CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 13, 2020
Expiration: April 12, 2021
As mentioned, MDD is an independent risk factor for cardiovascular mortality. MDD is common in outpatients with coronary heart disease, people undergoing coronary artery bypass surgery, and people who have had a major cardiac event.5,6
On the flip side, patients with obesity, hypertension, diabetes, and overall mortality are at increased risk of having MDD.7-10
Based on findings from a large meta‑analysis of cross‑sectional studies, we can conclude that patients with MDD have a significantly increased risk of cardiovascular disease and coronary heart disease and a numerically increased risk for cerebrovascular disease.11
In longitudinal studies, all of these risks were significantly increased.11
This interrelationship between depression and cardiovascular risk factors and disorders converges with downstream effects that are also stress related.1,2 In depression it is typical to find increased markers of inflammation, cortisol, and other mediators of stress responses.
Data on depressed subjects have shown that depression is associated with increased levels of C‑reactive protein, tumor necrosis factor-alpha, soluble interleukin‑2 receptor, interleukin‑6, and interleukin‑1 receptor antagonist.12-15
We also know that prolonged mental stress leads to oxidative stress, endothelial dysfunction, and inflammation, which predisposes these individuals to atheroma and coronary heart disease as well as myocardial infarction.16,17 In particular, increased platelet reactivity is a risk factor for myocardial infarction and the development of atheroma.18,19
When treating patients with MDD, we want their depressive symptoms to improve without increasing their cardiovascular risks. Ideally, we would select treatments that can reduce the risk for cardiovascular complications or at least not increase them further.
Data on SSRIs and selective norepinephrine reuptake inhibitors indicate that these drug classes can decrease inflammatory markers, including interleukin‑6 and C-reactive protein, especially in outpatients and men.20,21 This benefit may be a direct effect of the medication or may be a downstream result of improvement in depressive symptoms, which subsequently leads to a reduction in stress markers and inflammation.
With several second‑generation antipsychotics approved as adjunctive treatments for patients with MDD, it is also relevant to review how these agents affect inflammation. Unfortunately, current data are somewhat inconsistent.
On one hand, treatment-mediated improvements in depression may lead to reduced inflammation via reduced stress and depression‑related biological mechanisms.
On the other hand, antipsychotics have been associated, to varying degrees, with weight gain. Weight gain and obesity in turn can lead to inflammation and increases in insulin resistance and dyslipidemia, which are associated with cardiovascular illness and metabolic syndrome.22
There are currently 3 second-generation antipsychotic agents approved as adjunctive therapies for MDD in the United States: aripiprazole, brexpiprazole, and quetiapine XR.23-25 Olanzapine plus fluoxetine is the only combination treatment and is approved for patients with treatment-resistant depression, meaning that they have not responded to 2 separate trials of antidepressants.26
All of these approved agents have demonstrated good efficacy, although we do not have any head-to-head comparison data.
Not all second‑generation antipsychotic agents are approved for MDD because the dopamine modulation required for the treatment of psychosis and, potentially, mania is not the main pharmacodynamic effect that improves depression.
Other pharmacodynamic mechanisms are important and differ among the approved second‑generation antipsychotic agents. These include partial dopamine type 2 (D2) agonism, as seen with aripiprazole and brexpiprazole23,24; alpha-2 antagonism, as seen with quetiapine XR, which leads to an increase in noradrenaline and norepinephrine25; as well as varying degrees of serotonin type 2A (5HT2A) antagonism, which is shared across almost all second‑generation antipsychotics.25,26
Other second‑generation antipsychotics approved for bipolar depression seem to exert their effects via blockade of, for example, the serotonin 5HT7 receptor, as seen with lurasidone.27
As previously mentioned, second‑generation antipsychotics are associated with varying degrees of weight gain, metabolic, or cardiovascular abnormalities.
Weight gain differences among these antipsychotics are much larger and more easily predicted than differences in efficacy, including when used as augmentation therapy for patients with MDD who have a suboptimal response to antidepressants. Among antipsychotics FDA approved for MDD, the lowest risk for weight gain is seen with aripiprazole and brexpiprazole. Quetiapine XR and olanzapine plus fluoxetine have higher risk for weight gain and glucose or lipid abnormalities.28
Among agents not approved for MDD, lumateperone, lurasidone, and ziprasidone have a low risk of weight gain and metabolic abnormalities.28, 29
Obesity and MDD appear to be interrelated. There is a subgroup of patients with MDD who experience significant weight loss when they are depressed, but others tend to overeat and gain weight.
We also know that people in the general population who are overweight or obese and who have related increased inflammation are at an increased risk of developing MDD.30 Furthermore, sleep apnea that can be associated with MDD may affect cognition and increase fatigue, inflammation, and depression.31 Therefore, treating depression can potentially improve weight control in people who are overeating as a symptom of depression.
