Accepted Manuscript

Meta-analysis: Risk of dry mouth with second generation

antidepressants

Kiley Cappetta, Chad Beyer, Jessica A. Johnson, Michael H.

Bloch

PII: S0278-5846(17)30683-8
DOI: doi:10.1016/j.pnpbp.2017.12.012
Reference: PNP 9306
To appear in: Progress in Neuropsychopharmacology & Biological Psychiatry
Received date: 22 August 2017
Revised date: 7 December 2017
Accepted date: 18 December 2017

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Meta-Analysis: Risk of Dry Mouth with Second Generation Antidepressants

Kiley Cappetta BA, Chad Beyer, Jessica A. Johnson BS, Michael H. Bloch MD, MS.

Ms. Kiley Cappetta is affiliated with New York State Psychiatric Institute (New York, NY). Mr.

Chad Beyer is with the Yale Child Study Center (New Haven, CT), and is a medical student at

Stellenbosch University (Stellenbosch, South Africa). Ms. Jessica Johnson is a Postgraduate

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Associate with the Yale Child Study Center (New Haven, CT). Dr. Bloch is with the Yale Child

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Study Center and the Department of Psychiatry of Yale University (New Haven, CT).

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Correspondence: Michael Bloch, Child Study Center, Yale University School of Medicine, PO

Box 207900, New Haven, CT 06520, t: (203) 785-7683; email: Michael.Bloch@yale.edu

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ABSTRACT

Objective: The goal of this meta-analysis was to quantify the risk of dry mouth associated with

commonly prescribed antidepressant agents and examine the potential implications of medication

class, dose, and pharmacodynamics and dose on risk of treatment-induced dry mouth.

Data Sources and Study Selection: A PubMed search was conducted to identify double-blind,

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randomized, placebo-controlled trials examining the efficacy and tolerability of second

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generation antidepressant medications for adults with depressive disorders, anxiety disorders,

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and OCD.

Data Extraction: A random-effects meta-analysis was used to quantify the pooled risk ratio of

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treatment-emergent dry mouth with second generation antidepressants compared to placebo.
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Stratified subgroup analysis and meta-regression was utilized to further examine the effects

antidepressant agent, class, dosage, indication, and receptor affinity profile on the measured risk
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of dry mouth.
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Results: 99 trials involving 20,868 adults. SNRIs (Relative Risk (RR) = 2.24, 95% Confidence

Interval (CI): 1.95 – 2.58, z = 11.2, p < 0.001) were associated with a significantly greater risk of
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dry mouth (test for subgroup differences χ2 = 7.6, df = 1; p = 0.006) compared to placebo than
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SSRIs (RR = 1.65, 95% CI: 1.39 –1.95, z = 5.8, p < 0.001). There was a significant difference

found in the risk of dry mouth between diagnostic indications within the SNRI class (test for
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subgroup differences χ2 = 9.63, df = 1; p = 0.002). Anxiety diagnoses (RR = 2.78, 95% CI: 2.29

– 3.38, z = 10.32, p < 0.001) were associated with a greater risk of dry mouth compared to

depression (RR = 1.80, 95% CI: 1.48 – 2.18, z = 5.85, p < 0.001). Decreased affinity for Alpha-1

(PE = 0.18, 95% CI: 0.07 – 0.28, z = 3.26, p = 0.001) and Alpha-2 (PE = 0.49, 95% CI: 0.22 –
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0.75, z = 3.64, p < 0.001) receptors and SERT (PE = 0.07, 95% CI: 0.01 – 0.14, z = 2.10, p <

0.05) was significantly associated with increased risk of dry mouth.

Conclusions: The current meta-analysis suggests that SSRIs, SNRIs, and atypical

antidepressants are all associated with varying degrees of increased risk of dry mouth. SNRIs

were associated with a significantly greater risk of dry mouth compared to SSRIs.

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Highlights:

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 Meta-analysis suggests that SSRIs, SNRIs, and atypical antidepressants are all associated

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with increased risk of dry mouth

 SNRIs were associated with a significantly greater risk of dry mouth compared to SSRIs
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 Fluvoxamine demonstrated a non-statistically significant lower risk of dry mouth

compared to placebo and this risk was qualitatively less than other second generation
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antidepressants.
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KEYWORDS: dry mouth, xerostomia, second generation antidepressants, serotonin uptake

inhibitors, meta-analysis
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Abbreviations: All abbreviations are standard in this field.

Acknowledgements: None
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Funding: Dr. Bloch is on the Scientific Advisory Board of Therapix Biosciences and receives

research support from Biohaven Pharmaceuticals and Therapix Biosciences. Dr. Bloch also

receives research support from the National Institutes of Health, Tourette Association of

America, the Brain & Behavior Research Foundation (formerly NARSAD) and the Patterson

Foundation. Mr. Beyer reports research support from the Taylor Foundation.
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Role of Funding Agency: Funders did not provide any direct support for this work.

Disclosures: All authors have approved the final manuscript.

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INTRODUCTION
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake

inhibitors (SNRIs) are often prescribed as first-line treatment for Depressive Disorders,

Obsessive-Compulsive Disorder (OCD) and Anxiety Disorders.1-7 In addition, atypical

antidepressant agents, such as bupropion, mirtazapine, vortioxetine and vilazodone, are also

utilized in the treatment of Depressive Disorders.8-12 These medications, while generally well

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tolerated, are associated with treatment emergent side-effects. These effects are often cited as the

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primary reason for dose reduction.13, 14
Furthermore, roughly one-third to one-half of patients

discontinue pharmacological treatment, with a quarter of those patients reporting side effects to

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be the reason for their discontinuation.14 Meta-analyses of randomized controlled trials indicate

that young patients treated with SNRIs are significantly more likely to drop out due to side-
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effects.15, 16
Meta-analysis has also demonstrated that, although higher doses of SSRIs are
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modestly more effective than lower doses,17 but higher doses of antidepressants are associated

with higher rates of dropout due to side-effects.18 Further investigation into the likelihood of
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side-effects of common antidepressant medications as well as their relationship to individual

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agents and antidepressant dosing will help clinicians to make more informed, evidence-based

treatment decisions when side-effects occur during the course of treating Depressive Disorders,
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Anxiety Disorders, and OCD.

