Early Combination Therapy for Type 2 Diabetes Mellitus and Common Comorbid Mental Disorders

This article reviews the literature regarding metabolic interactions, pathological pathways, and protocols for screening, monitoring, and using combination therapy for individuals with type 2 diabetes mellitus and common comorbid mental health conditions. A narrative literature review for the years 2004–2016 used the search terms “type 2 diabetes mellitus,” “schizophrenia,” “depression,” and “anxiety” in PubMed, PubMed Central, and BioMed Central databases and in several medical journals.

Type 2 Diabetes Mellitus and Schizophrenia

In 1919, F. H. Kooy described 10 patients with hebephrenic schizophrenia and concluded that they had both “dementia praecox” and “hyperglycemia” (1). Thus, a link among diabetes, serious mental illnesses, and adverse side effects of antipsychotics has long been appreciated.

Rates of diabetes among patients with schizophrenia are estimated to be 16% to 25%, approximately double the rate in the general population (Figure 1). The greater risk may be attributed to metabolic disturbances and weight gain associated with atypical antipsychotics. Higher rates of insulin resistance of patients with schizophrenia than in the general population were noted even before the introduction of antipsychotic drugs in the 1950s. Patients with schizophrenia also possess other risk factors for the development of diabetes and cardiovascular disease, such as smoking, poor diet, reduced physical activity, and alcohol or drug abuse (2).

Type 2 diabetes mellitus (T2DM) involves at least seven organs and tissues, including the pancreas, liver, skeletal muscle, adipose tissue, brain, gastrointestinal tract, and kidney. In type 2 diabetes, the two main problems are insulin resistance and impaired insulin secretion. Insulin resistance refers to a decreased tissue sensitivity to insulin. Normally, insulin binds to special receptors on cell surfaces and initiates a series of reactions involved in glucose metabolism. In type 2 diabetes, these intracellular reactions are diminished, making insulin less effective at stimulating glucose uptake by the liver. Reduced sensitivity to insulin and progressive decline in pancreatic β-cell function, leading to impaired insulin secretion, eventually result in hyperglycemia, the hallmark of future T2DM (3).

Metabolic Brain Abnormalities and Their Clinical Implications for Patients With Schizophrenia and Comorbid T2DM

Brain tissue is highly dependent on glucose metabolism. Neuronal activity and biochemical processes require a steady supply of glucose. However, the central nervous system (CNS) has a minimum storage capacity, with low levels of glycogen or lipids. Thus, any changes in metabolic pathways may contribute to the pathophysiology of schizophrenia. A positron emission tomography study showed significantly decreased glucose uptake in all areas of the brain in patients diagnosed as having schizophrenia with negative symptoms. On the other hand, participants with a positive type of schizophrenia demonstrated markedly increased glucose metabolism in the parahippocampal region, striatum, and left thalamic area (4). These findings support the results of Dean et al.’s study, in which subjects given a diagnosis of schizophrenia had higher levels of pyruvate and acetyl-CoA in the striatum (5). Human studies of T2DM provide evidence that impaired glucose metabolism contributes to CNS damage, particularly within the hippocampus. Changes in hippocampal morphology in both, patients diagnosed as having schizophrenia and patients with T2DM, may contribute to cognitive deficits, mainly in immediate memory and attention. Research has shown that local delivery of insulin to the hippocampal area improves cognitive function (6). Collectively, these findings suggest that schizophrenia with comorbid diabetes results in more serious cognitive dysfunction than does schizophrenia alone (7). Several other authors came to the same conclusion regarding cognition of these patients. Takayanagi et al. (8) and Bora et al. (9) reported that patients with schizophrenia and comorbid T2DM demonstrated much worse cognitive performance than did patients with schizophrenia who did not have diabetes.

