Doubleâblind, randomized crossover study of ...

Psychiatry and Clinical Neurosciences 2017; 71: 204–211

doi:10.1111/pcn.12480

Regular Article

Double-blind, randomized crossover study of intravenous infusion of magnesium sulfate versus 5% dextrose on depressive symptoms in adults with treatment-resistant depression Syed M. A. Mehdi, MD,1 Steven E. Atlas, BS,1 Sidra Qadir, MD,1 Dominique Musselman, MD,1 Sharon Goldberg, MD,2 Judi M. Woolger, MD,2 Raul Corredor, MD, PhD,1 Muhammad H. Abbas, MD,1 Leopoldo Arosemena, MD,2 Simone Caccamo, MD,2 Carmen S. G. Campbell, PhD,1 Ashar Farooqi, MD,1 Jinrun Gao, MS, MBA,3 Janet Konefal, PhD,4 Lucas C. Lages, BS,1 Laura Lantigua, BS,1 Johanna Lopez, PhD,1 Vanessa Padilla, MD,1 Ammar Rasul, MD,1 Anna M. Ray, BS,2 Herbert G. Simões, PhD,1 Eduard Tiozzo, PhD1 and John E. Lewis, PhD1* Departments of 1Psychiatry and Behavioral Sciences, 2Medicine, University of Miami Miller School of Medicine, Miami, 3 Barclay’s, Inc., Wilmington, 4Department of Family Medicine and Community Health, University of Miami Miller School of Medicine, Miami, USA

Aim: Treatment-resistant depression patients are more likely to suffer from comorbid physical and mental disorders, experience marked and protracted functional impairment, and incur higher health-care costs than non-affected individuals. Magnesium sulfate is a treatment option that may offer great potential for patients with treatmentresistant depression based on prior work in animals and humans. Methods: Twelve subjects with mild or moderate treatment-resistant depression were randomized into a double-blind crossover trial to receive an infusion of 4 g of magnesium sulfate in 5% dextrose or placebo infusion of 5% dextrose with a 5-day washout in between the 8-day intervention period. Subjects were assessed before and after the intervention for serum and urine magnesium, lipid panel, the Hamilton Rating Scale for Depression, and the Patient Health Questionnaire-9.

*Correspondence: John E. Lewis, PhD, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite #1474 (D28), Miami, FL 33136, USA. Email: [email protected] Received 13 July 2016; revised 24 October 2016; accepted 6 November 2016.

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Results: We found a difference in serum magnesium from day 2 to 8 (pre-infusion) (P < 0.002) and from baseline to day 8 (P < 0.02). No changes were noted on the Hamilton Rating Scale for Depression or the Patient Health Questionnaire-9 24 h post-treatment, but as serum magnesium increased from baseline to day 7, the Patient Health Questionnaire-9 decreased from baseline to day 7 (P = 0.02). Conclusion: Magnesium sulfate did not significantly affect depression 24 h post-infusion, but other results were consistent with the literature. The association between changes in serum magnesium and the Patient Health Questionnaire-9 supports the idea that magnesium sulfate may be used to address treatmentresistant depression, an ongoing medical challenge. Key words: depressive symptoms, intervention study, intravenous infusions, magnesium sulfate, treatment-resistant depression.

M

AJOR DEPRESSIVE DISORDERS (MDD) constitute 40% of neuropsychiatric disorders and affect 25% of the US population at some point in their lives.1 As a common and often severe mental

