Abstract
Schizophrenia is a complex psychotic disorder with co-occurring conditions, including insulin resistance and type 2 diabetes (T2D). It is well established that T2D and its precursors (i.e., insulin resistance) are more prevalent in patients with schizophrenia who are treated with antipsychotics, as well as in antipsychotic-naïve patients experiencing their first episode of psychosis, compared with the general population. However, the mechanism(s) underlying the increased susceptibility, shared genetics, and possible cause–effect relationship between schizophrenia and T2D remain largely unknown. The objective of this narrative review was to synthesize important studies, including Mendelian randomization (MR) analyses that have integrated genome-wide association studies (GWAS), as well as results from in vitro models, in vivo models, and observational studies of patients with schizophrenia. Both GWAS and MR studies have found that schizophrenia and T2D/insulin resistance share genetic risk factors, and this may mediate a connection between peripheral or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in schizophrenia. Moreover, accumulating evidence supports a causal role for insulin resistance in schizophrenia and emphasizes the importance of a genetic basis for susceptibility to T2D in patients with schizophrenia before they receive psychotic treatment. The present findings and observations may have clinical implications for the development of better strategies to treat patients with schizophrenia, with both pharmacological (i.e., samidorphan, empagliflozin) and/or nonpharmacological (i.e., lifestyle changes) approaches. Additionally, this review may benefit the design of future studies by physicians and clinical investigators.
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Avoid common mistakes on your manuscript.
Comorbidity of schizophrenia and type 2 diabetes (T2D) has been well established, with T2D and its precursors (i.e., insulin resistance) being more prevalent in patients with schizophrenia independent of treatment with antipsychotics. |
Genome-wide association studies and Mendelian randomization analysis have identified a possible causal connection between insulin-related traits (i.e., a genetic predisposition to abnormally high fasting insulin and insulin resistance) and an increased risk of developing schizophrenia. |
Schizophrenia and T2D/insulin resistance share common genetic risk factors that may link peripheral or brain insulin resistance and T2D to cognition impairment. These factors may also increase the risk of developing prediabetes and T2D in patients with schizophrenia after antipsychotic treatment. |
These findings have clinical implications, particularly regarding the development of better strategies for treating and managing patients with schizophrenia with use of pharmacological interventions, such as empagliflozin, for antipsychotic treatment. |
1 Introduction
Schizophrenia is a serious psychiatric disorder associated with profound impairments in overall functioning. As a result, quality of life for both patients and their family members is adversely affected by the stress, financial strain, and disruption of daily life that are caused by this disorder. According to the World Health Organization, approximately 24 million individuals are diagnosed with schizophrenia worldwide [1]. Patients with schizophrenia commonly present a variety of co-occurring conditions, including insulin resistance (affected individuals do not properly respond to insulin), prediabetes, and type 2 diabetes (T2D). In fact, the comorbidity of schizophrenia and T2D has long been noted, with multiple studies reporting a higher prevalence of T2D, prediabetes, and insulin resistance in patients with schizophrenia [2,3,4]. Prediabetes and T2D may develop as side effects of certain psychotic agents, particularly second-generation antipsychotics (i.e., olanzapine, clozapine, quetiapine, risperidone, aripiprazole, paliperidone, ziprasidone, and lurasidone), which are commonly prescribed for treatment of psychotic disorders such as schizophrenia and bipolar disorder [5,6,7]. Interestingly, treatment-naïve patients experiencing their first episode of psychosis have also exhibited a higher incidence of prediabetes and T2D compared with an age-matched general population [8,9,10]. This observation suggests that the higher risk of T2D in schizophrenia may be unrelated to side effects induced by use of antipsychotic drugs. In addition, previous studies have reported a significant association of schizophrenia with increased odds of parental T2D [11,12,13]. However, overlap between schizophrenia and T2D is complex and multifactorial. Genetic factors, environmental factors, and use of antipsychotics may contribute to the common comorbidity of these two diseases and their pathologies [5, 6, 14, 15].
There are multiple risk factors which may contribute to the link between schizophrenia and T2D. It has been documented that genetic predisposition and loci are shared by the two disorders [2, 16,17,18]. In addition, prediabetes and T2D may develop as side effects of certain psychotic agents. Over the past decade, rapid advances and greater application of genome-wide association studies (GWAS) have allowed researchers to evaluate possible links between human genetic variations and disease risk. In fact, recent studies have identified overlapping loci and genetic variants of schizophrenia and T2D [19, 20]. These results have led to greater interest in exploring whether the connection between these two diseases is causal. By using the Mendelian randomization method and integrating GWAS data, researchers have made substantial progress in causal effect assessments [21, 22]. Understanding the genetic basis for susceptibility to T2D in patients with schizophrenia is particularly important in the clinical setting where strategies involving psychotic treatment need to be individualized and optimized for treatment and management of patients with schizophrenia and comorbidities.
