The Open Neurology Journal




ISSN: 1874-205X ― Volume 13, 2019
LETTER

Tiapride for the Treatment of REM Sleep Behaviour Disorder in Dementia with Lewy Bodies: A Case Series



Georg Adler*, Angelika E. Mautes
Institut für Studien zur Psychischen Gesundheit (ISPG), Mannheim, Germany

Abstract

Objective:

REM sleep Behaviour Disorder (RBD) in Dementia with Lewy bodies (DLB) may be attributed to a decrease in dopaminergic neurotransmission. Thus, we studied the therapeutic efficacy of the pre and postsynaptic D2 and D3 receptor antagonist tiapride, which at a low dosage preferentially blocks presynaptic dopamine receptors and consequently leads to feedback activation of dopamine synthesis and to increased extracellular levels of dopamine.

Methods:

Six consecutive patients presenting at our memory clinic with RBD in DLB, in whom melatonin had been ineffective and clonazepam was found inappropriate for clinical reasons, were treated with triapride at dosages between 50 and 150 mg for twelve weeks.

Results:

Tiapride was well tolerated by all patients. Five of the six patients, reported was a decrease of the self-perceived frequency of bad dreams and the intensity and severity of motor and vocal enactments during sleep. In four of these six patients, this was also the case in the view of the patients’ bed partners.

Conclusion:

Tiapride may by an effective and well-tolerated treatment for RBD in patients with DLB.

Keywords: Tiapride, Treatment, REM sleep behaviour disorder, Dementia with Lewy bodies, Neurodegenerative, Inhibitors.


Article Information


Identifiers and Pagination:

Year: 2019
Volume: 13
First Page: 63
Last Page: 66
Publisher Id: TONEUJ-13-63
DOI: 10.2174/1874205X01913010063

Article History:

Received Date: 31/07/2018
Revision Received Date: 20/03/2019
Acceptance Date: 02/04/2019
Electronic publication date: 30/04/2019
Collection year: 2019

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© 2019 Adler and Mautes.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Institut für Studien zur Psychischen Gesundheit (ISPG), Richard Wagner-Strasse 2, 68165 Mannheim, Tel: +4962140046190; Fax: +4962140046191; Email: adler@ispg-mannheim.de




1. INTRODUCTION

REM sleep Behaviour Disorder (RBD), a parasomnia with repeated episodes of dream-enactment behaviour [1Schenck CH, Mahowald MW. REM sleep behavior disorder: Clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25(2): 120-38.
[http://dx.doi.org/10.1093/sleep/25.2.120] [PMID: 11902423]
], is frequent in neurodegenerative diseases [2Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol 2006; 5(5): 424-32.
[http://dx.doi.org/10.1016/S1474-4422(06)70441-0] [PMID: 16632 313]
], particularly in Dementia with Lewy Bodies (DLB) [3Fujishiro H, Nakamura S, Sato K, Iseki E. Prodromal dementia with Lewy bodies. Geriatr Gerontol Int 2015; 15(7): 817-26.
[http://dx.doi.org/10.1111/ggi.12466] [PMID: 25690399]
]. Consequently, it has been given increased diagnostic weight as a core clinical feature in the revised criteria for the clinical diagnosis of probable and possible DLB [4McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 2017; 89(1): 88-100.
[http://dx.doi.org/10.1212/WNL.0000000000004058] [PMID: 28592 453]
].

The two best established drugs for the treatment of RBD are melatonin and clonazepam [5Jung Y, St Louis EK. Treatment of REM sleep behavior disorder. Curr Treat Options Neurol 2016; 18(11): 50.
[http://dx.doi.org/10.1007/s11940-016-0433-2] [PMID: 27752878]
]. Both have been found to be modestly effective. Melatonin may be advantageous because of its higher effectiveness for injury prevention and fewer side effects [6McCarter SJ, Boswell CL, St Louis EK, et al. Treatment outcomes in REM sleep behavior disorder. Sleep Med 2013; 14(3): 237-42.
[http://dx.doi.org/10.1016/j.sleep.2012.09.018] [PMID: 23352028]
] compared to clonazepam [7Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. Am J Med 1996; 100(3): 333-7.
[http://dx.doi.org/10.1016/S0002-9343(97)89493-4] [PMID: 8629680]
, 8Albin RL, Koeppe RA, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000; 55(9): 1410-2.
[http://dx.doi.org/10.1212/WNL.55.9.1410] [PMID: 11087796]
]. Second and third line alternatives for RBD treatment include acetylcholinesterase inhibitors, zopiclone, and Yi-Gan San [5Jung Y, St Louis EK. Treatment of REM sleep behavior disorder. Curr Treat Options Neurol 2016; 18(11): 50.
[http://dx.doi.org/10.1007/s11940-016-0433-2] [PMID: 27752878]
].

