Prospective studies support the assumption of a bidirectional association between depression and type 2 diabetes mellitus (DM2) . Depression is especially related to a prospectively increased risk for DM2 [odds ratio (OR) 1.37] . Thus, depression is highly prevalent in DM2  and antidepressant usage in DM2 patients may even exceed the prevalence of depression . Depression and diabetes mellitus are both related to increased all-cause and cardiovascular mortality, but the comorbidity seems to be especially toxic, even after testing for adverse health behavior and other comorbidities (OR 2.72) [5▪]. Affective disorders may increase metabolic disturbances and risks for DM2, as well as cardiovascular complications due to inflammatory factors, activity of the pituitary–adrenal and sympathoadrenergic system, and also due to behavioral effects. Especially, smoking, sedentary lifestyle, and nonadherence to medical advice are known to be related to depression . Additionally, there is concern that antidepressant treatment may modulate the metabolic risks.
Given these facts, this review intends to provide information on whether antidepressant treatment in nondiabetic patients induces risk for DM2 and whether antidepressant treatment in depressed diabetic patients is effective and whether it may improve the prognosis of diabetes mellitus.
SHORT-TERM EFFECTS ON GLUCOSE METABOLISM IN NONDIABETIC DEPRESSED PATIENTS
Often the course of depression is chronic or highly recurrent and most depressed patients require long-term antidepressant treatment. Thus, it is important to estimate antidepressants’ effects on glucose homeostasis in nondiabetic depressed patients. Short-term effects have been studied in small controlled trials, whereas long-term data on recurrence prevention are only available from epidemiological studies. Several small studies have shown indices of insulin resistance to improve or remain unchanged despite weight gain during short-term treatment with imipramine (12 weeks), venlafaxine, paroxetine, fluoxetine, mirtazapine, and amitriptyline after a 4–5-week treatment period, given that patients clearly responded to medication [7–11]. However, some trials showed no effect of antidepressants (maprotiline, venlafaxine, fluoxetine, citalopram, mirtazapine) or untoward effects during treatment with imipramine on glucose regulation in nondiabetic depressed patients [10–14]. Other studies gave clear-cut evidence for declining insulin sensitivity during treatment with maprotiline [15,16]. A number of case reports showed inhibitors of monoamine oxidase (e.g. tranylcypromine) in some cases to lead to hypoglycemia . Overall, it can be assumed that short-term treatment of nondiabetic depressed patients may at least not deteriorate, but rather improve, insulin sensitivity in the case of improved severity of depression. Noradrenergic antidepressants are an exception and may lead to impaired insulin sensitivity .
LONG-TERM RISK FOR DIABETES MELLITUS TYPE 2
Antidepressants affect a plethora of factors that may mediate the risk for DM2, with weight gain being considered one of the most important mechanisms. A recent meta-analysis showed amitriptyline, mirtazapine, and paroxetine to be especially related to weight gain, whereas fluoxetine and bupropion may lead to some weight loss, at least in the short run .
Some, but not all , epidemiological studies gave evidence for the assumption that long-term treatment with antidepressants may increase the risk for DM2 with duration of treatment, but less so, choice or combination of antidepressants contributing to the risk [20–25]. In the longitudinal Diabetes Prevention Program study, antidepressants rather than depression were related to incident DM2 (OR 2.3–3.5). Most observational nonrandomized studies found tricyclic antidepressants (TCAs) as well as SSRIs to be associated with incident DM2 . However, some studies showed increased rates of metabolic syndrome in tricyclic-treated patients  and lower rates in citalopram-treated patients . The fact that combined SSRI and TCA treatment, but not respective monotherapy, was related to increased rates of DM2 may suggest that severity of disease or duration of depression may play a role . In fact, in a cross-sectional study with 1217 depressed and/or anxious patients, severe depression (OR 2.21), but also usage of tricyclics (OR 2.30), was associated with an increased prevalence of the metabolic syndrome . Using the UK General Practice Research Database with a nested case–control approach based on 165 958 patients with 2243 cases of incident diabetes, recent long-term (>24 months) usage of antidepressants in moderate to high dosages was associated with an increased risk of DM2 (OR 1.84). Notably, the risk did not differ between tricyclic and SSRI-treated patients, whereas the duration of treatment and the dosage were critical . In accordance with these observations, a study using a pharmacy database with 49 543 diabetic patients showed an increased antidepressant prescription rate in the 2 months prior to incident diabetes and in the month after initiation of diabetes treatment. Also, some studies, like the Public Sector Study, which included 151 347 patients, with 9167 patients on antidepressant medication, for a mean follow-up of 4.8 years, found that long-term treatment (≥200 daily doses of antidepressants) was associated with a doubled risk for incident DM2. The 5-year risk for DM2 was increased in antidepressant users (1.7%) compared with nonusers (1.1%), although the absolute risk elevation was modest . In the Diabetes Prevention Program and Diabetes Prevention Outcome Study with a 10-year follow-up, continuous antidepressant use was related to a significant increase in incident DM2 in the placebo arm (OR 2.34), as well as in the lifestyle intervention arm (OR 2.48), even after controlling for various confounders [21,27]. The 7.6-year prospective Women's Health Initiative study followed 161 808 postmenopausal women and found elevated depressive symptoms at baseline (OR 1.13) as well as antidepressant use (OR 1.18) to be significantly associated with incident DM2 [28▪]. Taken together, these data suggest that depression and antidepressants contribute to increased risk for incident DM2. The data give the impression that, potentially, TCAs or combination treatment, as well as high-dosage and long-term antidepressant treatment, may somewhat increase the odds.