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According to meta-analysis, dry mouth, also known as xerostomia, has been cited as a

treatment-emergent side effect in 22% of patients treated with SSRIs19 and 21% of patients

treated with bupropion.20 Pooled analysis reports 11% of patients treated with SNRIs experience

dry mouth.21 In addition to negative effect on one’s quality of life, including difficulties with

eating and talking,22 xerostomia can result in dental complications and oral disease, such as

dental caries.23-26
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Salivary secretion is regulated by both the sympathetic and parasympathetic nervous

systems by means of salivary gland receptors.27, 28 Parasympathetic stimulation occurs through

cholinergic transmission, specifically acetylcholine acting on muscarinic M3 receptors –

resulting in an increase in saliva secretion. Sympathetic stimulation, on the other hand, occurs

through noradrenergic transmission, when norepinephrine acts on alpha (α) and beta (β)

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receptors – affecting the content of salivary proteins.29-31 Antidepressants, most notably tricyclic

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antidepressants (TCAs), have been proposed to decrease salivary flow rate by blocking the

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effects of acetylcholine on muscarinic M3 receptors, as this is the most commonly recognized

cause of reduced salivation.29

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Even with current understandings of the salivary reflex arc and its role in the
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development of antidepressant-induced dry mouth, several studies suggest that xerostomia and

objective measurements of hyposalivation are not reliably related.23, 32-43 As a result, it has been
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postulated that altered saliva composition, specifically a decrease in salivary mucins, may be
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more important in the development of dry mouth. 44 As the precise mechanisms of treatment-

emergent dry mouth remain unclear, medical literature, as well as the current investigation,
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defines xerostomia as a subjective feeling of dry mouth.

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Understanding differences in the risk of dry mouth between different antidepressant

agents has the potential to (1) aid in understanding the primary underlying mechanism for dry
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mouth; (2) aid in the selection of effective treatments for antidepressant- induced dry mouth; (3)

guide optimal management of this side-effect and underlying psychiatric illness and (4) provide

insight in to the implications of differential receptor affinities on the development of treatment-

emergent dry mouth. Previous meta-analyses have compared risk of dry mouth among

commonly prescribed antidepressant medications but have exclusively relied on the incidence of
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xeorstomia within the active medication group and have failed to normalize data to the reported

incidence of dry mouth in the placebo group.19, 45 This methodology is highly vulnerable to

confusing the different methods of reporting side effects between trials with actual differences

between agents. Previous meta-analyses have suggested that tricyclic antidepressants19, 45

are

most likely to cause increased risk of dry mouth, while the differences in risk between SRI

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agents are not clear.

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MATERIALS AND METHODS

Search Strategy for Identification of Studies

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Two reviewers searched the electronic database of PubMed on June 6, 2016 for relevant
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studies using the search: (fluoxetine OR fluvoxamine OR citalopram OR sertraline OR

paroxetine OR bupropion OR trazodone OR desvenlafaxine OR duloxetine OR mirtazapine OR

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venlafaxine OR vilazadone OR vortioxetine OR serotonin uptake inhibitors) AND (Depressive

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disorder OR anxiety disorders) AND (Humans). The search used only randomized controlled

trials. No language restrictions were applied. The references of relevant reviews and previous
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meta-analyses were searched for citations of further relevant published and unpublished research,
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and databases available from previous meta-analyses conducted by the team were also analyzed

for inclusion.17, 18
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Selection of Studies

The titles and abstracts of studies obtained by this search strategy were examined by 2

reviewers (KC, CB) to determine inclusion in this meta-analysis. Any discrepancies were

resolved by a final reviewer (MHB). Eligibility for the study was based upon analysis of the full

articles for the following criteria: they needed to (1) be randomized, double-blind, (2) placebo-
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controlled clinical trials of (3) a second generation antidepressant of interest (fluoxetine,

fluvoxamine, citalopram, sertraline, paroxetine, bupropion, trazodone, desvenlafaxine,

duloxetine, mirtazapine, venlafaxine, vilazadone, vortioxetine); targeting clinical symptoms in

Depression, Anxiety or OCD as defined by DSM-546 or International Classification of Diseases

(ICD-10)47 criteria. Discontinuation studies or studies which involved duplication of data from

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prior reported research included in this review were excluded. Head-to-head studies without a

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placebo control and crossover trials were also excluded. Studies requiring concomitant

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medication or behavioral intervention were excluded.

Meta-Analytic Procedures

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Data were extracted by independent reviewers (KC and CB) on Microsoft Excel. The
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primary outcome measure was the proportion of patients reporting dry mouth as a treatment-

emergent side effect. Reviewers gathered data on trial medication, trial design, maximum daily
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medication dose, and number of participants in active and placebo groups. Disagreement
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between reviewers was resolved through discussion or, if possible, acquiring further information

from the study investigators. When agreement could not be reached between the initial
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reviewers, the senior investigator (M.H.B.) resolved all disputes. When information about
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proportion of dry mouth was not published in the original manuscripts, the corresponding author

was contacted for further information. If contacting the corresponding author was unsuccessful,
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pharmaceutical company databases were searched for the data.

