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Bariatric surgery and psychiatry: A review

The links between bariatric surgery and psychiatry are assessed, including potential changes induced by the pharmacokinetics of medicine and concerns related to altering the vagus nerve to treat severe depression.

James E. Mitchell, MD, FACS, Bruce M. Wolfe, MD, FACS, Scott A. Shikora, MD, FACS, David Sarwer, PhD, Robin P. Blackstone, MD, FACS, James W. Maher, MD, FACS

March 1, 2019

This article focuses on two primary topics related to the discussion of bariatric surgery and psychiatry. First, it addresses psychiatric issues of direct relevance to bariatric surgery, including the pharmacokinetic changes involved in the use of antidepressant drugs and the risk of alcohol abuse after certain bariatric operations. Second, the article looks at concerns about a procedure that involves potentially altering the vagus nerve, which provides an important bidirectional link between the brain and certain parts of the gastrointestinal tract. The procedure results in ongoing electrical stimulation of the vagus nerve as a treatment for severe, intractable depression.

Bariatric surgery and psychiatry

Psychiatric issues of direct relevance to bariatric surgery include factors of importance both before and after an operation. Although several of these factors raise concerns, they must be considered in the context of the clear benefits of bariatric procedures for most patients. The benefits of bariatric surgery include profound and usually well-maintained weight loss, and the amelioration or improvement in the many obesity-related medical and psychiatric comorbidities, such as diabetes and depression. A majority of patients experienced these benefits after bariatric surgery, as is well documented elsewhere in this collection of articles.

Medications and alcohol

Changes induced by the pharmacokinetics of medication following a bariatric procedure, such as the Roux-en-Y gastric bypass (RYGB), have been reported, mostly in association with administration of antidepressant drugs.1 Whether such changes occur after sleeve gastrectomy (SG) is still unclear. Antidepressants are the most common drugs used among candidates for bariatric surgery. In the Longitudinal Assessment of Bariatric Surgery (LABS)-1 study, 39.9 percent of patients were taking antidepressants; the second most common drug was a statin/lipid-lowering agent, and the third was beta blockers.1 Pharmacokinetic studies of sertraline, a serotonin reuptake inhibitor, and duloxetine—a serotonin/norepinephrine reuptake inhibitor—have been published.2,3 Both drugs were studied in groups of subjects who were nine to 15 months post-RYGB, and the kinetic results were compared with the areas under the curve obtained in obese subjects following single-dose administration of the drugs. All underwent P450 enzyme analyses to exclude slow and ultrarapid metabolizers. Results indicated that both drugs were malabsorbed after bariatric surgery. The clinical implications of these findings include the possible need to monitor the serum levels of some medications, as well as the need for clinical monitoring in case-dosage adjustments.2,3

A related pharmacokinetic issue is alcohol absorption. A number of studies have shown that alcohol is absorbed more rapidly or achieves higher serum levels and sometimes has a longer half-life following RYGB but not after gastric banding procedures.4-6 Data regarding SG are still unclear. One RYGB study found that the peak serum levels following administration of modest amounts of alcohol occurred quite early, often in three to eight minutes, and were significantly higher than levels achieved after alcohol administration in non-bariatric surgery patients.7 This observation has been coupled with a growing awareness that certain forms of bariatric surgery are associated with increased rates of alcohol abuse disorders.4 The LABS-2 study results suggest evidence of a higher incidence of post-RYGB alcohol abuse, although most patients were free from this complication.6 These data suggest that alcohol use needs to be monitored closely after bariatric operations, particularly RYGB, and that patients with a history of alcohol or other substance abuse should be advised to pursue bariatric procedures with lower risks. Research in this area continues to evolve and may uncover more information about the causal factors involved and the means to mitigate risks associated with alcohol consumption.

Concern is growing about chronic opioid use in patients in general, including bariatric surgery patients. Data were reported after seven years from the LABS-2 study showing an increased overall use of opioids among bariatric surgery patients attributable to the initiation of postoperative drugs, as well as to the continuation of preoperative medications in a subgroup of patients.8 These findings have prompted renewed efforts to use nonopioids to manage pain in these patients.

Redundant skin folds

Another potential postoperative psychiatric concern is the existence of hanging redundant skin following bariatric surgery. Research demonstrates that most patients desire body contouring surgery in certain anatomic areas, in particular, the waist/abdomen (69.4 percent), the thighs (51.6 percent), the upper arms (46 percent), and the chest/breast area (43.6 percent).9 However, in the U.S., many patients do not receive body contouring surgery. The most frequently cited reason that patients do not receive this follow-up surgery is cost and lack of insurance coverage, which in the U.S. may necessitate out-of-pocket expenses. Consequently, patients should be made aware of such possible eventualities before surgery.

