The Effect of Venlafaxine on Language Function in Patients With Subcortical Aphasia: A fMRI Study

Ischemic Stroke Clinical Trial

Official title:

A Randomized, Single Blind, Controlled, Longitudinal Study of the Effects of Venlafaxine Hydrochloride Capsules on the Language Function of Stroke Patients With Subcortical Aphasia Using fMRI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03588572
• Other study ID #: LY-81471172
• Status: Completed
• Phase: N/A
• Start date: August 1, 2018
• Est. completion date: August 1, 2019

Study information

• Verified date: September 2021
• Source: Guangzhou General Hospital of Guangzhou Military Command
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Previous studies have demonstrated that venlafaxine significantly improves the language function of healthy subjects and increase of fMRI activation in cortical language area. This study was designed to investigate the relationship between venlafaxine on the cortical language functional reorganization and clinical language improvements in the stroke patients with subcortical aphasia. It is a randomized, controlled, single-blind, longitudinal trial which has approved by the ethics committee of Guangzhou General Hospital of Guangzhou Military Command, and all patients and their guardian should sign an informed consent. The patients will divide into the venlafaxine group and the control group according to the principle of randomization (random number table). The patients in the venlafaxine group begin to take a venlafaxine hydrochloride capsule after enrollment ( each containing venlafaxine 75mg), qd, until 4 weeks after randomization, and the control group do not. Assessments of language functional behavior and examines of functional magnetic resonance imaging (fMRI) should be performed on the first days (V1), 28±3 days (V2) and 90±3 days (V3) after randomization. Through all this procession, we expect improve the language function of participants in experiment and clarify its mechanism,the research may help develop a new treatment for other patients with similar conditions.

Description:

The cases will recruit from inpatients with acute ischemic stroke in Department of Cerebrovascular disease, The Guangzhou General Hospital of Guangzhou Military Command from June 2018 to June 2019. The diagnose of ischemic stroke is made using the diagnostic criteria of the International Association of Neurological Diseases and Stroke Association in 1982. The classification criteria for subcortical ischemic stroke are based on the current international TOAST etiological classification method. It is a randomized, controlled, single-blind, longitudinal trial which has approved by the ethics committee of Guangzhou General Hospital of Guangzhou Military Command, and all patients and their guardian should sign an informed consent. The patients will divide into the venlafaxine group and the control group according to the principle of randomization (random number table). The patients in the venlafaxine group begin to take a venlafaxine hydrochloride capsule after enrollment ( each containing venlafaxine 75mg), qd, until 4 weeks after randomization, and the control group do not. Assessments of language functional behavior and examines of functional magnetic resonance imaging (fMRI) should be performed on the first days (Visit1,V1), 28±3 days (Visit2, V2) and 90±3 days (Visit3, V3) after randomization. Language functional behavioral assessments included the Chinese version of Western Aphasia Battery(WAB), spontaneous language frequency test(SLFT) and picture naming test(PNT). Examines of fMRI included task-state fMRI and resting-state fMRI. All patients received language rehabilitation training (twice a week, one hour each) which will be conducted by a professional rehabilitation physiotherapist from the Visitation1 until the end of Visitation3. The blood pressure and heart rate of each patient will be monitored and recorded on each visit, and two routine blood tests are performed at V0 and V3, including the blood routine and the liver and kidney function. The test sample quantity is estimated using the sample size estimated by the professional software nQuery Advisor7.0. According to the main evaluation index of the effect of the previous literature on the efficacy of venlafaxine, the experimental group and the control group are 7.5±3.8 and 4.3±2.6，The standard deviation will be 3.26, and 0.05 will be the statistical meaning level (double tail). The test efficiency will be set to 0.83. The balance design will be used to estimate the sample size of the experimental group and the control group in 16 cases. In addition, considering the 20% missing rate, a total of 45 samples will be included in the study. Task-state fMRI: an fMRI block design will be adopted, and DMDX software will be used to present each picture in series alternated between baseline (B) and activation (A) [B-A-B-A-B…]. Thirty-six animal pictures and 36 tool pictures accurately recognized by all subjects will be selected from the Snodgrass picture database. Six blocks of animal naming and six blocks of tool naming will be repeated, and each block continued for 18s with six pictures.the block-design diagram of picture naming task. The abstract figure of an American skunk which is unrecognized by all the subjects will be selected for baseline of animal naming. A schematic drawn arrow will be chosen for baseline picture of tool naming.Patients will be required to silently name the object in each picture without moving their lips. To avoid practice effects, the pictures used for activation will be different from those used in the behavioral evaluation. In the baseline phase, the participants will be asked to identify the orientation of the pictures by silently saying "upright" or "inverted." The subjects will receive task familiarization training prior to the test to ensure that there will be no substantive picture naming but only positional judgment in the baseline task. Rest-state fMRI: During the rest-state fMRI scan, no task instruction will be given to the patient, and the patient will be completely relaxing, closing his eyes, breathing calmly, keeping his head still, but can not fall asleep, try to avoid any systematic thinking activities, scanning 8min. Functional magnetic resonance data acquisition The cranial brain scan will be performed using the US GE Signa HDx 3.0T Tesla superconducting magnetic resonance imaging system. The scanning sequence and parameters are as follows: 1. T1 structure imaging using FSPGR BRAVO sequence. The parameters included: time of repetition, 8.86 ms; time of echo, 3.52 ms; field of view, 24×24 cm2; in-plane resolution,256×256; slice thickness, 1 mm;interslice gap, 1 mm; and number of slices, 176. 2. Echo-Planar Imaging (EPI) is used to acquire task-state fMRI data.The parameters included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2; in-plane resolution,64×64; slice thickness, 4 mm; interslice gap, 1 mm; and number of slices, 34. Scan a sequence of 240s, a total of 12 min. 3. Echo-Planar Imaging (EPI) is used to acquire rest-state fMRI data.The parameters included: time of repetition, 3000ms; time of echo, 40 ms; field of view, 24×24 cm2; in-plane resolution,64×64; slice thickness, 4 mm; interslice gap, 1 mm; and number of slices, 34. A total of 8 min.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: August 1, 2019
• Est. primary completion date: July 1, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• The first stroke of the left single subcortical areas, within 72hours.
• Primary school or higher level,aged between 18-75, native language Chinese
• According to the commonly used eye chart examination, the corrected visual acuity is more than 1.0.
• According to the Edinburgh Handedness Questionnaire (EHQ) as the right handed.
• The language function was normal before the onset. After the onset, the language function was mildly to moderately impaired with Western Aphasia Battery (WAB) ( Aphasia Quotient (AQ) between in 60 to 88)
• The patient cooperate with the examination, they and their guardian signed the informed consent

