SPECIAL TOPIC Assessing the Risks Associated with Antidepressant Use in Plastic Surgery: A Systematic Review Isabel Teo, M.R.C.S. Christopher Tam Song, M.B.Ch.B. Dundee and Edinburgh, United Kingdom
Background: Antidepressant use has increased dramatically over the past decade. Although there is no question about the benefits of these medications, uncertainty exists with regard to the implications of antidepressant treatment surrounding plastic surgery. This systematic review collates all of the available literature that evaluates the risks of patient antidepressant treatment, in relation to plastic surgery. Methods: A comprehensive literature review of the PubMed and Cochrane databases was conducted. Articles were assessed by two independent reviewers using predefined data fields and selected using specific inclusion criteria. The two authors independently reviewed the literature and extracted data from included reviews, and discrepancies were resolved by consensus. Results: Twenty-six articles were included in the analysis and were categorized into five groups for comparison: risk of bleeding, risk of breast cancer, risk of breast cancer recurrence, breast enlargement, and miscellaneous (unique complications). Extracted information included study type, statistical analyses, conclusion, and limitations. Conclusions: This review does not support the cessation of antidepressants in patients before plastic surgery, as the numbers needed to harm are low and the implications of withdrawal may prove to be detrimental to postoperative management. However, the use of antidepressants for mental disorders may also implicate key patient risk factors for surgical complications, and sufficient exploration into the patient’s indications for the prescription is crucial. Evidence so far does not suggest that antidepressants increase the risk of breast cancer or recurrence in general, but caution should be exercised for those specifically on concurrent tamoxifen and paroxetine treatment. (Plast. Reconstr. Surg. 136: 1107, 2015.)
A
ntidepressant use is on the rise, and it has become crucial for the plastic surgeon to be cognizant of the possible undesired effects in relation to surgery. According to the Centers for Disease Control and Prevention, one in 10 Americans aged 12 years and older were taking antidepressant medication between 2005 and 2008.1 In the United Kingdom, antidepressant prescribing has nearly doubled since 2000, from 37 per 1000 to 71 per 1000 adults on antidepressants currently.2 Harirchian et al.3 found that 22 percent of their patients who had undergone face-lift surgery were taking serotonin reuptake inhibitors or selective noradrenaline reuptake inhibitors. Freedman4 reported a 17 percent use of From Ninewells Hospital and the University of Edinburgh. Received for publication May 24, 2015; accepted May 28, 2015 Dr. Teo and Dr. Song contributed equally to this article. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001696
antidepressants in his cosmetic cohort, whereas Fann et al.5 found an incidence of 25 percent of major depression in breast cancer patients. Post– cancer diagnosis depression, body disfigurement or dysmorphia, posttraumatic stress disorder, and chronic regional pain are some of the indications for antidepressant therapy in patients that may be involved with plastic surgery services. This review Disclosure: There are no sources of funding or financial interest to declare. There are no c ommercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article. A “Hot Topic Video” by Editor-in-Chief Rod J. Rohrich, M.D., accompanies this article. Go to PRSJournal.com and click on “Plastic Surgery Hot Topics” in the “Videos” tab to watch.” On the iPad, tap on the Hot Topics icon.
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Plastic and Reconstructive Surgery • November 2015 summarizes all available literature relevant to patient antidepressant use in aesthetic and reconstructive surgery, and aims to equip the plastic surgeon with valuable clinical knowledge of what may be a ubiquitous prescription in our patient population, in years to come.
PATIENTS AND METHODS This study collates all publications on antidepressant use in patients undergoing plastic and breast surgery, with particular focus on risks and complications. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This review and its authors also conform to the ethical principles of the Declaration of Helsinki of the World Medical Association. The literature search was performed by two independent reviewers (C.T.S. and I.T.) through the MEDLINE and Cochrane databases. The Medical Subject Headings search terms included “antidepressant,” “selective serotonin reuptake inhibitor,” “SSRI,” “selective norepinephrine reuptake inhibitor,” “SNRI,” “tricyclic antidepressant,” “TCA,” “bleeding surgery,” “burns,” “breast,” “breast cancer,” “cosmetic,” “reconstructive,” “aesthetic,” “plastic,” “burns,” and “cancer.” A free text search or a Medical Subject Headings term search was used wherever appropriate, and Boolean operators were used to combine the terms. There were no restrictions on publication date or status. Eligibility Criteria The inclusion criteria consisted of any metaanalyses, systematic reviews, case-control and cohort studies, or case reports involving antidepressant complications relevant to plastic surgery. Articles excluded were preclinical studies, studies constituted in the systematic reviews and metaanalyses, and expert opinions. Study Selection Citations found by means of searching the databases were screened for eligibility by title and/ or abstract. Full-text articles were then appraised for final inclusion in the systematic review. Data Collection Process Articles were examined for study design and outcomes measured, duration of exposure, statistical analysis, complications, and limitations. The two reviewers listed extracted data separately, and discrepancies were reviewed and discussed until a consensus was accomplished.
Data Analysis A formal statistical analysis of the eligible studies was not performed because of the clinical (i.e., multiple antidepressant classes) and methodologic heterogeneity (i.e., different study types, outcome measures, exposure duration, limitations, and confounding factors). A detailed systematic review of the diverse outcomes and complications was undertaken instead.
Results One thousand five hundred thirty-five articles were identified through the initial search (Fig. 1). After screening through the titles, 122 publications remained. This was further reduced to 76 articles after reading the abstracts. Of these 76 articles, 50 were omitted for individual analysis, as they were already included in the systematic reviews and meta-analyses. There were 26 remaining articles that fulfilled our inclusion criteria. We identified patterns of risks and pooled studies with similar findings to form five groups: risk of bleeding, risk of breast cancer, risk of breast cancer recurrence, breast enlargement, and miscellaneous (unique complications). Risk of Bleeding Two cohort studies, two case-control studies, and two case reports analyzed the relationship between bleeding and antidepressant use (Table 1).3,6–10 The clinical cases that were examined included patients undergoing breast cancer surgery (i.e., mastectomy or breast conserving surgery), rhytidectomy, cosmetic breast surgery (i.e., breast augmentation, reduction, or mastopexy), an orbital blowout fracture repair, and a clinical presentation of breast ecchymosis. The conclusions drawn from the breast cancer surgery cohort studies were conflicting. Gärtner et al.6 deduced an increased risk of bleeding of 4 percent with antidepressant use, whereas Lietzen et al.7 found no association and that age, type of surgery, and use of glucocorticoids instead were factors linked to increased risk of bleeding. The case-control study on rhytidectomy3 found no association with selective serotonin reuptake inhibitor use and bleeding, but the case-control study on cosmetic breast surgery8 calculated a four-fold increased risk of hematoma formation (requiring surgical drainage). Van Cann and Koole9 attributed the formation of postoperative hematoma in an orbital blowout fracture repair to the use of paroxetine, whereas Akbulut et al.10 concluded that fluoxetine use had resulted in breast ecchymosis in his patient.
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Volume 136, Number 5 • Risks Associated with Antidepressant Use
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the search and selection strategy of included articles.
Risk of Breast Cancer Six articles evaluated the risk of breast cancer with antidepressant use, and this encompassed two meta-analyses, two systematic reviews, one case-control study, and one case series (Table 2). The meta-analysis by Cosgrove et al.11 found that antidepressant users, especially those of selective serotonin reuptake inhibitors, had a modest increase in breast and ovarian cancer risk, whereas the meta-analysis by Eom et al.12 found no associated risk of breast cancer. The systematic review by Bahl et al.13 proposed a possible increase in the risk of breast cancer with paroxetine use, whereas the systematic review by Lawlor et al.14 found no association. The case-control study by Ashbury et al.15 assessed whether the degree of inhibition of serotonin reuptake had significance, and the analysis of both high- (paroxetine, sertraline, and fluoxetine) and low-inhibiting selective serotonin reuptake inhibitors (citalopram and fluvoxamine) supported no association. Wallace et al.16 reported three cases of male hormone receptor–positive breast carcinoma and a case of male ductal hyperplasia. The authors attributed this to the use of fluoxetine and paroxetine.
Outcomes in Breast Cancer The role of concurrent antidepressant use with tamoxifen therapy in recurrence of breast cancer was studied in one cohort and four casecontrol studies (Table 3). The cohort study by Kelly et al.17 on selective serotonin reuptake inhibitors found no association with recurrence of cancer, except for patients on paroxetine treatment. The study found an additional breast cancer death at 5 years for every 20 women on concurrent tamoxifen and paroxetine use, and concluded that “paroxetine can reduce or abolish the benefit of tamoxifen.” The two nested case-controls18,19 and the case-control study by Chubak et al.20 found no association with breast cancer recurrence and selective serotonin reuptake inhibitor use. Both Chubak et al. and Wernli et al.21 found no association with antidepressant use and mortality from breast cancer. On another note, the study by Wernli et al. also pooled deaths from cardiovascular disease and found a statistically significant higher risk of mortality from any cause for antidepressant users (especially tricyclic antidepressants).
1109 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Cohort
Denmark
Lietzen et al., 20147
Brazil
Turkey
Case report
263
Clinical presentation Fluoxetine of unexplained breast ecchymosis
Paroxetine
None SSRI
2089 196
None 205 SSRI or SNRI 58 Total 2285
Total
aRR
Analysis
95% CI
Conclusion
Limitations
Current SSRI use is TCA (526), TeCA associated with an (131), and other increased risk of ADs (358) were reoperation because of included in the bleeding after breast control cancer surgery, from approximately 3% to approximately 7% 338 Risk difference does SSRI prescription not merit pausing compliance 51 1.1 0.83–1.5 treatment in psychounknown 14 2.3 1.4–3.9 logically vulnerable 37 0.93 0.66–1.3 Unable to control for over-thecounter NSAIDs or alcohol Reoperation AD use not found to be Unable to account a risk factor for reoper- for over-theation Age, surgery type, counter glucocorand glucocorticoid use ticoids or NSAIDs instead affected the risk of reoperation Hematoma Unpaired SSRIs or SNRIs did not Low power, cannot t test seem to increase risk rule out small of bleeding increased risk of 4* p = 0.87 bleeding 1† Hematoma OR SSRI use is associPossible confound(surgical ated with a fourfold ing bias with draining) increase in risk of depression bleeding after breast 24 9 4.14 1.90–9.04 cosmetic surgery The decision to stop (p ≤ 0.001) SSRIs before surgery for psychologically vulnerable patients should not be made without a complete discussion of the risks and benefits Retrobulbar hemaIncreased risk of bleedtoma resulting in ing in orbital surgery increased intraocular pressure necessitating evacuation Breast ecchymosis SSRI-induced breast (no history of ecchymosis is rare or trauma or surgery) underreported
Reoperation
Complication
AD, antidepressant; aRR, adjusted risk ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant; NSAIDs, nonsteroidal antiinflammatory drugs; SNRI, selective norepinephrine reuptake inhibitor. *Minor hematomas contained ≤10 ml of blood and were treated by needle aspiration in the office. †Major hematomas were defined as expansile collections that required urgent surgical evacuation.
