The Correlation Between Depression and Diabetes

US Pharm. 2014;39(10)(Diabetes suppl):12-15.

ABSTRACT: Independently, depression and diabetes affect a large number of people in the United States. It is also known, while the mechanism remains unclear, that depression and diabetes may be comorbidities and exist in a bidirectional relationship. Patients with depression and diabetes may have poorer outcomes secondary to the lifestyle choices of this patient population. Patients with coexisting diabetes and depression are expected to have an earlier death attributed most commonly to cardiovascular disease. When treating patients with these coexisting disorders, the metabolic side effects of the pharmacologic treatment must be considered. Antidepressants are the primary treatment for depression; however, some classes may be more associated with weight gain than others. Weight gain is considered a modifiable risk factor for type 2 diabetes.

Major depressive disorder (MDD) is a mood disorder that affects approximately 121 million people worldwide.¹ MDD is diagnosed utilizing the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).² It is characterized by a loss of pleasure and/or a depressed mood. Patients may also present with symptoms such as changes in appetite, feelings of guilt or worthlessness, psychomotor agitation or retardation, fatigue, cognitive dysfunction, and suicidal ideation.³

The etiology of MDD remains largely unknown; contributing factors may include genetics, environmental components, and an imbalance of neurotransmitters. While depression may affect all people, in the United States it has been found to be more prevalent in women, persons aged 45-64 years, minorities, people previously married, the unemployed, and those without health insurance coverage.⁴

The prevalence of diabetes mellitus has increased in recent years. In 2012, it was estimated that 29.1 million Americans have been diagnosed with diabetes.⁵ Similar to depression, diabetes is more common in minority patient populations.⁵ There are two different types of diabetes, type 1 and type 2. Type 1 diabetes, which accounts for approximately 10% of diabetic patients, is due to the complete destruction of pancreatic beta cells. The body is unable to make insulin to aid in the metabolism of glucose, carbohydrates, and proteins, which is an indication of the need for manufactured insulin. Type 1 diabetes is most commonly first recognized in children, but there has been a growing incidence in older persons as well. In addition to the common symptoms experienced in type 2 diabetes, patients with type 1 diabetes may experience weight loss despite an increase in food intake, which is a symptom that helps to distinguish it from type 2 diabetes.⁶

Type 2 diabetes, which accounts for approximately 90% of diabetic patients, normally develops later in life.⁷ Type 2 diabetes is characterized by the inability of the pancreas to produce a sufficient amount of insulin or the body’s resistance to the insulin that is produced. Common symptoms of type 2 diabetes include increased hunger, thirst, or urination. Other symptoms that may present include fatigue, blurred vision, slow-healing wounds, and tingling, numbness, or pain in the hands or feet.⁶

Relationship Between Depression and Diabetes

The correlation of depression and metabolic syndrome is bidirectional, i.e., depression may be a cause of metabolic syndrome and metabolic syndrome may be a cause of depressive symptoms. The incidence of depression in patients with metabolic syndrome—a group of metabolic risk factors that increase a patient’s risk for heart disease, stroke, and type 2 diabetes—is increased, as is the occurrence of metabolic syndrome in patients with depression. Patients with depression are at an increased risked for early death, in which the most common cause is coronary vascular disease.¹

The relationship between depression and diabetes is also bidirectional. Patients with diabetes have twice the risk of developing depression than the general patient population.⁸ Studies have indicated that diabetic patients are more likely to have a diagnosis of depression than nondiabetic patients.⁸ A diagnosis of depression and diabetes may also be associated with poorer outcomes in these patients. Individuals suffering from depression are at risk of poor glycemic control, complications with diabetes, and mortality, while diabetic patients have been found to be at risk for the development of depressive episodes as well.⁹

