Clinical Trials in Psychiatry: Focusing on Antipsychotic Development

Overview Taiwanese Journal of Psychiatry (Taipei) Vol. 30 No. 2 2016 • 91 •

Shih-Ku Lin, M.D.1,2*

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 de- cades 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.

Key words: lurasidone, brexpiprazole, cariprazine, cognitive impairment associated with schizophrenia (Taiwanese Journal of Psychiatry [Taipei] 2016; 30: 91-100)

1 Shih-Ku Lin, Department of Adult Psychiatry, Taipei City Hospital and Psychiatric Center, Taipei, Taiwan 2 Department of Psy- chiatry, College of Medicine, Taipei Medical University, Taipei, Taiwan Received: April 13, 2016; revised: April 27, 2016; accepted: April 28, 2016 *Corresponding author. No.309, Songde Road, Taipei 110, Taiwan E-mail: Shih-Ku Lin • 92 • Antipsychotic Drug Development

treat patients with schizophrenia. Between 1917 Introduction and 1935, four methods for producing physiologi- cal shock were discovered, tested, and used in the Clinical trial is referred to an experiment to psychiatric practice in Europe [1]. They included investigate novel therapies including drug, vac- malaria-induced fever to treat neurosyphilitic pa- cines, dietary choices, dietary supplements, and resis, discovered in Vienna by Wagner-Jauregg in medical devices, or other intervention to treat a 1917; insulin-induced coma and convulsions to certain disease or illness, as well as to assess the treat schizophrenia, discovered in Berlin by Sakel contingent side effects. Currently any new com- in 1927; pentylenetetrazole-induced convulsions pound needs many clinical trials to be approved as to treat schizophrenia and affective psychoses, a prescribed medicine. There are strict regulations discovered in Budapest by von Meduna in 1934; such as following the good clinical practice (GCP) and electroconvulsive shock therapy to treat and ethical considerations such as approved by schizophrenia and affective psychoses, discov- the institutional review board (IRB) to run a clini- ered in Rome by Cerletti and Bini in 1937 [1]. cal trial. GCP is an international quality standard Prefrontal lobotomy or leucotomy was a widely that is provided by the International Council for accepted procedure to treat many mental disorders Harmonization (ICH), an international body that from 1940 to 1950 [2], but it was completely defi nes standards, which governments can trans- abandoned following the introduction of antipsy- pose into regulations for clinical trials involving chotic medications. Of four methods to cause sei- human subjects. The IRB is to protect human sub- zures, only electroconvulsive shock therapy is still jects from physical, psychological and social used as a treatment modality at present. harms when involved in a clinical trial in the ethi- The fi rst controlled clinical trial in psychia- cal and scientifi c points of view. try was to compare the surgical procedure of re- Pharmacotherapy is the mainstay of treat- moving infected teeth and tonsils to non-opera- ment for mental disorders in modern medicine, tion group, with the results showing no more while many interesting and strange therapies ex- mental benefi t [3, 4]. In 1935, the fi rst single isted in the early days. The psychotropic drugs blind (to patient), crossover randomized con- have helped stabilize and maintain the patients, as trolled trial (RCT) was done by Prinzmetal and well as recover to a certain degree. But some un- Bloomberg [3, 5] to compare benzedrine with met needs of the therapy still exist for the patients ephedrine and sodium chloride (placebo) in not to have full remission, and to return to their treating narcolepsy. normal lives. In this overview, I am reviewing psychiatric clinical trials for modern psychotropic Modern Clinical Trials in drugs, covering the past, at present, and the future. Psychiatry

History of Clinical Trials in The modern psychopharmacology was inau- Psychiatry gurated from the accidental ﬁ nding of chlorpromazine [6, 7], as well as the serendipitous discovery Before modern pharmacotherapy for psycho- of the ﬁ rst two antidepressants [8] in early 1950s. sis, many interesting therapies had ever tried to Between 1954 and 1975, about 15 antipsychotic Lin SK • 93 •

drugs had been introduced in the United States asidone versus aripiprazole in the treatment of pa- and about 40 throughout the world [9]. Most of tients with schizophrenia [15], the results showed these antipsychotic drugs carry a strong afﬁ nity to that lurasidone is likely to provide overall savings block D2 receptor and have many side effects such due to lower relapse rates and greater improve- as tremor, restlessness, dyskinesia, dry mouth, and ments in quality of life when compared with sedation. Neuroleptic malignant syndrome and aripiprazole. tardive dyskinesia are rare but serious side effects. Those compounds developed during this period Brexpiprazole are called ﬁ rst-generation antipsychotic (FGA). Brexpiprazole works through a combination