Since only some of these studies have been longitudinal and none has been a randomized controlled trial (RCT), all conclusions of these findings remain somewhat speculative. These data do not allow exclusion of bias due to depression as a potential contributor to DM2 or earlier detection of DM2 due to care for depression .
In contrast to the above-mentioned literature, the Prevalence, Prediction and Prevention of Diabetes-Botnia trial studied 4419 individuals using oral glucose tolerance and could confirm clinical studies  showing an association between depressive symptoms with impaired glucose tolerance as measured by fasting and 30-min insulin as well as Homeostasis Model Assessment index. However, no significant association of antidepressants with insulin resistance was shown [31▪▪]. Thus, several, but not all [19,31▪▪], large epidemiological studies found a significant association of antidepressant usage with incident DM2. Severity of depression may be related to usage of antidepressants. Thus, other factors secondary to severity of depression, like adverse lifestyle factors, may contribute to the risk being attributed to antidepressants. Evidence for this assumption stems from the longitudinal Medical Expenditure Panel Survey, which found the increased risk for incident diabetes in users of antidepressants to vanish when controlling for lifestyle factors [32▪]. Also, in most studies, DM2 was assessed by self-report and, clearly, depression leads to more frequent medical care that could allow detection of incident DM2. Therefore, a study was awaited that monitored glucose levels as study procedure. The Whitehall II study, which monitored diabetes status as well as glucose levels prospectively for 18 years in 5978 nondiabetic patients, found diagnosed (OR 3.10), but not undiagnosed, incident DM2 to be associated with usage of antidepressants. There was no difference at all in the prospective change of glucose levels between antidepressant users and nonusers [33▪▪]. Although incident DM2 was assessed by self-report, the 10-year longitudinal Melbourne Longitudinal Studies on Healthy Ageing study supports the idea by revealing that depression, both with and without antidepressant medication, is related to increased (OR 2.29) incident DM2 in 1000 elderly Australians .
In conclusion, the question whether antidepressants increase the rate of incident DM2 is unresolved, so far. The data are convincing that depression itself is a risk factor for DM2. When antidepressants have an additional effect, it seems as if TCAs, combination treatments, and noradrenergic antidepressants (see above), as well as antidepressant treatment leading to weight gain, should be avoided. Simply said, SSRIs might be the first choice in order to prevent long-term metabolic risks.
TREATMENT OF DEPRESSED DIABETIC PATIENTS
Depression is a frequent comorbid condition of DM2 patients. Therefore many DM2 patients require antidepressants.
Efficacy of antidepressants
Fluoxetine has been studied in several RCTs in depressed DM2 patients, showing efficacy of antidepressant treatment [35–43]. Also, nortriptyline was effective with regard to depression . It has to be mentioned that the St Louis group also studied cognitive behavioral therapy (CBT) in depressed diabetic patients, and CBT was effective with regard to depression . A meta-analysis included 14 antidepressant RCTs with a total of 1724 depressed patients with diabetes mellitus and found a generally moderate effect on depressive symptoms (−0.370), which was somewhat stronger for psychotherapy (−0.512), moderate for drug treatment (−0.467), and modest for collaborative care approaches (−0.292) . Other collaborative care approaches including antidepressants and behavioral interventions led to more depression-free days in depressed diabetic patients (Improving Mood-Promoting Access to Collaborative study , Pathways study ). In a secondary analysis of two antidepressant trials using sertraline or bupropion in 387 depressed patients with diabetes, pain, extant diabetes complications, and, especially in younger patients, higher severity of depression were negative predictors of response to the antidepressant .