All statistical analyses were completed in Comprehensive Meta-Analysis Version 3.48 For

outcome measures, proportion of participants experiencing dry mouth was analyzed using pooled

risk ratio (RR). For all outcome measures, 95% confidence intervals (CI) were conveyed. A

random-effects model for meta-analysis was used, as well as a fixed-effects model in sensitivity
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analysis. Publication bias was statistically tested using the Egger test and assessed by plotting the

effect size against standard error for each included trial (i.e., funnel plot).

For the primary analysis, antidepressant medications were grouped into the categories of

SSRI (fluvoxamine, sertraline, citalopram, fluoxetine, paroxetine, escitalopram), SNRI

(venlafaxine, duloxetine, desvenlafaxine) and atypical (vilazadone, bupropion, vortioxetine,

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mirtazapine, trazodone). The following questions were examined in meta-analysis: (1) is the risk

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for dry mouth different for SSRI, SNRI and atypical medications (analyzed individually) as

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compared to placebo (p < 0.05 for SSRI, SNRI and other medications in random-effects meta-

analysis using RR as primary outcome); (2) do different pharmacological agents within a

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medication class (e.g. SSRI, SNRI) differ in risk of dry mouth (test for subgroup difference with
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trials stratified by pharmacological agent and trials restricted to individual medication classes

(e.g. SSRIs, SNRIs); (3) is dosing of medications (SSRIs or SNRIs) associated with risk of dry
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mouth (meta-regression by dose with trials restricted to each medication class (e.g. SSRIs and
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SNRIs); (4) do SSRIs and SNRIs differ in risk of dry mouth when compared to placebo (test for

subgroup differences in random-effects meta-analysis with trials restricted to SSRIs and SNRIs)
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and (5) do differing receptor affinities among the antidepressants result in increased risk of dry
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mouth. All subgroup analyses were performed using a random-effects model to conduct a test for

subgroup differences (between-group heterogeneity χ2 ). Meta-regression analysis was used to

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examine the effects of maximum daily dose of medication used in trials. Daily doses of

medication were converted into venlafaxine (imipramine) equivalents using previously described

methodology.49 The threshold for statistical significance was p < 0.05 for the primary analysis, as

well as for all stratified subgroup analyses and meta-regression.

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The analysis investigating the relationship between pharmacological properties of

antidepressant medication and dry mouth was based on recent meta-analysis performed

examining the association between antidepressant receptor affinities and weight gain.50 Data on

receptor affinities of different antidepressants was obtained from published data and the

Psychoactive Drug Screening Program Ki database (http://pdsp.med.unc.edu/kidb.php). The

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inhibitory constant, Ki (the concentration of a ligand in which the receptor is 50% occupied),

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was used as the measure of binding affinity and, consistent with previous analysis, (1) only

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human data was used to estimate Ki, (2) all values of Ki were natural log-transformed, and (3) a

maximum value of 10000 nM was used for low-affinity interactions. Random-effects meta-

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regression was utilized to examine the association between log Ki at receptors of interest and the
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relative risk of dry mouth. Meta-regression was conducted for all receptors where data on

affinity is typically available for antidepressants – serotonin transporter (SERT), norepinephrine

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transporter (NET), dopamine transporter (DAT), H1-histamine receptor (H1), alpha-1 and alpha-
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2 adrenergic receptors, M3 muscarinic receptor (M3), and 5-HT1A, 5-HT2A and 5-HT2C

serotonin receptors. Analysis was restricted to SSRI and SNRI medications due to the limited
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availability of receptor binding for newer atypical antidepressant medications (vortioxetine,

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vilazodone) and the distinct pharmacological properties of other atypical antidepressants, which

would result in high leverage points in most of the receptor analyses (mirtazapine (SERT, H1,
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Alpha-2, 5-HT1A, 5-HT2A 5-HT2C), trazodone (Alpha-1, 5HT-2A) and bupropion (SERT).

When results of receptor affinity analyses were significant, atypical antidepressants were

incorporated as a sensitivity analysis to determine if these data affected the result.

RESULTS

Included Trials
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Figure 1 displays the selection of trials for the current meta-analysis. 382 studies were

identified using PubMed. 242 trials were eligible for inclusion after meeting screening criteria.

143 studies did not provide data on dry mouth and were excluded from this meta-analysis. The

current meta-analysis utilized data from 99 trials51-149 involving 20,868 adult patients treated

with a medication of interest. Studies that did not provide adequate side-effect data on dry mouth

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were excluded from meta-analysis. Included trials are shown in Table 1.

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Table 1. Included Trials. Table 1 displays the trials used in the current meta-analysis.

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Abbreviations: SSRI, selective serotonin reuptake inhibitor; mg, milligrams; ED, imipramine

equivalent dose; OCD, obsessive-compulsive disorder; SNRI, selective serotonin and

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norepinephrine reuptake inhibitor.
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INSERT FIGURE 1 HERE
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INSERT TABLE 1 HERE

Dry Mouth
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Figure 2 depicts a forest plot demonstrating the relative risk of dry mouth with
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antidepressant agents compared to placebo. Most antidepressant medications examined were

associated with a significantly increased risk of dry mouth compared to placebo. SNRIs (RR =
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2.24, 95% CI: 1.95 – 2.58, z = 11.2, p < 0.001) were associated with a significantly greater risk
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of dry mouth (test for subgroup differences χ2 = 7.6, df = 1; p = 0.006) compared to placebo than

SSRIs (RR = 1.65, 95% CI: 1.39 –1.95, z = 5.8, p < 0.001). Point estimates regarding the relative

risk of dry mouth compared to placebo for several medications were similar in magnitude to

other antidepressants but may not have reached statistical significance due to limited power

(sertraline (RR = 1.48, 95% CI: 0.94 – 2.32, z = 1.68, p = 0.09), mirtazapine (RR = 1.46, 95%

CI: 0.97 – 2.21, z = 1.79, p = 0.07) and trazodone (RR = 1.51, 95% CI: 0.77 – 2.93, z = 1.20, p =
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0.23). Other antidepressant medications appear to demonstrate a minimal difference in risk of

dry mouth compared to placebo (fluvoxamine (RR = 0.87, 95% CI: 0.49 – 1.55, z = -0.46, p =

0.64) and vortioxetine (RR = 1.16, 95% CI: 0.85 – 1.57, z = 0.94, p = 0.35) and may be different

from other medications examined.

