To our knowledge, this is the first real-world study investigating the relationship between psychiatric symptoms and adherence to liraglutide 3.0 as obesity therapy. We found an inverse correlation between adherence indicators and the presence and intensity of anxiety, depression, and eating compulsivity, as detected by psychometric tests. Through regression analysis, we showed that greater anxiety symptomatology might predict a lower MD; greater depressive symptomatology and significant BE may predict a shorter TD. Nevertheless, we were able to observe that, despite the effect on adherence, neither the presence of psychiatric symptoms nor being on psychoactive therapies led to a significant reduction in overall liraglutide effectiveness on weight loss.
Our results align with previous literature on poor adherence to therapy by obese patients presenting anxiety-depressive symptomatology [30]. It is generally known that depression and anxiety are associated with lower compliance and adherence to medication [31–34]. Moreover, it has been shown that antidepressants can diminish the weight loss effect of GLP-1 RAs, which could decrease compliance with therapy [35]. Overall, because the association between obesity, anxiety-depressive syndrome, and antidepressant therapy occurs frequently, patients often face multiple conditions that feed off each other clinically and in terms of treatment adherence [36].
In the present audit, being on psychotropic (mainly antidepressant) therapy did not affect adherence, although we observed in this subgroup a non-significant trend for lower weight loss (at 12 weeks and overall).
Regarding specific adherence to liraglutide, intrinsic aspects related to the drug should be considered. First, side effects such as nausea, constipation, diarrhea, and vomiting, usually mild and transient, might be differently tolerated in more anxious people [37, 18]. Second, we must consider that out-of-pocket medications (as in the case of liraglutide 3.0 mg for Italian patients) have been shown to have a negative impact on adherence [38, 39].
The uniqueness of this work lies in the fact that we identified a predictive effect of psychiatric symptoms on adherence to liraglutide therapy, a drug that has peculiarly demonstrated efficacy on both metabolic and psychiatric symptoms: we can now hypothesize that promoting greater compliance in our patients could foster a virtuous circle in which physical and mental health have a mutually beneficial effect. Indeed, research has demonstrated a bidirectional relationship between obesity and depression [40, 41], inflammation and depression [42, 43], obesity and inflammation [44, 45], and inflammation and anxiety [46]. Research has shown that anxious-depressive states and obesity are associated with similar changes in central nervous system cells due to the exaggerated action of glucocorticoids, proinflammatory cytokines, or glutamate [40, 20, 21]. In particular, an excess of glucocorticoids can lead to impaired insulin action and glucose metabolism, limited energy intake for proper neuronal functioning, and, consequently, disturbed synaptic plasticity [40, 20, 21].
Due to this complex link between metabolic, inflammatory, and psychic balance, therapies that reduce blood glucose levels, improve central inflammation, and regulate the hypothalamic-pituitary-adrenal axis have been shown to reduce depressive symptoms [25]. This mechanism is effective in traditional anti-hyperglycemic agents, such as insulin or metformin, and the newer GLP-1 RAs [21]. Indeed, research has amply demonstrated that the use of GLP-1 RAs in T2DM patients is associated with a lower incidence of depression and anxiety compared to controls treated with different therapies [47, 48, 23]. In addition, recent studies evaluating the gut microbiota have suggested that one of the roles of GLP-1 RAs in treating anxiety is related to improved glucoregulation, leading to reduced proinflammatory cytokines and increased neuroprotection [49]. It is worth mentioning that in the obesity treatment toolkit the drug naltrexone/bupropion is also available: this is a fixed-dose synergistic combination of two molecules originally used to treat opioid/alcohol use disorders and depression [50]. It is effective in reducing appetite and increasing energy expenditure, helping to stick to a calorie-controlled diet and to reduce body weight: according to Canadian guidelines, it is the first drug of choice for BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 plus obesity-related comorbidities who present symptoms such as craving or depression [51].
Thus, there are numerous reasons not only to counteract clinical inertia by offering pharmacological treatment for obesity to patients with psychiatric symptoms but also to direct therapy toward pathophysiological pathways shared between physical and mental health: taking care of one means taking care of the other as well.
4.1. Strength and limits
Strengths of this study include the real-life setting in a public outpatient obesity clinic, therefore less prone to selection bias than randomized controlled trials – which tend to select those patients with higher adherence [52, 53]. This setting was also more representative of the problems clinicians can face while prescribing a drug that is not covered by the National Health Service – unlike most medications for clinically relevant diseases. Furthermore, this study is based on the routine collection of psychiatric symptoms in the context of the first visit to the Unit of Clinical Nutrition and Metabolism, performing in the internal medicine setting, a type of assessment that is generally reserved for the psychiatric setting.
These findings should also be considered in light of the limitations that this clinical audit presents: (1) we observed subjects retrospectively; (2) the sample size was relatively small; only half of the sample had, in fact, completed/returned the psychodiagnostic scales, the main reason being the logistical difficulties related to Covid-19 pandemic; (3) it was only sometimes possible to precisely trace why the treatment was discontinued, denying the possibility of more specific statistical analyses on the issue of side effects.
4.2. Conclusions
In conclusion, we can observe a close relationship between psychiatric symptoms – i.e., depression, anxiety, and binge eating – and reduced adherence to liraglutide therapy. Deepening this knowledge could allow us to identify targeted treatments for our patients. An integrated approach to managing these individuals could ensure a reduction in psychiatric symptoms and greater therapeutic adherence, ultimately leading to better overall health.