© 2016 The Authors Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology

MgSO4 i.v. infusion in depression


disorder associated with substantial illness-related burden, MDD ranks second to cardiovascular disease (CVD) in the magnitude of disease burden in the developed world. It is also projected to be a leading cause of disability worldwide by 2030.2 Depression is well known for taking an episodic clinical course, with resistance to common treatment. Studies have shown that 30–50% of patients diagnosed with MDD do not respond to an initial anti-depressant trial, while 15% will continue to suffer from depression.3 Treatment-resistant depression (TRD) commonly refers to major depressive episodes that have not responded to two adequate trials of antidepressant monotherapy, each drug treatment given at a dosage equivalent to 150 mg of tricyclic antidepressant (TCA) for a period of 4–6 weeks.4,5 However, TRD has no standardized definition, as several criteria have been proposed, including staging systems that conceptualize treatment resistance as a continuum.3 In the first step of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 37% of the 3671 patients treated with an adequate trial of citalopram experienced remission. With the next treatment, 69% of the patients did not experience remission.6 Additionally, TRD leads to considerable financial cost, societal burden, and personal distress, which highlights the need for further research regarding the treatment.3 Several therapeutic options for TRD are being explored, targeting neurotransmitter systems outside of the standard monoamine hypothesis.4 Magnesium (Mg) administration is one of these therapeutic strategies, as it is one of the most abundant minerals in the human body and is involved in many enzymatic reactions.7 Mg use as a sedative for agitated depression was described in the literature as early as 1921.5 Mg is believed to have a role in the pathophysiology of depression, as it is a natural calcium (Ca) antagonist and a voltagedependent blocker of the N-methyl-D-aspartate (NMDA) channel, which makes Mg neuroprotective.8 Based on promising results as a treatment for depression with the glutamatergic NMDA receptor antagonist, ketamine, Mg homeostasis in the brain is also being evaluated.9 Furthermore, an inverse relation has been found between Mg and depression,10 and patients with severe MDD were noted to have a decreased level of Mg in erythrocytes.11 Several animal studies have shown that an Mg-deficient diet exacerbates depression,12 and the behavior of laboratory

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animals improved after being fed with Mg salts alone and in combination with vitamin B67. Previous clinical trials evaluating Mg on depression have been scarce and inconclusive because of their inferior study designs and limited sample sizes.13 Nonetheless, the overall combined effect of these studies provides a rationale for research with more rigorous study designs.3 Based on the extant literature, the purpose of the current study was to: (i) determine Mg status via 24-h urine assessment before and after intravenous (i.v.) infusion of Mg sulfate (SO4); and (ii) assess the effectiveness of i.v. infusion of MgSO4 on depressive symptoms.

METHODS Study participants The study was conducted with the approval of the University of Miami Institutional Review Board for human subjects research. Each subject signed informed consent and Health Insurance Portability and Accountability Act forms prior to study entry. Potential participants (n = 199) were identified through referrals from offices at the University of Miami Miller School of Medicine, the Department of Psychiatry and Behavioral Sciences clinics, and the Center for Complementary and Integrative Medicine, advertisements around the University of Miami campus, from clinicaltrials.gov, and from Life Extension Foundation from October 2011 to December 2014. Twenty-two subjects were enrolled for the baseline screening, 13 subjects were eligible after baseline screening, and 12 participants with mild or moderate TRD were enrolled and assigned to one of the two study conditions.

Inclusion and exclusion criteria Inclusion criteria were: (i) age 21–70 years; (ii) MDD diagnosis according to DSM-IV-TR criteria and TRD defined as failure of clinical improvement after 6 weeks with an approved, clinically adequate dose of a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a selective noradrenaline reuptake inhibitor (NRI); and (iii) if currently taking an SSRI, SNRI, NRI, aripiprazole, quetiapine, risperidone, bupropion, or a TCA for more than 90 days, the participant must have maintained the same dose for the past 90 days prior to study enrollment. Exclusion criteria were: (i) a baseline serum Mg level > 2.6 mg/dL; (ii) currently


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enrolled (or in the last 30 days) in another research trial for investigative nutritional or other therapies thought to have an impact on depression; (iii) currently taking a medication or nutritional supplement containing more than 100% RDA of Mg (for women over age 31, 320 mg/day and for men over age 31, 420 mg/day); (iv) diagnosed with any medical condition that would preclude participation in the study; (v) taking digoxin, penicillamine, any antibiotic, or any other psychotropic medication (other than aripiprazole, quetiapine, or risperidone) for any indication, except sedatives for sleep, in addition to the SSRI, SNRI, or NRI in the course of treatment for depression; (vi) pregnant, planning to become pregnant, currently breast-feeding, or unwilling to avoid pregnancy; (vii) systolic blood pressure > 160 mm Hg or diastolic blood pressure > 90 mm Hg; or (viii) any of the following abnormal laboratory test values: bilirubin > 2× upper normal limit; aspartate transaminase and alanine aminotransferase > 2× upper normal limit; serum creatinine > 1.5 mg/dL; blood glucose < 80 mg/dL or >110 mg/dL; Ca level < 8.6 mg/dL; or triglycerides > 200 mg/dL.

