Pharmacokinetic Changes in Medications After Bariatric Surgery: A Scoping Review

Abstract

There are no established guidelines for evaluating and managing those taking psychotropic medications postoperatively. This study reviews the pharmacokinetic changes in antidepressants after bariatric surgery and their clinical implications. A systematic search found 7 relevant articles out of 245, indicating significant alterations in the bioavailability and metabolism after surgery. Many patients require increased medication doses postoperatively to maintain therapeutic effects, with a gradual return to baseline within 6 to 12 months. The reviewed studies emphasize the importance of close monitoring and adjustments in medication formulations and dosages. The findings offer valuable insights for health care providers working with this patient group.

Introduction

Obesity is a prevalent issue in the United States, affecting 42% of adults aged 20, and older and leads to various associated medical conditions, including diabetes mellitus, which affects 15% of population.¹ Bariatric surgery has been shown to be an effective weight-loss strategy for patients with morbid obesity and those with associated medical conditions in addition to obesity across all body mass index (BMI) classes.² A meta-analysis by Chang et al demonstrates an overall mean BMI decrease of 12 to 17 kg/m² 5 years after surgery, although effectiveness varies by type of surgery.³ The mechanisms of weight loss of these procedures include restriction and reducing nutrient absorption. The 2 most common bariatric surgeries are Roux-en-Y gastric bypass (RYGB) and gastric sleeve. RYGB is a procedure that creates more anatomic modifications to the gastrointestinal (GI) tract, in which it bypasses the proximal small intestine and restricts food intake and absorption. Meanwhile, the gastric sleeve procedure is a more modest surgery. It is considered as a restrictive procedure that has fewer effects on the bioavailability of medications.⁴ After bariatric surgery, the anatomic changes to the GI system result in a considerable alteration in the bioavailability and metabolism of medications in the weeks and months.⁵ Specifically, surgery-induced changes in pharmacokinetics include the reduced dissolution of oral medications, impaired gastric motility, decreased gastric volume, decreased surface area, lower bile secretions, and a reduction in carrier proteins in the small intestine, but higher gastric pH and altered first-pass metabolism.

It is important to note that the population of patients who have had bariatric surgery has a high prevalence of mental health issues. In a cohort study involving 8,192 bariatric surgery patients, it was found that 57% had a preoperative mental illness, with depression being the most prevalent diagnosis.⁶ This is consistent with a meta-analysis by Dawes et al, who reported a preoperative prevalence of any mood disorders at 23% and depression at 19%.⁷ Approximately 35.3% of such patients are already taking antidepressant or anti-anxiety medications before surgery.⁸ However, after surgery, there is an increased risk of psychiatric relapse, antidepressant discontinuation syndrome, substance use, self-harm, and suicidality.⁹

There are no established guidelines for evaluating and managing these patients who take psychotropic medications postoperatively. Given the high prevalence of mental health conditions in this population, there is a knowledge gap in clinical practice. The purpose of this article is to conduct a scoping review of the pharmacokinetic changes in medications for depression and to identify the practical implications for health care providers in managing mental health conditions after bariatric surgery.

Methods

Following the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-Scar), a search was conducted in PubMed, Ovid Medline, and Embase on March 3, 2022.

Inclusion criteria included clinical trials involving adults who underwent bariatric surgery; the effect of surgery on pharmacokinetic parameters of medications; medications used for depression; and full-text articles published in English between 2012 and 2022. The time period was selected because we limited the publication to the previous 10 years. Exclusion criteria included animal studies and secondary sources of data such as review articles. Combinations of the following search terms were used: bariatric surgery, gastric sleeve, Roux-en-Y, pharmacokinetics, bioavailability, mental health, psychopharmacology, and antidepressant. The search was conducted by author ACC and reviewed by HYL. Seven articles met the inclusion criteria and were included in this review (see Figure 1).

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-Scar) Flow Diagram.

Results

Initial searches returned 245 articles, which eventually yielded 112 articles after the removal of duplicates and review of abstracts. These articles were then reviewed for relevance, and 105 articles were excluded. As a result, a final total of 7 articles that met all the screening criteria were included for further analysis (Table 1).

Table 1.