A decreased dopaminergic neurotransmission could be the reason for the development of RBD. In DLB, there is a loss of dopaminergic midbrain neurons [9Li SX, Lam SP, Zhang J, et al. A prospective, naturalistic follow-up study of treatment outcomes with clonazepam in rapid eye movement sleep behavior disorder. Sleep Med 2016; 21: 114-20.
[http://dx.doi.org/10.1016/j.sleep.2015.12.020] [PMID: 27448481]
] and a decrease of dopaminergic neurotransmission [10Gilman S, Koeppe RA, Chervin RD, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003; 61(1): 29-34.
[http://dx.doi.org/10.1212/01.WNL.0000073745.68744.94] [PMID: 12 847152]
, 11Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26(5): 507-12.
[http://dx.doi.org/10.1093/sleep/26.5.507] [PMID: 12938802]
]. On this background, therapy trials with the D2 and D3 dopamine receptor agonist pramipexol have been conducted. The majority of the authors found modest improvements in RBD symptom severity and frequency [12Fantini ML, Gagnon JF, Filipini D, Montplaisir J. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003; 61(10): 1418-20.
[http://dx.doi.org/10.1212/WNL.61.10.1418] [PMID: 14638967]
-14Sasai T, Matsuura M, Inoue Y. Factors associated with the effect of pramipexole on symptoms of idiopathic REM sleep behavior disorder. Parkinsonism Relat Disord 2013; 19(2): 153-7.
[http://dx.doi.org/10.1016/j.parkreldis.2012.08.010] [PMID: 22989 561]
], while others did not [15Kumru H, Iranzo A, Carrasco E, et al. Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease. Sleep 2008; 31(10): 1418-21.
[PMID: 18853939]
].

The benzamide derivate tiapride is a moderate, selective antagonist for both pre and postsynaptic D2 and D3 receptors [16Jenner P, Elliott PNC, Clow A, Reavill C, Marsden CD. A comparison of in vitro and in vivo dopamine receptor antagonism produced by substituted benzamide drugs. J Pharm Pharmacol 1978; 30(1): 46-8.
[http://dx.doi.org/10.1111/j.2042-7158.1978.tb13151.x] [PMID: 227 24]
, 17Steele JW, Faulds D, Sorkin EM. Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation. Drugs Aging 1993; 3(5): 460-78.
[http://dx.doi.org/10.2165/00002512-199303050-00007] [PMID: 824 1609]
]. Tiapride is used to treat various neurological and psychiatric disorders, particularly dyskinesia, alcohol withdrawal syndrome, negative symptoms of psychosis, agitation and aggression in the elderly [18Scatton B, Cohen C, Perrault G, et al. The preclinical pharmacologic profile of tiapride. Eur Psychiatry 2001; 16(Suppl. 1): 29s-34s.
[http://dx.doi.org/10.1016/S0924-9338(00)00526-5] [PMID: 11520 476]
]. Presynaptic dopamine receptors are generally blocked by lower antagonist concentrations than postsynaptic receptors [19Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011; 63(1): 182-217.
[http://dx.doi.org/10.1124/pr.110.002642] [PMID: 21303898]
]. The blockade of the presynaptic dopamine receptors by low dose tiapride leads to feedback activation of dopamine synthesis and to increased extracellular levels of dopamine [18Scatton B, Cohen C, Perrault G, et al. The preclinical pharmacologic profile of tiapride. Eur Psychiatry 2001; 16(Suppl. 1): 29s-34s.
[http://dx.doi.org/10.1016/S0924-9338(00)00526-5] [PMID: 11520 476]
]. Thus, the dopaminergic effect through the preferentially presynaptic blockade of dopamine receptors by low dosages of tiapride may warrant a trial for the treatment of RBD in DLB. Compared to pramipexole, which also has a dopaminergic effect, tiapride has a more favourable side effect profile.