Here, we conducted a narrative review of relevant literature by searching the PubMed and Wanfang Med Online databases through 31 October 2023 using the following keywords: schizophrenia, diabetes, prediabetes, insulin resistance, antipsychotic drug, GWAS, and Mendelian randomization analysis. We focused on genetic risk factors that are shared by schizophrenia and T2D, and which may explain the connection of peripheral tissue or brain insulin resistance and T2D with cognition impairment and an increased risk of developing prediabetes and T2D in patients with schizophrenia. By synthesizing important and relevant studies, treatment, and management of patients with schizophrenia can be improved. In addition, this review may help psychiatrists and researchers within the field to formulate future investigations to gain further insight into this disorder.
2 Insulin Resistance, Prediabetes, and Diabetes in Schizophrenia
2.1 Insulin Resistance/Prediabetes and Diabetes are Highly Prevalent Comorbidities in Schizophrenia
In older adults with schizophrenia, an age-associated confounding effect has been observed. In contrast, these confounding effects have not been observed in studies of younger drug-naïve patients. For example, Ryan et al. [23] conducted a landmark study that assessed fasting glucose tolerance in young patients (mean (SD) age, 33.6 (13.5) years) experiencing their first episode of schizophrenia. Before treatment of schizophrenia was initiated, more than 15% (n = 4) of the patients exhibited impaired fasting glucose tolerance compared with 0% of the age-matched healthy control individuals [23]. Incidence rates reported for T2D were also two to four times higher in patients with schizophrenia than in the general population [2,3,4]. Furthermore, a number of factors (i.e., ethnic origin, age, geographical region) have been identified as major contributors to the large variations observed in T2D incidence rates in cases of schizophrenia [2,3,4, 8, 24]. Subramaniam et al. performed a cross-sectional study involving a sample of 194 treatment-naïve patients with schizophrenia [males, 155; females, 39; mean (SD) age, 55.5 (8.7) years)] in Singapore [25]. When these patients were stratified according to age, their rates of diabetes were approximately two-fold higher than the general population of Singapore (17.3% versus 9.6% at 40–49 years and 50.0% versus 21.8% at 50–59 years, respectively in each case). These results suggest that diabetes is particularly more common in older individuals with schizophrenia compared with the general population. Notably, the risk of T2D is particularly increased in young male patients with schizophrenia, including among treatment-naïve patients experiencing their first episode of psychosis, compared with an age-matched general population [2,3,4]. It has further been observed that T2D may develop rapidly following the initial diagnosis of schizophrenia. For example, among a subset of individuals experiencing their first episode of psychosis prior to receiving antipsychotic treatment, indicators for T2D (i.e., high fasting plasma glucose and insulin, elevated insulin resistance, and reduced glucose tolerance) could already be detected [26, 27]. Thus, the latter characteristics do not necessarily represent the side effects of certain antipsychotic medications. Moreover, the mechanisms underlying the increased risk of insulin resistance, prediabetes, or T2D among patients with schizophrenia appear to be multifactorial and complex, with genetic risk factors, lifestyle risk factors, and certain medicines, including some antipsychotics, also playing a role.
2.2 Brain Insulin Resistance in Schizophrenia
Insulin is a key hormone that maintains glucose and energy homeostasis throughout the body. In particular, the brain is an insulin-sensitive organ that is metabolically and functionally affected by insulin [28, 29]. Additionally, insulin controls food intake and regulates cognitive ability in the brain, especially memory [29]. Thus, impairment of insulin action due to brain insulin resistance and hyperinsulinemia can potentially damage cognitive systems, thereby contributing to cognitive impairment [28, 29].