Most of them did not have placebo-controlled tri- of partial agonist activity at serotonin 5-HT1A and als, rather a head-to-dead comparison of efﬁ cacy dopamine D2 receptors, and antagonist activity at design. serotonin 5-HT2A receptors [16]. The term “sero- In the 1980s, the concept of serotonin-dopa- tonin-dopamine activity modulator” is used to de- mine antagonist antipsychotic emerged from clo- scribe the pharmacological characteristics of zapine, which is a potent serotonin 5-HT2A antag- brexpiprazole. It is considered a second-genera- onist [10]. They generally have lower risk of tion version of aripiprazole, and with slightly dif- motor side effects, but are associated with high ferent activity at the serotonin and dopamine re- frequencies of weight gain, serum lipid elevation, ceptors, could mean an improved clinical proﬁ le and the development of metabolic syndrome or with fewer side effects such as restlessness or type 2 diabetes. Contrary to FGAs, those new akathisia [17]. The indications approved by FDA compounds are second-generation antipsychotic in 2015 are schizophrenia and as an add-on treat- drugs (SGAs), and most of them have been run by ment to an antidepressant medication to treat ma- a placebo-controlled design [11] to be approved jor depressive disorder [18]. before being on the market. Lurasidone was approved in 2010 in the USA, and in 2015 in Taiwan. Cariprazine

In 2015, the FDA also approved two antipsychotic Unlike many antipsychotic drug that are D2 drugs ‒ brexpiprazole and cariprazine. Blonanserin and 5-HT2A receptor antagonists, cariprazine is a is approved for treatment of schizophrenia in D2 and D3 partial agonist, with preferential bind-

Japan and South Korea [12]. ing to D3 receptors, and partial agonism at sero-

tonin 5-HT1A receptors [17, 19]. A multinational, Lurasidone randomized, double-blind, placebo- and active-

Lurasidone has a potent dopamine D2 and se- controlled study revealed that cariprazine 3 and 6 rotonin 5HT2A antagonist and serotonin 5HT1A mg/day is efﬁ cacious in treating patients with partial agonist properties, with additional potent acute exacerbation of schizophrenia [20].

5HT7 and alpha2C noradrenergic antagonism [13]. Cariprazine has also shown to have efﬁ cacy on It is less likely to cause metabolic syndrome and/ bipolar mania [21] and bipolar depression [22]. or weight gain than most other SGAs [14]. Cariprazine was approved by the FDA to treat Lurasidone is approved by FDA to treat schizo- schizophrenia and bipolar disorder in adults. phrenia, bipolar depression as monotherapy or add-on regimen. In a cost-utility analysis of lur- • 94 • Antipsychotic Drug Development