Akbulut et al., 201410
Orbital blowout fracture
CaseBreast cosmetic control surgery
Case Van Cann The Netherlands report and Koole, 20099
Basile et al., 20128
12,872 1592 1391 201
None SSRI Current Former
19,919 15,964 3955
14,464
No. of Patients
Total
AD Type
Predictors of post- Total surgical bleeding None in breast cancer SSRI, TCA, surgery and TeCA
Breast cancer surgery
Subject
Rhytidectomy Harirchian United States Casecontrol et al., 20123
Cohort
Type of Study
Denmark
Country
Gärtner et al., 20106
Reference
Table 1. Six Articles Analyzing Antidepressant Use and the Risk of Bleeding in Breast Cancer Surgery, Rhytidectomy, Orbital Blowout Fracture, and Breast Ecchymosis
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Subject
MetaBreast and analysis ovarian cancer risk
Study
Canada
Systematic Breast review cancer risk
Canada
2
2
Fluoxetine
Paroxetine
0.67–1.25 0.89–1.53
61 1.17 Male breast neoplasia ER+ carcinoma and atypical ductal hyperplasia Both ER+ carcinoma
0.88–1.17
Limitations
Association of increased risk of male breast cancer
No association regardless of degree of inhibition or duration of use
Does not include other risk factors such as family history, menstrual and reproductive history TCA use among study not accounted for
Modest increase in 4 studies had industry ties, risk of ovarian or this study found statistically breast cancer with significant relationships use of ADs, between industry ties and especially SSRI researchers’ conclusion Study did not include EMBASE database search Includes pooled data from ovarian cancer patients No association Potential bias in observational data Study only includes Western population
Conclusion
0.96–1.08 0.95–1.10 0.94–1.03 Breast cancer Inconclusive but sugrecurrence gests no association Plausible increased risk with paroxetine use and inconsistent association of breast cancer risk with SSRIs No association
1.03–1.20 0.99–1.51 0.95–1.13
95% CI
0.92
44
1.02
aOR
1.02 1.02 0.98
aOR
1.11 1.07 1.04
Pooled OR
Complications Analysis
9 studies (1 efficacy trial, 4 casecontrol, and 4 cohort) 23,426 Breast cancer 17,908 1783 2622 241
6 studies (4 case-control and 2 cohort)
18 studies (11 case-control, 3 nested casecontrol, and 4 cohort)
26 studies (case-control and cohort)
No. of Patients
Total None SSRI high inhibitors* SSRI low 526 inhibitor† Both 587 Total 4 case reports
Total Any AD
SSRI or TCA
Any AD SSRI TCA Total
Total
Any AD SSRI TCA
Total
AD Type
AD, antidepressant; aOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; SNRI, selective norepinephrine reuptake inhibitor; ER+, estrogen receptor–positive. *High inhibitors: paroxetine, sertraline, and fluoxetine. †Low inhibitors: citalopram and fluvoxamine.
Clinical presentation
CaseBreast control cancer risk
Case Wallace United Kingdom series et al., 200016
Ashbury et al., 201215
United Systematic Breast Lawlor Kingdom review cancer et al., risk 200314
Bahl et al., 200313
Republic MetaBreast Eom of Korea analysis cancer et al., risk 201212
Cosgrove United et al., States 201111
Reference Country
Table 2. Six Articles Reviewing the Risk of Breast Cancer Surgery with Antidepressant Use
Volume 136, Number 5 • Risks Associated with Antidepressant Use
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Azoulay et al., 201119
United Nested Recurrence in Total Kingdom casebreast cancer control patients on con- None current tamoxifen Strong and SSRI therapy CYP2D6 inhibitors Weak CYP2D6 inhibitors Combination
Analysis
23 56
727
Cancer recurrence 198 26
ER+TAM+ ER−TAM− ER+TAM+ ER−TAM−
Cancer recurrence
0.82
1
0.75
1.1 0.9 0.9 0.6
aOR
Mortality aHR from breast cancer 105 1.24 (0.25)* 1.54 (0.50)* 1.91 (0.75)* 71 0.91 (0.75)* 115 0.99 (0.75)* 38 0.94 (0.75)* 29 1.33 (0.75)* 16 0.30 (0.75)*
254
2311 378
3670
366
732
Recurrence in Total Lash et al., Denmark Nested casebreast cancer 201018 control patients on con- None current tamoxifen Citalopram and SSRI therapy SSRI: fluoxetine, paroxetine, and sertraline
2430
253 541 174 467 365
Total
AD Type
Fluoxetine Sertraline Fluvoxamine Citalopram Venlafaxine
Cohort SSRI and breast cancer mortality in women receiving tamoxifen
Subject
630
Canada
Kelly et al., 201017
Study
Paroxetine
Country
Reference
No. of Patients Complication
0.59–1.13
0.63–1.58
0.49–1.15
95% CI
0.7–1.7 0.4–2.2 0.5–1.8 0.3–1.6
95% CI
1.08–1.42 1.11–1.50 1.15–1.84 0.55–1.51 0.67–1.47 0.53–1.66 0.56–3.17 0.07–1.31
95% CI
95% CI
Limitations
(Continued)
For every 19.7 Indication for AD not women with included Possible breast cancer selection bias with treated, an paroxetine users overlap of 41% of tamoxifen therapy with paroxetine could result in an additional breast cancer death at 5 yr No association with other ADs Critical role of CYP2D6 in metabolic activation of tamoxifen No association Does not factor duration of SSRI treatment together with tamoxifen therapy Low frequency of prescriptions for other SSRIs, unable to confidently conclude that they do not reduce the effectiveness of tamoxifen Indication for SSRI not included No association Does not factor duration of SSRI treatment together with tamoxifen therapy
Conclusion
Table 3. Five Articles Examining the Association of Antidepressant Use with Breast Cancer Recurrence, with Diagnosis of Recurrence, and/or Breast Cancer Mortality as Outcomes
Plastic and Reconstructive Surgery • November 2015
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United States
No. of Study Subject AD Type Patients Complication Case- Recurrence in Total 1306 Cancer control breast cancer recurrence patients on (5-yr risk) concurrent None 867 79 tamoxifen and Any AD 439 24 SSRI therapy SSRI 11 TCA 11 Miscellaneous 9 Total 1306 Mortality from breast cancer (5-yr risk) None 867 35 Any AD 439 11 SSRI 5 TCA 5 Miscellaneous 5 Case- Mortality in breast Total 3058 Mortality control cancer patients on from breast concurrent cancer tamoxifen and None 2750 145 SSRI therapy Any AD 308 18 SSRI 9 TCA 5 95% CI 95% CI
0.5–1.4 0.4–1.5 0.4–1.6 0.4–2.1
0.4–1.9 0.4–2.5) 0.3–2.3 (0.4–3.4)
0.55–1.56 0.51–2.79 0.41–2.51
Analysis aHR
0.8 0.8 0.8 1
0.9 1 0.8 1.2 aHR
0.93 1.4 1.01
Limitations Insufficient power to detect small differences Limited to first 5 yr following diagnosis Possible confounding with SSRI indication, diet, and physical activity
Unable to control for prior AD use in patients included in the study Possible misclassification of exposure to AD after diagnosis
No association Potential selection bias Increased risk of Did not include tumor all-cause mortalmarker characteristics ity with AD use, Indication for SSRI not specifically TCAs included
Conclusion No association with AD use and increased risk of recurrence or breast cancer mortality
AD, antidepressant; aHR, adjusted hazard ratio; aOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; SNRI, selective norepinephrine reuptake inhibitor; ER, estrogen receptor; TAM, tamoxifen; + positive; −, negative.
Wernli et al., 201121
Reference Country Chubak United et al., States 200820
Table 3. Continued
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AD, antidepressant; SSRI, selective serotonin reuptake inhibitor.
Kaufman al., United Case report Gynecomastia States 201325
Sertraline and duloxetine
1
Bilateral gynecomastia
SSRI may cause mammoplasia and mammographic changes Gynecomastia may be AD selective or secondary to additive AD adverse effects
1 1 Sertraline Fluvoxamine Marcus, 200124
United Case report Mammoplasia States
1
Hall, 199423 United Case series States
Breast pain and enlargement
Fluoxetine
Mammoplasia Weight gain
Significantly more patients Patient-reported mammo(p < 0.001) on SSRI plasia rather than bra size reported mammoplasia measurement than those on Dose of AD not fixed over venlafaxine course of treatment Weight gain reported in 84% with mammoplasia and in 30% without (p < 0.001) This SSRI adverse effect may be underreported Mammoplasia and weight gain 59 SSRI or venlafaxine Cohort Amsterdam United et al., States 199722
Mammoplasia during chronic AD therapy
Conclusion 95% Complication Analysis CI No. of Patients AD Type Subject Study
Antidepressants work by modulating neurotransmitter levels in the brain, although the exact mechanisms by which their effects are achieved are unknown. There are convincing statistical data that the use of antidepressants is on the rise. Unlike certain medications such as warfarin or rivaroxaban, plastic surgeons may often have little or no concern regarding the presence
Country
Discussion
Reference
Miscellaneous Table 5 illustrates five studies with unique complications. The case-control study by Gruber et al.26 examined the quantity of seroma formation following latissimus dorsi flap breast reconstruction and concluded that selective serotonin reuptake inhibitor use and patient body mass index were significant predictors of seroma formation requiring surgical drainage. One case report27 documents a patient with an adverse cutaneous reaction thought to be from an amitriptyline overdose. A second report28 attributed bullous skin necrosis from an adverse reaction to sertraline. Uppal et al.29 describe a morbidity in latissimus dorsi flap monitoring that ensued in a patient who developed acute mania from abrupt withdrawal of amitriptyline. The case report by Larson et al.30 describes an instance of serotonin toxicity in a patient on fluoxetine treatment, after undergoing methylene blue lymphatic mapping for squamous cell carcinoma of the scalp.