Evidence from several postmortem studies of patients with schizophrenia has revealed decreased expression of insulin receptors and their downstream signaling molecules [i.e., protein kinase B (AKT), glycogen synthase-3 beta (GSK3β), mammalian target rapamycin (mTOR)] in the frontal cortices of the brain [30,31,32]. These results are consistent with impaired brain insulin sensitivity or brain insulin resistance in schizophrenia. However, very few studies have investigated the role of brain insulin resistance in relation to memory in patients with schizophrenia. Wijtenburg et al. examined differences in brain glucose levels in the occipital cortex using magnetic resonance spectroscopy (MRS) and blood extracellular vesicle markers of neuronal insulin resistance (i.e., Akt and signaling effectors) between patients with schizophrenia and healthy control individuals. The results obtained suggest that brain insulin resistance may contribute to memory impairment [33]. Both groups also completed a brief visuospatial memory test (BVMT). The patients with schizophrenia exhibited a significantly poorer performance on the spatial memory portion of the test compared with the healthy control group. Furthermore, significant correlations between insulin resistance biomarkers and brain glucose with memory parameters were observed among the patients with schizophrenia [33]. Notably, an effector of insulin signaling was associated with verbal learning in the patients with schizophrenia [33]. Taken together, these findings demonstrate that memory impairment in schizophrenia is associated with brain glucose and brain insulin resistance, and also suggest a role for brain insulin resistance in the pathophysiology of cognitive impairment in patients with schizophrenia [33].
3 Potential Shared Genetic Underpinnings of Insulin Resistance/Diabetes and Schizophrenia
3.1 Evidence from a Mendelian Randomization Analyses Integrating Publicly Available Data from GWAS
Despite the link between insulin resistance/T2D and schizophrenia, it remains unclear whether the connection between the two disorders is causative. Mendelian randomization analysis of published GWAS data has been increasingly applied to test whether the relation between exposure and outcome is causal [34, 35]. In addition, bi-directional Mendelian randomization analysis of publicly available GWAS data has evaluated causality as well as the direction of the relationship [35, 36]. Various studies that have used genetic variants to investigate a putative causal relationship between schizophrenia and T2D/insulin resistance [21, 22, 36] are summarized in Table 1. Li et al. conducted a Mendelian randomization study to evaluate the potential causal effect of well-known genetic risk factors for T2D, as well as insulin- or glucose-related traits, on schizophrenia [22]. A causal connection between increased risk of schizophrenia and genetic predisposition to abnormally high fasting insulin or insulin-related traits was observed [22] (Table 1). Interestingly, however, neither of two glucose-related traits, fasting glucose nor hemoglobin A1c (HbA1c), were identified. Furthermore, no casual effects of genetic variants associated with schizophrenia on levels of fasting insulin were observed [22]. Taken together, these findings support a causal effect for abnormally high fasting insulin on increased risk of schizophrenia, and are consistent with those of a previous study [37]. When pathway enrichment analysis was subsequently performed using GWAS data from 108,341 individuals, the top two schizophrenia-associated pathways identified included glucagon-like peptide 1 (GLP-1), known to play a critical role in stimulation of insulin secretion, and adrenaline/noradrenaline which mediates inhibition of insulin secretion [19, 22]. In addition, Pillinger et al. detected significantly higher levels of fasting insulin and greater insulin resistance in patients with schizophrenia who experienced first-episode psychosis than healthy individuals [14]. However, HbA1c did not statistically differ between the two groups examined [14]. Thus, a causal connection between high fasting insulin (but neither glucose abnormality nor T2D) and schizophrenia has provided evidence to support the hypothesis that schizophrenia is, at least in part, a consequence of disturbed insulin action, rather than perturbed glucose homeostasis in the brain.
Currently, the observed findings remain to be validated, especially since different studies have reported inconsistent findings. For example, a separate Mendelian randomization study did not find a causal connection between schizophrenia and T2D or traits in relation to impaired glucose homeostasis (homeostatic model assessment-insulin resistance and fasting proinsulin values, all p > 0.05) [20] (Table 1). More recently, a bi-directional two-sample Mendelian randomization analysis of GWAS data conducted by Perry et al. investigated a possible causal association between insulin resistance and related cardiometabolic traits and schizophrenia [21]. The results indicate that an inflammation-related, insulin resistance phenotype with elevated levels of fasting insulin exhibited a significant causal association with schizophrenia (p < 0.05) [21] (Table 1). Interestingly, after adjusting for a well-known marker of systematic inflammation, C-reactive protein, in a multivariable Mendelian randomization analysis, evidence for the association attenuated to the null (p > 0.05). This result supports inflammation as a common mechanism for both insulin resistance and schizophrenia [21]. The fat that surrounds abdominal organs, also referred to as visceral adipose tissue, can release fatty acids and other substances that may cause chronic inflammation. Moreover, this type of inflammation plays a role in insulin resistance, prediabetes, T2D, and schizophrenia. It should be further noted that the Mendelian randomization analysis performed by Perry et al. did not show any evidence for significant causal associations between T2D, glycated hemoglobinA1c, glucose tolerance, fasting plasma glucose, or fasting insulin with schizophrenia [21]. In addition, no evidence for a causal association of schizophrenia with T2D or insulin- or glucose-related traits was obtained [21].