Blonanserin Blonanserin is an atypical antipsychotic Psychiatric Clinical Trials in agent indicated for use in patients with schizo- Taiwan phrenia in Japan and Korea [12]. In vitro, blonanserin acts as an antagonist at dopamine D2, D3, and The fi rst psychiatric clinical trial ever pub- serotonin 5-HT2A receptors. Blonanserin has low lished (text in Chinese language) in Taiwan was affi nity for 5-HT2C, adrenergic α1, histamine H1, done by Hwu [29] in this journal in 1995, while and muscarinic M1 receptors, but displays rela- Hong et al. in 1997 [30] and Lin et al. in 1997 [31] tively high affi nity for 5-HT6 receptors [23]. have published double-blind randomized con- Blonanserin is generally well-tolerated and ap- trolled trial in two separate international journals. pears to have an acceptable profi le in terms of In 1993, the administrative authority of bodyweight gain [24]. Currently, the world’s fi rst Department of Health announced a new strategy transdermal patch formulation is under phase 2 for new compound approval in Taiwan. It is re- clinical trial in Asian countries including Taiwan quired to have domestic clinical data for at least [www.ds-pharma.com/news/pdf/ ene20120727_2. 40 cases. Under this new regulation, numbers of pdf]. clinical trials have increased remarkably including psychotropic drugs. Most of these trials be- Unsuccessful trials long to bridging study, namely, an additional study After the promising trial results from gluta- executed in the new region to “build a bridge” mate modulators such as sarcosine and D-serine, with the foreign clinical data on effi cacy, safety, two potential compounds related to this mecha- dosage and dose regimen according to the nism ‒ bitopertin and pomaglumetad methionil International Council for Harmonization (ICH) were undergone trial in either as monotherapy or guideline E5. Such studies could include addition- add-on regimen. Bitopertin is a potent and non- al pharmacokinetic information. The representa- competitive GlyT1 inhibitor [25], and pomaglu- tive compounds include buspiron [29], lofexidine metad methionil is a potent and highly selective [31], zotepine [32], amisulpride [33], aripiprazole agonist for the metabotropic glutamate receptors 2 [34], atomoxetine [35], and milnacipran [36]. and 3 [26]. Unfortunately, both compounds did Besides these trials, Bai in 2012 has reviewed not separate from placebo in the phase III large- pharmacological studies on patients with schizo- scale randomized placebo controlled trial [27, 28]. phrenia published by Taiwanese researchers [37]. In the exploratory analysis for a targeted patient These studies covered from effi cacy trials to phar- population responsive to pomaglumetad methio- maco-economics and pharmaco-genetics, and nil in schizophrenia [29], it revealed that only pa- have offered empirical results of pharmacothera- tients early-in-disease or previously treated with py for schizophrenia in Taiwan, and will be the

D2 drugs have exhibited greater improvement rel- basis for the development of the Taiwan consen- ative to those receiving placebo in the dosage of sus of pharmacological treatment for schizophre- 40 mg twice a day. nia. López-Muñoz et al. in 2012 did a bibliometric study on research for SGA drugs in Taiwan [38]. They identiﬁ ed 359 original Taiwanese papers (original articles, reviews, editorials, case reports, Lin SK • 95 •

letters to the editor, etc.) dealing with different as- potential compounds under development as an pects related to SGAs including clozapine, risperi- antipsychotic drug with cognitive enhancing ef- done, aripiprazole, olanzapine, quetiapine, and fects and less side effects. others. The investigators concluded that there had been a markedly increased number of SGA papers ITI-007 generated from Taiwan over the previous 20 years, ITI-007 has a unique and novel mechanism and predicted that research in this ﬁ eld will pos- of action. It is regarded as a modulator of sero- sibly continue to grow in the coming years. tonin, dopamine and glutamate transmission. It

Along with those fl ourishing activities in acts as a 5-HT2A receptor antagonist, a partial ago- clinical trials in multiple disciplines, the infra- nist of presynaptic D2 receptors and an antagonist structure and study team are getting mature and of postsynaptic D2 receptors, and a serotonin sophisticated, more and more international, mul- transporter blocker [49]. ITI-007 also possesses tiple center registration trials for US Food and affi nity for the D1 receptor and weak affi nity for

Drug Administration (FDA) (www.clinicaltrials. the α1A- and α1B-adrenergic receptors and D4 re- gov) or Japan Pharmaceuticals and Medical ceptor, and has no afﬁ nity to the 5-HT2B, 5-HT2C,

Devices Agency (PMDA) (www.pmda.go.jp) H1, or mACh receptors. It is regarded as a multi- have been implemented. Most of these trials have acting receptor targeted antipsychotics (MARTA), been published without the authorship from yet the side effect profi les are much better than the Taiwan. On the other hand, lots of investigator- “pine”-category antipsychotics such as quetiapine initiated trials of existing compounds have been or olanzapine. In a phase II RCT for 4 weeks, ITI- published in Taiwan. Those drugs include sarco- 007, 60 mg/day but not 120 mg/day, has demon- sine and D-serine [39, 40], venlafaxine [41], met- strated to have antipsychotic effi cacy superiority formin [42], dextromethorphan [43, 44], meman- over placebo on the change of Positive and tine [45, 46], etc. Negative Syndrome Scale total score [50]. ITI- 007 was well-tolerated in this patient population, Psychiatric Clinical Trials as evidenced by low discontinuation and adverse in the Future event rates, and are associated with a benign metabolic profi le as evidenced by signifi cantly lower Cognitive impairment associated with levels of prolactin, fasting glucose, total choles- schizophrenia (CIAS) is a common consequence terol, and triglycerides than risperidone. ITI-007 of this disorder, causing a huge humanistic burden has also been tried on bipolar depression as a [47]. It is an important therapeutic target for many monotherapy (NCT02600494). pharmaceutical companies to develop, while no compounds have been approved by the authorities Pimavanserin yet. Garay et al. have published an article to re- Pimavanserin is a selective serotonin inverse view potential compounds currently under clinical agonist (SSIA) on the serotonin receptor subtype trials [48]. Many cognition enhancers to treat 5-HT2A, with 40 folds selectivity over 5-HT2C, and