Summary of Original Research on Pharmacokinetic Changes After Bariatric Surgery

Author	Medications	Design and Data Collection	Sample Size	Variables	Findings	Conclusion
Hamad et al, 201212	Venlafaxine, duloxetine, citalopram, escitalopram, sertraline	Prospective, nonblinded, longitudinal; preop and 1, 6, 12 months postop	12	AUC	54% drop in AUC 1 month postop, and return to baseline at 6 months postop	Depressive symptoms improved when AUC returned to baseline
Krieger et al, 201715	Venlafaxine XR 75 mg	Prospective nonblinded, single dose; preop and 3–4 months postop	10	AUC, Tmax, Cmax	AUC was the same before and after surgery, no change in Cmax or Tmax	Acceptable to use ER formulation
Marzinke et al, 2015	Escitalopram 10 or 20 mg PO	Prospective, nonblinded, longitudinal; preop and 2 and 6 weeks postop	4	AUC, lipids, CRP	2 weeks: AUC decreased 33% 6 weeks: AUC even more decreased; wide range 4% –71%	Need increased doses in days after surgery
Puris et al, 201910	Bupropion 75 mg + 8 drugs	Nonrandomized single group, healthy control; preop, 1 year postop	8	6hour pk profiles serum and urine	AUC mean decreased 1.8 fold, (43–67%), smaller Cmax	Need higher dose after surgery
Roerig et al, 201214	Sertraline 100 mg	Case-controlled, prospective, matched cohort; 1 year postop	5	AUC, Cmax, Tmax	AUC smaller, 124 compared with 314, Cmax smaller	Need higher dose
Roerig et al, 201316	Duloxetine 60 mg PO	Case controlled, prospective, matched controls; 1 year postop	10	AUC Cmax, Tmax	AUC smaller, Tmax shorter, no difference in Cmax; 57% total dose compared with nonsurgery group	Need higher dose postop
Wallerstedt et al, 202111	Sertraline, mirtazapine, duloxetine, citalopram	Naturalistic longitudinal prospective case series 1 year postop	85	Dose adjusted trough concentrations	Dose-adjusted concentration decreased Sertraline 51%, mirtazapine 41%, duloxetine 35%, citalopram 19%	The changes are partially explained by diet change, lipophilic drugs; wide range individually

AUC = area under the curve; Cmax = maximum concentration; CRP = C-reactive protein; ER = extended release; pk = pharmacokinetics; PO = by mouth; POD = postoperative day; preop = preoperative; postop = postoperative; Tmax = time to peak drug concentration.

Medications

The medications included in the selected studies after screening are a small number of antidepressants. Bupropion, mirtazapine, citalopram, duloxetine, escitalopram, sertraline, and venlafaxine were included in at least 1 study. These drugs belong to different drug classes according to their mechanism of action. For instance, bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI),¹⁰ whereas mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA).¹¹ The selective serotonin reuptake inhibitors (SSRIs) include citalopram, escitalopram, and sertraline.^11–14 Lastly, duloxetine and venlafaxine are the serotonin-norepinephrine reuptake inhibitors (SNRIs)^11,12,15,16 that have been studied.

Pharmacokinetic Changes

Significant reductions in the area under the curve (AUC), drug concentrations, maximal plasma concentration (Cmax), or time to Cmax (Tmax) were observed after surgery for most of the studied agents except for venlafaxine. Specifically, the presurgical drug concentration of escitalopram decreased by 22% to 71% at 6 weeks postoperation.¹³ In addition, the AUC and Cmax of bupropion had dropped by 54% (from 67.9 to 36.4 h ng/mL) and 60% (from 21 to 12.5 ng/mL), respectively, 1 year after the procedure.¹⁰ In fact, there were an average of 54% of the AUC reduction from baseline across all participants in the trial, although no change was detected for the SNRI medications (ie, venlafaxine, duloxetine) 1 month after bariatric surgery.¹² Inconsistent with this observation, there was no change in AUC, Cmax, or Tmax of venlafaxine even 3 to 4 months following surgery.¹⁵ However, in a 1-year follow-up study, it showed a decrease in the dose-adjusted concentration of sertraline by 51%, mirtazapine by 41%, duloxetine by 35%, and citalopram by 19%.¹¹

Furthermore, the AUC, Cmax, or Tmax of SSRI in participants who underwent bariatric surgery were lower than those of control group, except for Cmax of duloxetine. For example, the average AUC and Cmax of sertraline for participants with surgery were AUC 124.4 ± 55.5 ng × h/mL and Cmax 19 ± 7.8 ng/mL. Meanwhile, for participants in the control group, the AUC was 314.8 ± 129.6 ng × h/mL and Cmax was 48.7 ± 19.1 ng/mL. In other words, both AUC and Cmax of sertraline were reduced by approximately 60% after surgery relative to the control cohort.¹⁴

Interestingly, the mean of AUC and Tmax of duloxetine in participants who had bariatric surgery was considerably lower than of the control group (AUC 646.74 ± 79.70 ng × h/mL versus 1119.91 ± 593.40 ng × h/mL, P = 0.017)¹⁶ and Tmax 2.20 ± 0.86 h versus 6 ± 2.17 h (P = 0.005), but not the mean of Cmax, which was determined at 51.04 ± 11.88 versus 61.41 ± 34.93 (P = 0.575).¹⁶

Discussion

As many as 230,000 patients undergo bariatric surgery every year in the United States.¹⁷ Most candidates for bariatric surgery undergo psychiatric screening preoperatively as recommended by the American Society for Metabolic and Bariatric Surgery (ASMBS).¹⁸ The ASMBS guideline recommends establishing a plan for postoperative psychiatric follow-up before surgery. However, this guideline does not describe the duration and details of the follow-up. Moreover, there are no published specific guidelines regarding the modification or management of psychotropic medication following bariatric surgery.