Based on the results of these three Mendelian randomization studies performed by independent research groups, it is likely that a causal association exists between insulin-related traits and an increased risk of developing schizophrenia. These traits specifically include a genetic predisposition to abnormally high fasting insulin [22] and insulin resistance [21]. However, the aforementioned results from the Mendelian randomization studies have shown that a causal association of T2D with schizophrenia is unlikely to exist, and T2D is unlikely to exert a causal role in the pathogenesis of schizophrenia [20,21,22].
3.2 Evidence from Mechanistic Studies Support a Causal Association of Insulin-Related Traits and Insulin Resistance with an Increased Risk of Developing Schizophrenia
Insulin is well established as a master hormone that regulates blood sugar and plays a crucial role in modulating energy metabolism in various organs. Apart from its primary target organs, such as the liver and skeletal muscle, insulin also affects the brain. There are multiple lines of evidence that support a hypothetical role for brain insulin in schizophrenia. First, insulin has been shown to govern synapse development and plasticity in the brain, mainly through its mechanistic target, mTOR. This regulatory capacity is consistent with important processes that are associated with the pathogenesis of schizophrenia [38, 39]. Second, the Akt signaling pathway, which mediates signaling in the insulin receptor signal transduction network, is also shared by schizophrenia-associated neurotransmitters, inflammatory cytokines, and brain-derived neurotrophic factor. Accordingly, the Akt signaling pathway may contribute to the pathophysiology of schizophrenia [40]. As such, brain insulin resistance may lead to glucose deprivation through downregulation of GLUT-4 via the insulin signaling pathway and insulin-responding glucose transporter. Furthermore, via shared molecular pathways, brain insulin resistance may perturb the balance of schizophrenia-associated neurotransmitters [39]. Kapogiannis et al. demonstrated abnormalities of insulin signaling in drug-naïve patients with schizophrenia who experienced a first episode of psychosis [18]. The severity of their symptoms inversely correlated with activity of the insulin transduction signaling network [18]. Thus, data obtained from patients with drug-naïve, first-episode schizophrenia have provided valuable evidence regarding brain insulin resistance in schizophrenia [18]. Third, impaired insulin action and dysregulated insulin metabolism have been reported to affect critical neurotransmitter pathways associated with the neurobiology of schizophrenia. For example, a meta-analysis was recently conducted by de Bartolomeis et al., in which the effects of impaired insulin action or metabolism (i.e., systemic or brain insulin resistance, abnormal insulin levels) on key molecular pathways related to schizophrenia-associated neurotransmitters, such as glutamatergic, dopaminergic, γ-aminobutyric acid (GABA)ergic, and serotonergic pathways, were assessed [41]. This latter study revealed significant impairments in synaptic plasticity processes as a result of insulin manipulations. Specifically, insulin-resistant animals exhibited significantly impaired dopamine transporter activity. Additionally, insulin action was found to modulate glutamate and GABA release, as well as enzymes involved in GABA and serotonin synthesis. Collectively, these findings suggest that abnormalities in insulin signaling can impact neurotransmitter systems involved in the development of schizophrenia.
Fasting insulin is considered an accurate marker for early prediction of prediabetes. Impairment of fasting insulin generally occurs prior to hemoglobinA1c, fasting plasma glucose, or glucose tolerance. Thus, a fasting insulin test is referred to as a pre-prediabetes test. Abnormally elevated levels of fasting insulin may denote impaired insulin sensitivity, and this can result in tolerance to insulin, also known as insulin resistance. The aforementioned two Mendelian randomization studies agree on a causal association between insulin-related traits and schizophrenia; specifically, increased fasting insulin [22] and insulin resistance [21]. These two traits may partly explain the observed co-occurrence of impaired insulin sensitivity and schizophrenia. In addition, previous studies, including our own, have shown that prediabetes and diabetes can rapidly develop after initiation of treatment with certain antipsychotics, particularly when the treatment includes second-generation antipsychotics such as clozapine and olanzapine. Moreover, this rapid onset has been observed in a high proportion of patients with schizophrenia. For example, after 16 weeks of treatment with clozapine, a high incidence of developing prediabetes (73.91%) and T2D (2.61%) was observed in patients with early treatment-resistant schizophrenia [42]. Multivariate analysis has also shown that a family history of T2D is an independent risk factor for clozapine-induced prediabetes in patients with early treatment-resistant schizophrenia [42]. Furthermore, insulin resistance has been observed in a proportion of young adult patients with schizophrenia who experienced a first episode of psychosis and did not receive subsequent antipsychotic treatment [23]. However, the mechanisms whereby certain antipsychotic drugs accelerate the transition from insulin resistance to prediabetes, and from prediabetes to full diabetes, remain to be elucidated. Usually, prediabetes characterized by an abnormally high fasting blood sugar occurs in individuals with insulin resistance that is due to destruction of beta cells in their pancreas [43].