Table 4. Four Articles Studying the Relationship between Antidepressant Use and Risk of Gynecomastia or Mammoplasia
Breast Enlargement The literature search revealed four publications discussing breast enlargement in relation to antidepressant use: a cohort study, a case series study, and two case reports (Table 4).22–25 The cohort study22 reported a 38.9 percent rate of mammoplasia in selective serotonin reuptake inhibitor or venlafaxine users. It also found that selective serotonin reuptake inhibitor use was associated with a statistically significant higher number of patients diagnosed with mammoplasia in comparison with venlafaxine use. This study also reported weight gain in a larger portion of patients with mammoplasia than in those without (86 percent and 30 percent, respectively). Hall’s case report23 describes mastalgia with breast enlargement in a patient on fluoxetine and in a sertraline user. Marcus24 noted mammoplasia with mammographic changes in a patient using fluvoxamine, whereas Kaufman et al.25 reported bilateral gynecomastia in a patient on concurrent sertraline and duloxetine.
Limitations
Plastic and Reconstructive Surgery • November 2015
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Likely that sertraline induced a severe skin reaction Poor management of TCA medication around surgery for reconstructive patients can result in psychiatric morbidity and hinder flap monitoring Small doses of methylene blue (7 mg used in the case) when administered with SSRIs and fentanyl may contribute to serotonin toxicity in scalp region
First reported case
SSRIs and BMI shown to be significant predictors of increased seroma volume drained
of an antidepressant in a patient’s drug history. Antidepressants are not widely known to increase surgical risks, but it is apparent from our literature search that there is an expansion of articles examining potential associations of complications with antidepressant use.
Case report United States Larson et al., 201430
AD, antidepressant; SSRI, selective serotonin reuptake inhibitor; BMI, body mass index; TCA, tricyclic antidepressant. *Including volume of seroma formation, cutaneous drug reaction, TCA withdrawal, and serotonin toxicity in methylene blue dye application.
Case report Case report United Kingdom United Kingdom
Sentinel lymph node biopsy with methylene blue for squamous cell carcinoma of scalp
Fluoxetine
1
Acute mania hindered flap monitoring Flap was found to be fine after resolution of mania Intraoperative seizures Serotonin syndrome 1 Amitriptyline
Skin grafting 1 Sertraline
Case report United Kingdom
Fogarty and Kahn, 199927 Kirkup et al., 200428 Uppal et al., 200929
Cutaneous drug reaction from overdose Severe deep bullous skin necrosis TCA withdrawal after breast reconstruction
Amitriptyline
1
Skin necrosis Confusion Skin grafting
Multivariate analysis F = 4.1 p = 0.047 Seroma requiring drainage 87 SSRI Casecontrol Austria Gruber et al., 201126
Latissimus dorsi flap breast reconstruction
AD Subject Study Country Reference
Table 5. Evaluation of Unique Complications with Antidepressant Use*
No. of Patients
Complication
Analysis
95% CI
Conclusion
Volume 136, Number 5 • Risks Associated with Antidepressant Use
Risk of Bleeding Serotonin is a weak platelet activator, and platelet stores of serotonin are released during coagulation. A proposed mechanism of action for bleeding with antidepressant use is a suppression of platelet function caused by an inhibition of platelet serotonin reuptake transporters.31 However, the results of other studies32,33 do not support this hypothesis. Multiple prospective laboratory studies have looked into the effects of antidepressant use on bleeding, with heterogenous results. Lederbogen et al.34 found that prothrombin time was increased after treatment with either amitriptyline or paroxetine. On the contrary, Berk et al.35 analyzed 10 patients before and after administration of fluoxetine and found no changes in coagulation. Similarly, Alderman et al.36 did not demonstrate any changes in coagulation parameters after 28 days of fluoxetine or paroxetine use. Both cohort studies examining bleeding following mastectomy and breast conserving surgery were of large scale. However, Gärtner et al.6 examined selective serotonin reuptake inhibitors more selectively, and factored in latency of use and users of other classes of antidepressants in the control. Lietzen et al.7 pooled data from selective serotonin reuptake inhibitor, tricyclic antidepressant, and tetracycline antidepressant users, and this makes for a difficult comparison. The largest multicenter study37 on antidepressant use and the risk of bleeding in orthopedic surgery involved 530,416 patients and found a positive association (adjusted OR, 1.09; 95 percent CI, 1.04 to 1.15). The authors demonstrated that patients receiving selective serotonin reuptake inhibitors also had higher odds of in-hospital mortality, bleeding, and readmission. Despite this, the numbers needed to harm were large and the consequent increase in absolute risk for the average selective serotonin reuptake inhibitor user would be very small. Conversely, the preoperative cessation of selective serotonin reuptake inhibitors before may precipitate a discontinuation syndrome, worsen depression, or increase sensitivity to postoperative pain.38 The potential disaster from discontinuation syndrome has been highlighted by a former case report.29 Therefore, routine discontinuation
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Plastic and Reconstructive Surgery • November 2015 of antidepressants before surgery in the absence of a careful evaluation should be avoided. A study39 found a positive association with degree of serotonin uptake inhibition and abnormal bleeding. High inhibitors include paroxetine, sertraline, and fluoxetine, and perhaps there may be a role of temporarily substituting these selective serotonin reuptake inhibitors with lower inhibitors before surgery. Risk of Breast Cancer The biological mechanism by which antidepressant use relates to breast cancer is hypothesized to involve an increase in serum prolactin.40,41 Hyperprolactinemia is postulated to directly involve dopaminergic cells in the tuberoinfundibular pathway through GABAergic neurons. Alternate pathways may involve stimulation of vasoactive intestinal peptide or oxytocin release.42 Another explanatory factor may be the role of depression itself.43 Depression has been shown to induce immunosuppression, and antidepressants have been shown to cause immunosuppression in experimental studies.44,45 Other hypotheses involve modification to cellular proliferation and altered estrogen metabolism.12 A relationship between the risk of breast cancer and antidepressant use is not supported by this review; nevertheless, there may be plausibility with paroxetine use. The meta-analyses drew contrasting results despite sharing 16 identical articles. The study by Cosgrove et al.11 had pooled data from ovarian cancer patients, and this may explain the discrepancy. Neither systematic reviews nor case-control studies have found evidence supporting a positive association, although Bahl et al.13 suggest caution with paroxetine and concluded that there is a “plausible increased risk” of breast cancer with its use. Further studies are needed to evaluate long-term outcomes; however, this may prove to be challenging given that 50 to 80 percent of users discontinue treatment at less than 1 year.39,46 Wallace et al.16 describe four cases of male breast neoplasia. Risk factors for breast cancer development in men and women are likely to be complex and multifactorial. Even in large epidemiologic studies, the relative contribution of minor risk factors may be difficult to detect. Wallace et al. suggest that the rarity of male breast cancer because of an absence of the complex physiologic changes in the female breast may make such risk factors more luminous.
Outcomes in Breast Cancer Patients Tamoxifen is a selective estrogen receptor modulator that is metabolized by the hepatic P450 isoenzyme 2D6. Selective serotonin reuptake inhibitors, by nature of their biological activity, inhibit the hepatic P450 isoenzyme 2D6 to varying degrees and therefore may reduce the benefits of tamoxifen.47,48 In theory, the blunting of tamoxifen therapy may increase recurrence rates or death from breast cancer. Paroxetine, in particular, is an exceptionally potent hepatic P450 isoenzyme 2D6 inhibitor and is the only selective serotonin reuptake inhibitor with an irreversible mechanism.49,50 Although evidence has shown that hepatic P450 isoenzyme 2D6 inhibitors do reduce tamoxifen levels,48,51 randomized controlled trials have shown that lower doses of tamoxifen still confer the same antiproliferative activity.52,53 Four of five of the studies in our analysis found no evidence to support cancer recurrence or cancer mortality associated with antidepressant treatment. The fifth study,17 which included 2430 women, found a statistically significant increased risk of death from breast cancer in women taking paroxetine. The study’s design criteria excluded patients who had never used selective serotonin reuptake inhibitors concurrently with tamoxifen and those who had switched from one selective serotonin reuptake inhibitor to another. It is unclear whether these restrictive inclusion criteria may have influenced the generalizability of the results.19 Breast Enlargement and Pain Increased prolactin secretion has been proposed as a cause for mammoplasia and gynecomastia associated with antidepressant use.54 Mammoplasia and gynecomastia are reported to be infrequent developments, and this may be attributable to underreporting from both patients and doctors.22,23 Selective serotonin reuptake inhibitor use is also associated with weight gain, and a higher proportion of patients with mammoplasia reported weight gain (86 percent) than did the control patients (30 percent) in the study by Amsterdam et al.22 However, the development of mammoplasia did not seem to be related to age, menopausal status, or duration of antidepressant treatment. However, it may be dose dependent, and this might explain the lack of mammoplasia reported in the prospective control group of 322 women who were treated with a fixed low dose of 20 mg of fluoxetine in the study by Amsterdam et al.22
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Volume 136, Number 5 • Risks Associated with Antidepressant Use Miscellaneous Five of the studies we found did not fit into any clear category and have been pooled under “miscellaneous.” Gruber et al.26 analyzed 87 patients undergoing latissimus dorsi breast reconstruction and found that an increased risk of seroma formation (requiring surgical drainage) was associated with higher body mass index and selective serotonin reuptake inhibitor use. There was no specification as to which selective serotonin reuptake inhibitors were taken, and the linear regression analysis was only just within the range of significance (p = 0.047). Fogarty and Kahn27 and Kirkup et al.28 both highlight rare cutaneous reactions to amitriptyline and sertraline, of which both cases required skin grafting. The case reported by Uppal et al.29 is an admonition with regard to the potential catastrophic effects of flap monitoring from poor antidepressant management around surgery, where drains and the latissimus dorsi flap could not be monitored. Larson et al.30 describe the onset of serotonin toxicity in a low-dose (7 mg) subcutaneous methylene blue lymph node mapping for squamous cell carcinoma of the scalp. Serotonin toxicity is characterized by change in mental status, autonomic dysfunction, and muscular manifestations. Larson et al. postulate that the close proximity of the brain to the lymphatic drainage of the highly vascular scalp or the addition of the serotonergic agent fentanyl may have precipitated the development of serotonin toxicity in this case. Beyond its diagnostic application as a dye, methylene blue is now understood to also be a potent monoamine oxidase inhibitor with serotonergic properties.55,56 Therefore, its use with antidepressants may precipitate serotonin toxicity. Shah-Khan et al.57 have emphasized the safety of methylene blue lymphatic mapping in breast surgery and concluded from an in vitro study58 that the subcutaneous injection dose of 5 mg/kg for breast lymphatic mapping carries very little risk of serotonin toxicity. This, however, is not supported by the case reported by Schweibert et al.59 of serotonin toxicity in a patient on a selective serotonin reuptake inhibitor who underwent low-dose methylene blue (1 mg/kg) cystoscopy for ureteral ostia. The U.S. Food and Drug Administration has since released a safety announcement to discourage concomitant use of methylene blue and selective serotonin reuptake inhibitors.55
Limitations We have attempted to summarize all articles relevant to plastic surgical procedures and risks with antidepressant use. Our search terms were diverse and broad, but we may still have missed other obscure and indirect adverse outcomes significant to plastic surgery. Mastectomy, breast conserving surgery, and breast cancer mortality arguably may fall more within the realm of breast surgery. However, we have included this in our analysis because (1) there are oncoplastic surgeons who perform these operations, and (2) any possible implications of antidepressant use in breast cancer patients could influence reconstructive options. Our search found no prospective, randomized studies, and we were unable to perform any statistical analysis given the heterogeneity of articles. For analysis of bleeding risk, because of the retrospective design of most studies, measurements of blood loss were not standardized, and the surgeon’s decision to reoperate on hematomas may not have been objective. Some articles were specific regarding the type of antidepressant, whereas others pooled all antidepressants together, making direct comparisons difficult. Evidence has shown that mental disorders, especially depressive disorders, are strongly linked to diabetes; cancer; obesity; and risky behaviors such as smoking, excessive alcohol intake, and insufficient sleep.60 Therefore, depression itself may be associated with poor surgical outcomes and may have played a confounding role in results of the studies.