INSERT FIGURE 2 HERE

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There was significant evidence of heterogeneity between trials when all included trials

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were examined together (test for heterogeneity χ2 = 192, df = 112 ; p < 0.001, I2 = 41%) and

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within SSRI (test for heterogeneity χ2 = 97.4, df = 52; p < 0.001, I2 = 47%) but not SNRI trials

(test for heterogeneity χ2 = 32.5, df = 31; p = 0.39, I2 = 5%). There was also evidence of funnel

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plot asymmetry when all included trials were examined together (Egger’s test intercept = 1.09
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(95% CI: 0.47 – 1.90, t = 3.51, p = 0.0007) and when medication classes were analyzed

individually (Egger’s test intercept: SSRI = 1.08 (95% CI: 0.22 – 1.95, t = 2.52, p = 0.01 and
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SNRI = 1.52 (95% CI: 0.52 – 2.52, t = 3.10, p = 0.004). Figure 3 depicts an asymmetrical funnel
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plot illustrating suggesting reporting bias of dry mouth as a side-effect in antidepressant trials.

INSERT FIGURE 3 HERE

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Selective Serotonin Reuptake Inhibitors

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SSRIs were associated with a significantly increased risk of dry mouth when compared to

placebo (RR = 1.59, 95% CI: 1.38 – 1.84, z = 6.26, p < 0.001). Stratified subgroup analysis
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demonstrated no significant difference in the risk of dry mouth between individual medications

within the SSRI class (test for subgroup differences χ2 = 8.74, df = 5; p = 0.12). Among

individual SSRI agents the relative risk of dry mouth was as follows: citalopram (RR = 2.01,

95% CI: 1.40 – 2.89, z = 3.79, p < 0.001) paroxetine (RR = 1.98, 95% CI: 1.42 – 2.78, z = 3.98,

p < 0.001), fluoxetine (RR = 1.64, 95% CI: 1.21 – 2.23, z = 3.16, p < 0.005), sertraline (RR =
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1.48, 95% CI: 0.94 – 2.32, z = 1.68, p = 0.09) and escitalopram (RR = 1.37, 95% CI: 1.03 – 1.81,

z = 2.16, p < 0.05). Fluvoxamine (RR = 0.87, 95% CI: 0.49 – 1.54, z = -0.46, p = 0.64) was not

associated with an increased risk of dry mouth, but rather demonstrated a non-statistically

significant lower risk of dry mouth compared to placebo.

There was no significant difference demonstrated in the risk of dry mouth between

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diagnostic indications for SSRI pharmacotherapy (test for subgroup differences χ2 = 2.2, df = 2; p

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= 0.33). Increased risk of dry mouth for SSRIs compared to placebo was demonstrated for

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subjects with OCD (RR = 1.90, 95% CI: 1.33 – 2.71, z = 3.55, p < 0.001), anxiety (RR = 1.87,

95% CI: 1.36 – 2.59, p < 0.001), and depression (RR = 1.47, 95% CI: 1.17 – 1.84, p < 0.001).

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Meta-regression demonstrated no association between dosing of SSRIs and risk of dry
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mouth as compared to placebo (Parameter Estimate (PE) = -0.0001, 95% CI: -0.0020 – 0.0018, z

= -0.1, p = 0.92). There was still no association between SSRI dosing and measured risk of dry
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mouth when specific SSRI agents and/or diagnostic indication was adjusted in the analysis.
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Serotonin Norepinephrine Reuptake Inhibitors

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SNRIs were associated with a significantly increased risk of dry mouth compared to
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placebo (RR = 2.31, 95% CI: 2.00 – 2.67, z = 11.37, p < 0.001). There was no significant

difference between SNRI agents in the risk of dry mouth compared to placebo (test for subgroup
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differences χ2 = 5.5, df = 2; p = 0.067). Venlafaxine (RR = 2.67, 95% CI: 2.21 –

3.24, z = 10.06, p < 0.001) was associated with the greatest risk of dry mouth, followed by

duloxetine (RR = 1.98, 95% CI: 1.54 – 2.53, z = 5.41, p < 0.001) and desvenlafaxine (RR = 1.67,

95% CI = 1.02 – 2.72, z = 2.06, p < 0.05).

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There was a significant difference found in the risk of dry mouth between diagnostic

indications within the SNRI class (test for subgroup differences χ2 = 9.63, df = 1; p = 0.002) A

diagnostic indication of anxiety (RR = 2.78, 95% CI: 2.29 – 3.38, z = 10.32, p < 0.001) was

associated with a greater risk of dry mouth compared to depression (RR = 1.80, 95% CI: 1.48 –

2.18, z = 5.85, p < 0.001). There were no trials reporting incidence of dry mouth as a result of

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SNRI treatment in subjects with OCD. Meta-regression demonstrated no association between

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SNRI dosing and risk of dry mouth (PE = 0.0001, 95% CI: -0.0022 – 0.0024, z = 0.1, p= 0.91).