Our understanding of possible prevention and treatment strategies for schizophrenia and T2D continues to expand. However, the mechanisms underlying the comorbidity of schizophrenia and T2D remain unclear. It continues to be debated whether comorbidity of these two diseases reflect shared genetic risk factors, lifestyle risk factors, and/or antipsychotic-related side effects.
3.3 Evidence from Observational Studies in Humans and Other Clinical Studies in Support of a Potential Shared Genetic Basis
A growing body of evidence obtained from large-scale across-trait GWAS supports a shared genetic basis for comorbidity of schizophrenia and T2D. Most recently, Ding et al. investigated potential shared genetic overlap between T2D and psychiatric disorders, including schizophrenia, by conducting a large-scale across-trait GWAS [16]. A protein–protein interaction (PPI) analysis identified transcription factor 7-like 2 (TCF7L2) and fat mass and obesity-associated (FTO) protein, also known as alpha-ketoglutarate-dependent dioxygenase. The genes encoding these two proteins (TCF7L2 and FTO) play key roles in the differentially expressed gene (DEG)-based PPI network [16] and are well-known T2D susceptibility genes.
An association of a TCF7L2 variant with T2D risk was first reported in 2006 [44]. Since then, multiple studies conducted among various populations have demonstrated results that are consistent with the original finding by Grant et al. [45,46,47]. Evidence for the TCF7L2 gene in T2D susceptibility has been demonstrated in meta-analyses and in a review of Human Genome Epidemiology (HuGE) [48, 49]. In addition to the general population, TCF7L2 variants in patients with schizophrenia have been associated with an increased risk of T2D development [50]. Active research regarding the relationship between TCF7L2 gene variants and risk of T2D has led to further study of whether TCF7L2 genetic risk variants for T2D are shared by schizophrenia, with the goal of explaining the co-occurrence of these two diseases.
Major genetic variants of TCF7L2 that are associated with schizophrenia and T2D are summarized in Table 2. Strong evidence has been obtained from a series of genetic studies conducted with a unique, homogenous sample of Arab-Israeli families having a relatively large number of individuals affected by schizophrenia [51]. With a total of 189 genotyped individuals from this extended sample of Arab-Israeli families, Alkelai et al. examined a total of 2089 single nucleotide polymorphisms [51] Two schizophrenia susceptibility variants of the TCF7L2 gene, including rs12573128 within intron 4 of the TCF7L2 gene and an intergenic rs1033772 located 318 kb downstream of TCF7L2 and 65 kb upstream of HABP2, were identified. Moreover, these two variants exhibited a significant association with schizophrenia (p = 7.016 × 1026 and p = 6.596 × 1026, respectively) [51]. In another study, Liu et al. examined the relationship between TCF7L2 polymorphisms and susceptibility to schizophrenia among 499 patients with schizophrenia and 500 matched healthy control individuals from the Han Chinese population [52]. Their genetic model and Chi-square analysis revealed that the TCF7L2 gene variant, rs12573128, within intron 4 significantly correlated with an increased risk of schizophrenia in their cohort [odds ratio (OR): 1.33; 95% confidence interval (95% CI): 1.08–1.63; p = 0.006, 52]. Moreover, after adjusting for age and gender, the association remained significant (p = 0.030). This finding is consistent with that of Alkelai et al. [51]. Furthermore, in a study of 410 Danish patients with schizophrenia and matched healthy control individuals, 11 known T2D-associated genetic variants were examined for their association with risk of schizophrenia [53]. The TCF7L2 gene variant, rs7903146 [T], was found to be significantly associated with an increased risk of schizophrenia, and this was confirmed in a larger sample that included 4089 patients with schizophrenia and 17,597 controls [53]. Considering that the aforementioned TCF7L2 gene variants are well documented as T2D variants, the studies described above provide evidence that susceptibility to T2D in patients with schizophrenia can involve genetic risk variants [51,52,53]. In particular, genetic variants of the TCF7L2 gene may contribute to the comorbidity of schizophrenia and T2D.