Screening Study staff conducted a preliminary screening to determine if the potential participant met criteria to take part in the study. If preliminary screening was acceptable, the participant was scheduled for informed consent and study protocol procedures.

Randomization After screening and baseline measurements, participants were randomly assigned to one of two conditions: (i) i.v. infusion of MgSO4 in 5% dextrose followed by i.v. infusion of 5% dextrose 1 week later (Treatment A); or (ii) i.v. infusion of 5% dextrose followed by i.v. infusion of MgSO4 in 5% dextrose 1 week later (Treatment B). Treatment assignment was done with a table of random permutations, which balanced the number of participants in each group, by the University of Miami research pharmacy. All subjects and investigators were blind to treatment condition and remained blinded until after data analysis; only a staff member at the research pharmacy knew the assignment. Infusion materials were provided by the study sponsor (Life Extension Foundation, Ft. Lauderdale, FL, USA).


Intervention schedule Participants were scheduled for assessments and/or treatments at baseline and days 1, 2, 7, and 8. Each participant was required to fast prior to and for the 4 h during each i.v. infusion on days 1 and 7. The 4-g dose of MgSO4 in 5% dextrose or 5% dextrose alone was administered through an i.v. infusion over 240 min. Baseline At baseline, a health history form was completed, which elicited allergy information, medical and surgical histories, concomitant or recently taken medications, over-the-counter non-prescription products, nutritional supplements, and investigational products. Vital signs were assessed, and participants also underwent a full physical examination to verify eligibility. After the Hamilton Rating Scale for Depression (HAM-D) and the Patient Health Questionnaire (PHQ-9) were completed, the participant had fasting blood drawn. Days 1 and 7 During each day, fasting blood and urine were collected. The mental status assessment occurred at predose and at 60, 120, 180, and 240 min. The HAM-D and PHQ-9 were also completed. Days 2 and 8 The participants completed all questionnaires, underwent a brief routine physical exam, and had basic vital signs taken. The HAM-D and PHQ-9 were also completed. After finishing the procedures for day 8, the participants were discharged from the study.

Outcomes and assessments All participants completed an extensive sociodemographics and medical history questionnaire and reported their list of medications at baseline. At the baseline visit, complete blood count (CBC)/chemistry, serum and urine Mg, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol and triglycerides, urinalysis, and 24-h urine output were assessed. During the i.v. infusion phase (days 1 and 2 and days 7 and 8), the following assessments were taken: (i) CBC/chemistry, HDL and LDL cholesterol and triglycerides, and serum Mg at pre-dose on days 1 and 7, at infusion




completion on days 1 and 7, and 24 h after infusion completion on days 2 and 8; (ii) 24-h urine Mg at pre-dose on days 1 and 7 and 24 h after infusion completion on days 2 and 8; (iii) the HAM-D and PHQ-9 for depression; and (iv) a pregnancy test via serum or urine was conducted at baseline and day 8. The HAM-D is a clinician-used questionnaire to assess severity of depressive symptoms related to mood, feelings of guilt, suicidal ideation, insomnia, agitation or retardation, anxiety, weight loss, and somatic symptoms.14,15 The PHQ-9 is a brief self-report tool that can be rapidly used by clinicians to determine the response to treatment and scores of 5, 10, 15, and 20 correspond to mild, moderate, moderately severe, and severe depression.16 Depending on the day, the administration of the assessment battery required 30–90 min.