Schizophrenia Neurotransmitters and Glucose Homeostasis

The mechanism of schizophrenia has been well defined in the literature. It is thought that dopamine, serotonin, and glutamate formulate the neurotransmitter hypothesis of schizophrenia, the same neurotransmitters found to interfere with glucose metabolism. This might partially explain the increased frequency of obesity, diabetes, and metabolic syndrome in individuals diagnosed as having schizophrenia. Dopamine has been shown to inhibit glucose-stimulated insulin production in the pancreas (10). Other studies demonstrated that insulin controls the brain’s supply of dopamine. Disrupted insulin signaling results in an excessive level of norepinephrine transporter protein. It would potentially lead to reduced dopamine and elevated norepinephrine in the prefrontal cortex. This situation creates hypodopaminergia (11). Could this vicious cycle of “dopamine-insulin-dopamine” explain the high rates of impaired glucose metabolism in patients given a diagnosis of schizophrenia, even prior to treatment with antipsychotics? This conclusion certainly deserves closer attention and further investigation. Serotonin, on the other hand, mediates insulin secretion in response to elevated glucose levels. Clozapine, perhaps the most effective antipsychotic agent, is a partial serotonin (5-HT2A) antagonist. Some authors offered a serotonergic model for clozapine- and olanzapine-associated diabetes. The review of animal data showed that 5-HT antagonism reduces insulin secretion by blocking pancreatic β-cell responsiveness, thereby increasing serum glucose levels (12). The data on glutamate and its influence on glucose metabolism are controversial. It was well documented that glutamate could induce insulin secretion and improve glucose tolerance in animals. It would have easily explained why patients who were diagnosed with schizophrenia, also known as “hypoglutamatergic” disorder (13), were predisposed to metabolic abnormalities. Today, some scientists are more careful and agree instead that glutamate “modulates” insulin production. However, the mechanism of this regulation is still unclear. Overactivation of the immune system (e.g., from prenatal infection or postnatal stress) may result in overexpression of inflammatory cytokines and subsequent alteration of brain structure and function. Patients diagnosed with schizophrenia have elevated levels of proinflammatory cytokines that activate the kynurenine pathway, producing metabolites that regulate glutamate receptor activity and may also be involved in dopamine regulation. Insulin resistance and metabolic disturbances, which are common in the schizophrenic population, have also been linked to inflammation. Thus, inflammation might be related both to the psychopathology of schizophrenia and to comorbid metabolic disturbances (14).

Prolactin as a Link Between Schizophrenia and T2DM

It is well known that dopamine influences prolactin secretion. Dopamine action is mediated by five dopamine receptors: DR1D, DR2D, DR3D, DR4D, and DR5D. Both increased dopamine function in some brain areas and decreased dopamine action in others may contribute to schizophrenia as well as to T2DM. Prolactin regulates β-cell survival and has a role in glucose metabolism via glucokinase activity and in insulin secretion (15). Sari et al showed that patients with poorly controlled diabetes have reduced serum prolactin levels (16). An altered dopamine pathway in schizophrenia may reduce the prolactin level, impairing carbohydrate metabolism and contributing to the onset of T2DM.

Pathogenetic Links and Other Contributing Factors

Patients with schizophrenia diagnoses and their first-degree relatives have a two- to five-fold greater risk of T2DM than does the general population, independent of body mass index and antipsychotic medication, suggesting that shared genetic components may contribute to both diseases (17).

Disrupted in schizophrenia 1 (DISC1) is a well-characterized schizophrenia susceptibility gene, also involved with several other psychiatric illnesses including bipolar disorder and major depression. It has also been identified as a major player controlling pancreatic β-cell proliferation and insulin secretion. Loss of DISC1 function results in decreased β-cell proliferation, increased apoptosis, glucose intolerance, reduced insulin secretion, and decreased critical β-cell transcription factors. This suggests that DISC1 dysregulation contributes to T2DM independently of its importance for cognition.