CIAS are under development through the mecha- no signiﬁ cant afﬁ nity or activity at 5-HT2B or do- nism of glutamate system, phosphodiesterase in- pamine receptors [51]. Inverse agonist is an agent hibitors and many others. Followings are some that binds to the same receptor as an agonist but • 96 • Antipsychotic Drug Development

induces a pharmacological response opposite to nicline [61], AQW051 [62] and RG3487 [63]. So that agonist [52]. Pimavanserin has been tried for far those compounds have shown effi cacious ef- patients with Parkinson’s disease psychosis [53] fect on CIAS to a certain degree. Table 1 com- and had shown effi cacy without prominent side pares the characteristics of mode of action and effects. Pimavanserin was recently approved by clinical indication of approved and potential com- FDA for this indication in 2016. For the treatment pounds mentioned in this overview. of schizophrenia, adjunctive pimavanserin can re- duce the antipsychotic dose (such as risperidone 2 Conclusion mg/day) and side-effects [54]. In the future, precise medicine or personal- Phosphodiesterase inhibitors ized medication as getting the right treatment at A phosphodiesterase (PDE) is any enzyme the right time to the right person is also important that breaks or degrades the phosphodiester bond for mental disorders. For example, genetic varia- in the second messenger molecules cyclic ade- tions in GADL1 are associated with the response nosine monophosphate (cAMP) and cyclic gua- to lithium maintenance treatment for bipolar I dis- nosine monophosphate (cGMP). PDE inhibitor, order in patients of Han Chinese descent [64]; on the other way, prevents the inactivation of the 6-marker genotype combinations to predict en- intracellular second messengers cyclic adenosine hanced response to iloperidone [65]. For unwant- monophosphate (cAMP) and cyclic guanosine ed side effects, genetic marker, the human monophosphate (cGMP). Several PDE types HLA-B*1502 is associated with carbamazepine- have been identifi ed as therapeutic targets for induced Stevens-Johnson syndrome [66]; meta- immune/infl ammatory diseases [55], and erectile bolic syndrome causes by SGA is associated with dysfunction [56], cardiovascular disease and hy- several genes [67]. Clinical trials targeting differ- pertension [57]. The PDE 5 inhibitor sildenafi l ent patient group from the same diagnosis might has been trialed to improve the CIAS in a single be a strategy for the precise medicine, as suggest- dose design but did not show any benefi t [58]. ed from the results of pomaglumetad methionil Other PDE subtype inhibitors are studied on the [29]. More precise diagnostic categories based on way such as PDE 1 inhibitor [59], PDE 9 inhibi- biological, psychological, and socio-cultural vari- tor BI 409306 (NCT02281773) and PDE 10 in- ables are also warranted to reach personalized hibitor OMS-824 (NCT01952132) and TAK-063 medication. (NCT02477020). Acknowledgements α7 ACh nicotinic receptor agonist Nicotinic receptor has been associated with The author thanks Winston W. Shen for his sensory gating defi cit characterized in patients suggestion and English editing. The author de- with schizophrenia [60]. Activation of the α7 nic- clares no potential confl icts of interest in writing otinic ACh receptor (nACh receptor) is consid- this overview. ered a potential target for the treatment of CIAS. To date, many compounds of this mechanism were trialed as cognition enhancers such as ence- Lin SK • 97 •

Table 1. Characteristics of mode of action and clinical indication of approved and potential compounds References Modes of receptor action FDA indications

Lurasidone Bruijneed et al. 2015 [13] D2 and 5HT2A antagonist, 5HT1A Schizophrenia, bipolar

