LETTERS TO THE EDITORS Effect of Tandospirone on and anxiolytic,12,13 was effective for en- occasionally reported anxiety, which be- hancing MMN and improving cognitive came more frequent and severe when she Mismatch Negativity and performance. began to take care of her nephew whose Cognitive Performance in mother had obtained a job. At this time, the patient was able to help the household Schizophrenia CASE REPORT of her brother’s family, which she lived A Case Report The patient is a 37-year-old woman with, but was not motivated enough to go meeting Diagnostic and Statistical Manual out by herself. For anxiolytic purpose, tan- To the Editors: of Mental Disorders, Fourth Edition crite- dospirone, 30 mg/d as initial dose, was isturbances of cognitive function, eval- ria for schizophrenia. She graduated from added, which was titrated to 60 mg/d (re- D uated by neurophysiological1Y3 and a mainstream high school and entered a commended maximum dose) during the psychological4 measures, have been shown university. At age 20, she experienced au- initial month, because of the insufficient to predict outcome in patients with schizo- ditory hallucinations, delusion of persecu- effect of the lower dose. The dose of olan- phrenia. Mismatch negativity (MMN) is an tion, and emotional instability and was zapine was unchanged. By 3 months after event-related potential (ERP) generated in admitted to a local psychiatric hospital im- the start of tandospirone, her anxiety symp- response to occasional variations of acoustic mediately after the police spotted her wan- toms almost disappeared, and remained so stimuli and is suggested to reflect preatten- dering around in the rain. After discharge, at 6 months. By this time, she gained moti- tive cognitive operations.5 Specifically, re- she gave up studying and took a part time vation to shop at a grocery store by herself duced MMN amplitudes in response to job, which did not last long because of and pursue her favorite hobbies (embroidery frequent-deviant stimuli have been associ- social withdrawal despite treatment with and others). ated with the pathophysiology of schizo- haloperidol (up to 6 mg/d) and sulpiride (up Electroencephalograms (EEG) were phrenia, including decreased gray matter to 150 mg/d). At age 35, she was rehospi- recorded before the start of tandospirone volumes of the prefrontal cortex and superior talized because of severe auditory halluci- and 3 and 6 months thereafter, according to temporal gyrus.6 nations, delusion of persecution, thought a regimen previously reported.14 Mismatch A limited number of studies report the disturbance, and stupor. Switching to mon- negativity, in response to frequency-deviant ability of dopamine,7 serotonin (5-HT),7Y11 otherapy with olanzapine at 20 mg/d was tones, was measured with an oddball para- 9 and N-methyl-D-aspartate acid (NMDA) effective in treating these symptoms, and digm. Auditory stimuli were delivered transmissions to modulate MMN in healthy the patient was discharged after a 3-month binaurally through headphones with inter- human subjects. Here, we report a case hospitalization. stimulus intervals of 0.5 second. Deviant of schizophrenia in which adjunctive use Although her general psychiatric tones of 1500 Hz were randomly presented of tandospirone, a 5-HT1A partial agonist conditions remained relatively well, she in a series of standard tones of 1000 Hz, FIGURE 1. Effect of adjunctive use of tandospirone, a 5-HT1A partial agonist, on MMN in a patient with schizophrenia receiving olanzapine. Mismatch negativity amplitudes (indicated by an arrow) in response to frequent-deviant stimuli were increased both at 3 and 6 months after the addition of tandospirone. Inset: cognitive performance, as evaluated by the Brief Assessment of Cognition in Schizophrenia-Japanese version (BACS-J) composite score, was improved at 6 months compared with baseline. 732 www.psychopharmacology.com Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Journal of Clinical Psychopharmacology & Volume 30, Number 6, December 2010 Letters to the Editors with the presentation probability of 0.1 for that the change in MMN waveforms pre- 4. Matsui M, Sumiyoshi T, Arai H, et al. the deviant tones. During the recordings, ceded the improvement of behavioral per- Cognitive functioning related to quality subjects were requested to watch anima- formance during treatment (Fig. 1). This of life in schizophrenia. Prog tion. All electrodes were referred to the divergence in time suggests that some of Neuropsychopharmacol Biol Psychiatry. average amplitude of ear electrodes (band- the