Occasionally, patients develop T2DM within a few weeks or months of beginning antipsychotic treatment—for the most part with clozapine or olanzapine. In 2015 Thomas highlighted the work of Koller and Doraiswamy, whose findings indicated that 80% of patients experienced improvements in glycemic control after discontinuing therapy with clozapine and olanzapine (18). Obesity, sedentary lifestyle, and social health determinants, such as income and housing, are major contributing factors for patients with both diabetes and schizophrenia diagnoses (19).

Management

Antipsychotic medications are different in their propensity to cause weight gain and impair glucose tolerance. Clozapine and olanzapine, which are metabolically the most unfavorable antipsychotics, are also the most effective antipsychotic medications. However, medication changes may be possible, and antipsychotics with a low risk of metabolic side effects are preferred for people with schizophrenia with comorbid T2DM. Among antipsychotic agents, ziprasidone is the least likely to cause significant weight gain and should be considered in all patients (Table 1). Aripiprazole and other antipsychotics such as perphenazine, fluphenazine, and haloperidol can be considered as second-line agents for attenuation of weight gain. In primary care settings, such a change should be coordinated with a psychiatrist, because some patients require a certain medication, despite its metabolic side effect, because they did not respond to other medications in the past. In other cases, a medication switch poses a high risk for psychiatric decompensation, so treatment should be directed toward lifestyle changes or other indicated interventions (20). Individuals with schizophrenia may also be taking drugs other than antipsychotics that have metabolic side effects, for example, valproate and some antidepressants, and the possibility of changing these medications should also be assessed (21). It is important to screen for metabolic side effects such as metabolic syndrome. This syndrome is defined as a waist circumference of greater than 40 inches in men or 35 inches in women, high-density lipoprotein concentrations less than 40 mg/dL, and triglyceride concentrations above 150 mg/dL. Among patients with a mental disorder, adherence and follow-up may be an issue, and so glycosylated hemoglobin (HbA1c) testing may be preferable to obtaining a fasting glucose level as a screening test. For those taking antipsychotics, screening should be done at baseline and then at three-month intervals. If the HbA1c levels remain stable, screening can be reduced to six-month or one-year intervals (22). A minimum of 150 minutes of “moderate” intensity physical activity per week is recommended, although this may depend on the patient’s baseline activity levels and comorbidities (23). Metformin is usually indicated as a first-line pharmacotherapy for patients with type 2 diabetes who do not achieve adequate glucose control with diet and lifestyle change alone. Metformin, alone or in combination with lifestyle modification in the treatment and prevention of antipsychotic weight gain, has been studied in several meta-analyses and controlled trials (24). The best result was achieved by adding metformin to lifestyle changes (24). Among patients with chronic schizophrenia on olanzapine, metformin was effective in lessening both weight and HbA1c levels. Orlistat may also be indicated for patients with significant antipsychotic-induced weight gain (25).

Type 2 Diabetes Mellitus and Depression

Depression remains unrecognized and untreated in approximately two thirds of patients with diabetes. The prevalence of major depressive disorder among individuals with T2DM is approximately 12%, which is double the overall prevalence among people without a chronic medical illness (26). It has been shown that patients with T2DM have a 24% higher risk of developing depression than do nondiabetic individuals (27). Patients with depression have an approximately 60% increased risk of developing type 2 diabetes. Episodes of depressive disorder occurring among patients with diabetes are likely to last longer and have a higher chance of recurrence than do episodes occurring among the nondiabetic population. Comorbid depression worsens clinical outcomes in diabetes, possibly because the accompanying lethargy diminishes motivation for self-care, resulting in lowered physical and psychological fitness, higher utilization of healthcare services, and reduced adherence to treatment plans. Treating depressive symptoms improves mood more reliably than it does glycemic control (28). Up to 80% of patients with diabetes and depression will experience a relapse of depressive symptoms over a five-year period (29).