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Atypical Antidepressants

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Several atypical antidepressants were associated with a significantly increased risk of dry
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mouth compared to placebo. Bupropion (RR = 2.00, 95% CI: 1.65 – 2.43, z = 7.02, p < 0.001),

mirtazapine (RR = 1.42, 95% CI: 1.05 – 1.92, z = 2.28, p < 0.05) and vilazodone (RR = 1.50,
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95% CI: 1.01 – 2.22, z = 2.01, p < 0.05) were associated with an increased risk of dry mouth
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compared to placebo. Studies examining trazodone (RR = 1.51, 95% CI: 0.77 – 2.93, z = 1.20, p

= 0.23) demonstrated that its used was associated with a mild risk of xerostomia, although this
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relationship was not found to be significant. Vortioxetine (RR = 1.15, 95% CI: 0.91 – 1.46, z =
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1.17, p = 0.24) was associated with a minimally, yet insignificant, increased risk in dry mouth

compared to placebo.
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Receptor analysis

Analysis of the relationship between receptor affinity and measured relative risk of dry

mouth for SSRI and SNRI medications demonstrated that decreased affinity for Alpha-1 (PE =

0.18, 95% CI: 0.07 – 0.28, z = 3.26, p = 0.001) and Alpha-2 (PE = 0.49, 95% CI: 0.22 – 0.75, z

= 3.64, p < 0.001) receptors and SERT (PE = 0.07, 95% CI: 0.01 – 0.14, z = 2.10, p < 0.05) was
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significantly associated with increased risk of dry mouth. Figure 4 is a scatterplot displaying

relative affinity of second generation antidepressants to the SERT, Alpha-1, and Alpha-2

receptors and measured relative risk of dry mouth. Increased risk of dry mouth was not found for

affinity for NET (PE = -0.01, 95% CI: -0.07 – 0.05, z = -0.37, p = 0.71), DAT (PE = 0.03, 95%

CI: -0.04 – 0.09, z = 0.82, p = 0.41), H1 (PE = 0.00, 95% CI: -0.12 – 0.13, z = 0.05, p = 0.96),

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M3 (PE = 0.03, 95% CI: -0.04 – 0.11, z = 0.84, p = 0.40), 5HT1A (PE = -0.18, 95% CI: -0.73 –

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0.38, z = -0.62, p = 0.53), 5HT2A (PE = 0.03, 95% CI: -0.07 – 0.12, z = 0.56, p = 0.57), and

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5HT2C (PE = -0.05, 95% CI: -0.16 – 0.07, z = -0.76, p = 0.45).

INSERT FIGURE 4 HERE

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Discussion
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The current meta-analysis indicated that most antidepressants are associated with a

significantly increased risk of dry mouth, with SNRIs showing a greater risk compared to
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placebo than SSRIs. Fluvoxamine demonstrated a non-statistically significant lower risk of dry
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mouth compared to placebo and vortioxetine demonstrated a minimal difference in risk of dry

mouth compared to placebo. Receptor analysis of SSRI and SNRI medications demonstrated that
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decreased affinity for ALPHA-1 and ALPHA-2 receptors as well as SERT was associated with
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an increased risk of dry mouth.

Traditional explanations of antidepressant- induced dry mouth have focused on

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anticholinergic effects (particularly antagonism of M3 receptors), as the likely mechanism of

action.25, 27, 150, 151 Anticholinergic effects are likely the cause of dry mouth among several

antidepressants not included in the current meta-analysis such as tricyclic antidepressants. Meta-

regression analysis restricted to SSRI and SNRI medications did not indicate a significant

association between M3 receptor affinity and risk of dry mouth. Few studies have investigated
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alternative mechanisms of antidepressant-induced dry mouth, such as changes in salivary protein

content,44, 152, 153 that are associated with sympathetic salivary neuron stimulation.

Prior reviews have agreed with the current finding that dry mouth is more likely to occur

in patients treated with SNRIs than those treated with SSRIs. 154 With regards to SNRIs, it is

hypothesized that dry mouth results from central accumulation of norepinephrine, which causes

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activation of ALPHA-2 receptors and concurrent inhibition of parasympathetic salivary neurons

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in the brainstem,155, 156
leading to decreased salivary flow. SSRIs, on the other hand, have less

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affinity for muscarinic cholinergic receptors, ALPHA receptors, and NET, and, as a result, have

less impact on salivary flow rate.154, 156-158 As patients treated with SSRIs still experience dry

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mouth at increased rates, it has alternatively been suggested that dry mouth may also occur as a
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result of changes in salivary protein composition. 152

Meta-regression also demonstrated that reduced SERT affinity was associated with an
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increased risk of dry mouth. Further examination of the role of serotonin suggests that 5HT
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exerts indirect effects on the central nervous system,31, 57 such as through action on 5HT

receptors in peripheral microcirculation.159 It has been postulated that SERT inhibitors cause dry
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mouth by increasing serotonin resulting in activation of ALPHA-2 receptors increasing levels of

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norepinephrine and reducing the activity of parasympathetic salivary neurons in the

brainstem.155, 156
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Meta-regression demonstrated that decreased affinity for ALPHA receptors (ALPHA 1

and ALPHA2 receptors) was associated with increased risk of dry mouth compared to placebo.