Lin et al conducted a population-based study in patients diagnosed with diabetes and depression.¹⁰ The objective of the study was to assess the association between depression and diabetes self-care, medication adherence, and the use of preventive services. A total of 4,463 subjects (9,063 surveys were initially mailed out) completed the study questionnaires. Results indicated that patients with depression were more likely to lack diabetes self-care activities (i.e., nonsmoking, diet, exercise, glucose monitoring, and foot checks) than patients with diabetes but without depression. The same association was found for medication adherence to oral hypoglycemic agents, antihypertensive agents, and lipid-lowering agents. Patients with depression and diabetes were less adherent to their oral medications when compared to diabetic patients without depression. With the exception of the glycosylated hemoglobin (HbA_1c or A1C) test, there were no differences in preventive services and diabetes monitoring between diabetic patients with or without depression.¹⁰

Mechanism of Correlation and Risk Factors

The causal relationship between diabetes and depression is unclear.⁸ There are two major hypotheses to explain the relationship of diabetes and depression. One hypothesis states that depression may be secondary to the stress of having a chronic medical condition (i.e., type 1 or 2 diabetes) and not to the disease itself. Some studies have indicated that as the chronic medical condition worsens, the probability of mood symptoms increases. It has also been suggested that the mood symptoms secondary to a chronic condition may be strongest just after the initial development of the condition.^8,11

The other hypothesis states that diabetes is secondary to the development of depression. This risk may be a result of an increase in counterregulatory hormone release and function, alterations in the glucose transport system, and increased immune-inflammatory activation. These developments then lead to insulin resistance and islet beta-cell dysfunction.⁸

Depression may serve as a risk factor for diabetes. This may be due to lifestyle habits associated with depression. These lifestyle habits may include poor health behaviors such as smoking, high-fat diet, and excessive alcohol intake, all of which contribute to an increased risk of diabetes.¹²

Antidepressant Mechanisms of Action in Relation to Diabetes

There are several different classes of antidepressants (TABLE 1).^13-15 One of the oldest classes is the tricyclic antidepressants (TCAs). TCAs, such as amitriptyline (Elavil), have a primary mechanism of action of binding to the serotonin transporter (SERT) and norepinephrine transporter (NET). These agents have a high affinity to histamine, acetylcholine, and alpha-adrenoreceptors. Due to the histamine₁ antagonism, TCAs are associated with weight gain, which is one of the risk factors of developing type 2 diabetes.¹³ TCAs have also been associated with insulin resistance, a defect that leads to the development of type 2 diabetes.^14,15

Monoamine oxidase inhibitors (MAOIs) are another older drug class of antidepressants. MAOIs, such as phenelzine (Nardil), are classified as either hydrazines or nonhydrazines. Hydrazines bind irreversibly and non-selectively with MAO-A and MAO-B, while nonhydrazines are more selective or have reversible properties. One of the most common adverse effects of MAOIs is weight gain, which often leads to the discontinuation of these agents as well as to the development of type 2 diabetes.¹³

One of the newer classes of antidepressants is the selective serotonin reuptake inhibitors (SSRIs). These agents were developed in an effort to decrease the number of adverse effects seen with antidepressants. SSRIs, such as fluoxetine (Prozac), inhibit the SERT. Another drug class, similar to SSRIs, is the serotonin-norepinephrine reuptake inhibitors (SNRIs). SNRIs, such as venlafaxine (Effexor), bind to the SERT and NET. Both SSRIs and SNRIs have little to no affinity to histamine, acetylcholine, and alpha-adrenoreceptors, which eliminates some of the side effects seen with TCAs and MAOIs. However, SSRIs and SNRIs may still be associated with some weight gain due to serotonergic effects of these agents.¹³ Again, weight gain is one of the risk factors for developing type 2 diabetes.^14,15

Another class of antidepressants is the 5-HT₂ antagonists. These agents, such as trazodone (Oleptro), are inhibitors of 5-HT₂ receptors. Due to the specificity of these agents to 5-HT₂ rather than SERT, side effects such as weight gain are uncommon.¹³

Tetracyclic and unicyclic anti-depressants are a group of agents that do not fit into any other class of antidepressants. Examples of these agents are bupropion (Wellbutrin) and mirtazapine (Remeron). Based on their unique structures, these drugs have a different side-effect profile than most antidepressants. Adverse effects such as weight gain are specific to each agent.¹³

Treatment of Depression, Diabetes, and Comorbid Depression and Diabetes

Antidepressants are the primary pharmacologic agents used to treat MDD. There are three main phases of treatment for patients diagnosed with MDD: 1) the acute phase, which lasts about 6 to 12 weeks, in which the goal is remission; 2) the continuation phase, lasting 4 to 9 months after remission is achieved, in which the goal is to eliminate residual symptoms or prevent relapse; and 3) the maintenance phase, lasting at least 12 to 36 months, in which the goal is to prevent recurrence.¹⁶ Failure to respond to one antidepressant class or one antidepressant drug within a class does not predict a failed response to another drug class or another drug within the same class.