Structural Brain Changes Associated With Depression and T2DM

Individuals with depression and comorbid diabetes showed decreased cortical gray matter thickness in bilateral prefrontal regions (30). A recent functional magnetic resonance imaging study demonstrated that patients with major depression had pathological activation within the medial prefrontal cortex. This correlates with specific symptoms among patients given a diagnosis of depression, such as feelings of guilt and rumination. Subjects with diabetes demonstrated more diffused functional changes, predominantly in frontotemporal region, hippocampus, and amygdala (31). T2DM is specifically linked to microvascular and neurodegenerative diseases. It is worthy of mentioning that depression among elderly populations is also associated with neurodegeneration, especially at the level of the hippocampus and prefrontal cortex (32). The association between T2DM and major depression is modest and understudied. It certainly requires further investigation.

The Role of Neuroendocrine and Inflammatory Pathways in the Comorbidity of Depression and T2DM

The hypothalamic-pituitary-adrenal (HPA) axis responds to a stressor by triggering a cascade of reactions. It starts from corticotropin-releasing hormone (CRH) production in the hypothalamus, which stimulates the anterior pituitary gland to release adrenocorticotropin hormone, which then causes cortisol release from the adrenal glands. An excess amount of glucocorticoids can result in increased glucose production via stimulation of gluconeogenesis in the liver and skeletal muscles and reduced insulin sensitivity (33). There are several hypotheses for the mechanisms underlying the association between depression and cortisol-induced diabetes. It is suggested that glucocorticoid receptor (GR) abnormalities, such as their dysfunction or reduced receptor number, could cause hypercortisolemia and oversecretion of CRH. This observation was supported by the demonstration of GR impairment in postmortem studies of patients who had diagnoses of severe mood disorders. Researchers have found that tricyclic antidepressants have the ability to control GR expression and show greater therapeutic effect for patients with depression who have comorbid hypercorticolism (34).

The pancreatic tissue is extremely susceptible to different kinds of stress, such as oxidative stress and cellular stress. The pancreatic β cells respond to that stress with the initiation of an inflammatory process. Numerous studies have shown that tumor necrosis factor α (TNF-α), an inflammatory biomarker, was produced by adipose tissue and could be responsible for increased local and systemic insulin resistance (35). High serum levels of inflammatory cytokines, especially interleukin-6 (IL-6) and C-reactive protein (CRP), have been found in subjects with diabetes. Increased concentration of inflammatory agents might alter the tryptophan-kynurenine pathway and increase serotonin turnover. Thus, low-grade inflammation could be considered a possible link between major depression and T2DM. Serum levels of TNF-α, IL-6, and CRP in patients with diabetes and comorbid depressive symptoms were notably higher than in patients with diabetes mellitus alone (36).

Genetic Link and Other Risk Factors for Depression and T2DM

To determine whether there is a relationship between T2DM and major depression, scientists performed a genetic analysis on 160,000 twins from Sweden and Denmark. When evaluating a sample of Swedish twins, there was a 31% correlation between diabetes and depression in males and a 75% correlation in females. When analyzing data from Danish twins, an overlap between diabetes and depression was found in 87% of men and 74% of women (37). However, there is little knowledge about the genetic interaction between T2DM and major depression. Therefore, more research is necessary on this topic. Risk factors for patients with diabetes developing depression include female gender, poor social support, stress, recurrent hypoglycemia, longer duration of diabetes, and presence of long-term complications (38).

Management

While treating patients with depression and comorbid diabetes, primary care providers face tough challenges. Some patients reported that the stigma associated with depression prevented them from seeking help (39). Undiagnosed subclinical depression in diabetic patients requires more extensive measures, such as careful medical history taking and screening. Commonly used screening measures are Becks Depression Inventory, Well-Being Questionnaire, and Patient Health Questionnaire (PHQ). These are simple tools for general practitioners to diagnose depression, monitor patients over time, and guide them to the next level of disease management (40). Psychiatric referral is indicated for individuals with a history of severe emotional distress/ suicidal ideations or suicidal attempts in the past. In other cases, the primary care provider can request psychiatric consultation to clarify a proper treatment plan or if the patient fails to respond to antidepressants prescribed by the primary care physician. The goal of collaborative care of patients with comorbid depression and diabetes is not just to improve the courses of both diseases but also to prevent a number of complications and decrease the level of disability in such patients (41).