Conclusions This review does not support the cessation of antidepressant use in patients before plastic surgery, as the numbers needed to harm are low and the implications of withdrawal may prove to be detrimental to postoperative management. However, the use of antidepressants for mental disorders may also implicate key patient risk factors for surgical complications, and sufficient exploration into the patient’s indications for the prescription is crucial. Evidence so far does not suggest that antidepressants increase the risk of breast cancer or recurrence in general, but caution should be used for those specifically on concurrent tamoxifen and paroxetine treatment. Paroxetine is both a high serotonin uptake inhibitor and a potent irreversible hepatic P450 isoenzyme 2D6 enzyme inhibitor, and its adverse effects profile needs further
1117 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Plastic and Reconstructive Surgery • November 2015 evaluation in comparison with the other selective serotonin reuptake inhibitors. Other risks mentioned in the articles summarized in this review include breast ecchymosis, retrobulbar hematoma, mammoplasia, gynecomastia, skin reactions, serotonin syndrome, cutaneous reactions, and seroma formation. Unfortunately, more data are mandatory to warrant specific recommendations. Christopher Tam Song, Jr. University of Edinburgh Medicine and Veterinary Medicine 47 Little France Crescent Edinburgh, Midlothian EH16 4TJ, United Kingdom [email protected]
references 1. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief 2011;76:1–8. 2. OECD. Health at a Glance 2013: OECD Indicators. Paris: OECD Publishing; 2013. 3. Harirchian S, Zoumalan RA, Rosenberg DB. Antidepressants and bleeding risk after face-lift surgery. Arch Facial Plast Surg. 2012;14:248–252. 4. Freedman B. Cosmetic surgery and the use of antidepressant medication. Paper presented at: Plastic Surgery 2006: Annual Meeting of the American Society for Plastic Surgeons; October 6 through 11, 2006; San Francisco, Calif. 5. Fann JR, Thomas-Rich AM, Katon WJ, et al. Major depression after breast cancer: A review of epidemiology and treatment. Gen Hosp Psychiatry 2008;30:112–126. 6. Gärtner R, Cronin-Fenton D, Hundborg HH, et al. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: A Danish population-based cohort study. BMC Surg. 2010;10:3. 7. Lietzen LW, Ahern T, Christiansen P, et al. Glucocorticoid prescriptions and breast cancer recurrence: A Danish nationwide prospective cohort study. Ann Oncol. 2014;25:2419–2425. 8. Basile FV, Basile AR, Basile VV. Use of selective serotonin reuptake inhibitors antidepressants and bleeding risk in breast cosmetic surgery. Aesthetic Plast Surg. 2013;37:561–566. 9. Van Cann EM, Koole R. Retrobulbar hematoma associated with selective serotonin reuptake inhibitor: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:e1–e2. 10. Akbulut S, Yagmur Y, Gumus S, Babur M. Breast ecchymosis: Unusual complication of an antidepressant agent. Int J Surg Case Rep. 2014;5:129–130. 11. Cosgrove L, Shi L, Creasey DE, Anaya-McKivergan M, Myers JA, Huybrechts KF. Antidepressants and breast and ovarian cancer risk: A review of the literature and researchers’ financial associations with industry. PLoS One 2011;6:e18210. 12. Eom CS, Park SM, Cho KH. Use of antidepressants and the risk of breast cancer: A meta-analysis. Breast Cancer Res Treat. 2012;136:635–645. 13. Bahl S, Cotterchio M, Kreiger N. Use of antidepressant medications and the possible association with breast cancer risk: A review. Psychother Psychosom. 2003;72:185–194. 14. Lawlor DA, Jüni P, Ebrahim S, Egger M. Systematic review of the epidemiologic and trial evidence of an association between antidepressant medication and breast cancer. J Clin Epidemiol. 2003;56:155–163.
15. Ashbury JE, Lévesque LE, Beck PA, Aronson KJ. Selective serotonin reuptake inhibitor (SSRI) antidepressants, prolactin and breast cancer. Front Oncol. 2012;2:177. 16. Wallace WA, Balsitis M, Harrison BJ. Male breast neoplasia in association with selective serotonin re-uptake inhibitor therapy: A report of three cases. Eur J Surg Oncol. 2001;27:429–431. 17. Kelly CM, Juurlink DN, Gomes T, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: A population based cohort study. BMJ 2010;340:c693. 18. Lash TL, Cronin-Fenton D, Ahern TP, et al. Breast cancer recurrence risk related to concurrent use of SSRI antidepressants and tamoxifen. Acta Oncol. 2010;49:305–312. 19. Azoulay L, Dell’Aniello S, Huiart L, du Fort GG, Suissa S. Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence. Breast Cancer Res Treat. 2011;126:695–703. 20. Chubak J, Buist DS, Boudreau DM, Ross MA, Lumley T, Weiss NS. Breast cancer recurrence risk in relation to antidepressant use after diagnosis. Breast Cancer Res Treat. 2008;112:123–132. 21. Wernli KJ, Hampton JM, Trentham-Dietz A, Newcomb PA. Antidepressant medication use and breast cancer risk. Pharmacoepidemiol Drug Saf. 2009;18:284–290. 22. Amsterdam JD, Garcia-España F, Goodman D, Hooper M, Hornig-Rohan M. Breast enlargement during chronic antidepressant therapy. J Affect Disord. 1997;46:151–156. 23. Hall MJ. Breast tenderness and enlargement induced by sertraline. Am J Psychiatry 1994;151:1395–1396. 24. Marcus P. SSRIs and mammoplasia. Am J Psychiatry 2001;158:967. 25. Kaufman KR, Podolsky D, Greenman D, Madraswala R. Antidepressant-selective gynecomastia. Ann Pharmacother. 2013;47:e6. 26. Gruber S, Whitworth AB, Kemmler G, Papp C. New risk factors for donor site seroma formation after latissimus dorsi flap breast reconstruction: 10-year period outcome analysis. J Plast Reconstr Aesthet Surg. 2011;64:69–74. 27. Fogarty BJ, Khan K. Drug induced blistering and the plastic surgeon: A case of amitriptyline induced skin necrosis. Burns 1999;25:768–770. 28. Kirkup ME, Sheffield EA, Sacks LJ, Sansom JE. Delayed onset of bullous reaction with severe deep skin necrosis in association with sertraline. Br J Dermatol. 2004;150:164–166. 29. Uppal HS, Makrides P, Eltigani EA, Joshi RN. A case report of acute mania secondary to pedicled latissimus dorsi breast reconstruction and amitriptyline withdrawal. J Plast Reconstr Aesthet Surg. 2009;62:e117–e118. 30. Larson KJ, Wittwer ED, Nicholson WT, Weingarten TN, Price DL, Sprung J. Myoclonus in patient on fluoxetine after receiving fentanyl and low-dose methylene blue during sentinel lymph node biopsy. J Clin Anesth. 2015;27:247–251. 31. Jeong BO, Kim SW, Kim SY, Kim JM, Shin IS, Yoon JS. Use of serotonergic antidepressants and bleeding risk in patients undergoing surgery. Psychosomatics 2014;55:213–220. 32. Hougardy DM, Egberts TC, van der Graaf F, Brenninkmeijer VJ, Derijks LJ. Serotonin transporter polymorphism and bleeding time during SSRI therapy. Br J Clin Pharmacol. 2008;65:761–766. 33. Abdelmalik N, Ruhé HG, Barwari K, et al. Effect of the selective serotonin reuptake inhibitor paroxetine on platelet function is modified by a SLC6A4 serotonin transporter polymorphism. J Thromb Haemost. 2008;6:2168–2174.