electrophysiological signals reflecting 2008;32:280Y287. width, 0.16Y120Hz;notchfilter,60Hz). preattentive cognitive process may be able 5. Garrido MI, Kilner JM, Stephan KE, et al. Electrode impedance was less than 10 k6. to predict treatment efficacy in neuropsy- The mismatch negativity: a review of Data were collected with a sampling rate chological performance. underlying mechanisms. Clin Neurophysiol. Y of 500 Hz. Averaging of ERP waves and The effect of 5-HT1A agonism on 2009;120:453 463. related procedures were performed using MMN may be mediated by its influence on 6. Rasser PE, Schall U, Todd J, et al. Gray EPLYZER II software (Kissei Comtec, Co glutamatergic and, possibly, GABAergic matter deficits, mismatch negativity, and Ltd, Nagano, Japan). The epoch was 600 function. This assumption is based on ob- outcomes in schizophrenia. Schizophr Bull. milliseconds, including a 100- millisecond servations that blockade of NMDA recep- 2009 [Epub ahead of print]. 9,19 prestimulus baseline. Neuropsychological tors reduces MMN and that 8-OH-DPAT, 7. Leung S, Croft RJ, Guille V, et al. Acute assessment was conducted with the Brief a5-HT1A agonist, modulates cortical acti- dopamine and/or serotonin depletion does Assessment of Cognition in Schizophrenia- vity through 5-HT1A receptors located on not modulate mismatch negativity 15 Japanese version (BACS-J) at the elec- GABAergic interneurons and those on pyra- (MMN) in healthy human participants. 20 troencephalogram measurement. Alternate midal neurons. Further study is needed Psychopharmacology (Berl). 2010;208: forms, where appropriate, were used at re- to confirm the potential benefit of agents 233Y244. assessments. Written informed consent was acting on 5-HT receptors for improving 1A 8. Kahkonen S, Makinen V, Jaaskelainen IP, obtained for these clinical evaluations. MMN and other components of ERPs in et al. Serotonergic modulation of mismatch As shown in Figure 1, MMN ampli- people with schizophrenia. negativity. Psychiatry Res. 2005;138: tudes were increased as early as 3 months 61Y74. from the start of augmentation therapy with tandospirone and remained so at 6 months. 9. Heekeren K, Daumann J, Neukirch A, et al. AUTHOR DISCLOSURE Mismatch negativity generation in the The BACS-J composite scores (in Z-score) INFORMATION human 5HT2A agonist and NMDA at baseline, 3 months, and 6 months were This study was funded by grants-in- antagonist model of psychosis. j0.88, j0.95, and j0.32, respectively aid for Scientific Research from the Japan Psychopharmacology (Berl). 2008;199: (Fig. 1, inset), suggesting improved perfor- Society for the Promotion of Science and 77Y88. mance after a 6-month adjunctive treatment. grants-in-aid from the Ministry of Health, 10. Oranje B, Jensen K, Wienberg M, et al. Labour and Welfare, Japan. Divergent effects of increased serotonergic DISCUSSION The authors declare no further con- activity on psychophysiological flicts of interest. parameters of human attention. To our knowledge, these findings pro- Int J Neuropsychopharmacol. 2008;11: vide the first evidence for the ability of 453Y463. 5-HT1A partial agonists to improve MMN in subjects with schizophrenia. So far, only Yuko Higuchi, MD, PhD 11. Wienberg M, Glenthoj B, Jensen K, et al. a limited number of neurochemical mani- A single high dose of escitalopram increases Tomiki Sumiyoshi, MD, PhD mismatch negativity without affecting pulations have been reported to enhance Yasuhiro Kawasaki, MD, PhD processing negativity or P300 amplitude in MMN in healthy volunteers, for example, 10,11 Toru Ito, MD, PhD healthy volunteers. J Psychopharmacol. 5-HT reuptake inhibitors, tryptophan 2009. depletion,8 and nicotinic receptor stimula- Tomonori Seo, MD, PhD tion,5 whereas N-acetyl-cysteine, a glutathi- 12. Sumiyoshi T, Matsui M, Nohara S, et al. Michio Suzuki, MD, PhD Enhancement of cognitive performance in one precursor, has been shown to enhance Department of Neuropsychiatry schizophrenia by addition of tandospirone to MMN in patients with schizophrenia.16 University of Toyama Graduate School neuroleptic treatment. Am J Psychiatry. Whether increased or decreased serotonergic of Medicine and Pharmaceutical Sciences 2001;158:1722Y1725. tones enhance MMN amplitudes has been Toyama, Japan controversial,7,8,10,11 suggesting a role for [email protected] 13. Sumiyoshi T, Matsui M, Yamashita I, et al. specific 5-HT receptor subtypes, such as 5- Effect of adjunctive treatment with serotonin-1A agonist tandospirone on HT1A and 5-HT2A receptors, in the modu- lation of MMN. 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