From Medscape Medical News
Antidepressants Linked to Increased Risk for Diabetes
Weight Gain a Likely Factor
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April 9, 2009 — Taking moderate to high daily doses of antidepressants for more than 2 years is associated with an 84% increased risk for diabetes, according to a large observational study.
The increased risk was particularly notable for the selective serotonin-reuptake inhibitor (SSRI) paroxetine and the tricyclic antidepressant amitriptyline.
Weight gain might explain much of the relation between antidepressant use and diabetes, according to the study authors.
The study was published online April 1 in the American Journal of Psychiatry.
It is too early for these results to have any major impact on clinical practice, said lead author Frank Andersohn, MD, from Charité-University Medical Center, in Berlin, Germany. He added that although early evidence shows that combining an antidiabetes drug with an antidepressant might prevent diabetes among depressed patients, the benefits and risks of this approach need to be considered.
Lifestyle Changes
Meanwhile, there are documented methods to reduce the risk for diabetes, including engaging in physical activity and attaining optimal body weight. "For patients needing long-term treatment with antidepressants, compliance with such lifestyle recommendations is probably the most important way to prevent diabetes," Dr. Andersohn told Medscape Psychiatry.
For the study, researchers obtained data from United Kingdom's General Practice Research Database, which contains medical records for more than 6.4 million patients from about 450 general practices across the country.
The recorded information includes patient characteristics such as age, sex, smoking status, height, and weight, as well as information on prescribed drugs, diagnoses, referrals to consultants and hospitals, and medical history.
The study cohort consisted of 165,958 patients who received at least 1 new prescription for an antidepressant between January 1, 1990 and June 30, 2005.
To be included in the study, patients had to be at least 30 years of age, to have no diagnosis of diabetes or impaired glucose tolerance, and to have been diagnosed with depression during the 180 days before or the 90 days after cohort entry.
In addition, participants were eligible for study entry only if they had received no treatment with antidepressants in the preceding year and had at least 1 database entry of a body-mass index (BMI).
Follow-up was from cohort entry until the first of the following events: the onset of diabetes, switching to or adding another antidepressant, death or end of registration with the practice, or end of the study period. The mean follow-up time was 2.8 years.
Researchers categorized cumulative use of antidepressants into short-term (less than 12 months), medium-term (12-24 months), and long-term (more than 24 months) use. They divided drug doses into 2 categories: low and medium/high.
Investigators identified a total of 2243 cases of diabetes mellitus and 8963 randomly matched comparison subjects. Onset of diabetes was determined using predefined diabetes codes and prescriptions for oral antidiabetics or insulin. A high BMI at baseline was the strongest predictor of new-onset diabetes.
Investigators controlled for hyperlipidemia, hypertension, smoking status, BMI at cohort entry, and prescriptions of other drugs during the 3 months before the index date that could lead to weight gain and/or increased risk for diabetes.
No Increased Risk With Shorter Duration
Compared with no use of antidepressants, recent long-term use of antidepressants in moderate to high daily doses was associated with an increased risk for diabetes (odds ratio [OR], 1.84; 95% CI, 1.35 – 2.52). Recent antidepressant use of shorter duration, use in lower daily doses, and past use were not associated with increased risk.
For patients taking tricyclic antidepressants and SSRIs, the risk for diabetes was increased with recent long-term use of moderate or high daily doses (OR, 1.77 and 2.06, respectively).
In the analysis of individual antidepressants, researchers found that the incidence-rate ratios associated with long-term use were 2.49 for amitriptyline and 1.75 for paroxetine. The analysis also found that the incidence-rate ratios for fluvoxamine and venlafaxine were increased, but that finding was based on relatively few exposed case and comparison subjects.
The study supports the results from the recent Diabetes Prevention Program (DPP) trial, which investigated the development of diabetes in high-risk patients with depression who were receiving the antidiabetic drug metformin, lifestyle intervention, or placebo.
The DPP study found that antidepressant use over an average of 3.2 years was associated with an increased risk for diabetes of 2.60 in the placebo group and 3.39 in the lifestyle-intervention group, but there was no increased risk in the metformin group.
Why do antidepressants raise risks for diabetes? Weight gain is certainly a likely cause. It is a common adverse effect of tricyclic antidepressants, although it is not clear whether individual agents differ in the potential for causing weight gain.