Citrome 2011 [14] partial agonist, 5HT7 and alpha 2C depression (monotherapy Rajagopalan et al. in press [15] antagonism or add-on)

Brexpiprazole Maeda et al. 2014 [16] 5-HT1A and D2 partial agonist Schizophrenia, add-on Stahl 2016 [17] treatment to an antide- McKeage 2016 [18] pressant for major depressive disorder

Cariprazine Grunder 2010 [19] D2 and D3 partial agonist, 5-HT1A Schizophrenia, bipolar Durgam et al. 2015 [20] partial agonist disorder Vietal et al. 2015 [21] Durgam et al. et al. 2016 [22]

Blonanserin Deeks and Keating 2010 [12] D2 and 5-HT2A antagonist Schizophrenia (Japan and Tenjin et al. 2013 [23,] Korea) Garcia et al. 2009 [24]

ITI-007 Synder et al. 2015 [49] 5-HT2A antagonist, presynaptic D2 Targeted indication: Lieberman et al. 2015 [50] partial a gonist and postsynaptic, schizophrenia, bipolar

D2 antagonist, serotonin transport- depression er blocker

Pimavanserin Hacksell et al. 2014 [51] 5-HT2A inverse agonist Psychosis in patients with Parra and Bond 2007 [52] Parkinson’s disease Cummings et al. 2014 [53] Garay et al. 2016 [54] BI 409306 NCT02281773 PDE9 inhibitor Targeted indication: CIAS OMS-824 NCT01952132 PDE10 inhibitor Targeted indication: CIAS TAK-063 NCT02477020 PDE10 inhibitor Targeted indication: CIAS Encenicline Alder et al. 1998 [60] α7 ACh nicotinic receptor agonist Targeted indication: CIAS AQW051 Feuerbach et al. 2015 [62] α7 ACh nicotinic receptor agonist Targeted indication: CIAS RG3487 Umbricht et al. 2014 [63] α7 ACh nicotinic receptor agonist Targeted indication: CIAS D, dopamine; 5-HT, serotonin; PDE, phosphodiesterase; NCT, ClinicalTrials.gov Identiﬁ er; CIAS, cognitive impairment associated with schizophrenia

its presence and elimination in the functional psycho- References ses. Am J Psychiatry 1922; 79: 139-56. 5. Prinzmetal M, Bloomberg W: The use of benzedrine 1. Sabbatini RME: The history of shock therapy in psy- for the treatment of narcolepsy. JAMA 1935; 105: chiatry. Brain and Mind. (Teleneurosciences Center, 2051. Brazil) Volume 4, 1997. 6. Lopez-Munoz F, Alamo C, Cuenca E, et al.: History 2. Dax EC, Freudenberg RK, et al.: Prefrontal leucoto- of the discovery and clinical introduction of chlor- my; a review. Postgrad Med J 1948; 24: 415-26. promazine. Ann Clin Psychiatry 2005; 17: 113-35. 3. Shorter E: A brief history of placebos and clinical tri- 7. Ban TA: Fifty years chlorpromazine: a historical per- als in psychiatry. Can J Psychiatry 2011; 56: 193-7. spective. Neuropsychiatr Dis Treat 2007; 3: 4. Kopeloff N, Cheney CO: Studies in focal infection: 495-500. • 98 • Antipsychotic Drug Development