Antidepressant affinity for ALPHA-1 and ALPHA-2 receptors is highly correlated. ALPHA-1

stimulation elicits profuse salivary secretion whereas ALPHA-2 stimulation inhibits salivary

secretion by inducing inhibition of parasympathetic salivary neurons. 155, 156, 160 Increased
 ACCEPTED MANUSCRIPT

antagonism of ALPHA-2 receptors by some antidepressants may partially compensate for the

increased risk of dry mouth caused by other characteristics of antidepressants (e.g.

anticholinergic and serotonergic effects). Specifically, antagonism of ALPHA-2 receptors may

inhibit the biological pathway by which SERT inhibition causes decreased salivation. Dry

mouth is a common adverse effect of alpha-2 agonist medications such as clonidine and

T
guanfacine. Several previous studies have suggested that yohimbine, a selective alpha-2

IP
antagonist is effective at reducing dry mouth and increasing salivary secretion in patients with

CR
antidepressant-induced dry mouth (albeit causes by tricyclic antidepressants). 161, 162
Further

research is needed to examine the efficacy of yohimbine or other alpha-2 antagonists in reducing

antidepressant associated dry mouth.

US
AN
Pharmacological and behavioral measures can be taken in order to ameliorate symptoms

of dry mouth regardless of the exact pharmacological cause. Patients experiencing dry mouth are
M

advised to sip water and avoid irritants like diuretics, alcohol, and smoking. 163 Salivary
ED

substitutes, oral moisturizers, and artificial saliva can be effective in mild cases.163 In more

severe cases, salivary stimulants, such as recently approved muscarinic agonists pilocarpine HCl
PT

(Salagen) and cevimeline HCl (Evoxac);164-166 however, pilocarpine carries potentially dangerous
CE

contraindications163 and regular dental evaluations are required in order to manage dosage of

these medications.167 Furthermore, conclusive results have not been drawn with regards to the
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tolerability and efficacy of either of these interventions.168-172 Prior to employing these measures,

it may be advisable for clinicians to prescribe fluvoxamine or vortioxetine in cases where

depressed patients experience bothersome dry mouth, as this meta-analysis suggests that these

agents show a minimal difference in risk of dry mouth compared to placebo.

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There are several limitations in the current meta-analysis. Different measures were used

across studies in the reporting of dry mouth as a side-effect of antidepressants and reports were

not collected randomly, potentially leading to increased incidence of side-effects when

significant differences between medication and placebo are observed. It has also been suggested

that depression has a direct relationship with dry mouth44, 154, 173, 174
due to stimulation of the

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sympathetic system resulting from chronic stress. 40 Therefore, it is difficult to determine the

IP
degree to which medication is responsible for the presentation and severity of dry mouth as a

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side-effect (especially considering that these medications are more effective at reducing

depressive symptoms than placebo). Also, medical causes of dry mouth and concomitant

US
medications likely to produce dry mouth were likely not screened for and assessed in these
AN
clinical trials of psychiatric conditions. Therefore, it is quite possible that differences between

trials in terms of inclusion/exclusion criteria in terms of these factors could have explained some
M

of the observed differences between agents. Finally, although our meta-regression analysis
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showed no effect of dosing on the risk of dry mouth for SSRI or SNRI medication, examining

dosing effects within trials with objective measures of dry mouth and salivation would be a much
PT

more sensitive technique to examine dosing effects.

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The current meta-analysis demonstrates that (1) significant risk of dry mouth is

associated with SSRIs, SNRIs, and, to some degree, atypical antidepressants; (2) SNRIs exhibit a
AC

moderately higher risk of dry mouth compared to placebo than SSRIs; (3) fluvoxamine and

vortioxetine were not associated with an increased risk of dry mouth; (4) there is no significant

dosing effect for dry mouth with either SSRIs or SNRIs; (5) while there is no significant

difference in risk between diagnostic indications for SSRIs, anxiety was associated with a greater
 ACCEPTED MANUSCRIPT

increased risk of dry mouth compared to depression for SNRIs; and (6) increased risk of dry

mouth was associated with decreased affinity for SERT, ALPHA-1 and ALPHA-2 receptors.

T
IP
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AN
M
ED
PT
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 ACCEPTED MANUSCRIPT

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TABLE LEGENDS:

Table 1: Characteristics of included trials. Table 1 reports the characteristics of trials included

in this meta-analysis. References to included trials are listed as supplementary references 1-99.

Abbreviations: ED = imipramine (or fluvoxamine) equivalent dose; SSRI - selective serotonin

reuptake inhibitor and SNRI - serotonin norepinephrine reuptake inhibitor.

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FIGURE LEGENDS:

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Figure 1: Flow diagram illustrating the selection of studies for inclusion in the meta-

analysis. Figure 1 demonstrates the process involved in the selection of studies for the meta-

analysis.
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Figure 2: Forest plot demonstrating the relative risk of dry mouth among SSRI, SNRI and

atypical agents. A forest plot of the relative risk of the relative risk of dry mouth in each studied
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medication, within studied class (SSRI, SNRI, Atypical), plotted logarithmically. Medication
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specific relative risks (including 95% CI) are donated by black lines. Class specific relative risk

(including 95% CI) is represented by a black square. SSRI - selective serotonin reuptake
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inhibitor; SNRI - serotonin norepinephrine reuptake inhibitor; k = number of studies; N =

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number of participants.

Figure 3: Funnel plot examining publication bias for risk of dry mouth. Figure 3 examines
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publication bias using a funnel plot which depicts log transformed risk ratio of dry mouth

compared to placebo (x axis) and standard error of included trials (y axis) for SSRIs (figure 3A),

SNRIs (figure 3B) and atypical antidepressants (figure 3C). SSRI - selective serotonin reuptake

inhibitor; SNRI - serotonin norepinephrine reuptake inhibitor.

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Figure 4: Association between SERT, ALPHA-1 and ALPHA-2 receptor affinity and risk

of dry mouth. Figure 4 is a scatterplot displaying relative affinity of second generation

antidepressants to the SERT (Figure 4A), Alpha-1 (Figure 4B), and Alpha-2 (Figure 4C)

receptors and measured relative risk of dry mouth for each medication. The circle size is

proportional to weight of each medication within the analyses. CIT – citalopram; ESC –

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escitalopram; FLU – fluoxetine; FLV – fluvoxamine; MIR – mirtazapine; PAR – paroxetine;

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SER – sertraline; TRA – trazodone; DVL – desvenlafaxine; DUL – duloxetine; VIL –

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vilazodone; VLF – venlafaxine; BUP – bupropion; VOR – vortioxetine.

