2016).Adjunctive brexpiprazole: a review in major depressive disorder.CNS Drugs,30,91-99.
54. Miller, FG(2000).Placebo-controlled trials in psychiatric research: an ethical perspective.Biol Psychiatry,47,707-716.
55. Parra, S,Bond, RA(2007).Inverse agonism: from curiosity to accepted dogma, but is it clinically relevant?.Curr Opin Pharmacol,7,146-150.
56. Prinzmetal M, Bloomberg W: The use of benzedrine for the treatment of narcolepsy. JAMA 1935; 105: 2051.
57. Rajagopalan, K,Trueman, D,Crowe, L,Squirrell, D,Loebel, A.Cost-utility analysis of lurasidone versus aripiprazole in adults with schizophrenia.Pharmacoeconomics
58. Sabbatini, RME(1997).The history of shock therapy in psychiatry.Brain and Mind,4
59. Shen, WW(1999).A history of antipsychotic drug development.Compr Psychiatry,40,407-414.
60. Shorter, E(2011).A brief history of placebos and clinical trials in psychiatry.Can J Psychiatry,56,193-197.
61. Snyder, GL,Vanover, KE,Zhu, H(2015).Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission.Psychopharmacology,232,605-921.
62. Stahl, SM(2016).Mechanism of action of brexpiprazole: comparison with aripiprazole.CNS Spectr,21,1-6.
63. Tenjin, T,Miyamoto, S,Ninomiya, Y(2013).Profile of blonanserin for the treatment of schizophrenia.Neuropsychiatr Dis Treat,9,587-594.
64. Umbricht, D,Alberati, D,Martin-Facklam, M(2014).Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study.JAMA Psychiatry,71,637-646.
65. Umbricht, D,Keefe, RS,Murray, S(2014).A randomized, placebo-controlled study investigating the nicotinic alpha7 agonist, RG3487, for cognitive deficits in schizophrenia.Neuropsychopharmacology,39,1568-1577.
66. Vieta, E,Durgam, S,Lu, K(2015).Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials.Eur Neuropsychopharmacol,25,1882-1891.
67. Volpi, S,Potkin, SG,Malhotra, AK,Licamele, L,Lavedan, C(2009).Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia.J Clin Psychiatry,70,801-809.