Effective MDD treatment may also reduce inflammation. SSRIs are generally weight neutral, whereas patients taking tricyclic antidepressants and mirtazapine have an increased risk for weight gain.30
Weight gain and obesity are risk factors not only for inflammation, depression, and cardiovascular events, but also for decreased adherence.
In a survey of 350 people with mild to severe depression, weight gain was the most common reason cited for nonadherence.32
Data from patients with bipolar disorder also support the idea that patients see weight gain as a key factor to avoid.33
Data from people with schizophrenia treated with first- and second‑generation antipsychotics also indicate that cardiometabolic adverse events, including weight gain, rank high in reducing adherence to antipsychotic medications, reducing adherence by 36%.34 These adverse event clusters were second only to extrapyramidal adverse events and agitation, which led to a 43% reduction in adherence.
Knowing that both depression and some treatments for depression are associated with weight gain and cardiometabolic risk, clinicians need to be aware of monitoring guidelines.
Current guidelines recommend that clinicians discuss personal and family history of cardiometabolic illness at baseline and annually.35 Height and body weight should be assessed at baseline, with frequent weight and body mass index assessments at each visit in the first 3 months (unless visits occur more frequently than monthly). After the first 3 months, when the risk for weight gain is greatest, quarterly assessments of body weight can be implemented, unless the patient has severe weight gain.
Waist circumference should ideally be measured at baseline and annually, but body mass index is a good proxy measure.
Additional baseline assessments should include blood pressure and fasting glucose and lipid parameters. These assessments should be repeated after 3 months and then annually. However, when a patient gains ≥ 7% of his or her body weight or other cardiovascular risk factors have increased and are potentially abnormal, more frequent monitoring should be implemented.
When monitoring cardiovascular parameters, clinicians should also be aware of thresholds that indicate an increased risk for cardiovascular morbidity and mortality.
Metabolic syndrome has emerged as a constellation of risk factors that is of particular importance for predicting 10‑year cardiovascular risk. It consists of 5 criteria, of which at least 3 must be present to make a diagnosis of metabolic syndrome.36
Each of the 5 criteria is important and should be measured and addressed individually.
Why are we so concerned about abdominal obesity and obesity in general? We are concerned because obesity is related to insulin resistance and insulin resistance is related to the other factors associated with metabolic syndrome including glucose intolerance, dyslipidemia, and arterial hypertension.37
In addition, other cardiovascular risk factors not included in the criteria for metabolic syndrome are also associated with obesity and insulin resistance. These include endothelial dysfunction, impaired thrombolysis, and inflammation. Notably, each of these parameters, and smoking, is also associated with MDD. Hence, all these risk factors converge to elevate the overall risk of atherosclerosis, coronary artery disease, and cerebrovascular disease.
To maximize the efficacy of pharmacologic treatment in people with mental illness, we need to combine medication interventions with psychoeducation and psychotherapy.38 In addition, we need to consider treatment tolerability because, as shown earlier, tolerability issues can impair adherence. Without proper adherence to medications, patients are less likely to achieve the higher order goals of subjective wellbeing, quality of life, and functional capacity. Moreover, as mentioned earlier, if tolerability issues include obesity and weight gain, these can impair the antidepressant efficacy, potentially because of increased inflammation and oxidative stress that may interact adversely with depression.
For patients with suboptimally responsive or treatment‑resistant MDD, which may occur in as many as 30% of patients receiving antidepressants, augmentation strategies are available.39
Currently, the only approved agents for augmentation are select second‑generation antipsychotics. As mentioned previously, among antipsychotics FDA approved for MDD, the least potential for weight gain and cardiometabolic burden are with aripiprazole and brexpiprazole,28 so I would consider these the preferred agents for augmentation from a safety/efficacy standpoint.
However, when prescribing any of the second‑generation antipsychotics, clinicians should monitor for cardiometabolic adverse events, including all the components of metabolic syndrome: abdominal obesity, blood pressure, glucose, HDL cholesterol, and triglycerides.35
Weight gain must also be measured because it is the core adverse event from which many of the other cardiovascular adverse events emerge. When weight gain is observed, healthy lifestyle instruction (including smoking cessation) or even weight reduction treatments should be implemented. These could include healthy lifestyle interventions or cotreatment with either metformin or topiramate, which have been associated with significantly lower weight gain when combined with second‑generation antipsychotics.40
At the same time, clinicians should be aware that medications used to manage cardiovascular disease can contribute to depression, including beta blockers, clonidine, or reserpine.41 Patients receiving these medications should be closely monitored, and clinicians should consider avoiding reserpine.
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