In this study, the only tricyclic antidepressant that increased risk for diabetes over the long term was amitriptyline. Risk estimates associated with other tricyclic antidepressants were elevated more than 2-fold, but they did not reach statistical significance, probably because too few subjects were exposed to these drugs.
Paroxetine Linked to Highest Weight Gain
Weight gain is also linked to long-term use of some SSRIs. The study found a 4-fold increased risk for diabetes associated with the long-term use of paroxetine in daily doses above 20 mg/day, but not of fluoxetine, citalopram, or sertraline.
"We know from randomized clinical trials of SSRIs that paroxetine is associated with the highest weight gain," said Dr. Andersohn. "This corresponds to our findings of an increased risk of diabetes associated with this drug."
Other than weight gain, mechanisms leading to increased risk for diabetes could include the hyperglycemic effects of noradrenergic activity of antidepressants. If this were the case, however, "we would have expected to see diabetogenic effects much earlier in the course of treatment — not only after a period of about 2 years," said Dr. Andersohn.
Depression itself might increase the risk for diabetes. Research shows that patients with depression have a 35% higher risk of developing diabetes than nondepressed people. Patients in this study treated with antidepressants for more than 24 months might represent a special subgroup, with an increased risk for diabetes because of their active depressive disorder, said Dr. Andersohn.
However, he said that this explanation is unlikely. For one thing, if depression and not drugs caused the increased risk for diabetes, most antidepressants used for longer than 24 months would raise the risks, which was not the case.
"As well, in an explorative analysis using the number of days with a diagnosis of depression as a proxy for depression severity, there was no indication of increased severity in long-term users, so it's likely the drugs, not the depression, that are linked to diabetes," said Dr. Andersohn.
Major Public-Health Issue
Should doctors switch patients to SSRI drugs, such as citalopram, fluoxetine, or the tricyclic drug dothiepin, agents the study found did not have a link to diabetes? "One might prefer these drugs over paroxetine or amitriptyline with respect to the long-term risk of diabetes," said Dr. Andersohn.
However, he added, drug selection should be considered on an individual basis. "If a patient who has responded well to amitriptyline in the past presents again with severe depressive episode, antidepressive effectiveness might outweigh an increased risk of diabetes."
Dr. Andersohn stressed that because the risk for diabetes develops slowly, doctors should not take immediate action in treating individual patients. "Abrupt withdrawal of antidepressants might cause unintended effects."
In some cases, though, doctors might consider cognitive behavioral therapy to avoid the adverse effect of weight gain associated with some antidepressant drugs, he said.
As the number of people diagnosed with diabetes soars across the globe, it is becoming increasingly important to study this disease as a public-health issue, said Dr. Andersohn.
Diabetes is 1 of the major causes of renal disorders and cardiovascular morbidity and mortality and has a tremendous impact not only on individual patients but also on society in general, he added. "Clinical research to identify, characterize, and quantify potential risk factors of diabetes is vitally important."
List of Concerns
Asked by Medscape Psychiatry to comment on the study, Richard Bergenstal, MD, president-elect of the American Diabetes Association and executive director of the International Diabetes Center, in Minneapolis, Minnesota, said the research is interesting, especially in light of the pending diabetes epidemic. "We should perhaps add the use of antidepressants to the list of things we should be concerned about."
He added that he is not totally convinced that weight gain from long-term use of antidepressants explains the entire relation between depression and diabetes. He believes that depression itself might be somehow connected to diabetes and pointed out that there is evidence that patients who treat their depression in ways other than with antidepressants (for example, with cognitive behavior therapy) are also at higher risk of developing diabetes.
The bottom line, he added, is that "the data are not conclusive" and "we need more studies."
Dr. Andersohn disclosed no relevant financial relationships. Investigator Rene Schade, MD, has received grant support from Schering and investigator Samy Suissa, PhD, has received grant support from the Canadian Institute of Health Research, AstraZeneca Pharmaceuticals, Boehringer Ingelheim, Organon, and Wyeth; consulting fees from Bristol-Myers Squibb, Merck, GlaxoSmithKline, and Bayer Schering Pharma AG; and lecture fees from Boehringer Ingelheim and Pfizer. Adeltraut Garbe, MD, PhD, has received consulting feels from Byk-Gulden and consulting fees and an unrestricted grant from Bayer Schering Pharma AG for acquisition of access to the UK General Practice Research Database.
Am J Psychiatry. Published online before print April 1, 2009.
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