Aside from a role in beta cell function in the pancreas, little is known about the role of TCF7L2 in health and disease states of the brain. Most recently, Qi et al. has shown a role for TCF7L2 as a molecular switch in controlling mammal vocalization in the midbrain via its DNA binding domain rather than its transcription activation domain [54]. In addition, de Bartolomeis et al. conducted a recent systematic review and meta-analysis that included 180 cell culture, animal, and human studies [41]. They investigated the effects of impaired insulin action, such as systemic and brain insulin resistance or hyperinsulinemia (usually as a result of insulin resistance), on key neurotransmitter pathways known to be associated with the neurobiology of schizophrenia [41]. One key finding was that impairment of insulin action (i.e., insulin resistance, hyperinsulinemia) in model systems was associated with reduced synaptic plasticity. The latter biological process is considered critical for brain development, as well as for learning and memory functions. Moreover, in humans, a deficit in synaptic plasticity has been demonstrated in schizophrenia, and it is hypothesized to contribute, at least in part, to cognitive impairment. In line with this, one of the core symptoms experienced by a large proportion of patients with schizophrenia during, or even prior to, disease onset is reduced synaptic plasticity [55]. However, the etiology of schizophrenia-related cognitive impairment is complex and multifactorial as it involves genetic, biochemical, and neuroanatomic factors [56]. These factors may concur and contribute to the challenges associated with developing effective treatments [56]. Considering that there is no drug currently approved to treat schizophrenia-related cognitive impairment, and that decreased insulin action, especially brain insulin resistance, is associated with deficits in synaptic plasticity, it is possible that nonpharmacological interventions or add-on medications that reverse insulin resistance and improve hyperinsulinemia may be of clinical benefit to patients with schizophrenia. Secondly, data from a meta-analysis of preclinical studies have provided evidence that reduced insulin action, such as insulin resistance and hyperinsulinemia, is associated with dysfunction of glutamate receptor signaling [41]. In the latter pathway, glutamate serves as a key excitatory neurotransmitter which interacts with glutamate receptors to activate downstream signaling pathways and contribute to the neurobiology of schizophrenia [41, 57,58,59]. An abundance of evidence from cell culture systems, animal models, and human studies of schizophrenia support the hypothesis that altered glutamatergic neurotransmission, in particular via the N-methyl-d-aspartate receptor (NMDAR), is a critical causative factor contributing to schizophrenia [57, 60]. Consistent with this, abnormalities of NMDARs have been demonstrated in post-mortem studies, genetic studies, and in neuroimaging studies of humans [57,58,59]. Notably, meta-analysis results suggest that dysregulation of glutamatergic pathways associated with decreased insulin action (i.e., insulin resistance, hyperinsulinemia) may represent a molecular pattern specific to treatment-resistant schizophrenia, while alteration of dopaminergic function may contribute to psychotic symptoms exhibited by patients with schizophrenia who respond to antipsychotic treatment [41]. Consequently, determining whether reversal of insulin resistance using medications or nonpharmacological approaches (i.e., plant-based diets, exercise [61,62,63]) would clinically benefit patients with schizophrenia, particularly patients with treatment-resistant schizophrenia, is important. Third, dysregulation of dopaminergic pathways in animal models with decreased insulin action, such as hyperinsulinemia and brain insulin resistance, has been demonstrated by the following lines of evidence. Dopamine concentrations are significantly decreased in animal models with decreased insulin action, including hyperinsulinemia and brain insulin resistance [41]. In addition, functional parameters of dopamine transport are significantly impaired in an animal model of brain insulin resistance [41]. Of particular interest is the observation that dopamine concentrations are much lower in the limbic and striatal regions of the brain, which suggests a potential pathological role for brain insulin resistance in psychotic symptoms of schizophrenia through an augmentation role in the mesolimbic dopamine pathways [41]. Furthermore, two studies have found that compromise of the mesolimbic pathway due to hyperdopaminergia in the striatal region is associated with cognitive impairment, as well as psychotic symptoms among patients with schizophrenia [64, 65]. Consistent with the results of animal studies, a recent study involving healthy individuals has described a central role for insulin in modulating dopamine signaling in the striatum of the brain [66]. Furthermore, a recent meta-analysis found that insulin-resistant animal models exhibit decreases in both dopamine transporter activity and NMDAR protein levels [41]. These findings indicate that the brain dopaminergic pathway may be negatively affected by abnormal insulin action in the brain, including brain insulin resistance or hyperinsulinemia [41].
A number of studies have highlighted hormonal and neurotransmitter pathways that are shared between insulin resistance/T2D and schizophrenia [17, 67,68,69]. For example, in addition to disruption of the well-known insulin signaling pathway, abnormalities in adiponectin and leptin, hormones secreted by adipose tissue, have been found in both T2D and schizophrenia [69]. The signaling pathways of neurotransmitters, especially dopamine, have long been noted in patients with schizophrenia. The role of neurotransmitters in insulin resistance and T2D has also gained attention. For instance, disruptions in dopamine signaling have been implicated in insulin resistance, while abnormalities in glutamate and GABA systems have been associated with impaired glucose metabolism in patients with diabetes [68]. These findings suggest that both hormonal and neurotransmitter pathways contribute to the co-occurrence of insulin resistance/T2D and schizophrenia.