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Volume 136, Number 5 • Risks Associated with Antidepressant Use 34. Lederbogen F, Weber B, Colla M, Heuser I, Deuschle M, Dempfle CE. Antidepressant treatment and global tests of coagulation and fibrinolysis. J Clin Psychiatry 2001;62:130. 35. Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: A pilot study. J Clin Psychiatry 1995;56:14–16. 36. Alderman CP, Seshadri P, Ben-Tovim DI. Effects of serotonin reuptake inhibitors on hemostasis. Ann Pharmacother. 1996;30:1232–1234. 37. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173:1075–1081. 38. Mrkobrada M, Hackam DG. Selective serotonin reuptake inhibitors and surgery: To hold or not to hold, that is the question: Comment on “Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery”. JAMA Intern Med. 2013;173:1082–1083. 39. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004;164:2367–2370. 40. Turkington RW. Prolactin secretion in patients treated with various drugs: Phenothiazines, tricyclic antidepressants, reserpine, and methyldopa. Arch Intern Med. 1972;130:349–354. 41. Urban RJ, Veldhuis JD. A selective serotonin reuptake inhibitor, fluoxetine hydrochloride, modulates the pulsatile release of prolactin in postmenopausal women. Am J Obstet Gynecol. 1991;164:147–152. 42. Emiliano AB, Fudge JL. From galactorrhea to osteo penia: Rethinking serotonin-prolactin interactions. Neuro psychopharmacology 2004;29:833–846. 43. Spiegel D, Giese-Davis J. Depression and cancer: Mechanisms and disease progression. Biol Psychiatry 2003;54:269–282. 44. Laudenslager ML, Clarke AS. Antidepressant treatment during social challenge prior to 1 year of age affects immune and endocrine responses in adult macaques. Psychiatry Res. 2000;95:25–34. 45. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol. 1995;48:1407–1412. 46. Aikens JE, Kroenke K, Swindle RW, Eckert GJ. Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. Gen Hosp Psychiatry 2005;27:229–236. 47. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310:1062–1075. 48. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration
of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst. 2003;95:1758–1764. 49. Bertelsen KM, Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: Comparison with fluoxetine and quinidine. Drug Metab Dispos. 2003;31:289–293. 50. Venkatakrishnan K, Obach RS. In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: Prediction of nonstationary pharmacokinetics and drug interaction magnitude. Drug Metab Dispos. 2005;33:845–852. 51. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst. 2005;97:30–39. 52. Decensi A, Robertson C, Viale G, et al. A randomized trial of low-dose tamoxifen on breast cancer proliferation and blood estrogenic biomarkers. J Natl Cancer Inst. 2003;95:779–790. 53. Kisanga ER, Gjerde J, Guerrieri-Gonzaga A, et al. Tamoxifen and metabolite concentrations in serum and breast cancer tissue during three dose regimens in a randomized preoperative trial. Clin Cancer Res. 2004;10:2336–2343. 54. Jeffries J, Bezchlibnyk-Butler K, Remington G. Amenorrhea and galactorrhea associated with fluvoxamine in a loxapinetreated patient. J Clin Psychopharmacol. 1992;12:296–297. 55. U.S. Food and Drug Administration. FDA drug safety communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. Available at: http://www.fda.gov/Drugs/DrugSafety/ ucm263190.htm. Accessed February 25, 2015. 56. Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: An update on a case report of post-operative delirium. J Psychopharmacol. 2010;24:1433–1438. 57. Shah-Khan MG, Lovely J, Degnim AC. Safety of methylene blue dye for lymphatic mapping in patients taking selective serotonin reuptake inhibitors. Am J Surg. 2012;204:798–799. 58. Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: Inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol. 2007;152:946–951. 59. Schwiebert C, Irving C, Gillman PK. Small doses of methylene blue, previously considered safe, can precipitate serotonin toxicity. Anaesthesia 2009;64:924. 60. Centers for Disease Control and Prevention. Mental health basics. Available at: http://www.cdc.gov/mentalhealth/ basics.htm. Accessed February 25, 2015.
1119 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Background: Antidepressant use has increased dramatically over the past decade. Although there is no question about the benefits of these medications, uncertainty exists with regard to the implications of antidepressant treatment surrounding plastic surgery. This systematic review collates all of the available literature that evaluates the risks of patient antidepressant treatment, in relation to plastic surgery. Methods: A comprehensive literature review of the PubMed and Cochrane databases was conducted. Articles were assessed by two independent reviewers using predefined data fields and selected using specific inclusion criteria. The two authors independently reviewed the literature and extracted data from included reviews, and discrepancies were resolved by consensus. Results: Twenty-six articles were included in the analysis and were categorized into five groups for comparison: risk of bleeding, risk of breast cancer, risk of breast cancer recurrence, breast enlargement, and miscellaneous (unique complications). Extracted information included study type, statistical analyses, conclusion, and limitations. Conclusions: This review does not support the cessation of antidepressants in patients before plastic surgery, as the numbers needed to harm are low and the implications of withdrawal may prove to be detrimental to postoperative management. However, the use of antidepressants for mental disorders may also implicate key patient risk factors for surgical complications, and sufficient exploration into the patient’s indications for the prescription is crucial. Evidence so far does not suggest that antidepressants increase the risk of breast cancer or recurrence in general, but caution should be exercised for those specifically on concurrent tamoxifen and paroxetine treatment. (Plast. Reconstr. Surg. 136: 1107, 2015.)
A
ntidepressant use is on the rise, and it has become crucial for the plastic surgeon to be cognizant of the possible undesired effects in relation to surgery. According to the Centers for Disease Control and Prevention, one in 10 Americans aged 12 years and older were taking antidepressant medication between 2005 and 2008.1 In the United Kingdom, antidepressant prescribing has nearly doubled since 2000, from 37 per 1000 to 71 per 1000 adults on antidepressants currently.2 Harirchian et al.3 found that 22 percent of their patients who had undergone face-lift surgery were taking serotonin reuptake inhibitors or selective noradrenaline reuptake inhibitors. Freedman4 reported a 17 percent use of From Ninewells Hospital and the University of Edinburgh. Received for publication May 24, 2015; accepted May 28, 2015 Dr. Teo and Dr. Song contributed equally to this article. Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001696
antidepressants in his cosmetic cohort, whereas Fann et al.5 found an incidence of 25 percent of major depression in breast cancer patients. Post– cancer diagnosis depression, body disfigurement or dysmorphia, posttraumatic stress disorder, and chronic regional pain are some of the indications for antidepressant therapy in patients that may be involved with plastic surgery services. This review Disclosure: There are no sources of funding or financial interest to declare. There are no c ommercial associations or financial disclosures that might pose or create a conflict of interest with information presented in this article. A “Hot Topic Video” by Editor-in-Chief Rod J. Rohrich, M.D., accompanies this article. Go to PRSJournal.com and click on “Plastic Surgery Hot Topics” in the “Videos” tab to watch.” On the iPad, tap on the Hot Topics icon.
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1107
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Plastic and Reconstructive Surgery • November 2015 summarizes all available literature relevant to patient antidepressant use in aesthetic and reconstructive surgery, and aims to equip the plastic surgeon with valuable clinical knowledge of what may be a ubiquitous prescription in our patient population, in years to come.
PATIENTS AND METHODS This study collates all publications on antidepressant use in patients undergoing plastic and breast surgery, with particular focus on risks and complications. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This review and its authors also conform to the ethical principles of the Declaration of Helsinki of the World Medical Association. The literature search was performed by two independent reviewers (C.T.S. and I.T.) through the MEDLINE and Cochrane databases. The Medical Subject Headings search terms included “antidepressant,” “selective serotonin reuptake inhibitor,” “SSRI,” “selective norepinephrine reuptake inhibitor,” “SNRI,” “tricyclic antidepressant,” “TCA,” “bleeding surgery,” “burns,” “breast,” “breast cancer,” “cosmetic,” “reconstructive,” “aesthetic,” “plastic,” “burns,” and “cancer.” A free text search or a Medical Subject Headings term search was used wherever appropriate, and Boolean operators were used to combine the terms. There were no restrictions on publication date or status. Eligibility Criteria The inclusion criteria consisted of any metaanalyses, systematic reviews, case-control and cohort studies, or case reports involving antidepressant complications relevant to plastic surgery. Articles excluded were preclinical studies, studies constituted in the systematic reviews and metaanalyses, and expert opinions. Study Selection Citations found by means of searching the databases were screened for eligibility by title and/ or abstract. Full-text articles were then appraised for final inclusion in the systematic review. Data Collection Process Articles were examined for study design and outcomes measured, duration of exposure, statistical analysis, complications, and limitations. The two reviewers listed extracted data separately, and discrepancies were reviewed and discussed until a consensus was accomplished.
Data Analysis A formal statistical analysis of the eligible studies was not performed because of the clinical (i.e., multiple antidepressant classes) and methodologic heterogeneity (i.e., different study types, outcome measures, exposure duration, limitations, and confounding factors). A detailed systematic review of the diverse outcomes and complications was undertaken instead.
Results One thousand five hundred thirty-five articles were identified through the initial search (Fig. 1). After screening through the titles, 122 publications remained. This was further reduced to 76 articles after reading the abstracts. Of these 76 articles, 50 were omitted for individual analysis, as they were already included in the systematic reviews and meta-analyses. There were 26 remaining articles that fulfilled our inclusion criteria. We identified patterns of risks and pooled studies with similar findings to form five groups: risk of bleeding, risk of breast cancer, risk of breast cancer recurrence, breast enlargement, and miscellaneous (unique complications). Risk of Bleeding Two cohort studies, two case-control studies, and two case reports analyzed the relationship between bleeding and antidepressant use (Table 1).3,6–10 The clinical cases that were examined included patients undergoing breast cancer surgery (i.e., mastectomy or breast conserving surgery), rhytidectomy, cosmetic breast surgery (i.e., breast augmentation, reduction, or mastopexy), an orbital blowout fracture repair, and a clinical presentation of breast ecchymosis. The conclusions drawn from the breast cancer surgery cohort studies were conflicting. Gärtner et al.6 deduced an increased risk of bleeding of 4 percent with antidepressant use, whereas Lietzen et al.7 found no association and that age, type of surgery, and use of glucocorticoids instead were factors linked to increased risk of bleeding. The case-control study on rhytidectomy3 found no association with selective serotonin reuptake inhibitor use and bleeding, but the case-control study on cosmetic breast surgery8 calculated a four-fold increased risk of hematoma formation (requiring surgical drainage). Van Cann and Koole9 attributed the formation of postoperative hematoma in an orbital blowout fracture repair to the use of paroxetine, whereas Akbulut et al.10 concluded that fluoxetine use had resulted in breast ecchymosis in his patient.
1108 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Volume 136, Number 5 • Risks Associated with Antidepressant Use
Fig. 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the search and selection strategy of included articles.
Risk of Breast Cancer Six articles evaluated the risk of breast cancer with antidepressant use, and this encompassed two meta-analyses, two systematic reviews, one case-control study, and one case series (Table 2). The meta-analysis by Cosgrove et al.11 found that antidepressant users, especially those of selective serotonin reuptake inhibitors, had a modest increase in breast and ovarian cancer risk, whereas the meta-analysis by Eom et al.12 found no associated risk of breast cancer. The systematic review by Bahl et al.13 proposed a possible increase in the risk of breast cancer with paroxetine use, whereas the systematic review by Lawlor et al.14 found no association. The case-control study by Ashbury et al.15 assessed whether the degree of inhibition of serotonin reuptake had significance, and the analysis of both high- (paroxetine, sertraline, and fluoxetine) and low-inhibiting selective serotonin reuptake inhibitors (citalopram and fluvoxamine) supported no association. Wallace et al.16 reported three cases of male hormone receptor–positive breast carcinoma and a case of male ductal hyperplasia. The authors attributed this to the use of fluoxetine and paroxetine.