2. METHODS

The trial was performed in six consecutive patients with probable mild to moderate DLB [4McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 2017; 89(1): 88-100.
[http://dx.doi.org/10.1212/WNL.0000000000004058] [PMID: 28592 453]
] and RBD, in whom treatment with clonazepam was considered inappropriate because of the risk of falls, cognitive impairment, or sleep apnea and treatment with melatonin at dosages between 2 and 8 mg had had little or no effect. Patients had to have a bed partner, who could serve as an external information source.

RBD was ascertained by patient and bed partner history as well as polysomnography (PSG). All patients had a history of at least weekly violent dream enactment behavior. PSG showed tonic and phasic EMG activity during REM sleep in all patients and complex behavioral activity during REM sleep in four of six patients.

The patients were asked to score the frequency of unpleasant dreams according to Item 5 (h) of the Pittsburgh Sleep Quality Index (PSQI) [20Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res 1989; 28(2): 193-213.
[http://dx.doi.org/10.1016/0165-1781(89)90047-4] [PMID: 2748771]
] as either “0” (not during the past month), “1” (less than once a week), “2” (once or twice a week), or “3” (three or more times a week) before and twelve weeks after the initiation of tiapride treatment. After twelve weeks of tiapride, the patients and their bed partners were also asked whether frequency or severity of the motor and vocal behaviors during sleep improved, remained unchanged, or worsened. Due to cognitive problems, the self-assessments of the patients should be interpreted with due caution. They and the caregivers were encouraged to make notes on a preceding night immediately after waking up. Mild psychotic symptoms were present in some of the patients, as scenic visual hallucinations or as passing delusional misinterpretations of visual and auditory perceptions. As the applied dosages of tiapride were to low to expect an antipsychotic effect, we did not ask for psychotic symptoms in a standardized manner and did not observe an obvious effect of tiapride on psychotic symptoms. Tiapride has been found to cause increased prolactin levels in plasma, which can cause decreased libido, infertility and increased risk of breast cancer [21Perényi A, Arató M, Bagdy G, Frecska E, Szücs R. Tiapride in the treatment of tardive dyskinesia: A clinical and biochemical study. J Clin Psychiatry 1985; 46(6): 229-31.
[PMID: 2860098]
]. A side effect rarely reported to the FDA is rhabdomyolysis. Cardiac abnormalities such as prolongation of the QT interval and torsades de point also have been observed. Dosages above approximately 300 mg/day may induce tardive dyskinesia [22Peters DH, Faulds D. Tiapride. A review of its pharmacology and therapeutic potential in the management of alcohol dependence syndrome. Drugs 1994; 47(6): 1010-32.
[http://dx.doi.org/10.2165/00003495-199447060-00009] [PMID: 7521 826]
].

Treatment with tiapride was initiated with a dosage of 50 mg before going to sleep. The patients were seen every four weeks. At weeks 4 and 8 after treatment initiation, the dosage of tiapride was adjusted. If there was no or little therapeutic effect, the dosage would be increased in 50-mg steps. If the respective reports of patient and caregiver were discordant, which may be the case because the patient’s report refers to subjective experience, the caregiver’s report to external observation, we aimed for a consensus integrating both views and suggested dose changes on this basis. In case of side effects, the dosage would be reduced by 50 mg or the treatment would be discontinued.

All procedures involving human subjects were done in accordance with the ethical standards of the Committee on Human Experimentation of Mannheim Medical Faculty and in accord with the Helsinki Declaration of 1975.

3. RESULTS

The patients were five men and one woman at ages between 63 and 78 years (mean: 71.8 years). Individual patient data are given in Table 1.

Table 1
Individual patient data.


The age of onset of DLB was between 61 and 72 years (mean: 68.8. years). All patients were treated with levodopa and a cholinesterase inhibitor (rivastigmine in four patients, donepezil in two); two patients were additionally under treatment with a dopamine agonist (one with pramipexole, one with rotigotine). The age at onset of RBD was between 62 and 75 years (mean: 69.2 years); in two patients, the onset of RBD preceded the onset of DLB. The mean duration of RBD was between one and six years (mean: 2.7 years). The frequency of bad dreams as assessed by the PSQI was reported as “once or twice a week” by four patients, as “three or more times a week” by two patients.

Tiapride was well tolerated by all patients. Extrapyramidal side effects were not observed. The final dose was 50 mg in two patients, 100 mg in three, and 150 mg in one patient. One patient reported that under 50 mg tiapride, the frequency of bad dreams decreased from twice or three times a week down to less than once a week. When we further increased the dose to 100 mg, the bad dreams appeared more frequently and more vividly again. After subsequent reduction of the dosage to 50 mg, frequency and intensity of the bad dreams decreased again.