Intervention protocol Participants had a staff member with them at all times to promote greater compliance. Subjects were not advised to modify eating or physical activity habits or prescription medication use during the protocol. In addition, they were instructed not to consume any dietary supplement containing Mg during the trial. Subjects listed all dietary supplements taken on the health history form, and products were reviewed to ensure none of these nutrients was consumed during the course of the trial.

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RESULTS Safety and tolerability During the entire study period, one subject had an elevated blood pressure response during the infusion of MgSO4, but it was apparently due to not taking her hypertension medication the morning of the infusion. Once her medication was administered, her blood pressure normalized. No other adverse events were reported.

Sociodemographics, health risk, and medication use The sample comprised 75% women (n = 9) and 25% men (n = 3) with a mean age of 46.5 years (SD, 9.0; range, 30–64). The sample had an average body mass index (BMI) of 30.3 (SD, 7.0; range, 19.1–41.5), which is grade 1 obesity. The most common co-morbid diseases and disorders among the participants included: anxiety (75%), high blood pressure (33.3%), HIV (33.3%), chemical dependency (17%), arthritis (17%), anemia (17%), and low back pain/herniated disc (17%). The most typically used current prescription medications and over-the-counter remedies were: antidepressant (100%), anti-anxiety (50%), anti-viral (33%), sleep (33%), gastrointestinal (25%), vitamin/mineral (25%), anti-hypertensive (17%), and anti-inflammatory (17%).

Serum and urine Mg Statistical analysis Data were analyzed using SAS 9.3 (SAS Inc., Durham, NC, USA). We used the general linear model to assess changes over the course of the intervention among the primary outcome variables, serum and urine Mg, the HAM-D, and the PHQ-9. For each outcome variable, we tested the following changes: (i) baseline from day 2; (ii) day 1 pre-infusion from day 2; (iii) baseline from day 8; (iv) day 1 pre-infusion from day 8; (v) day 2 from day 8; (vi) day 7 pre-infusion from day 8; (vii) baseline from day 7 pre-infusion; and (viii) day 1 preinfusion from day 7 pre-infusion. We also used Pearson product-moment correlations to assess the relations between the changes in the outcome variables. The criterion for statistical significance was α = 0.05.

Table 1 presents the descriptive statistics for serum Mg. Controlling for sex and age, we found a difference in serum Mg from day 2 to 8 (F[3, 10] = 14.5, P < 0.002) with an r2 = 0.86. The uncontrolled model for serum Mg from day 2 to 8 showed a similar finding (F[1, 10] = 34.4, P < 0.0002) with an r2 = 0.79. We also found a significant change in serum Mg from baseline to day 8 with no covariates (F[1, 10] = 8.3, P < 0.02) with an r2 = 0.48. No other changes were noted for serum Mg. Controlling for sex and age, we found a difference in urine Mg from day 7 to 8 (F[3, 9] = 18.4, P = 0.002) with an r2 = 0.90. The uncontrolled model for urine Mg from day 7 to 8 showed a similar finding (F[1, 9] = 28.9, P < 0.0001) with an r2 = 0.78. We also found a significant change in urine Mg from baseline to day 2 with no covariates (F[1, 9] = 13.0,



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Table 1. Descriptive information of serum magnesium at each assessment during the intervention period Assessment

MgSO4† – Dextrose (n = 6)

Dextrose – MgSO4† (n = 6)

Baseline Day 1 pre-infusion Day 1 end of infusion Day 2 Day 7 pre-infusion Day 7 end of infusion Day 8

M M M M M M M

M M M M M M M

= = = = = = =

2.0 (SD, 0.17; R, 1.7–2.2) 1.9 (SD, 0.16; R, 1.7–2.1) 3.4 (SD, 0.44; R, 2.8–4.0) 2.2 (SD, 0.12; R, 2.0–2.3) 1.9 (SD, 0.15; R, 1.7–2.1) 1.9 (SD, 0.17; R, 1.6–2.0) 1.9 (SD, 0.07; R, 1.8–2.0)

= = = = = = =

2.0 (SD = 0.23; R, 1.6–2.3) 1.9 (SD, 0.22; R, 1.7–2.3) 2.0 (SD, 0.24; R, 1.8–2.4) 2.0 (SD, 0.18; R, 1.8–2.3) 2.0 (SD, 0.15; R, 1.8–2.2) 3.1 (SD, 0.15; R, 2.9–3.3) 2.2 (SD, 0.24; R, 1.8–2.4)

†

MgSO4 = magnesium sulfate. Data are in mg/dL. M, mean; R, range.