Exclusion Criteria:

• History of organic diseases of the nervous system and history of craniocerebral trauma.
• History of epilepsy and psychosis.
• History of material dependence.
• Decompensation of important organ function.
• Hamilton Depression Scale(HAMD )>8 points.
• Hamilton Anxiety Scale(HAMA )>7 points.
• The Mini-Mental State Examination (MMSE)score <20 points.
• Dysphagia(difficult to take capsules).
• A history of allergens in component of venlafaxine.
• Pregnant women and breast-feeding women.
• Contraindication of MRI.

Related Conditions & MeSH terms

• Aphasia
• Ischemic Stroke
• Subcortical Aphasia

Intervention

Drug:
• Venlafaxine hydrochloride capsules
The patients in venlafaxine group begin to take the venlafaxine hydrochloride capsules after the first visitation(the first day after randomization), each containing venlafaxine 75mg, 1 capsule per day, until 4 weeks after randomization

Locations

Country	Name	City	State
China	Cerebrovascular Department of General Hospital of Guangzhou Military Command of PLA	GuangZhou	Guangdong
China	Guangzhou General Hospital of Guangzhou Military Command	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Guangzhou General Hospital of Guangzhou Military Command

Country where clinical trial is conducted

China, 

References & Publications (32)

Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993 Jan;24(1):35-41. — View Citation

Bauer M, Tharmanathan P, Volz HP, Moeller HJ, Freemantle N. The effect of venlafaxine compared with other antidepressants and placebo in the treatment of major depression: a meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2009 Apr;259(3):172-85. doi: 10.1007/s00406-008-0849-0. Epub 2009 Jan 22. — View Citation

Béïque J, de Montigny C, Blier P, Debonnel G. Effects of sustained administration of the serotonin and norepinephrine reuptake inhibitor venlafaxine: II. In vitro studies in the rat. Neuropharmacology. 2000 Jul 24;39(10):1813-22. — View Citation

Berrocoso E, Mico JA. Role of serotonin 5-HT1A receptors in the antidepressant-like effect and the antinociceptive effect of venlafaxine in mice. Int J Neuropsychopharmacol. 2009 Feb;12(1):61-71. doi: 10.1017/S1461145708008766. Epub 2008 Apr 14. — View Citation

Berthier ML, Pulvermüller F, Dávila G, Casares NG, Gutiérrez A. Drug therapy of post-stroke aphasia: a review of current evidence. Neuropsychol Rev. 2011 Sep;21(3):302-17. doi: 10.1007/s11065-011-9177-7. Epub 2011 Aug 16. Review. — View Citation

Berthier ML. Poststroke aphasia : epidemiology, pathophysiology and treatment. Drugs Aging. 2005;22(2):163-82. Review. — View Citation

Beversdorf DQ, Sharma UK, Phillips NN, Notestine MA, Slivka AP, Friedman NM, Schneider SL, Nagaraja HN, Hillier A. Effect of propranolol on naming in chronic Broca's aphasia with anomia. Neurocase. 2007 Aug;13(4):256-9. — View Citation