Psychiatric issues

A postoperative bariatric surgery issue that requires further investigation is the development of clinical eating disorders that resemble classic eating disorders, such as anorexia nervosa and bulimia nervosa. The most common diagnoses are anorexia nervosa and atypical anorexia nervosa. Data are not yet available to determine the frequency of these disorders, but reported cases have been rare.10-12

Also of concern, and an impetus to facilitate bariatric surgery, is the high rate of depression in obese and morbidly obese bariatric surgery candidates.13,14 Previous publications from LABS-2 indicate that depression scores generally improve six months to a year after bariatric surgery, followed by some deterioration in this improvement between one and three years.15 Overall, rates of depression improve.

In some patients, however, the literature suggests an increased risk of suicide after bariatric surgery. A 2007 report by Adams and colleagues found that, at follow-up, overall mortality from various comorbidities (such as diabetes and cancer) was reduced markedly, while risk for suicide and accidents causing death increased threefold, although the increase was not statistically significant.16 Another report by Tindle and colleagues in 2010 looked at the prevalence of suicide among Pennsylvania residents reported to the Pennsylvania State Department of Health who had undergone surgery between 1995 and 2004. The suicide rate among bariatric surgery patients was 13.7 per 10,000 among men (U.S. norm 2.4) and 5.2 per 10,000 among women (U.S. norm 0.7), suggesting an increased risk.17 The reason for increased suicidality is unclear, but various reasons have been suggested, including persistence or recurrence of medical comorbidities, disinhibition secondary to alcohol abuse, antidepressant medication malabsorption, microbiome changes affecting the central nervous system (CNS), disappointment with weight outcomes or other outcomes, and worsening depression.13 The most recent data suggest that the risks may be at least partially attributable to the fact that many of these patients postoperatively report a history of self-harm and suicidal ideation prior to surgery.18 Therefore, these patients may represent a high-risk group. Yet, suicide remains a rare outcome among people in general, as well as among these bariatric surgical patients.

Cognitive function testing in the severely obese frequently shows impairment. Overall, 53.8 percent of bariatric surgery patients meet criteria for mild cognitive impairment.19-21 These conditions all improve significantly after bariatric surgery, although the mechanism for these impairments and subsequent improvements have yet to be established.22,23

Vagal nerve stimulation

The second focus of this article involves the vagus nerve and its stimulation in the treatment of refractory major depression. Major depressive disorder is common, frequently begins in young adulthood, is often characterized by a chronic or recurrent course, and is usually accompanied by serious psychosocial impairment and substantial rates of suicide. Because of these factors, major depressive disorder is a public health concern around the world. Fortunately, a variety of interventions have been developed for these patients through the years, most introduced in the mid- to late-20th century.24 Treatment includes generally safe and effective antidepressant medications in a variety of classes, including inhibitors of the monoamine oxidase enzyme systems (MAO inhibitors); tricyclic medications, which represented the mainstay of treatment from the 1960s through 1980s; and serotonin-specific, mixed serotonin/norepinephrine, and norepinephrine-specific reuptake inhibitors, as well as new, atypical agents with novel mechanisms.24

Electroconvulsive therapy (ECT), which tends to be used in treatment-resistant patients, also is effective, but its use continues to carry a significant social stigma. Although it remains difficult to predict which patients will respond to which treatments, and treatment-matching algorithms based on genetic or other factors are evolving and only now becoming clinically applicable, most patients will respond to early interventions.25-27 However, a subgroup of patients, perhaps as many as 30 percent, will fail to respond adequately to repeated trials of antidepressant drugs, even when the medications are administered for a sufficient period of time and at adequate dosages, or to ECT when administered in an adequate trial.28 As a result, investigators have continued to develop other effective interventions. The group of treatment-resistant patients is generally characterized as having failed four adequate treatment trials, which may include ECT, and being symptomatic for at least two years.

Novel treatment approaches that have emerged in the last 20 years include forms of neurostimulation treatment that affect the CNS indirectly or directly (for example, through implantable electrodes).27,29-32 Regarding direct stimulation, targets for deep brain stimulation in depression have included the subgenuate cingulate gyrus, the anterior limb of the internal capsule, the nucleus accumbens, the subcallosal cingulate gyrus, the superolateral branch of the medial forebrain bundle, the ventral capsule/ventral striatum, and the posterior gyrus rectus region.27,33,34 Various mechanisms have been postulated for the mechanisms involved in the effect, including monoaminergic and glutaminergic neurostimulation, neurotropic and neuroinflammatory mechanisms, as well as effects on various intracellular signaling pathways.35 A recent review found nine studies involving 100 patients treated with deep brain stimulation for depression involving five brain areas.32 So, the evidence to support this technique remains limited and suggests that such procedures should continue to be regarded as experimental.