In five of the six patients, self-perceived frequency of bad dreams and intensity and severity of motor and vocal enactments during sleep decreased under tiapride treatment. In four of the six patients, this was also the case in the view of the patients’ bed partners. At all assessments, the association between patient and caregiver reports was high. No effects were observed on motor or psychotic symptoms or on daytime behavior, particularly no sedation. However, fluctuations as a typical symptom of DLB may have impaired the assessment of such side effects.

4. DISCUSSION

Tiapride was found effective for the treatment of RBD in DLB in four to five out of six patients. The effective dose was between 50 and 150 mg. In one patient, we observed decreased efficacy at increasing dosage. Thus, tiapride may be considered as a treatment option in patients with RBD in DLB, in whom melatonin was found ineffective or little effective and clonazepam could not be used because of the increased risk for falls, cognitive impairment and worsening of sleep apnea.

At the comparatively small dosages applied, tiapride mainly blocks the presynaptic dopamine receptors and enhances dopaminergic neurotransmission [18Scatton B, Cohen C, Perrault G, et al. The preclinical pharmacologic profile of tiapride. Eur Psychiatry 2001; 16(Suppl. 1): 29s-34s.
[http://dx.doi.org/10.1016/S0924-9338(00)00526-5] [PMID: 11520 476]
]. Thus, improvement of RBD under a low-dose tiapride treatment supports the assumption of a role of the dopaminergic system in the generation of DLB [8Albin RL, Koeppe RA, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000; 55(9): 1410-2.
[http://dx.doi.org/10.1212/WNL.55.9.1410] [PMID: 11087796]
, 11Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26(5): 507-12.
[http://dx.doi.org/10.1093/sleep/26.5.507] [PMID: 12938802]
].

At the dosages we applied, tiapride has a very low risk for extrapyramidal side effects, such as akinesia or akathisia. Additionally, tiapride has a relatively high regional selectivity for limbic areas. One study found that, in contrast to haloperidol, tiapride shows over three times as much affinity for limbic than for striatal areas [18Scatton B, Cohen C, Perrault G, et al. The preclinical pharmacologic profile of tiapride. Eur Psychiatry 2001; 16(Suppl. 1): 29s-34s.
[http://dx.doi.org/10.1016/S0924-9338(00)00526-5] [PMID: 11520 476]
]. However, under long-term treatment, it may increase the prolactin level [21Perényi A, Arató M, Bagdy G, Frecska E, Szücs R. Tiapride in the treatment of tardive dyskinesia: A clinical and biochemical study. J Clin Psychiatry 1985; 46(6): 229-31.
[PMID: 2860098]
], which may in turn decrease libido and increase the risk of breast cancer and osteoporosis. Tiapride has only a small potential for pharmacokinetic interactions and its serum level is well controllable, because it has no relevant oxidative liver metabolism and is eliminated renally with a serum half-life of three to four hours [22Peters DH, Faulds D. Tiapride. A review of its pharmacology and therapeutic potential in the management of alcohol dependence syndrome. Drugs 1994; 47(6): 1010-32.
[http://dx.doi.org/10.2165/00003495-199447060-00009] [PMID: 7521 826]
].

Given the considerable impairment caused by RBD in patients with DLB and the limitations of alternative treatments, the further exploration of the therapeutic potential of tiapride may be warranted.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All procedures involving human subjects were done in accordance with the ethical standards of the Committee on Human Experimentation of Mannheim Medical Faculty.