4 Implications for Better Management of Patients with Schizophrenia and Future Directions
The findings in this review, including the causal role of insulin-related traits (i.e., high fasting insulin and insulin resistance) in schizophrenia, shared genetic risk factors, and the connection of peripheral or brain insulin resistance with cognition impairment and increased risk of developing prediabetes and T2D in schizophrenia following the use of antipsychotics, have important clinical implications for the development of better strategies to treat patients with schizophrenia.
4.1 Potential Nonpharmacological Approaches
Exercise has been well documented to improve sensitivity to insulin in peripheral tissues, the brain, and especially in the hypothalamus [28, 29, 62]. These promising findings suggest that exercise can be an effective nonpharmacological approach to enhance insulin sensitively in the brain and prevent cognitive impairment in patients with schizophrenia. However, it remains to be determined whether exercise itself, or factors associated with exercise such as visceral fat loss or weight loss resulting from exercise, contribute to improved insulin sensitivity. Additionally, further research is needed to investigate whether physical exercise can reverse insulin resistance in the brain.
Impaired insulin sensitivity is considered a precursor of T2D, yet it occurs long before glucose tolerance is impaired and onset of T2D manifests [70]. Consequently, it is possible that preventive measures may preclude T2D development. Accumulating evidence has demonstrated that early impaired insulin sensitivity and prediabetes can be addressed by nonpharmacological measures [62, 71, 72]. The latter may include reducing carbohydrate intake and increasing intake of healthy fats in combination with an anti-inflammatory diet (a dietary approach that emphasizes the consumption of foods with anti-inflammatory properties while minimizing or avoiding foods that can promote inflammation) to reduce systemic inflammation [73]. Furthermore, enhanced physical activity and exercise, especially exercises which build skeletal muscle (i.e., weight lifting, burst training, or high-intensity interval training), as well as effective management of psychological stress, can improve insulin sensitivity [62, 71, 72]. Given that antipsychotic agents are essential in treating schizophrenia, and that the risk of prediabetes and T2D rapidly increases following the initiation of antipsychotic treatment, nonpharmacological measures may be clinically beneficial. This is especially relevant for patients who carry genetic variants that increase the risk of insulin resistance, prediabetes, or T2D, and for patients taking second generation antipsychotics, such as clozapine and olanzapine, which have the highest potential metabolic disturbance and liability [74, 75].
4.2 Potential Pharmacological Interventions
In addition to nonpharmacological lifestyle changes, pharmacological interventions may be considered. Emerging treatment strategies for minimizing the risk of developing antipsychotic-induced prediabetes and T2D in schizophrenia involve the combination of antipsychotics with medications that can potentially mitigate adverse metabolic effects [76, 77]. One notable example is a combination treatment for schizophrenia which was approved by the US Food and Drug Administration in June 2021. This combination treatment includes the second-generation antipsychotic, olanzapine, with samidorphan, a μ-opioid antagonist and partial κ- and δ-opioid agonists [77]. In a 24-week phase 3 double-blind trial in adults with schizophrenia, this treatment combination achieved an effective reduction in medication-induced weight gain and metabolic dysfunction, which is relevant to the development of T2D [78]. Furthermore, in a post hoc analyses from this clinical trial, in patients without a metabolic syndrome, the olanzapine–samidorphan combination decreased the incidence of metabolic syndrome by approximately 50% compared with olanzapine alone [79]. These findings, along with data from studies using the glucagon-like peptide-1 receptor agonist, liraglutide, as an augmentation therapy, highlight the potential for these pharmacological approaches to reduce the risks associated with dopamine receptor-blocking antipsychotics [80, 81].
To address concerns regarding increased risk of weight gain, prediabetes, and T2D that are associated with use of antipsychotic medications that block the D2 receptor, researchers have been exploring alternative treatments that modulate nonpostsynaptic dopamine receptors and target other receptor systems implicated in schizophrenia. For example, ulotaront (SEP-363856) acts as an agonist for both trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors [82]. Ulotaront has demonstrated efficacy in the treatment of patients with schizophrenia, and importantly, is associated with a low risk of adverse weight and metabolic effects [82, 83]. However, despite these promising findings, further studies are needed to confirm the long-term efficacy and safety of ulotaront in patients with schizophrenia.