Damasio H, Grabowski TJ, Tranel D, Hichwa RD, Damasio AR. A neural basis for lexical retrieval. Nature. 1996 Apr 11;380(6574):499-505. Erratum in: Nature 1996 Jun 27;381(6595):810. — View Citation

Debonnel G, Saint-André E, Hébert C, de Montigny C, Lavoie N, Blier P. Differential physiological effects of a low dose and high doses of venlafaxine in major depression. Int J Neuropsychopharmacol. 2007 Feb;10(1):51-61. Epub 2006 May 11. — View Citation

Dickey L, Kagan A, Lindsay MP, Fang J, Rowland A, Black S. Incidence and profile of inpatient stroke-induced aphasia in Ontario, Canada. Arch Phys Med Rehabil. 2010 Feb;91(2):196-202. doi: 10.1016/j.apmr.2009.09.020. — View Citation

Engelter ST, Gostynski M, Papa S, Frei M, Born C, Ajdacic-Gross V, Gutzwiller F, Lyrer PA. Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, etiology, and thrombolysis. Stroke. 2006 Jun;37(6):1379-84. Epub 2006 May 11. — View Citation

Feeney DM, Sutton RL. Pharmacotherapy for recovery of function after brain injury. Crit Rev Neurobiol. 1987;3(2):135-97. Review. — View Citation

Fernandez B, Cardebat D, Demonet JF, Joseph PA, Mazaux JM, Barat M, Allard M. Functional MRI follow-up study of language processes in healthy subjects and during recovery in a case of aphasia. Stroke. 2004 Sep;35(9):2171-6. Epub 2004 Aug 5. — View Citation

Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. — View Citation

Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967 Dec;6(4):278-96. — View Citation

HAMILTON M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-5. — View Citation

Herrera-Guzmán I, Herrera-Abarca JE, Gudayol-Ferré E, Herrera-Guzmán D, Gómez-Carbajal L, Peña-Olvira M, Villuendas-González E, Joan GO. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder. Psychiatry Res. 2010 May 30;177(3):323-9. doi: 10.1016/j.psychres.2010.03.006. Epub 2010 Apr 10. — View Citation

Kertesz A. Western Aphasia Battery test manual. New York:NY: Grune & Stratton,1982.

Kim H, Na DL. Normative data on the Korean version of the Western Aphasia Battery. J Clin Exp Neuropsychol. 2004 Nov;26(8):1011-20. — View Citation

Kim YH, You SH, Ko MH, Park JW, Lee KH, Jang SH, Yoo WK, Hallett M. Repetitive transcranial magnetic stimulation-induced corticomotor excitability and associated motor skill acquisition in chronic stroke. Stroke. 2006 Jun;37(6):1471-6. Epub 2006 May 4. Erratum in: Stroke. 2006 Nov;37(11):2861. — View Citation

Li CY, Song XZ, Han LX, Xie Q, Wang J, Li YK, Liu FD, Liu Y. The effects of venlafaxine on cortical motor area activity in healthy subjects: a pilot study. J Clin Psychopharmacol. 2014 Feb;34(1):93-8. doi: 10.1097/JCP.0000000000000056. — View Citation

Luria AR, Simernitskaya EG, Tubylevich B. The structure of psychological processes in relation to cerebral organization. Neuropsychologia. 1970 Jan;8(1):13-9. — View Citation

Nemeroff CB, Entsuah R, Benattia I, Demitrack M, Sloan DM, Thase ME. Comprehensive analysis of remission (COMPARE) with venlafaxine versus SSRIs. Biol Psychiatry. 2008 Feb 15;63(4):424-34. Epub 2007 Sep 24. — View Citation

Pedersen PM, Jørgensen HS, Nakayama H, Raaschou HO, Olsen TS. Aphasia in acute stroke: incidence, determinants, and recovery. Ann Neurol. 1995 Oct;38(4):659-66. — View Citation

Rickels K, Mangano R, Khan A. A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder. J Clin Psychopharmacol. 2004 Oct;24(5):488-96. — View Citation

Rudolph RL, Entsuah R, Chitra R. A meta-analysis of the effects of venlafaxine on anxiety associated with depression. J Clin Psychopharmacol. 1998 Apr;18(2):136-44. — View Citation

Schmitt AB, Bauer M, Volz HP, Moeller HJ, Jiang Q, Ninan PT, Loeschmann PA. Differential effects of venlafaxine in the treatment of major depressive disorder according to baseline severity. Eur Arch Psychiatry Clin Neurosci. 2009 Sep;259(6):329-39. doi: 10.1007/s00406-009-0003-7. Epub 2009 Mar 3. — View Citation