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TABLE 1: Characteristics of Included Trials

SSRI
Study Medication Class Dose (mg/d) ED Active: Placebo Indication
79
Feighner_1999 Citalopram SSRI 60 199.8 521:129 Depression
Lenze_200599 Citalopram SSRI 30 100 17:17 Anxiety
Lepola_2003100 Citalopram SSRI 40 133.2 160:154 Depression
Mathews_2015115 Citalopram SSRI 40 133.2 282:281 Depression
Mendels_1999116 Citalopram SSRI 80 266.4 89:91 Depression
Montgomery_2001117 Citalopram SSRI 60 199.8 300:101 OCD
Stahl_2003140 Citalopram SSRI 40 133 119:119 Anxiety

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Baldwin_200656 Escitalopram SSRI 20 133.2 403:139 Anxiety

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Bose_200859 Escitalopram SSRI 20 133.2 45:52 Anxiety
Clayton_200667 Escitalopram SSRI 20 133.2 281:273 Depression

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Coric_201070 Escitalopram SSRI 20 133.2 51:101 Anxiety
Lepola_2003100 Escitalopram SSRI 20 133.2 155:154 Depression
Nierenberg_2007121 Escitalopram SSRI 10 66.6 274:137 Depression

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Stahl_2003140 Escitalopram SSRI 20 133.2 128:119 Anxiety
Stein_2007141 Escitalopram SSRI 20 133.2 232:115 OCD
Byerley_198863 Fluoxetine SSRI 80 400 32:29 Depression
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Feighner_198977 Fluoxetine SSRI 80 400 61:59 Depression
Rickels_1986131 Fluoxetine SSRI 80 400 18:24 Depression
Silverstone_1999137 Fluoxetine SSRI 60 300 119:118 Depression
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Silverstone_2001138 Fluoxetine SSRI 60 300 121:119 Depression

Asakura_200755 Fluvoxamine SSRI 300 300 182:89 Anxiety
ED

Dominguez_198572 Fluvoxamine SSRI 300 300 35:31 Depression

Fabre_199674 Fluvoxamine SSRI 150 150 46:44 Depression
Feighner_1989b76 Fluvoxamine SSRI 300 300 31:19 Depression
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Hoehn-Saric_199387 Fluvoxamine SSRI 50 50 18:18 Anxiety

Jenike_199094 Fluvoxamine SSRI 300 300 18:20 OCD
Lydiard_1989108 Fluvoxamine SSRI 300 300 18:17 Depression
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Porro_1988127 Fluvoxamine SSRI 150 150 21:20 Depression

Allgulander_200454 Paroxetine SSRI 50 250 144:146 Anxiety
Baldwin_200656 Paroxetine SSRI 20 100 139:139 Anxiety
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Ballenger_199858 Paroxetine SSRI 40 200 209:69 Anxiety

Claghorn_199266 Paroxetine SSRI 50 250 36:35 Depression
Claghorn_199665 Paroxetine SSRI 150 150 32:36 Depression
Detke_200471 Paroxetine SSRI 20 100 86:93 Depression
Dunbar_199173 Paroxetine SSRI 50 250 240:240 Depression
Feighner_199378 Paroxetine SSRI 50 250 240:240 Depression
Hollander_200388 Paroxetine SSRI 60 300 255:89 OCD
Lecrubier_199798 Paroxetine SSRI 20 100 123:123 Anxiety
Liebowitz_2002106 Paroxetine SSRI 60 300 289:95 Anxiety
Liebowitz_2005103 Paroxetine SSRI 50 250 142:146 Anxiety
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Perahia_2006122 Paroxetine SSRI 20 100 97:99 Depression

Pollack_2001126 Paroxetine SSRI 50 250 161:163 Anxiety
Rickels_1989130 Paroxetine SSRI 50 250 55:56 Depression
Rickels_2003135 Paroxetine SSRI 40 200 386:180 Anxiety
Stein_1998142 Paroxetine SSRI 50 250 94:93 Anxiety
Stein_2007141 Paroxetine SSRI 40 200 119:115 OCD
Zohar_1996149 Paroxetine SSRI 60 300 201:99 OCD
Chouinard_199264 Sertraline SSRI 200 240 260:260 OCD
Fabre_199575 Sertraline SSRI 200 240 91:91 Depression

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Greist_199582 Sertraline SSRI 241:84 OCD

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Jenike_199094 Sertraline SSRI 200 240 10:9 OCD
Liebowitz_2003102 Sertraline SSRI 200 240 205:196 Anxiety

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Mao_2015114 Sertraline SSRI 50 60 19:18 Depression
Pollack_1998124 Sertraline SSRI 200 240 88:88 Anxiety
Reimherr_1990128 Sertraline SSRI 200 240 149:150 Depression

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Van Amerigen_2001144 Sertraline SSRI 200 240 135:69 OCD
SNRI
Study Medication Class Dose (mg/d) ED Active: Placebo Indication
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51
Alaka_2014 Duloxetine SNRI 120 225 or 151:140 Anxiety
300
Allgulander_200153 Venlafaxine SNRI 75 75 254:131 Anxiety
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Allgulander_200153 Venlafaxine SNRI 150 150 411:130 Anxiety

