Liraglutide for psychiatric disorders: clinical evidence and challenges

Introduction

Obesity and diabetes have been considered as independent risk factors for psychiatric disorders. Obesity and diabetes may play a pathogenic role in psychiatric disorders, but they can also be consequences of psychiatric conditions and their treatment [1]. For instance, metabolic syndrome is a frequent side-effect of antipsychotic treatment [2]. The strong relationship between these two entities and psychiatric conditions led to the investigation of potential shared therapeutic targets.

Glucagon like peptide-1 (GLP-1) is an incretin hormone secreted from the small intestine in response to food ingestion. The GLP-1 receptor is a G-protein coupled receptor with seven transmembrane domains. Activation of GLP-1 receptor results in increased cAMP levels which facilitate the secretion of insulin [3], [4], [5]. GLP-1 has other physiological effects such as slowing gastric emptying and decreasing glucagon release. Liraglutide is a derivative of human GLP-1 that is used as a long-acting GLP-1 receptor agonist for the treatment of diabetes mellitus type 2 and obesity.

Liraglutide is an interesting candidate for being a therapeutic strategy for both diabetes/obesity and psychiatric disorders. Based on the accumulating knowledge in the area, here in this review, we aimed to discuss existing clinical evidence pertaining to liraglutide use in neuropsychiatry.

Effects of liraglutide on the brain

Several studies have pointed out that liraglutide could have potential benefits on neuronal development and protection. For example, liraglutide can cross the blood-brain barrier, increasing neurogenesis in the mouse brain [6]. GLP-1 mimetics were found to promote progenitor cell proliferation in dentate gyrus, while GLP-1 receptor antagonists reduced progenitor cell proliferation [7]. A study with neuronal cells in vitro and a mouse model of traumatic brain injury reported the neurotrophic and neuroprotective effects of liraglutide [8]. Liraglutide was also found to have enhancing effects on synaptic plasticity [9]. It is worth mentioning that that the human brain expresses GLP-1 receptors in the parietal cortex, hypothalamus and medulla [10].

Along with its neuroprotective effects, liraglutide has anti-inflammatory, anti-oxidant and anti-apoptotic effects. Parthsarathy et al. showed that application of liraglutide decreased chronic inflammation after exposure of the mouse brain to radiation [11]. In a rat model of cerebral ischemia, pre-treatment with liraglutide resulted in smaller infarct size, less neurologic deficit, less oxidative stress and anti-apoptotic effects [12]. The aforementioned preclinical data formed the background that fostered the investigation of liraglutide in neuropsychiatric disorders which will be discussed in more detail below.

Mood disorders

Mood disorders and obesity seem to have a bi-directional association. Subjects with obesity have increased rates of depression and bipolar disorder [13]. On the other hand, patients diagnosed with a mood disorder have increased risk of developing overweight and abdominal obesity [14]. There are a few explanations for this association. Certain clinical features of mood disorders such as decreased psychomotor activity and increased appetite could lead to weight gain. Some antidepressants and most antipsychotics are also implicated in weight gain [15]. Finally, dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis might be a shared factor underlying the link between obesity/diabetes and mood disorders [16].

Increased prevalence of depression is observed in people with diabetes, while depression is considered a strong risk factor for developing diabetes [17], [18]. From a mechanistic standpoint, brain-derived neurotrophic factor (BDNF) has been implicated in both the neurobiology of depression and the physiopathology of diabetes [19], [20]. Indeed, BDNF blood levels are consistently reduced in depression and diabetes [19], [20].

In a preclinical mouse model of epilepsy, administration of liraglutide resulted in improvement of seizure severity and comorbid conditions, i.e. depression-like behavior and cognitive impairment [21]. An independent study showed that liraglutide promoted cognitive enhancement in memory deficits induced by pentylenetetrazole or scopolamine but did not influence depression-like behaviors as assessed by the forced swim test and the tail-suspension test [22].

There is promising clinical evidence in this area. Because of concerns of potential adverse effects of anti-obesity medications on mental health, neuropsychiatric safety data from all phase 2 and 3 randomized, double-blind trials with liraglutide 3.0 mg were evaluated post hoc, and liraglutide was deemed safe in this regard [23].

In an open-label study, Mansur et al. investigated 19 patients diagnosed with either major depressive disorder or bipolar disorder. All patients had impairment in cognitive function as assessed by the Trail Making Test B (TMTB). After 4 weeks of treatment with liraglutide (0.6 mg/day in the 1st week, 1.2 mg/day in the 2nd week, 1.8 mg/day in the 3rd and 4th weeks), the patients showed a significant increase in TMTB scores [24]. Interestingly, this cognitive improvement was associated with changes in brain volumes, including caudate, putamen, middle frontal cortex, superior frontal cortex and lateral orbitofrontal cortex [25].

These preliminary results suggest that liraglutide could be a potential add-on therapeutic strategy against mood disorders to control not only the weight and metabolic dysfunction of patients, but also coexistent cognitive impairment. It could also open new venues of investigation of the neurobiology of mood disorders.

Schizophrenia

The association between obesity/diabetes and schizophrenia is noteworthy. Although psychomotor activity may increase during acute psychotic episodes, patients with schizophrenia usually have decreased psychomotor activity between these episodes [26]. Furthermore, antipsychotics, especially the atypical ones, can induce obesity, metabolic syndrome and diabetes [2]. Conversely, increased prevalence of obesity and diabetes among patients may cause problems with treatment adherence, social interaction and daily functioning, and liraglutide could play a role to address these issues [27].