P < 0.02) with an r2 = 0.62. No other changes were noted for urine Mg.

HDL cholesterol, LDL cholesterol, and triglycerides

HAM-D and PHQ-9

No significant changes were noted for HDL, LDL, or triglycerides in response to the MgSO4 treatment.

Figures 1 and 2 present the descriptive statistics for the HAM-D and the PHQ-9, respectively. No significant changes were noted after 24 h for either measure in response to the MgSO4 treatment. The change in HAM-D score from day 2 to 8 was positively correlated with the change in PHQ-9 score in the same period (r = 0.81, P = 0.001).

Relation between changes in LDL and changes in HAM-D and PHQ-9 The change in LDL cholesterol from baseline to day 7 was positively correlated with a change in the HAM-D from baseline to day 7 (r = 0.76, P = 0.01). The change in LDL cholesterol from day 2 to 8 was positively correlated with a change in the PHQ-9 from day 2 to 8 (r = 0.69, P = 0.02).

Relation between changes in serum Mg and PHQ-9

DISCUSSION

As serum Mg increased from baseline to day 7, the PHQ-9 score decreased from baseline to day 7 (r = −0.70, P = 0.02).

Depression accounts for 40% of all neuropsychiatric disorders in the entire population. The incidence of

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Figure 1. Descriptive information of the Hamilton Rating Scale for Depression (HAM-D) at each assessment during the intervention period. ( ) MgSO4 – Dextrose (n = 6). ( ) Dextrose – MgSO4 (n = 6).




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depression has greatly increased and is affecting people much earlier in their lives. MDD and dysthymia significantly contribute to suicide and ischemic heart disease, bringing the overall global burden of depressive disorders to 3.8% of global disabilityadjusted life years.2 Additionally, 25% of the American population is affected by MDD at some point in their lives,1 which translates into a huge disease burden. The emergence of TRD is of concern due to its impact on disease burden and cost. It lacks both standardized and/or effective treatment options.3 Given the lack of efficacy of existing treatments for TRD, the relation between depression and hypomagnesemia,17 and the association between oral intake of Mg with anti-depressant effects,18 the primary purpose of our study was to determine the effect of i.v. infusion of MgSO4 (4 g/100 mL) in 5% dextrose over 4 h in patients with mild or moderate TRD in a double-blind, randomized crossover trial. To the best of our knowledge, this is the first and only such study and also appears to be the only one in which MgSO4 was administered at a low dose over a long period of time. We noted a significant increase in serum Mg levels in response to the MgSO4 infusion. Although no significant changes were observed in the values of either HAM-D or PHQ-9 24 h post-infusion, it is interesting to note that as serum Mg increased from baseline to day 7, the PHQ-9 score decreased during the same timeframe, which suggests an improvement in depression and adds credence to the role of Mg in TRD. The HAM-D score change from day 2 to 8 was

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Figure 2. Descriptive informa-

also positively correlated with the PHQ-9 score change in the same time period, which demonstrates the internal validity of both depression inventories. A recent trial compared magnesium chloride (MgCl) with imipramine, a TCA, for 12 weeks in 23 elderly (>60 years) subjects with type 2 diabetes who had newly diagnosed depression. Both groups showed significant improvement in depression symptoms with no difference between the interventions.19 Subjects in this study were enrolled with a serum Mg level below 1.8 mg/dL, whereas in our trial only two subjects had a serum Mg level below 1.8 mg/dL at day 1 pre-infusion. Additionally, we excluded potential subjects who had a serum Mg level greater than 2.6 mg/dL. Like BarraganRodriguez et al.,19 we excluded subjects with hypomagnesemia, so our results could have been affected by either a type II error (a false negative finding) and/or influenced by low power. The effect of Mg as an NMDA receptor antagonist, such as ketamine and zinc, on depressive symptoms may be explained through its interaction with the glutamatergic system, where Mg restriction leads to a reduction of amygdala-hypothalamic protein GluN1containing NMDA complexes.18 Although a single i.v. infusion of ketamine showed positive short-term responses in 163 depressed patients, it is associated with potential risks, and the data regarding its longterm effects are limited.20 Thus, MgSO4, MgCl, or other forms of Mg may offer a better alternative to improving depression with a lower risk of adverse effects.