Schweizer E, Thielen RJ, Frazer A. Venlafaxine:a novel antidepressant compound. Expert Opin Investig Drugs. 1997 Jan;6(1):65-78. — View Citation

Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001 Mar;178:234-41. — View Citation

Thase ME, Entsuah R, Cantillon M, Kornstein SG. Relative antidepressant efficacy of venlafaxine and SSRIs: sex-age interactions. J Womens Health (Larchmt). 2005 Sep;14(7):609-16. — View Citation

Walker-Batson D, Curtis S, Natarajan R, Ford J, Dronkers N, Salmeron E, Lai J, Unwin DH. A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Stroke. 2001 Sep;32(9):2093-8. — View Citation

Xie Q, Liu Y, Li CY, Song XZ, Wang J, Han LX, Bai HM. The modulation of venlafaxine on cortical activation of language area in healthy subjects with fMRI study. Psychopharmacology (Berl). 2012 Oct;223(4):417-25. Epub 2012 May 4. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	A Change of Outcome Measure:the Chinese Version of Western Aphasia Battery(WAB)	The main outcome measure for this scale is Aphasia Quotient(AQ) which mainly tests the ability of spontaneous speech, oral comprehension, repetition, and naming, and reflects the severity of aphasia, and can be used as a reliable indicator to evaluate the improvement and deterioration of aphasia. Score fluctuation is 0-100 points, the normal value is 98.4-100 points, AQ<93.8 can be judged as language dysfunction.	This is an outcome measure to assess the improvement of language function from onset to 3 months after treatment. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.
Secondary	A Change of Outcome Measure:Spontaneous Language Frequency Test(SLFT)	This test mainly assesses spontaneous speech fluency of participants.It requires participants name as many food names as possible within one minute, and each correct one to give one point.The higher the score, the better the language function.	This is an outcome measure to assess the improvement of language function from onset to 3 months after treatment. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.
Secondary	A Change of Outcome Measure:Picture Naming Test(PNT)	This test mainly assesses the ability of picture name of participants.we used a program for displaying named pictures on a computer screen (60 photos in total, of which 20 were Chinese celebrity faces). Each image was displayed in 3 seconds, and 1 point was correctly named for an image.The faces of celebrities were selected from the picture database of Chinese celebrities in the State Key Laboratory of Cognitive Neuroscience and Learning at Beijing Normal University.Score fluctuation is 0-60 points, the higher the score, the better the ability of picture name.	This is an outcome measure to assess the improvement of language function from onset to 3 months after treatment. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.
Secondary	Follow-up Measurement: Hamilton Depression Rating Scale (HAMD)	The Hamilton Depression Rating Scale (HAMD) has proven useful for many years as a way of determining a patient's level of depression before, during, and after treatment. It generally takes 15-20 minutes to complete the interview and score the results. Eight items are scored on a 5-point scale, ranging from 0 = not present to 4 = severe. Nine items are scored from 0-2. HAMD Scoring Instructions:0-7=Normal, 8-13 = Mild Depression, 14-18 = Moderate Depression, 19-22 = Severe Depression, = 23 = Very Severe Depression(i.e.,Minimum 0 points and maximum 50 points, the higher the score, the greater the likelihood of depression).	We must determine that the participant is not in depression at each follow-up. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.
Secondary	Follow-up Measurement: Hamilton Anxiety Rating Scale (HAMA)	The Hamilton Anxiety Rating Scale (HAMA) is a widely used and well-validated tool for measuring the severity of a patient's anxiety. The HAMA is composed of 14 items and takes 15-20 minutes to complete the interview and score the results. Each item is scored on a 5-point scale, ranging from 0=not present to 4=severe.HAMA Scoring Instructions:0-8=Normal, 8-13= Possible Anxiety, 14-17 = Mild Anxiety, 18-24 = Moderate Anxiety, 25-30 = Severe Anxiety(i.e.,the higher the score, the greater the likelihood of anxiety).	We must determine that the participant is not in anxiety at each follow-up. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.
Secondary	Follow-up Measurement: Mini-Mental State Examination (MMSE)	The Mini-Mental State Examination (MMSE) is a 30-point questionnaire that is used extensively in clinical and research settings to measure cognitive impairment. Administration of the test takes between 5 and 10 minutes. The MMSE test includes simple questions and problems in a number of areas: the time and place of the test, repeating lists of words, arithmetic such as the serial sevens, language use and comprehension, and basic motor skills. Any score greater than or equal to 24 points (out of 30) indicates a normal cognition. Below this, scores can indicate severe (=9 points), moderate (10-18 points) or mild (19-23 points) cognitive impairment.The raw score may also need to be corrected for educational attainment and age.	We must determine that the participant is not in moderate or more cognitive impairment at each follow-up. Thus, participates will undergo this assessment on the first days (V1), 28±3 days (V2), and 90±3 days (V3) after randomization.