Inflammation and Anti-Inflammatories in Depression
Depression is often associated with increases in markers of inflammation in blood, which include IL-1, IL-6, TNF-alpha, and CRP. Risk factors for increased inflammation include stress, obesity, a diet high in omega-6 fatty acids, sedentary lifestyle, social isolation, low socio-economic status, smoking, and being female. Treatments such as lithium, other mood stabilizers, and antidepressants can all have anti-inflammatory effects.
At the International Congress of Neuropsychopharmacology in 2012, researcher Michael Berk reviewed data on inflammation in depression. Berk shared prospective data that in the general population, people whose levels of CRP fall within the highest third have the highest risk for a new onset of depression over the next 9 years, while those with CRP values in the lowest third (indicating low inflammation) had the least likelihood of becoming depressed.
Drugs with more direct anti-inflammatory properties are beginning to be studied in unipolar depression with some success. In a trial by Abbasi et al. published in the Journal of Affective Disorders in 2012, the anti-inflammatory COX-2 inhibitor celecoxib (Celebrex) when added to the selective serotonin reuptake inhibit (SSRI) sertraline (Zoloft) had better antidepressant effects than the addition of placebo.
Sepaujnia et al. reported in Neuropsychopharmacology in 2012 that an anti-diabetes drug that also has anti-inflammatory properties, pioglitazone (Actos), also beat placebo in depression.
Laan et al. reported in the Journal of Clinical Psychiatry that the same was true of acetylsalicylic acid (ASA or aspirin).
Finally, Berk summarized data that the class of cholesterol-lowering drugs called statins are also able to decrease CRP and improve or prevent depression. Epidemiological data by Pasco et al. published in Psychotherapy and Psychosomatics showed that subjects without depression were less likely to develop a new onset of depression if they were treated with statins compared to those who were not. Stafford et al. reported in the Journal of Clinical Psychiatry in 2010 that patients taking statins had a 79% decreased likelihood of depression at 9 months of follow-up. A third study in Sweden showed that simvastatin, a lipophilic (fat-soluble) drug that can readily enter the brain, decreases the incidence of depression more than some of the non-lipophilic statins.
Moreover, a meta-analysis by O’Neil et al. reported that overall, statins had positive effects on mood.
Editor’s Note: All these data come from studies of unipolar depression, so one must consider how relevant they are to bipolar depression. They may be pertinent, since elevated inflammatory markers have consistently been reported in bipolar depression. However, this cannot be assumed until appropriate studies are performed. (As usual, research in bipolar depression lags far behind that in unipolar depression.)
Preliminary uncontrolled retrospective data from one study did suggest that those treated with lithium plus aspirin did better than those on lithium and no anti-inflammatory.
Thus it may make sense for unipolar and bipolar depressed patients with risk factors for heart disease such as a positive family history of heart disease and elevated cholesterol and triglycerides to discuss with their doctors the possibility of starting statin treatment earlier rather than later. This is because depression itself is a major risk factor for heart disease, so statins might lower risk both by their approved indication of lowering cholesterol and by their apparent ability to help fend off new episodes of depression.
A more complicated issue would be the question of when, if at all, to use primary anti-inflammatory drugs in the adjunctive treatment of unipolar or bipolar depression. If nothing else works, they might be worth a try as an add-on. They might be used earlier in those with higher levels of inflammation, especially if there were more data indicating that those with inflammatory markers responded preferentially to primary anti-inflammatory drugs.
In the study by Abbasi et al., patients with elevated IL-6 had improvement in their depression after taking celecoxib, while in the study of a TNF-alpha inhibitor there was no overall positive effect in unipolar depression, but those who had the highest levels of CRP at baseline did show the most significant improvement and a significant drug-placebo difference. Anti-inflammatory agents might be considered in those with elevated inflammatory markers if their depressions did not respond adequately to first, second, or third attempts with more conventional options.
What about treating depression in the absence of available tests for inflammation? Based on the findings to date, using anti-inflammatory treatments would possibly be worthy of consideration in those with treatment resistant illness, since in most of the positive studies, depressed patients were not specifically screened for inflammatory markers.
However, this section must close with a reminder that patients and physicians should carefully discuss the risks and benefits of any treatment before it is begun. While we attempt to discuss both positive effects and side effects in BNN, the preliminary data we report cannot be considered comprehensive, current, or even precisely accurate. We summarize data that has not been formally accepted in peer-reviewed literature, with the idea that patients, family members, and clinicians may find interesting information that prompts discussions between patient and doctor. Readers must consult primary sources for a more complete view of any topic discussed in BNN.
These cautions are especially important here because anti-inflammatory drugs have a range of potentially dangerous or even lethal side effects. Even aspirin carries a substantial risk of gastrointestinal bleeding (perhaps in about 1 in 500 users), and patients die each year from this presumably safe over-the-counter medication. Cardiac risks are also being revealed for some non-steroidal anti-inflammatory drugs (NSAIDs). Given these potential side effects, discussions between patient and physician must take place before anti-inflammatory treatment is begun.
Since safety is an issue, it might make sense to use the safest agents first. The drugs with the best utility for treating inflammation may turn out to be the primary psychiatric drugs themselves, like antidepressants and lithium.
Other relatively safe anti-inflammatory drugs might include N-acetylcysteine (NAC), co-enzyme Q10, curcumin (a plant extract related to turmeric), and possibly statins and minocycline. The next group, with more potential side effects, might include NSAIDs such as the COX-2 inhibitor celecoxib and aspirin. The next group, which gets more exotic, expensive, and data-poor, might include erythropoietin (often used to treat anemia) and the TNF-alpha inhibitors used to treat rheumatoid arthritis.