Allgulander_200452 Venlafaxine SNRI 225 225 144:146 Anxiety
Bose_200859
ED

Venlafaxine SNRI 225 225 37:52 Anxiety

Boulenger_201460 Duloxetine SNRI 60 150 147:158 Depression
Bradwejn_200561 Venlafaxine SNRI 225 225 177:178 Anxiety
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Clayton_201368 Desvenlafaxine SNRI 50 217 217:217 Depression

Iwata_201389 Desvenlafaxine SNRI 50 217 422:231 Depression
Liebowitz_2008105 Desvenlafaxine SNRI 100 434 315:159 Depression
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Liebowitz_2013107 Desvenlafaxine SNRI 50 217 450:223 Depression

Wyeth/Pfizer_2011147 Desvenlafaxine SNRI 50 217 285:142 Depression
Detke_200471 Duloxetine SNRI 120 300 120:93 Depression
AC

Gaynor_2011a 80 Duloxetine SNRI 60 150 261:266 Depression

Gaynor_2011b81 Duloxetine SNRI 60 150 262:266 Depression
Hartford_200783 Duloxetine SNRI 120 300 162:161 Anxiety
Mahableshwarkar_2014a 11 Duloxetine SNRI 60 150 156:157 Anxiety
0

Nierenberg_2007121 Duloxetine SNRI 60 150 273:137 Depression

Perahia_2006122 Duloxetine SNRI 120 300 196:99 Depression
Wu_2011146 Duloxetine SNRI 120 300 108:102 Anxiety
Gelenberg_200061 Venlafaxine SNRI 225 225 124:127 Anxiety
Hartford_200783 Venlafaxine SNRI 225 225 164:161 Anxiety
Kasper_200995 Venlafaxine SNRI 225 225 125:128 Anxiety
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Liebowitz_2005a 103 Venlafaxine SNRI 225 225 133:144 Anxiety

Liebowitz_2005b104 Venlafaxine SNR 225 225 133:138 Anxiety
I
Liebowitz_2009101 Venlafaxine SNR 225 225 164:159 Anxiety
I
Montgomery_2006119 Venlafaxine SNR 75 75 113:101 Anxiety
I
Pollack_1996125 Venlafaxine SNR 225 225 13:12 Anxiety
I
Pollack_2007123 Venlafaxine SNR 150 150 334:163 Anxiety

T
I
Rickels_2000134 Venlafaxine SNR 225 225 253:96 Anxiety

IP
I
Rickels_2004133 Venlafaxine SNR 225 225 126:135 Anxiety

CR
I
Silverstone_1999137 Venlafaxine SNR 225 225 122:118 Depression
I
Silverstone_1999137 Venlafaxine SNR 225 225 128:119 Depression

US
I
Silverstone_2001138 Venlafaxine SNR 225 225 128:119 Depression
I
Stein_2005143
AN
Venlafaxine SNR 225 225 238:126 Anxiety
I
M

Atypical
Study Medication Class Dos Active: Placebo Indication
ED

e (mg/d)
Branconnier_1995 Bupropion Atypical 450 36:9 Depression
Clayton_200667 Bupropion Atypical 450 276:273 Depression
PT

Coleman_199969 Bupropion Atypical 400 119:121 Depression

Hewett_200985 Bupropion Atypical 150 187:197 Depression
Hewett_2010a 86
CE

Bupropion Atypical 300 204:198 Depression

Hewett_2010b84 Bupropion Atypical 300 211:207 Depression
Jain_200291 Bupropion Atypical 400 213:209 Depression
Jefferson_200693
AC

Bupropion Atypical 450 135:139 Depression

Reimherr_1998129 Bupropion Atypical 300 236:117 Depression
Safarinejad_2010136 Bupropion Atypical 300 117:117 Depression
Weihs_2002145 Bupropion Atypical 300 210:213 Depression
Bremner_199562 Mirtazapine Atypical 35 50:50 Depression
Montgomery_1998118 Mirtazapine Atypical 35 74:57 Depression
Muehlbacher_2005120 Mirtazapine Atypical 30 33:33 Anxiety
Smith_1990139 Mirtazapine Atypical 30 50:50 Depression
Zhang_2014148 Trazodone Atypical 450 185:181 Depression
Khan_201197 Vilazodone Atypical 40 235:233 Depression
Mathews_2015115 Vilazodone Atypical 40 575:281 Depression
 ACCEPTED MANUSCRIPT

Rickels_2009132 Vilazodone Atypical 40 205:204 Depression

Baldwin_201257 Vortioxetine Atypical 10 463:148 Depression
Boulenger_201460 Vortioxetine Atypical 20 302:158 Depression
Jacobsen_201590 Vortioxetine Atypical 20 305:157 Depression
Jain_201392 Vortioxetine Atypical 5 150:157 Depression
Katona_201296 Vortioxetine Atypical 5 150:157 Depression
Mahableshwarkar_2014a 110 Vortioxetine Atypical 10 468:157 Anxiety
Mahableshwarkar_2014b111 Vortioxetine Atypical 10 304:153 Anxiety
Mahableshwarkar_2015a 112 Vortioxetine Atypical 15 309:160 Depression

T
Mahableshwarkar_2015b113 Vortioxetine Atypical 20 196:191 Depression

IP
Mahableshwarkar_2015c 109 Vortioxetine Atypical 20 301:159 Depression

CR
US
AN
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ED
PT
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FIGURE 1: Flow diagram illustrating the selection of studies for inclusion in the meta-analysis.

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FIGURE 2: Forest plot demonstrating the relative risk of dry mouth among SSRI, SNRI and
atypical agents.

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FIGURE 3: Funnel plots examining publication bias for risk of dry mouth.

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FIGURE 4. Association between SERT, ALPHA-1 and ALPHA-2 receptor affinity and risk of

dry mouth.

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