HUMAN AND ANIMAL RIGHTS

No animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

Informed consent was obtained from all participants prior to publication.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Schenck CH, Mahowald MW. REM sleep behavior disorder: Clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 2002; 25(2): 120-38.
[http://dx.doi.org/10.1093/sleep/25.2.120] [PMID: 11902423]
[2] Gagnon JF, Postuma RB, Mazza S, Doyon J, Montplaisir J. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol 2006; 5(5): 424-32.
[http://dx.doi.org/10.1016/S1474-4422(06)70441-0] [PMID: 16632 313]
[3] Fujishiro H, Nakamura S, Sato K, Iseki E. Prodromal dementia with Lewy bodies. Geriatr Gerontol Int 2015; 15(7): 817-26.
[http://dx.doi.org/10.1111/ggi.12466] [PMID: 25690399]
[4] McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 2017; 89(1): 88-100.
[http://dx.doi.org/10.1212/WNL.0000000000004058] [PMID: 28592 453]
[5] Jung Y, St Louis EK. Treatment of REM sleep behavior disorder. Curr Treat Options Neurol 2016; 18(11): 50.
[http://dx.doi.org/10.1007/s11940-016-0433-2] [PMID: 27752878]
[6] McCarter SJ, Boswell CL, St Louis EK, et al. Treatment outcomes in REM sleep behavior disorder. Sleep Med 2013; 14(3): 237-42.
[http://dx.doi.org/10.1016/j.sleep.2012.09.018] [PMID: 23352028]
[7] Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. Am J Med 1996; 100(3): 333-7.
[http://dx.doi.org/10.1016/S0002-9343(97)89493-4] [PMID: 8629680]
[8] Albin RL, Koeppe RA, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000; 55(9): 1410-2.
[http://dx.doi.org/10.1212/WNL.55.9.1410] [PMID: 11087796]
[9] Li SX, Lam SP, Zhang J, et al. A prospective, naturalistic follow-up study of treatment outcomes with clonazepam in rapid eye movement sleep behavior disorder. Sleep Med 2016; 21: 114-20.
[http://dx.doi.org/10.1016/j.sleep.2015.12.020] [PMID: 27448481]
[10] Gilman S, Koeppe RA, Chervin RD, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003; 61(1): 29-34.
[http://dx.doi.org/10.1212/01.WNL.0000073745.68744.94] [PMID: 12 847152]
[11] Eisensehr I, Linke R, Tatsch K, et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26(5): 507-12.
[http://dx.doi.org/10.1093/sleep/26.5.507] [PMID: 12938802]
[12] Fantini ML, Gagnon JF, Filipini D, Montplaisir J. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003; 61(10): 1418-20.
[http://dx.doi.org/10.1212/WNL.61.10.1418] [PMID: 14638967]
[13] Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behavior disorder: Results from a case series. Sleep Med 2006; 7(5): 418-23.
[http://dx.doi.org/10.1016/j.sleep.2006.03.018] [PMID: 16815751]
[14] Sasai T, Matsuura M, Inoue Y. Factors associated with the effect of pramipexole on symptoms of idiopathic REM sleep behavior disorder. Parkinsonism Relat Disord 2013; 19(2): 153-7.
[http://dx.doi.org/10.1016/j.parkreldis.2012.08.010] [PMID: 22989 561]
[15] Kumru H, Iranzo A, Carrasco E, et al. Lack of effects of pramipexole on REM sleep behavior disorder in Parkinson disease. Sleep 2008; 31(10): 1418-21.
[PMID: 18853939]
[16] Jenner P, Elliott PNC, Clow A, Reavill C, Marsden CD. A comparison of in vitro and in vivo dopamine receptor antagonism produced by substituted benzamide drugs. J Pharm Pharmacol 1978; 30(1): 46-8.
[http://dx.doi.org/10.1111/j.2042-7158.1978.tb13151.x] [PMID: 227 24]
[17] Steele JW, Faulds D, Sorkin EM. Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation. Drugs Aging 1993; 3(5): 460-78.
[http://dx.doi.org/10.2165/00002512-199303050-00007] [PMID: 824 1609]
[18] Scatton B, Cohen C, Perrault G, et al. The preclinical pharmacologic profile of tiapride. Eur Psychiatry 2001; 16(Suppl. 1): 29s-34s.
[http://dx.doi.org/10.1016/S0924-9338(00)00526-5] [PMID: 11520 476]
[19] Beaulieu J-M, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 2011; 63(1): 182-217.
[http://dx.doi.org/10.1124/pr.110.002642] [PMID: 21303898]
[20] Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: A new instrument for psychiatric practice and research. Psychiatry Res 1989; 28(2): 193-213.
[http://dx.doi.org/10.1016/0165-1781(89)90047-4] [PMID: 2748771]
[21] Perényi A, Arató M, Bagdy G, Frecska E, Szücs R. Tiapride in the treatment of tardive dyskinesia: A clinical and biochemical study. J Clin Psychiatry 1985; 46(6): 229-31.
[PMID: 2860098]
[22] Peters DH, Faulds D. Tiapride. A review of its pharmacology and therapeutic potential in the management of alcohol dependence syndrome. Drugs 1994; 47(6): 1010-32.
[http://dx.doi.org/10.2165/00003495-199447060-00009] [PMID: 7521 826]

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"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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