8. Lopez-Munoz F, Shen WW, Alamo C, Cacabelos R, phase 3, randomized, double-blind, placebo- and ac- Lai TJ: Serendipitous discovery of fi rst two antide- tive-controlled trial. J Clin Psychiatry 2015; 76: pressants. Taiwaneses Journal of Psychiatry (Taipei) e1574-82. 2014; 28: 70. 21. Vieta E, Durgam S, Lu K, et al.: Effect of cariprazine 9. Shen WW: A history of antipsychotic drug develop- across the symptoms of mania in bipolar I disorder: ment. Compr Psychiatry 1999; 40: 407-14. Analyses of pooled data from phase II/III trials. Eur 10. Huttunen M: The evolution of the serotonin-dopa- Neuropsychopharmacol 2015; 25: 1882-91. mine antagonist concept. J Clin Psychopharmacol 22. Durgam S, Earley W, Lipschitz A, et al.: An 8-week 1995; 15 (1 Suppl 1): 4S-10S. randomized, double-blind, placebo-controlled evalu- 11. Miller FG: Placebo-controlled trials in psychiatric ation of the safety and effi cacy of cariprazine in pa- research: an ethical perspective. Biol Psychiatry tients with bipolar I depression. Am J Psychiatry 2000; 47: 707-16. 2016; 173: 271-81. 12. Deeks ED, Keating GM: Blonanserin: a review of its 23. Tenjin T, Miyamoto S, Ninomiya Y, et al.: Profi le of use in the management of schizophrenia. CNS Drugs blonanserin for the treatment of schizophrenia. 2010; 24: 65-84. Neuropsychiatr Dis Treat 2013; 9:587-94. 13. Bruijnzeel D, Yazdanpanah M, Suryadevara U, 24. Garcia E, Robert M, Peris F, et al.: The effi cacy and Tandon R: Lurasidone in the treatment of schizophre- safety of blonanserin compared with haloperidol in nia: a critical evaluation. Exp Opin Pharmacother acute-phase schizophrenia: a randomized, double- 2015; 16: 1559-65. blind, placebo-controlled, multicentre study. CNS 14. Citrome L: Lurasidone for schizophrenia: a review of Drugs 2009; 23: 615-25. the effi cacy and safety profi le for this newly ap- 25. Umbricht D, Alberati D, Martin-Facklam M, et al.: proved second-generation antipsychotic. Int J Clin Effect of bitopertin, a glycine reuptake inhibitor, on Pract 2011; 65: 189-210. negative symptoms of schizophrenia: a randomized, 15. Rajagopalan K, Trueman D, Crowe L, Squirrell D, double-blind, proof-of-concept study. JAMA Loebel A: Cost-utility analysis of lurasidone versus Psychiatry 2014; 71: 637-46. aripiprazole in adults with schizophrenia. 26. Adams DH, Kinon BJ, Baygani S, et al.: A long-term, Pharmacoeconomics, in press. phase 2, multicenter, randomized, open-label, com- 16. Maeda K, Lerdrup L, Sugino H, et al.: Brexpiprazole parative safety study of pomaglumetad methionil II: antipsychotic-like and procognitive effects of a (LY2140023 monohydrate) versus atypical antipsy- novel serotonin-dopamine activity modulator. J chotic standard of care in patients with schizophre- Pharmacol Exp Ther 2014; 350: 605-14. nia. BMC Psychiatry 2013; 13: 143. 17. Stahl SM: Mechanism of action of brexpiprazole: 27. Bugarski-Kirola D, Wang A, Abi-Saab D, Blattler T: comparison with aripiprazole. CNS Spectr 2016; 21: A phase II/III trial of bitopertin monotherapy com- 1-6. pared with placebo in patients with an acute exacer- 18. McKeage K: Adjunctive brexpiprazole: a review in bation of schizophrenia - results from the CandleLyte major depressive disorder. CNS Drugs 2016; 30: study. Eur Neuropsychopharmacol 2014; 24: 1024- 91-9. 36. 19. Grunder G: Cariprazine, an orally active D2/D3 re- 28. Kinon BJ, Millen BA, Zhang L, McKinzie DL: ceptor antagonist, for the potential treatment of Exploratory analysis for a targeted patient population schizophrenia, bipolar mania and depression. Curr responsive to the metabotropic glutamate 2/3 recep- Opin Investig Drugs 2010; 11: 823-32. tor agonist pomaglumetad methionil in schizophre- 20. Durgam S, Cutler AJ, Lu K, et al.: Cariprazine in nia. Biol Psychiatry 2015; 78: 754-62. acute exacerbation of schizophrenia: a fi xed-dose, 29. Hwu HG: Therapeutic effect of buspiron and loraze- Lin SK • 99 •