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In our study, changes in HAM-D (baseline to day 7) and PHQ-9 (day 2–8) were positively correlated with the change in LDL cholesterol. We also found that 33% of our sample was taking an antihypertensive medication, and the average BMI of our sample was over 30, which is grade 1 obesity. Depression is associated with many co-morbid behaviors and disorders, including unhealthy diet, sedentary lifestyle,21 and obesity.22 These factors portend a high risk of developing CVD. Depression has also been hypothesized as an independent risk factor for CVD23 and increases the associated morbidity and mortality via different mechanisms and pathways.24 Unhealthy dietary patterns associated with depression result in the inadequate consumption of folate, Mg, and omega-3 fatty acids,25 which is a risk factor for CVD as well.25,26 Thus, given our findings and the extant literature, the links between depression and risk factors for CVD should be weighed judiciously.


MDD patients who are struggling with current standard approaches.

ACKNOWLEDGMENTS We thank Life Extension Foundation for providing financial support to conduct the study. We thank the volunteers who graciously took the time and effort to participate in this study. We thank the nursing and administrative staff at the University of Miami Hospital and Clinics who provided the space, facilities, and expertise to conduct the trial. Our study was also supported by Grant Number 1UL1TR000460, University of Miami Clinical and Translational Science Institute, from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities. ClinicalTrials.gov Identifier: https://clinicaltrials.gov/ct2/show/ NCT01597167.

DISCLOSURE STATEMENT Conclusions Although only 12 subjects completed the study, it was well-controlled to account for confounding factors. The diagnosis of TRD brings with it a very complicated medical history and does not allow for a homogenous sample without preemptively excluding many potential participants. Even though we did not find a significant effect of MgSO4 on depression symptoms 24 h post-infusion, we found an improvement in depression symptoms (PHQ-9) with an increase in serum Mg and a diminution of depression symptoms (HAMD). Hence, in light of the existing literature and in combination with our findings, the overall evidence suggests that administering Mg may be beneficial for patients with TRD. Additionally, conventional treatments for TRD and MDD in general with pharmacological therapy are fraught with challenges and are unable to reduce the burden of depressive diseases. Medical regimens are also costly to apply over a typical lifetime, have untoward side-effects and uncertain adherence, and many patients fail to achieve a significant improvement from the disease. In comparison, various forms of Mg may offer an alternative that has a favorable side-effect profile along with short-term beneficial effects in depressive symptoms. Additional research is required to validate the long-term efficacy of Mg as a treatment option for TRD and

Life Extension Foundation provided the financial support to conduct this study.

AUTHOR CONTRIBUTIONS S.G., J.M.W., J.K., E.T., and J.E.L. contributed to the conception and design of the study. S.M.A.M., S.E.A., S.Q., D.M., S.G., J.M.W., R.C., H.A., L.A., S.C., C.S.G.C., A.F., J.G., J.K., L.L., L.C.L., J.L., V.P., A.R., A.M.R., H.G.S., E.T., and J.E.L. contributed to the acquisition and analysis of data. S.M.A.M., S.E.A., S.Q., S.G., J.M.W., H.A., C.S.G.C., A.F., J.G., J.K., A.R., A.M.R., H.G.S., E.T., and J.E.L. contributed to the drafting of the manuscript, table, and figures.

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Doubleâblind, randomized crossover study of ...

Doubleâblind, randomized crossover study of ...

Doubleâblind, randomized crossover study of ...

Doubleâblind, randomized crossover study of ...