Outcomes in Breast Cancer The role of concurrent antidepressant use with tamoxifen therapy in recurrence of breast cancer was studied in one cohort and four casecontrol studies (Table 3). The cohort study by Kelly et al.17 on selective serotonin reuptake inhibitors found no association with recurrence of cancer, except for patients on paroxetine treatment. The study found an additional breast cancer death at 5 years for every 20 women on concurrent tamoxifen and paroxetine use, and concluded that “paroxetine can reduce or abolish the benefit of tamoxifen.” The two nested case-controls18,19 and the case-control study by Chubak et al.20 found no association with breast cancer recurrence and selective serotonin reuptake inhibitor use. Both Chubak et al. and Wernli et al.21 found no association with antidepressant use and mortality from breast cancer. On another note, the study by Wernli et al. also pooled deaths from cardiovascular disease and found a statistically significant higher risk of mortality from any cause for antidepressant users (especially tricyclic antidepressants).
1109 Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Cohort
Denmark
Lietzen et al., 20147
Brazil
Turkey
Case report
263
Clinical presentation Fluoxetine of unexplained breast ecchymosis
Paroxetine
None SSRI
2089 196
None 205 SSRI or SNRI 58 Total 2285
Total
aRR
Analysis
95% CI
Conclusion
Limitations
Current SSRI use is TCA (526), TeCA associated with an (131), and other increased risk of ADs (358) were reoperation because of included in the bleeding after breast control cancer surgery, from approximately 3% to approximately 7% 338 Risk difference does SSRI prescription not merit pausing compliance 51 1.1 0.83–1.5 treatment in psychounknown 14 2.3 1.4–3.9 logically vulnerable 37 0.93 0.66–1.3 Unable to control for over-thecounter NSAIDs or alcohol Reoperation AD use not found to be Unable to account a risk factor for reoper- for over-theation Age, surgery type, counter glucocorand glucocorticoid use ticoids or NSAIDs instead affected the risk of reoperation Hematoma Unpaired SSRIs or SNRIs did not Low power, cannot t test seem to increase risk rule out small of bleeding increased risk of 4* p = 0.87 bleeding 1† Hematoma OR SSRI use is associPossible confound(surgical ated with a fourfold ing bias with draining) increase in risk of depression bleeding after breast 24 9 4.14 1.90–9.04 cosmetic surgery The decision to stop (p ≤ 0.001) SSRIs before surgery for psychologically vulnerable patients should not be made without a complete discussion of the risks and benefits Retrobulbar hemaIncreased risk of bleedtoma resulting in ing in orbital surgery increased intraocular pressure necessitating evacuation Breast ecchymosis SSRI-induced breast (no history of ecchymosis is rare or trauma or surgery) underreported
Reoperation
Complication
AD, antidepressant; aRR, adjusted risk ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TeCA, tetracyclic antidepressant; NSAIDs, nonsteroidal antiinflammatory drugs; SNRI, selective norepinephrine reuptake inhibitor. *Minor hematomas contained ≤10 ml of blood and were treated by needle aspiration in the office. †Major hematomas were defined as expansile collections that required urgent surgical evacuation.
Akbulut et al., 201410
Orbital blowout fracture
CaseBreast cosmetic control surgery
Case Van Cann The Netherlands report and Koole, 20099
Basile et al., 20128
12,872 1592 1391 201
None SSRI Current Former
19,919 15,964 3955
14,464
No. of Patients
Total
AD Type
Predictors of post- Total surgical bleeding None in breast cancer SSRI, TCA, surgery and TeCA
Breast cancer surgery
Subject
Rhytidectomy Harirchian United States Casecontrol et al., 20123
Cohort
Type of Study
Denmark
Country
Gärtner et al., 20106
Reference
Table 1. Six Articles Analyzing Antidepressant Use and the Risk of Bleeding in Breast Cancer Surgery, Rhytidectomy, Orbital Blowout Fracture, and Breast Ecchymosis
Plastic and Reconstructive Surgery • November 2015
1110
Copyright © 2015 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Subject
MetaBreast and analysis ovarian cancer risk
Study
Canada
Systematic Breast review cancer risk
Canada
2
2
Fluoxetine
Paroxetine
0.67–1.25 0.89–1.53
61 1.17 Male breast neoplasia ER+ carcinoma and atypical ductal hyperplasia Both ER+ carcinoma
0.88–1.17
Limitations
Association of increased risk of male breast cancer
No association regardless of degree of inhibition or duration of use
Does not include other risk factors such as family history, menstrual and reproductive history TCA use among study not accounted for
Modest increase in 4 studies had industry ties, risk of ovarian or this study found statistically breast cancer with significant relationships use of ADs, between industry ties and especially SSRI researchers’ conclusion Study did not include EMBASE database search Includes pooled data from ovarian cancer patients No association Potential bias in observational data Study only includes Western population
Conclusion
0.96–1.08 0.95–1.10 0.94–1.03 Breast cancer Inconclusive but sugrecurrence gests no association Plausible increased risk with paroxetine use and inconsistent association of breast cancer risk with SSRIs No association
1.03–1.20 0.99–1.51 0.95–1.13
95% CI
0.92
44
1.02
aOR
1.02 1.02 0.98
aOR
1.11 1.07 1.04
Pooled OR
Complications Analysis
9 studies (1 efficacy trial, 4 casecontrol, and 4 cohort) 23,426 Breast cancer 17,908 1783 2622 241
6 studies (4 case-control and 2 cohort)
18 studies (11 case-control, 3 nested casecontrol, and 4 cohort)
26 studies (case-control and cohort)
No. of Patients
Total None SSRI high inhibitors* SSRI low 526 inhibitor† Both 587 Total 4 case reports
Total Any AD
SSRI or TCA
Any AD SSRI TCA Total
Total
Any AD SSRI TCA
Total
AD Type
AD, antidepressant; aOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; SNRI, selective norepinephrine reuptake inhibitor; ER+, estrogen receptor–positive. *High inhibitors: paroxetine, sertraline, and fluoxetine. †Low inhibitors: citalopram and fluvoxamine.
Clinical presentation
CaseBreast control cancer risk
Case Wallace United Kingdom series et al., 200016
Ashbury et al., 201215
United Systematic Breast Lawlor Kingdom review cancer et al., risk 200314
Bahl et al., 200313
Republic MetaBreast Eom of Korea analysis cancer et al., risk 201212
Cosgrove United et al., States 201111
Reference Country
Table 2. Six Articles Reviewing the Risk of Breast Cancer Surgery with Antidepressant Use
Volume 136, Number 5 • Risks Associated with Antidepressant Use
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Azoulay et al., 201119
United Nested Recurrence in Total Kingdom casebreast cancer control patients on con- None current tamoxifen Strong and SSRI therapy CYP2D6 inhibitors Weak CYP2D6 inhibitors Combination
Analysis
23 56
727
Cancer recurrence 198 26
ER+TAM+ ER−TAM− ER+TAM+ ER−TAM−
Cancer recurrence
0.82
1
0.75
1.1 0.9 0.9 0.6
aOR
Mortality aHR from breast cancer 105 1.24 (0.25)* 1.54 (0.50)* 1.91 (0.75)* 71 0.91 (0.75)* 115 0.99 (0.75)* 38 0.94 (0.75)* 29 1.33 (0.75)* 16 0.30 (0.75)*
254
2311 378
3670
366
732
Recurrence in Total Lash et al., Denmark Nested casebreast cancer 201018 control patients on con- None current tamoxifen Citalopram and SSRI therapy SSRI: fluoxetine, paroxetine, and sertraline
2430
253 541 174 467 365
Total
AD Type
Fluoxetine Sertraline Fluvoxamine Citalopram Venlafaxine
Cohort SSRI and breast cancer mortality in women receiving tamoxifen
Subject
630
Canada
Kelly et al., 201017
Study
Paroxetine
Country
Reference
No. of Patients Complication
0.59–1.13
0.63–1.58
0.49–1.15
95% CI
0.7–1.7 0.4–2.2 0.5–1.8 0.3–1.6
95% CI
1.08–1.42 1.11–1.50 1.15–1.84 0.55–1.51 0.67–1.47 0.53–1.66 0.56–3.17 0.07–1.31
95% CI
95% CI
Limitations
(Continued)
For every 19.7 Indication for AD not women with included Possible breast cancer selection bias with treated, an paroxetine users overlap of 41% of tamoxifen therapy with paroxetine could result in an additional breast cancer death at 5 yr No association with other ADs Critical role of CYP2D6 in metabolic activation of tamoxifen No association Does not factor duration of SSRI treatment together with tamoxifen therapy Low frequency of prescriptions for other SSRIs, unable to confidently conclude that they do not reduce the effectiveness of tamoxifen Indication for SSRI not included No association Does not factor duration of SSRI treatment together with tamoxifen therapy
Conclusion
Table 3. Five Articles Examining the Association of Antidepressant Use with Breast Cancer Recurrence, with Diagnosis of Recurrence, and/or Breast Cancer Mortality as Outcomes
Plastic and Reconstructive Surgery • November 2015
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United States
No. of Study Subject AD Type Patients Complication Case- Recurrence in Total 1306 Cancer control breast cancer recurrence patients on (5-yr risk) concurrent None 867 79 tamoxifen and Any AD 439 24 SSRI therapy SSRI 11 TCA 11 Miscellaneous 9 Total 1306 Mortality from breast cancer (5-yr risk) None 867 35 Any AD 439 11 SSRI 5 TCA 5 Miscellaneous 5 Case- Mortality in breast Total 3058 Mortality control cancer patients on from breast concurrent cancer tamoxifen and None 2750 145 SSRI therapy Any AD 308 18 SSRI 9 TCA 5 95% CI 95% CI
0.5–1.4 0.4–1.5 0.4–1.6 0.4–2.1
0.4–1.9 0.4–2.5) 0.3–2.3 (0.4–3.4)
0.55–1.56 0.51–2.79 0.41–2.51
Analysis aHR
0.8 0.8 0.8 1
0.9 1 0.8 1.2 aHR
0.93 1.4 1.01
Limitations Insufficient power to detect small differences Limited to first 5 yr following diagnosis Possible confounding with SSRI indication, diet, and physical activity
Unable to control for prior AD use in patients included in the study Possible misclassification of exposure to AD after diagnosis
No association Potential selection bias Increased risk of Did not include tumor all-cause mortalmarker characteristics ity with AD use, Indication for SSRI not specifically TCAs included
Conclusion No association with AD use and increased risk of recurrence or breast cancer mortality
AD, antidepressant; aHR, adjusted hazard ratio; aOR, adjusted odds ratio; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; SNRI, selective norepinephrine reuptake inhibitor; ER, estrogen receptor; TAM, tamoxifen; + positive; −, negative.