pam in generalized anxiety disorder patients. 2012; 26: 114-29. Taiwanese Journal of Psychiatry (Taipei) 1995; 9: 39. Lane HY, Chang YC, Liu YC, Chiu CC, Tsai GE: 310-8. Sarcosine or D-serine add-on treatment for acute ex- 30. Hong CJ, Chen JY, Chiu HJ, Sim CB: A double-blind acerbation of schizophrenia: a randomized, double- comparative study of clozapine versus chlorproma- blind, placebo-controlled study. Arch Gen Psychiatry zine on Chinese patients with treatment-refractory 2005; 62: 1196-204. schizophrenia. Int Clin Psychopharmacol 1997; 12: 40. Lane HY, Lin CH, Huang YJ, et al.: A randomized, 123-30. double-blind, placebo-controlled comparison study 31. Lin SK, Strang J, Su LW, Tsai CJ, Hu WH: Double- of sarcosine (N-methylglycine) and D-serine add-on blind randomised controlled trial of lofexidine versus treatment for schizophrenia. Int J Neuropsychophar- clonidine in the treatment of heroin withdrawal. macol 2010; 13: 451-60. Drug Alcohol Depend 1997; 48: 127-33. 41. Lin SK, Chen CH, Pan CH: Venlafaxine for acute 32. Hwang TJ, Lin SK, Lin HN: Effi cacy and safety of heroin detoxifi cation: a double-blind, randomized, zotepine for the treatment of Taiwanese schizophren- control trial. J Clin Psychopharmacol 2008; 28: ic patients: a double-blind comparison with haloperi- 189-94. dol. J Formos Med Assoc 2001; 100: 811-6. 42. Chen CH, Chiu CC, Huang MC, et al.: Metformin for 33. Hwang TJ, Lee SM, Sun HJ, et al.: Amisulpride ver- metabolic dysregulation in schizophrenic patients sus risperidone in the treatment of schizophrenic pa- treated with olanzapine. Prog Neuropsychopharmacol tients: a double-blind pilot study in Taiwan. J Formos Biol Psychiatry 2008; 32: 925-31. Med Assoc 2003; 102: 30-6. 43. Lin SK, Pan CH, Chen CH: A double-blind, placebo- 34. Chan HY, Lin WW, Lin SK, et al.: Effi cacy and safe- controlled trial of dextromethorphan combined with ty of aripiprazole in the acute treatment of schizo- clonidine in the treatment of heroin withdrawal. J phrenia in Chinese patients with risperidone as an Clin Psychopharmacol 2014; 34: 508-12. active control: a randomized trial. J Clin Psychiatry 44. Lee SY, Chen SL, Chang YH, et al.: A placebo-con- 2007; 68: 29-36. trolled trial of dextromethorphan as an adjunct in 35. Gau SS, Huang YS, Soong WT, et al.: A randomized, opioid-dependent patients undergoing methadone double-blind, placebo-controlled clinical trial on maintenance treatment. Int J Neuropsychopharmacol once-daily atomoxetine in Taiwanese children and 2015; 18: pyv008. adolescents with attention-defi cit/hyperactivity dis- 45. Chang YH, Chen SL, Lee SY, et al.: Low-dose add- order. J Child Adolesc Psychopharmacol 2007; 17: on memantine treatment may improve cognitive per- 447-60. formance and self-reported health conditions in opi- 36. Chang TT, Leng CH, Wu JY, et al.: Lower side ef- oid-dependent patients undergoing methadone- fects of milnacipran than paroxetine in the treatment maintenance-therapy. Sci Rep 2015; 5: 9708. of major depression disorder among Han Chinese in 46. Lee SY, Chen SL, Chang YH, et al.: Low-dose me- Taiwan. Chin J Physiol 2008; 51: 387-93. mantine attenuated methadone dose in opioid-depen- 37. Bai YM: Pharmacological studies on patients with dent patients: a 12-week double-blind randomized schizophrenia in Taiwan: a compilation of literature. controlled trial. Sci Rep 2015; 5: 10140. Taiwanese Journal of Psychiatry (Taipei) 2012; 26: 47. Kitchen H, Rofail D, Heron L, Sacco P: Cognitive 6-18. impairment associated with schizophrenia: a review 38. Lopez-Munoz F, Shen WW, Moreno R, et al.: of the humanistic burden. Adv Ther 2012; 29: International scientifi c productivity on second gen- 148-62. eration antipsychotic drugs in Taiwan: a bibliometric 48. Garay RP, Citrome L, Samalin L, et al.: Therapeutic study. Taiwanese Journal of Psychiatry (Taipei) improvements expected in the near future for schizo- • 100 • Antipsychotic Drug Development