Relapse prevention is a hard-to-achieve goal and, if effective, an even stronger argument for drug efficacy than acute response. In depressed diabetic patients responding to acute sertraline treatment, a RCT relapse-prevention study showed sertraline to lower the risk for recurrence of depression in patients and also to lead to sustained improvement of glycosylated hemoglobin (HbA1c) .
Antidepressants and direct effects on glucose regulation in diabetic patients
A meta-analysis of five placebo-controlled trials of fluoxetine in adults with DM2 found fluoxetine to lead to weight loss (−4.3 kg) as well as improvement of fasting glucose and triglycerides in fluoxetine compared with placebo-treated diabetic patients [51▪]. Thus, there is evidence for increased insulin sensitivity due to fluoxetine treatment which is partly independent of weight loss [35–43]. Similar findings have been shown for sertraline . Paroxetine treatment was shown to lead to short-term improvement, whereas the difference from placebo lost significance after 6 months . In an open study, bupropion  was shown to have some beneficial effect on BMI and HbA1c in responders to treatment. Nortriptyline, rather, deteriorated glucose homeostasis in depressed diabetic patients , whereas CBT led to reduced HbA1c in the long run . There is meta-analytic evidence that there is no effect on glycemic control in drug or collaborative care-treated patients . It has to be considered that in some cases SSRI treatment may lead to increased insulin sensitivity necessitating adoption of antidiabetic medication . It remains unclear whether intensified antidepressant treatment may lead to improvements of health behaviors, like diet, physical activity, and nicotine abstinence [55▪], or improved glucose regulation .
Antidepressant treatment with SSRIs, especially fluoxetine, and CBT may lead to improved glucose, which implicates that behavioral effects of antidepressant drug treatment strongly contribute to the metabolic effect. Tricyclic antidepressants may have untoward metabolic effects, and antidepressants associated with weight gain should be avoided in depressed diabetic patients.
Antidepressants and diabetes complications
Rare side effects, like antidepressant-induced hypoglycemia, may, rather, be detected using pharmacoepidemiological approaches. Although with large variation, these studies suggest that SSRIs, but not tricyclics, lower the amount of insulin used by antidepressant-treated patients . Similarly, another study using the same Dutch database found antidepressants in general not to be associated with a significantly increased risk for hypoglycemia [hazard ratio 1.36; confidence interval (CI) 0.84–2.20], whereas SSRIs after 3-year usage led to a higher risk for severe hypoglycemia (hazard ratio 2.75) .
Both depression and diabetes may lead to impaired sexual functions. A secondary analysis of Lustman's bupropion study in depressed diabetic patients showed antidepressant treatment with bupropion to lead to improved sexual function [58▪]. Duloxetine and tricyclics may be considered for neuropathic pain. While several studies and meta-analyses show duloxetine  and venlafaxine  to be effective in the treatment of diabetic polyneuropathia, the effects on glycemic control are not well studied . Duloxetine treatment may lead to modest increases of fasting glucose during long-term treatment of polyneuropathy .
Duloxetine and venlafaxine are standard approaches for pain due to diabetic neuropathy, while their long-term metabolic effects are not well studied.
There seems to be a bidirectional association between depression and DM2. Therefore, both prevention of DM2 in depressed patients and treatment of depression in DM2 patients are of considerable clinical significance. It may be assumed that antidepressants are effective in the treatment of depression in DM2 patients. Some antidepressants, like fluoxetine, may improve glucose homeostasis, whereas other antidepressants, like nortriptyline, may have untoward effects on glucose regulation. The effect of other antidepressants than SSRIs and TCAs has not been as well studied. In nondiabetic depressed patients effective antidepressant treatment seems to improve glucose regulation in the short run, which might, at least partially, be due to behavioral activation. There is evidence that noradrenergic antidepressants may cause glucose homeostasis to deteriorate, and, until adequately studied, noradrenergic effects of so-called dual-acting antidepressants should be considered. Of course, in the choice of medication the clinician should avoid long-term weight gain in order to prevent increased DM2 risk simply due to weight gain.
Conflicts of interest
M.D. is on the speaker's board of Bristol Myers Squibb, Otsuka Pharma, and Lilly. He was a member of the advisory boards of Bristol Myers Squibb and Otsuka Pharma.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 128).
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