Another such approach is vagus nerve stimulation (VNS).36,37 Substantial literature has been published on the development, rationale, putative mechanism(s) for, and efficacy of this approach, which now has Food and Drug Administration approval.

Much of the treatment literature on VNS consists of case reports and case series.38-40 Research in the area of VNS has accumulated somewhat slowly, owing to the difficulties in designing, implementing, and interpreting trials. However, some definitive work has been published. In 2013, Berry and colleagues published a patient-level meta-analysis of studies evaluating VNS for treatment-resistant depression, which included an evaluation of six outpatient multicenter clinical trials, two of which involved the randomization of participants. As summarized in that report, outcomes were tracked from baseline out to 96 weeks with VNS + treatment as usual (TAU) (n = 1,035) versus TAU alone (n = 425). The conclusion was that for patients with chronic treatment-resistant depression, VNS + TAU results in remission rates that are modestly superior to those achieved with TAU.41

In 2017, Aaronson and colleagues published a five-year observational study of patients with treatment-resistant depression treated with VNS using prospective observational registry data from 61 U.S. sites. The study involved 795 patients with major depressive disorder of at least two years’ duration and/or who had experienced three or more depressive episodes. All of the subjects failed to respond to four or more depression treatments, including ECT. The registry represented the longest naturalistic study of efficacy outcomes in treatment-resistant depression and provided additional evidence that VNS has enhanced antidepressant effects compared with TAU in this severely ill outpatient population. Retention at one and five years favored the VNS group (93 percent and 61 percent versus 74 percent and 46 percent, respectively), as did the response rate (defined as ≤50 percent reduction in depression score; 67.6 percent versus 40.9 percent) and remission rates (defined as a final depression score using the Montgomery-Åsberg scale of 9 or less; 43.3 percent versus 25.7 percent). However, the response and remission rates increased gradually out to five years, with many patients showing minimal improvement for one to three years and less than 40 percent responding in the first six months. Relapse curves suggested deterioration in more than 50 percent at 3.5 years. Therefore, the advantage of VNS was clear, but again, as in the meta-analysis mentioned previously, far from dramatic.42

Although various tuning parameters for the devices have been tried, the literature suggests some possible targets that can be used. A published review of some of the ethical issues in VNS addresses the complex topics of informed consent in this chronically ill, treatment-resistant population.43

Although the usual approach to administering VNS is to implant the pulse generator under the skin by tunneling in the upper chest wall and attaching the electrodes to the vagus nerve in the neck (invasive VNS), a transcutaneous approach also has been developed that involves attaching the device to the auricular concha to stimulate the auricular branch of the afferent vagus.44

In addition, an fMRI study has examined optimal placement, suggesting the cymba conchae as the preferred target site.45 Outcomes of a nonrandomized, controlled, pilot trial were published that suggest the effectiveness of this approach.46

Although the mechanism(s) of efficacy of VNS have yet to be established, various mechanisms have been suggested, including an increase in gray matter in the hippocampus, activation of the insula, increased amygdala connectivity, and enhancement of noradrenergic activity outflow from the locus coeruleus.47-51 Nonetheless, the available evidence suggests that VNS is a reasonably effective approach for treatment-resistant depression patients, although the evidence remains limited.52

Conclusion

Changes in postoperative drug absorption require intense monitoring for alcohol misuse because of the hyperabsorption of alcohol. The malabsorption of certain antidepressants may require serum monitoring and dosage adjustments. Postoperative problems with hanging, redundant skin may indicate the need for referral for body contouring, which some insurers may not cover. The rare development of eating disorders such as anorexia nervosa after surgery may be of clinical concern. The use of electrical stimulation of the vagus nerve in severe depression, which can improve outcomes in a subgroup of treatment-resistant depression patients who have responded poorly to trials of drug therapy and/or ECT should be considered and requires surgical implantation of vagal stimulation devices.

Acknowledgments

This work was supported by the American College of Surgeons (ACS). The authors declare that they have no relevant conflict of interest.

We are grateful to the ACS for their generous sponsorship of the Metabolic Surgery Symposium and associated journal publication development. We thank Jane N. Buchwald, Chief Scientific Research Writer, Medwrite Medical Communications, Maiden Rock, WI, for manuscript editing and publication coordination. And we thank Patrick Beebe and Donna Coulombe, ACS Executive Services, for their expert organization of the Metabolic Surgery Symposium.

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