phrenia and schizoaffective disorder: an appraisal of 202: 411-7. phase III clinical trials of schizophrenia-targeted 59. Li P, Zheng H, Zhao J, et al.: Discovery of potent and therapies as found in US and EU clinical trial regis- selective inhibitors of phosphodiesterase 1 for the tries. Expert Opin Pharmacother 2016: 17: 921-36. treatment of cognitive impairment associated with 49. Snyder GL, Vanover KE, Zhu H, et al.: Functional neurodegenerative and neuropsychiatric diseases. J profi le of a novel modulator of serotonin, dopamine, Med Chem 2016; 59: 1149-64. and glutamate neurotransmission. Psychopharmac- 60. Adler LE, Olincy A, Waldo M, et al.: Schizophrenia, ology (Berl) 2015; 232: 605-21. sensory gating, and nicotinic receptors. Schizophr 50. Lieberman JA, Davis RE, Correll CU, et al.: ITI-007 Bull 1998; 24: 189-202. for the treatment of schizophrenia: a 4-week random- 61. Keefe RS, Meltzer HA, Dgetluck N, et al.: ized, double-blind, controlled trial. Biol Psychiatry Randomized, double-blind, placebo-controlled study 2015; pii: S0006-3223(15) 00694-0 of encenicline, an alpha7 nicotinic acetylcholine re- 51. Hacksell U, Burstein ES, McFarland K, Mills RG, ceptor agonist, as a treatment for cognitive impair- Williams H: On the discovery and development of ment in schizophrenia. Neuropsychopharmacology pimavanserin: a novel drug candidate for Parkinson’s 2015; 40: 3053-60. psychosis. Neurochem Res 2014; 39: 2008-17. 62. Feuerbach D, Pezous N, Weiss M, et al.: AQW051, a 52. Parra S, Bond RA: Inverse agonism: from curiosity novel, potent and selective alpha7 nicotinic ACh re- to accepted dogma, but is it clinically relevant? Curr ceptor partial agonist: pharmacological characteriza- Opin Pharmacol 2007; 7: 146-50. tion and phase I evaluation. Br J Pharmacol 2015; 53. Cummings J, Isaacson S, Mills R, et al.: Pimavanserin 172: 1292-304. for patients with Parkinson’s disease psychosis: a 63. Umbricht D, Keefe RS, Murray S, et al.: A random- randomised, placebo-controlled phase 3 trial. Lancet ized, placebo-controlled study investigating the nico- 2014; 383: 533-40. tinic alpha7 agonist, RG3487, for cognitive defi cits 54. Garay RP, Bourin M, de Paillette E, et al.: Potential in schizophrenia. Neuropsychopharmacology 2014; serotonergic agents for the treatment of schizophre- 39: 1568-77. nia. Expert Opin Investig Drugs 2016; 25: 159-70. 64. Chen CH, Lee CS, Lee MT, et al.: Variant GADL1 55. Essayan DM: Cyclic nucleotide phosphodiesterases. and response to lithium therapy in bipolar I disorder. J Allergy Clin Immunol 2001; 108: 671-80. N Engl J Med 2014; 370: 119-28. 56. Bruzziches R, Francomano D, Gareri P, Lenzi A, 65. Volpi S, Potkin SG, Malhotra AK, Licamele L, Aversa A: An update on pharmacological treatment Lavedan C: Applicability of a genetic signature for of erectile dysfunction with phosphodiesterase type 5 enhanced iloperidone effi cacy in the treatment of inhibitors. Expert Opin Pharmacother 2013; 14: schizophrenia. J Clin Psychiatry 2009; 70: 801-9. 1333-44. 66. Chung WH, Hung SI, Hong HS, et al.: Medical ge- 57. Chrysant SG: Effectiveness and safety of phosphodi- netics: a marker for Stevens-Johnson syndrome. esterase 5 inhibitors in patients with cardiovascular Nature 2004; 428: 486. disease and hypertension. Curr Hypertens Rep 2013; 67. Malan-Muller S, Kilian S, van den Heuvel LL, et al.: 15: 475-83. A systematic review of genetic variants associated 58. Goff DC, Cather C, Freudenreich O, et al.: A place- with metabolic syndrome in patients with schizo- bo-controlled study of sildenafi l effects on cognition phrenia. Schizophr Res 2016; 170: 1-17. in schizophrenia. Psychopharmacology (Berl) 2009;