Wernli et al., 201121
Reference Country Chubak United et al., States 200820
Table 3. Continued
Volume 136, Number 5 • Risks Associated with Antidepressant Use
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AD, antidepressant; SSRI, selective serotonin reuptake inhibitor.
Kaufman al., United Case report Gynecomastia States 201325
Sertraline and duloxetine
1
Bilateral gynecomastia
SSRI may cause mammoplasia and mammographic changes Gynecomastia may be AD selective or secondary to additive AD adverse effects
1 1 Sertraline Fluvoxamine Marcus, 200124
United Case report Mammoplasia States
1
Hall, 199423 United Case series States
Breast pain and enlargement
Fluoxetine
Mammoplasia Weight gain
Significantly more patients Patient-reported mammo(p < 0.001) on SSRI plasia rather than bra size reported mammoplasia measurement than those on Dose of AD not fixed over venlafaxine course of treatment Weight gain reported in 84% with mammoplasia and in 30% without (p < 0.001) This SSRI adverse effect may be underreported Mammoplasia and weight gain 59 SSRI or venlafaxine Cohort Amsterdam United et al., States 199722
Mammoplasia during chronic AD therapy
Conclusion 95% Complication Analysis CI No. of Patients AD Type Subject Study
Antidepressants work by modulating neurotransmitter levels in the brain, although the exact mechanisms by which their effects are achieved are unknown. There are convincing statistical data that the use of antidepressants is on the rise. Unlike certain medications such as warfarin or rivaroxaban, plastic surgeons may often have little or no concern regarding the presence
Country
Discussion
Reference
Miscellaneous Table 5 illustrates five studies with unique complications. The case-control study by Gruber et al.26 examined the quantity of seroma formation following latissimus dorsi flap breast reconstruction and concluded that selective serotonin reuptake inhibitor use and patient body mass index were significant predictors of seroma formation requiring surgical drainage. One case report27 documents a patient with an adverse cutaneous reaction thought to be from an amitriptyline overdose. A second report28 attributed bullous skin necrosis from an adverse reaction to sertraline. Uppal et al.29 describe a morbidity in latissimus dorsi flap monitoring that ensued in a patient who developed acute mania from abrupt withdrawal of amitriptyline. The case report by Larson et al.30 describes an instance of serotonin toxicity in a patient on fluoxetine treatment, after undergoing methylene blue lymphatic mapping for squamous cell carcinoma of the scalp.
Table 4. Four Articles Studying the Relationship between Antidepressant Use and Risk of Gynecomastia or Mammoplasia
Breast Enlargement The literature search revealed four publications discussing breast enlargement in relation to antidepressant use: a cohort study, a case series study, and two case reports (Table 4).22–25 The cohort study22 reported a 38.9 percent rate of mammoplasia in selective serotonin reuptake inhibitor or venlafaxine users. It also found that selective serotonin reuptake inhibitor use was associated with a statistically significant higher number of patients diagnosed with mammoplasia in comparison with venlafaxine use. This study also reported weight gain in a larger portion of patients with mammoplasia than in those without (86 percent and 30 percent, respectively). Hall’s case report23 describes mastalgia with breast enlargement in a patient on fluoxetine and in a sertraline user. Marcus24 noted mammoplasia with mammographic changes in a patient using fluvoxamine, whereas Kaufman et al.25 reported bilateral gynecomastia in a patient on concurrent sertraline and duloxetine.
Limitations
Plastic and Reconstructive Surgery • November 2015
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Likely that sertraline induced a severe skin reaction Poor management of TCA medication around surgery for reconstructive patients can result in psychiatric morbidity and hinder flap monitoring Small doses of methylene blue (7 mg used in the case) when administered with SSRIs and fentanyl may contribute to serotonin toxicity in scalp region
First reported case
SSRIs and BMI shown to be significant predictors of increased seroma volume drained
of an antidepressant in a patient’s drug history. Antidepressants are not widely known to increase surgical risks, but it is apparent from our literature search that there is an expansion of articles examining potential associations of complications with antidepressant use.
Case report United States Larson et al., 201430
AD, antidepressant; SSRI, selective serotonin reuptake inhibitor; BMI, body mass index; TCA, tricyclic antidepressant. *Including volume of seroma formation, cutaneous drug reaction, TCA withdrawal, and serotonin toxicity in methylene blue dye application.
Case report Case report United Kingdom United Kingdom
Sentinel lymph node biopsy with methylene blue for squamous cell carcinoma of scalp
Fluoxetine
1
Acute mania hindered flap monitoring Flap was found to be fine after resolution of mania Intraoperative seizures Serotonin syndrome 1 Amitriptyline
Skin grafting 1 Sertraline
Case report United Kingdom
Fogarty and Kahn, 199927 Kirkup et al., 200428 Uppal et al., 200929
Cutaneous drug reaction from overdose Severe deep bullous skin necrosis TCA withdrawal after breast reconstruction
Amitriptyline
1
Skin necrosis Confusion Skin grafting
Multivariate analysis F = 4.1 p = 0.047 Seroma requiring drainage 87 SSRI Casecontrol Austria Gruber et al., 201126
Latissimus dorsi flap breast reconstruction
AD Subject Study Country Reference
Table 5. Evaluation of Unique Complications with Antidepressant Use*
No. of Patients
Complication
Analysis
95% CI
Conclusion
Volume 136, Number 5 • Risks Associated with Antidepressant Use
Risk of Bleeding Serotonin is a weak platelet activator, and platelet stores of serotonin are released during coagulation. A proposed mechanism of action for bleeding with antidepressant use is a suppression of platelet function caused by an inhibition of platelet serotonin reuptake transporters.31 However, the results of other studies32,33 do not support this hypothesis. Multiple prospective laboratory studies have looked into the effects of antidepressant use on bleeding, with heterogenous results. Lederbogen et al.34 found that prothrombin time was increased after treatment with either amitriptyline or paroxetine. On the contrary, Berk et al.35 analyzed 10 patients before and after administration of fluoxetine and found no changes in coagulation. Similarly, Alderman et al.36 did not demonstrate any changes in coagulation parameters after 28 days of fluoxetine or paroxetine use. Both cohort studies examining bleeding following mastectomy and breast conserving surgery were of large scale. However, Gärtner et al.6 examined selective serotonin reuptake inhibitors more selectively, and factored in latency of use and users of other classes of antidepressants in the control. Lietzen et al.7 pooled data from selective serotonin reuptake inhibitor, tricyclic antidepressant, and tetracycline antidepressant users, and this makes for a difficult comparison. The largest multicenter study37 on antidepressant use and the risk of bleeding in orthopedic surgery involved 530,416 patients and found a positive association (adjusted OR, 1.09; 95 percent CI, 1.04 to 1.15). The authors demonstrated that patients receiving selective serotonin reuptake inhibitors also had higher odds of in-hospital mortality, bleeding, and readmission. Despite this, the numbers needed to harm were large and the consequent increase in absolute risk for the average selective serotonin reuptake inhibitor user would be very small. Conversely, the preoperative cessation of selective serotonin reuptake inhibitors before may precipitate a discontinuation syndrome, worsen depression, or increase sensitivity to postoperative pain.38 The potential disaster from discontinuation syndrome has been highlighted by a former case report.29 Therefore, routine discontinuation
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Plastic and Reconstructive Surgery • November 2015 of antidepressants before surgery in the absence of a careful evaluation should be avoided. A study39 found a positive association with degree of serotonin uptake inhibition and abnormal bleeding. High inhibitors include paroxetine, sertraline, and fluoxetine, and perhaps there may be a role of temporarily substituting these selective serotonin reuptake inhibitors with lower inhibitors before surgery. Risk of Breast Cancer The biological mechanism by which antidepressant use relates to breast cancer is hypothesized to involve an increase in serum prolactin.40,41 Hyperprolactinemia is postulated to directly involve dopaminergic cells in the tuberoinfundibular pathway through GABAergic neurons. Alternate pathways may involve stimulation of vasoactive intestinal peptide or oxytocin release.42 Another explanatory factor may be the role of depression itself.43 Depression has been shown to induce immunosuppression, and antidepressants have been shown to cause immunosuppression in experimental studies.44,45 Other hypotheses involve modification to cellular proliferation and altered estrogen metabolism.12 A relationship between the risk of breast cancer and antidepressant use is not supported by this review; nevertheless, there may be plausibility with paroxetine use. The meta-analyses drew contrasting results despite sharing 16 identical articles. The study by Cosgrove et al.11 had pooled data from ovarian cancer patients, and this may explain the discrepancy. Neither systematic reviews nor case-control studies have found evidence supporting a positive association, although Bahl et al.13 suggest caution with paroxetine and concluded that there is a “plausible increased risk” of breast cancer with its use. Further studies are needed to evaluate long-term outcomes; however, this may prove to be challenging given that 50 to 80 percent of users discontinue treatment at less than 1 year.39,46 Wallace et al.16 describe four cases of male breast neoplasia. Risk factors for breast cancer development in men and women are likely to be complex and multifactorial. Even in large epidemiologic studies, the relative contribution of minor risk factors may be difficult to detect. Wallace et al. suggest that the rarity of male breast cancer because of an absence of the complex physiologic changes in the female breast may make such risk factors more luminous.