Dixit et al. studied the potential antipsychotic effects of liraglutide in an apomorphine-induced cage climbing behavior model of psychosis. Acute liraglutide treatment resulted in a significant decrease in climbing behavior, indicating that the drug could have antipsychotic effects in dopamine-mediated psychosis [28]. Another experimental study focused on whether liraglutide could prevent metabolic side effects and improve cognitive function in rats. Liraglutide improved olanzapine-induced weight gain and clozapine-induced glucose intolerance. Liraglutide also improved cognition as evaluated by the novel object recognition and T-maze tests [29]. Sharma et al. observed that liraglutide could reverse long-term atypical antipsychotic-related depression and metabolic abnormalities in rats [30].

From a clinical perspective, case reports pointed out the likelihood of liraglutide use to alleviate glucose intolerance and facilitate weight loss. After addition of liraglutide to clozapine, glycated hemoglobin (HbA_1c) of a patient with schizophrenia decreased from 10.0% to 6.5%. This patient also experienced an 8.7% body weight loss [31]. A randomized clinical trial of liraglutide add-on to olanzapine or clozapine treatment recruited 214 participants who were overweight or obese and had prediabetes. Participants received either liraglutide or placebo for 16 weeks as once daily injections of 1.8 mg/day. Liraglutide significantly improved glucose intolerance, body weight and cardiometabolic disturbances [32].

Exenatide is also a GLP-1 receptor agonist with similar mechanism of action of liraglutide. There are two studies evaluating the effects of exenatide in schizophrenia. A randomized controlled trial in obese patients with schizophrenia being treated with antipsychotic drugs compared subcutaneous injection of exenatide and placebo. They did not find a significant difference between placebo and exenatide in terms of weight loss [33]. The same group investigated the effects of 3-month administration of exenatide on cognition in schizophrenia patients, not showing any significant effect of treatment on cognition [34].

Current evidence suggests that liraglutide can be promising to alleviate glucose intolerance and facilitate weight loss in patients who are on antipsychotics. It remains to be addressed whether liraglutide plays any role on cognitive functioning in schizophrenia.

Alzheimer’s disease

There is a strong association between Alzheimer’s disease (AD) and diabetes. Diabetes increases the risk of developing AD and this risk is higher in patients with cerebrovascular diseases. Moreover, patients with AD who have comorbid diabetes tend to have more AD-related neuropathological changes, i.e. amyloid plaques and neurofibrillary tangles [35]. Along with diabetes, obesity is a significant risk factor for development of AD [36]. Obesity is a risk factor for developing both diabetes, hypertension and cardiovascular diseases. In addition, a growing body of evidence points out that obesity may cause cognitive abnormalities. There is also increased risk of AD in obese populations [37].

McClean et al. evaluated amyloid plaque load in APP/PS1 mice, an animal model of AD, treated with liraglutide. Plaque load and related inflammation decreased around 30% after treatment, concluding that liraglutide may have preventive properties and may be able to reverse some of the neuropathological processes of AD [38]. Using the same animal model, Chen et al. observed that liraglutide increased learning and memory, while decreasing hyperphosphorylation of tau and neurofilaments [39]. Another study showed that liraglutide prevented amyloid plaque deposition and chronic inflammation [40].

Outstanding results from preclinical studies led researchers to further evaluate benefits of liraglutide for AD patients. Currently, there is a finished randomized, controlled, double-blinded trial in Denmark, investigating effects of liraglutide on neurodegeneration, blood flow and cognition in AD [41]. This trial enrolled 38 patients and lasted 26 weeks. Liraglutide treatment resulted in insignificant increase of glucose metabolism after 6 months, but cognitive scores did not change [42].

Eating disorders

Activation of the GLP-1 receptor in the ventral hippocampal field CA1 has been shown to inhibit eating behavior through connections between CA1 and the medial prefrontal cortex [43]. This finding suggests that GLP-1 receptor agonists such as liraglutide might be effective in treating binge eating. Indeed, a preliminary study with liraglutide involving obese individuals with subclinical binge eating showed significant improvement in binge eating behavior, body mass index and weight circumference [44].

While there are currently no studies on the effects of liraglutide in bulimia nervosa, there is some preliminary evidence that GLP-1 signaling might be involved in the pathophysiology of bulimia nervosa. Post-meal GLP-1 levels were found to be reduced in women with bulimia nervosa compared to healthy controls [45], [46]. A third study did not find differences in post-meal GLP-1 levels between 20 women with bulimia and 20 healthy controls, but in patients with bulimia GLP-1 levels correlated positively with bingeing-vomiting frequency [47].

Overall, these results strongly support the need of further study of liraglutide in eating disorders characterized by binge eating.

Future directions

One major challenge for liraglutide is its injectable formulation. To facilitate the use of GLP-1 agonists, the development of oral formulations would be important. There is also the need of studies to address whether drugs with similar mechanisms of action will present the same therapeutic profile. Evidence so far did not show therapeutic effects of exenatide, also a GLP-1 receptor agonist, in schizophrenia. It has not been established yet the effects of liraglutide in schizophrenia.

There are promising findings on the role for liraglutide in the management of mood disorders, with potential effects on both weight control and cognition. Randomized controlled clinical trials enrolling well-characterized patients (e.g. major depression vs. bipolar depression; overweight vs. obese; prediabetes/diabetes vs. non-diabetes) are needed to confirm these preliminary results, and to evaluate if liraglutide has any effect on mood symptoms and/or progression of these conditions.

Several preclinical studies showed that liraglutide improved cognition or prevented cognitive decline. Accordingly, further studies are warranted to evaluate the impact of liraglutide in neurodegenerative diseases, mainly AD. These studies should address not only the potential effects of liraglutide on cognition, but also on other outcome measures, including behavior and social functioning. It must also be investigated by which mechanisms liraglutide can improve cognitive function, i.e. through indirect effects based on a better glycemic control and anti-inflammation properties or through direct effects on neurons. This could open new directions of search for therapeutic strategies against neurodegeneration.