In addition to the pharmacologic treatment of MDD, nonpharmacologic treatment, such as psychotherapy or electroconvulsive therapy, may also play an important role in the overall treatment regimen. The effects of psychotherapy and antidepressant medications are considered to be additive in the overall resolution of depressive symptoms.^16,17

Medical nutrition therapy is recommended for all patients with diabetes and, along with physical activity, is the cornerstone of treatment. Aerobic exercise improves insulin sensitivity and mildly improves glycemic control in the majority of individuals, reduces cardiovascular risk factors, and contributes to weight loss or maintenance, thereby improving well-being. All patients with type 1 diabetes will require exogenous insulin.¹⁸

Pharmacotherapy for type 2 diabetes has changed dramatically in the last few years with the addition of several new drug classes and recommendations to achieve more stringent glycemic control. Patients with type 2 diabetes are able to take oral agents to help with the production of and sensitization to insulin. Patients may also be initiated on insulin as well to augment treatment.⁷

There are nine classes of oral agents that are approved for the treatment of type 2 diabetes (TABLE 2).^7,18 These drugs are typically grouped according to their glucose-lowering mechanism of action. Knowledge of the patient’s quantitative and qualitative meal patterns and activity levels, the pharma-cokinetics of insulin preparations and other injectables, and the pharmacology of oral and antidiabetic agents for type 2 diabetes is essential to individualize the treatment plan and optimize blood glucose control while minimizing risks for hypoglycemia and other adverse effects of pharmacologic therapies.

Because of the weight gain associated with some antidepressants, patients experiencing depression are at risk of the development of type 2 diabetes. More emphasis on nonpharmacologic treatment is the main focus for patients with an elevated risk for diabetes, such as a family risk of diabetes, gestational diabetes, or overweight. TCAs and MOAIs are more likely to cause weight gain than SSRIs, SNRIs, 5-HT₂ antagonists, or tetracyclic and unicyclic antidepressants, with the exception of mirtazapine. Mirtazapine would likely be placed between TCAs and SSRIs. Of the SSRIs, paroxetine (Paxil) would be considered the most likely to cause weight gain. Bupropion is the least likely to cause weight gain of all the antidepressants.¹⁵

In a population-based study by Kivimäki et al, the use of antidepressants was associated with approximately 0.3 kg of weight gained yearly, which in turn increases the risk of developing type 2 diabetes.¹⁹ Additionally, weight gain was greater with long-term use of antidepressants. It has been shown that patients who have achieved control through diet, oral hypoglycemic agents, insulin, or combinations of oral agents with insulin therapy have a better sense of well-being, improving their mood.²⁰

Conclusion

There is a bidirectional relationship between depression and diabetes. While there are hypotheses that explain this relationship, the exact pathophysiology remains unclear. It is known that patients with depression are at an increased risk of early death most commonly associated with cardiovascular disease. It is projected that by the year 2020, depression will be the second leading contributor to the global burden of disease.¹ Many behaviors seen in patients with depression may contribute to the greater risk of diabetes.

While the lifestyle factors of depressed patients should be considered, if drugs are used to address depressive symptoms, their effect on the risk of diabetes should also be considered. The use of antidepressants for the treatment of depression may contribute to this risk of diabetes; specifically, anti-depressants that are associated with significant weight gain (i.e., TCAs, MAOIs, mirtazapine). An increase in weight is considered to be a risk factor for type 2 diabetes. When treating a patient with comorbid depression and diabetes, one should consider the use of antidepressants that are known to have less risk of increased weight (i.e., bupropion, SSRIs, SNRIs).

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