Cognitive-behavioral therapy can be effective at treating depressive symptoms and may also reduce HbA1c levels (42). Fluoxetine and sertraline demonstrated results consistent with lower glucose levels in T2DM patients with comorbid depression. Nortriptyline has shown a worsening of indices of glucose control. However, the improvement of depression with nortriptyline showed independent beneficial changes on HbA1c (43). Patients should be assessed for complications or long-term effects of diabetes. Bupropion, venlafaxine, or duloxetine should be considered before serotonin selective receptor inhibitors (SSRIs), when appropriate. They have been shown to relieve different kinds of chronic pain, associated with comorbid T2DM.

Type 2 Diabetes Mellitus and Anxiety

A cross-sectional study in China, with 893 participants, ages between 18 and 84 years, with a history of T2DM, demonstrated the prevalence of anxiety symptoms reaching up to 43.6%. This investigation indicated that anxiety symptoms were associated with being a female, having low income, chronic disease, and poor sleep quality (44). Rajput et al.’s findings suggested that patients with T2DM have a higher risk of developing anxiety than do nondiabetic individuals (26.3% vs 11.2%) (45). Anxiety disorders correlate directly with poor adherence to medications, insufficient glycemic control, and increased adrenergic activity. Some diabetic patients report having anxiety symptoms due to fears of hypoglycemia, complications, or mortality (46).

Metabolic Interactions in Anxiety Disorders and T2DM

When triggered by a stressor, the HPA axis and sympathetic nervous system create a response. Corticosterone and catecholamines could also influence glucose metabolism. It is a well-known fact that epinephrine and norepinephrine can stimulate glucose production via gluconeogenesis and glycogenolysis (47). It could aggravate the course of T2DM in the setting of comorbid anxiety disorders. A recent animal study showed that mice with insulin resistance in the brain would exhibit a high rate of dopamine turnover, which clinically manifests in anxiety-like behavior (48).

Management

Primary care providers might have difficulties in differentiating anxiety disorder with comorbid diabetes from primary anxiety illness. Some anxiety disorders can mask or mimic symptoms of hypoglycemia occurring among patients with diabetes. In other cases, patients with preexisting anxiety and T2DM can experience increased severity of their anxiety symptoms (49). All individuals with diabetes in the collaborating general practices should be screened for signs of anxiety, using the Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 scale (GAD-7). If a patient scores below 7 for PHQ-9 and below 8 for GAD-7, only monitoring is needed. If patient scores above these cut-offs, education on “coping with anxiety” for at least 10 weeks should be offered. If this education is not helpful or if symptoms of anxiety worsen, treatment with medication is indicated (50). However, medications used for the treatment of anxiety disorders, such as SSRIs, benzodiazepines, and beta-adrenergic blockers, could possibly interfere with glycemic control and mask normal physiological warning signs of an upcoming hypoglycemic episode (51).

Conclusions

Common mental disorders are frequently comorbid with physical illnesses such as T2DM. There are some shared pathological pathways between diabetes and mental health conditions. The treatment of both comorbid illnesses at the same time is necessary and should be available. Treatment consists of psychological/pharmacological interventions with careful consideration of each patient’s comorbidity, possible complications, and adverse side effects of medications.

The collaborative care model remains a valid tool for primary care providers treating mental disorders in association with physical illnesses, such as diabetes. General practitioners may experience some challenges while trying to deliver care to patients with comorbid mental disorders, due to the lack of expertise and stigma of psychiatric illness among them. To overcome these issues, primary care physicians should have knowledge of mental disorders and be educated in treatment challenges and health risks. However, excellent care for such patients could also be achieved in collaboration with a psychiatrist. Some of the preventative measures, such as screening and regular metabolic monitoring, would not only diminish the incidence of complications but would also lead to a decreased level of disability.