Many studies included in this review are characterized by small sample sizes, typically ranging from 4 to 85 participants. Furthermore, most are observational studies, which limit their generalizability. Nevertheless, this review has highlighted the complex variability of drug pharmacokinetic profile after bariatric surgery, which has certainly caused changes in medication absorption and metabolism. It also implies the importance of close monitoring of patients after the procedure. Additionally, there are significant gaps that have not yet been investigated involving fluoxetine and paroxetine, the 2 most commonly used antidepressants. Further studies should be conducted to examine the relationship between pharmacokinetic changes and symptom changes. Well-powered longitudinal trials are needed to establish standardized management guidelines for patients who have undergone these specific surgical procedures.

Many of the commonly prescribed medications for anxiety and depression (see Table 2) have significant changes in bioavailability months after the surgery. As a result, their doses should be increased postoperatively to maintain therapeutic effect; however, a gradual return to baseline may need to be adjusted 6 to 12 months after the procedure. Although the existing research is limited, studies indicate that extended-release formulations of venlafaxine are unaffected by the surgery, whereas extended-release bupropion should be changed to the immediate-release formulations after surgery.

Table 2.

Prescribing Recommendations after Bariatric Surgery

Class	Medication/Formulation19/Usual Total Dose per Day (mg)20	Prescribing Recommendations
SSRI	Sertraline11,12,14 Tablet, solution 50—200 mg	Increase dose postop, frequent monitoring
	Escitalopram12,13 Tablet, solution 10—20 mg	Increase dose postop, interpersonal variations
	Citalopram11,12 Capsule, tablet, solution 20—40 mg (max dose is 20 mg for people >60 years old)	Increase dose postop
SNRI	Duloxetine11,12,16 Capsule, delayed release 60 mg	Need nearly 2 times preop dose
	Venlafaxine12,15/ Tablet or capsule: intermediate or extended-release form 75—225 mg	Leave dosage the sameExtended-release formulation is acceptable.
NaSSA	Mirtazapine11 Tablet or orally disintegrating tablet 15—45 mg	Monitor concentrations over the low-calorie diet period
NDRI	Bupropion10,21 Tablet: intermediate-release, sustained-release, and extended release 300 mg	Change to immediate release Crush pill Consider dividing into 3–4 daily doses; no more than 150 mg per single dose; no more than 450 mg per day.

NaSSA = noradrenergic and specific serotonergic antidepressant; NDRI = norepinephrine-dopamine reuptake inhibitor; preop = preoperative; postop = postoperative; SNRI = serotonin-norepinephrine reuptake inhibitors; SSRI = selective serotonin reuptake inhibitors.

Table 3 summarizes the recommendations for psychiatric management in the postoperative period for bariatric surgery patients. Before surgery, advanced practice registered nurses should complete a thorough medication review and plan with the patient for long-term follow-up after surgery. Medications should be switched to easily digested formulations, such as liquid, orally dissolving, chewable, or immediate-release tablets (except in the case of venlafaxine).²¹ Nonoral formulations should be considered to avoid first-pass metabolism. Careful monitoring of highly lipophilic drugs is always warranted because bariatric surgery decreases bile secretion, affecting the absorption of such medications.^22,23 Individuals who use antidepressants and have undergone gastric bypass surgery may be at risk of relapse of their psychiatric conditions. As a result, the integrated care model, which involves not only surgical but also mental and primary care, should be emphasized, especially in the first 6 to 12 months postsurgery. In addition, the contributing effect of psychotropic medications on weight should be closely monitored because medications such as mirtazapine have the potential to induce weight gain. Lastly, patients who have undergone bariatric surgery are vulnerable to new development of mental health conditions in the years after surgery.⁹ Body dysmorphia, disordered eating, interpersonal conflict, and substance use disorders are particularly prevalent. These patients should have regular follow-up with a clinical interview to screen for these conditions even in the years after surgery.

Table 3.

General Recommendations for Psychiatric Care After Bariatric Surgery

Category	Recommendations
Comprehensive medication review18	Make a plan before surgery Ensure patient has modified prescriptions and understands the care plan Provide patient education
Monitor nutritional status24	Perform frequent micronutrient levels Supplementation
Switch formulation21	Switch to immediate release Switch to liquid, orally dissolving, crushable, chewable, capsules that can be open Switch to non-PO formulations
Change dose5,11,21	Higher dose initially (except venlafaxine) Start decreasing at 6—12 months postop
Change to different medication5,25	Avoid lipophilic medications25 Choose medications with less first-pass metabolism5
Monitor for relapse, medication abstinence syndrome24	High risk of relapse of depression, anxiety disorders High risk of body dysmorphia, disordered eating High risk for interpersonal conflict Increased risk for intimate partner violence
Monitor for SUD, alcohol use, and other behavioral addictions (ie, gambling, sex addiction)9	High risk for substance use, alcohol use
Consider polypharmacy5	Hormonal birth control Antiseizure medications Pain medications Decreased need for cardio-metabolic medication or other weight loss medication Discontinue NSAIDS, corticosteroids, bisphosphonates

NSAIDS = nonsteroidal antiinflammatory drugs; PO = by mouth; postop = post-operatively; SUD = substance use disorder.