Outcomes in Breast Cancer Patients Tamoxifen is a selective estrogen receptor modulator that is metabolized by the hepatic P450 isoenzyme 2D6. Selective serotonin reuptake inhibitors, by nature of their biological activity, inhibit the hepatic P450 isoenzyme 2D6 to varying degrees and therefore may reduce the benefits of tamoxifen.47,48 In theory, the blunting of tamoxifen therapy may increase recurrence rates or death from breast cancer. Paroxetine, in particular, is an exceptionally potent hepatic P450 isoenzyme 2D6 inhibitor and is the only selective serotonin reuptake inhibitor with an irreversible mechanism.49,50 Although evidence has shown that hepatic P450 isoenzyme 2D6 inhibitors do reduce tamoxifen levels,48,51 randomized controlled trials have shown that lower doses of tamoxifen still confer the same antiproliferative activity.52,53 Four of five of the studies in our analysis found no evidence to support cancer recurrence or cancer mortality associated with antidepressant treatment. The fifth study,17 which included 2430 women, found a statistically significant increased risk of death from breast cancer in women taking paroxetine. The study’s design criteria excluded patients who had never used selective serotonin reuptake inhibitors concurrently with tamoxifen and those who had switched from one selective serotonin reuptake inhibitor to another. It is unclear whether these restrictive inclusion criteria may have influenced the generalizability of the results.19 Breast Enlargement and Pain Increased prolactin secretion has been proposed as a cause for mammoplasia and gynecomastia associated with antidepressant use.54 Mammoplasia and gynecomastia are reported to be infrequent developments, and this may be attributable to underreporting from both patients and doctors.22,23 Selective serotonin reuptake inhibitor use is also associated with weight gain, and a higher proportion of patients with mammoplasia reported weight gain (86 percent) than did the control patients (30 percent) in the study by Amsterdam et al.22 However, the development of mammoplasia did not seem to be related to age, menopausal status, or duration of antidepressant treatment. However, it may be dose dependent, and this might explain the lack of mammoplasia reported in the prospective control group of 322 women who were treated with a fixed low dose of 20 mg of fluoxetine in the study by Amsterdam et al.22
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Volume 136, Number 5 • Risks Associated with Antidepressant Use Miscellaneous Five of the studies we found did not fit into any clear category and have been pooled under “miscellaneous.” Gruber et al.26 analyzed 87 patients undergoing latissimus dorsi breast reconstruction and found that an increased risk of seroma formation (requiring surgical drainage) was associated with higher body mass index and selective serotonin reuptake inhibitor use. There was no specification as to which selective serotonin reuptake inhibitors were taken, and the linear regression analysis was only just within the range of significance (p = 0.047). Fogarty and Kahn27 and Kirkup et al.28 both highlight rare cutaneous reactions to amitriptyline and sertraline, of which both cases required skin grafting. The case reported by Uppal et al.29 is an admonition with regard to the potential catastrophic effects of flap monitoring from poor antidepressant management around surgery, where drains and the latissimus dorsi flap could not be monitored. Larson et al.30 describe the onset of serotonin toxicity in a low-dose (7 mg) subcutaneous methylene blue lymph node mapping for squamous cell carcinoma of the scalp. Serotonin toxicity is characterized by change in mental status, autonomic dysfunction, and muscular manifestations. Larson et al. postulate that the close proximity of the brain to the lymphatic drainage of the highly vascular scalp or the addition of the serotonergic agent fentanyl may have precipitated the development of serotonin toxicity in this case. Beyond its diagnostic application as a dye, methylene blue is now understood to also be a potent monoamine oxidase inhibitor with serotonergic properties.55,56 Therefore, its use with antidepressants may precipitate serotonin toxicity. Shah-Khan et al.57 have emphasized the safety of methylene blue lymphatic mapping in breast surgery and concluded from an in vitro study58 that the subcutaneous injection dose of 5 mg/kg for breast lymphatic mapping carries very little risk of serotonin toxicity. This, however, is not supported by the case reported by Schweibert et al.59 of serotonin toxicity in a patient on a selective serotonin reuptake inhibitor who underwent low-dose methylene blue (1 mg/kg) cystoscopy for ureteral ostia. The U.S. Food and Drug Administration has since released a safety announcement to discourage concomitant use of methylene blue and selective serotonin reuptake inhibitors.55
Limitations We have attempted to summarize all articles relevant to plastic surgical procedures and risks with antidepressant use. Our search terms were diverse and broad, but we may still have missed other obscure and indirect adverse outcomes significant to plastic surgery. Mastectomy, breast conserving surgery, and breast cancer mortality arguably may fall more within the realm of breast surgery. However, we have included this in our analysis because (1) there are oncoplastic surgeons who perform these operations, and (2) any possible implications of antidepressant use in breast cancer patients could influence reconstructive options. Our search found no prospective, randomized studies, and we were unable to perform any statistical analysis given the heterogeneity of articles. For analysis of bleeding risk, because of the retrospective design of most studies, measurements of blood loss were not standardized, and the surgeon’s decision to reoperate on hematomas may not have been objective. Some articles were specific regarding the type of antidepressant, whereas others pooled all antidepressants together, making direct comparisons difficult. Evidence has shown that mental disorders, especially depressive disorders, are strongly linked to diabetes; cancer; obesity; and risky behaviors such as smoking, excessive alcohol intake, and insufficient sleep.60 Therefore, depression itself may be associated with poor surgical outcomes and may have played a confounding role in results of the studies.
Conclusions This review does not support the cessation of antidepressant use in patients before plastic surgery, as the numbers needed to harm are low and the implications of withdrawal may prove to be detrimental to postoperative management. However, the use of antidepressants for mental disorders may also implicate key patient risk factors for surgical complications, and sufficient exploration into the patient’s indications for the prescription is crucial. Evidence so far does not suggest that antidepressants increase the risk of breast cancer or recurrence in general, but caution should be used for those specifically on concurrent tamoxifen and paroxetine treatment. Paroxetine is both a high serotonin uptake inhibitor and a potent irreversible hepatic P450 isoenzyme 2D6 enzyme inhibitor, and its adverse effects profile needs further
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Plastic and Reconstructive Surgery • November 2015 evaluation in comparison with the other selective serotonin reuptake inhibitors. Other risks mentioned in the articles summarized in this review include breast ecchymosis, retrobulbar hematoma, mammoplasia, gynecomastia, skin reactions, serotonin syndrome, cutaneous reactions, and seroma formation. Unfortunately, more data are mandatory to warrant specific recommendations. Christopher Tam Song, Jr. University of Edinburgh Medicine and Veterinary Medicine 47 Little France Crescent Edinburgh, Midlothian EH16 4TJ, United Kingdom [email protected]
references 1. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005–2008. NCHS Data Brief 2011;76:1–8. 2. OECD. Health at a Glance 2013: OECD Indicators. Paris: OECD Publishing; 2013. 3. Harirchian S, Zoumalan RA, Rosenberg DB. Antidepressants and bleeding risk after face-lift surgery. Arch Facial Plast Surg. 2012;14:248–252. 4. Freedman B. Cosmetic surgery and the use of antidepressant medication. Paper presented at: Plastic Surgery 2006: Annual Meeting of the American Society for Plastic Surgeons; October 6 through 11, 2006; San Francisco, Calif. 5. Fann JR, Thomas-Rich AM, Katon WJ, et al. Major depression after breast cancer: A review of epidemiology and treatment. Gen Hosp Psychiatry 2008;30:112–126. 6. Gärtner R, Cronin-Fenton D, Hundborg HH, et al. Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: A Danish population-based cohort study. BMC Surg. 2010;10:3. 7. Lietzen LW, Ahern T, Christiansen P, et al. Glucocorticoid prescriptions and breast cancer recurrence: A Danish nationwide prospective cohort study. Ann Oncol. 2014;25:2419–2425. 8. Basile FV, Basile AR, Basile VV. Use of selective serotonin reuptake inhibitors antidepressants and bleeding risk in breast cosmetic surgery. Aesthetic Plast Surg. 2013;37:561–566. 9. Van Cann EM, Koole R. Retrobulbar hematoma associated with selective serotonin reuptake inhibitor: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:e1–e2. 10. Akbulut S, Yagmur Y, Gumus S, Babur M. Breast ecchymosis: Unusual complication of an antidepressant agent. Int J Surg Case Rep. 2014;5:129–130. 11. Cosgrove L, Shi L, Creasey DE, Anaya-McKivergan M, Myers JA, Huybrechts KF. Antidepressants and breast and ovarian cancer risk: A review of the literature and researchers’ financial associations with industry. PLoS One 2011;6:e18210. 12. Eom CS, Park SM, Cho KH. Use of antidepressants and the risk of breast cancer: A meta-analysis. Breast Cancer Res Treat. 2012;136:635–645. 13. Bahl S, Cotterchio M, Kreiger N. Use of antidepressant medications and the possible association with breast cancer risk: A review. Psychother Psychosom. 2003;72:185–194. 14. Lawlor DA, Jüni P, Ebrahim S, Egger M. Systematic review of the epidemiologic and trial evidence of an association between antidepressant medication and breast cancer. J Clin Epidemiol. 2003;56:155–163.
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Volume 136, Number 5 • Risks Associated with Antidepressant Use 34. Lederbogen F, Weber B, Colla M, Heuser I, Deuschle M, Dempfle CE. Antidepressant treatment and global tests of coagulation and fibrinolysis. J Clin Psychiatry 2001;62:130. 35. Berk M, Jacobson BF, Hurly E. Fluoxetine and hemostatic function: A pilot study. J Clin Psychiatry 1995;56:14–16. 36. Alderman CP, Seshadri P, Ben-Tovim DI. Effects of serotonin reuptake inhibitors on hemostasis. Ann Pharmacother. 1996;30:1232–1234. 37. Auerbach AD, Vittinghoff E, Maselli J, Pekow PS, Young JQ, Lindenauer PK. Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery. JAMA Intern Med. 2013;173:1075–1081. 38. Mrkobrada M, Hackam DG. Selective serotonin reuptake inhibitors and surgery: To hold or not to hold, that is the question: Comment on “Perioperative use of selective serotonin reuptake inhibitors and risks for adverse outcomes of surgery”. JAMA Intern Med. 2013;173:1082–1083. 39. Meijer WE, Heerdink ER, Nolen WA, Herings RM, Leufkens HG, Egberts AC. Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants. Arch Intern Med. 2004;164:2367–2370. 40. Turkington RW. Prolactin secretion in patients treated with various drugs: Phenothiazines, tricyclic antidepressants, reserpine, and methyldopa. Arch Intern Med. 1972;130:349–354. 41. Urban RJ, Veldhuis JD. A selective serotonin reuptake inhibitor, fluoxetine hydrochloride, modulates the pulsatile release of prolactin in postmenopausal women. Am J Obstet Gynecol. 1991;164:147–152. 42. Emiliano AB, Fudge JL. From galactorrhea to osteo penia: Rethinking serotonin-prolactin interactions. Neuro psychopharmacology 2004;29:833–846. 43. Spiegel D, Giese-Davis J. Depression and cancer: Mechanisms and disease progression. Biol Psychiatry 2003;54:269–282. 44. Laudenslager ML, Clarke AS. Antidepressant treatment during social challenge prior to 1 year of age affects immune and endocrine responses in adult macaques. Psychiatry Res. 2000;95:25–34. 45. Steingart AB, Cotterchio M. Do antidepressants cause, promote, or inhibit cancers? J Clin Epidemiol. 1995;48:1407–1412. 46. Aikens JE, Kroenke K, Swindle RW, Eckert GJ. Nine-month predictors and outcomes of SSRI antidepressant continuation in primary care. Gen Hosp Psychiatry 2005;27:229–236. 47. Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: Prominent roles for CYP3A and CYP2D6. J Pharmacol Exp Ther. 2004;310:1062–1075. 48. Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metabolite plasma concentrations after coadministration
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