In addition, metformin is a widely prescribed medication for diabetes, which may help prevent or reverse insulin resistance and prediabetes. Metformin may also delay the progression of prediabetes to diabetes in obese individuals [71]. In patients with schizophrenia, metformin has been used as an adjunct treatment and has improved comorbid glucose dysregulation [84]. Furthermore, an open-label, evaluator-blinded study in clinically stable patients with schizophrenia provided promising evidence that metformin also improves cognitive impairment in patients with schizophrenia [85]. These findings highlight the potential of metformin to serve as a therapeutic option for addressing metabolic disturbances and cognitive impairment in patients with schizophrenia. However, despite efforts to develop drugs for treatment of cognitive impairment in schizophrenia, no medication has yet been approved. Moreover, treatment of schizophrenia-related cognitive impairment remains a challenge. Considering recent findings of a role for brain insulin in regulating dopamine signaling in the striatum [66], an association of brain insulin resistance with decreased dopamine transporter activity and NMDAR protein expression, and susceptibility of the brain dopaminergic pathway to abnormal brain insulin [41], targeting the insulin signaling pathway of the brain may represent a valuable strategy for the development of novel therapeutic agents which counteract psychotic symptoms and cognitive impairments in patients with schizophrenia [57, 59, 64, 65, 69].
4.3 Future Directions
In clinical practice, it remains a challenge to achieve early detection of predisposing genetic risk factors for cognitive impairment in schizophrenia, and to identify patients with schizophrenia at high-risk for developing psychotic-associated prediabetes/diabetes. In addition, there is currently no drug approved for treatment of schizophrenia-related cognitive impairment. Empagliflozin is a relatively novel oral medication that belongs to a class of drugs called sodium-glucose cotransporter 2 (SGLT2) inhibitors [86]. It was originally developed for the treatment of T2D. Empagliflozin works by blocking the reabsorption of glucose in the kidneys, leading to increased urinary glucose excretion [86]. This mechanism of action contributes to improved glycemic control, enhanced glucose metabolism, and reduced glucotoxicity and insulin resistance. In a recent phase 2 clinical trial, empagliflozin was able to restore insulin sensitivity in the brain at the hypothalamus to maintain a preliminary stage of diabetes/prediabetes [87]. Therefore, if the relationship between lower insulin sensitivity in the brain, or brain insulin resistance, and cognition impairment/antipsychotic-related diabetes in patients with schizophrenia is causal, it is important to investigate whether a pharmacological approach (empagliflozin) can prevent cognition impairment, or development of schizophrenia, in individuals who carry relevant genetic factors. Future studies also need to assess whether empagliflozin can be used as an adjunct treatment to antipsychotics in patients with schizophrenia who carry genetic risk factors to reduce the risk of developing antipsychotic-related prediabetes/diabetes.
Interestingly, the Tcf7l2 gene is expressed at high levels in the medial habenula region of the brain in both mice and rats [88]. Functional studies have further demonstrated that TCF7L2 exerts a critical role in nicotine-mediated, diabetes-promoting actions through a habenula-pancreas axis [88]. Additional studies are still needed to elucidate whether TCF7L2 plays a critical role in relevant mechanism(s) underlying the susceptibility of patients with schizophrenia to prediabetes and diabetes.
5 Conclusions
Mendelian randomization studies performed to date suggest a likely causal connection between insulin-related traits (i.e., a genetic predisposition to abnormally high fasting insulin and insulin resistance) and risk of developing schizophrenia. In contrast, the reverse causal effect of schizophrenia on insulin-related traits appears unlikely. It is observational studies in humans, as well as mechanistic studies conducted with cell culture and animal models, that have provided evidence to support a causal association of insulin-related traits and insulin resistance with an increased risk of developing schizophrenia. In addition, the shared genetic risk factors identified in the present review, which may predispose individuals to systemic and brain insulin resistance, may increase the risk of developing cognition impairment and other symptoms of schizophrenia. These genetic factors may also increase the risk of developing prediabetes/diabetes following antipsychotic treatment in patients with schizophrenia. Thus, the findings described in this review have clinical implications, especially regarding the development of better strategies for treating and managing patients with schizophrenia, with the goal of achieving benefits for both patients and their families.
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Zhuo, C., Zhang, Q., Wang, L. et al. Insulin Resistance/Diabetes and Schizophrenia: Potential Shared Genetic Factors and Implications for Better Management of Patients with Schizophrenia. CNS Drugs 38, 33–44 (2024). https://doi.org/10.1007/s40263-023-01057-w
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DOI: https://doi.org/10.1007/s40263-023-01057-w