It has been clear for some time that depression and inflammation are linked. This has led researchers to explore a variety of anti-inflammatory agents to treat depression. A meta-analysis of studies examining anti-inflammatory treatments for bipolar depression was published in the journal Bipolar Disorders in 2016.
Researcher Joshua D. Rosenblat and colleagues identified eight randomized controlled trials that met their criteria for anti-inflammatory treatments of bipolar disorder. These treatments included nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen and aspirin), omega-3 fatty acids, the antioxidant N-acetylcysteine, and pioglitazone (used to treat diabetes). Overall, the anti-inflammatory treatments had a moderate and statistically significant antidepressant effects. No serious side effects were reported, and the anti-inflammatory treatments did not cause a switch into mania in any of the participants.
The diversity of the anti-inflammatory treatments reviewed in this meta-analysis limit the extent to which it can be interpreted, but it is clear that more research on anti-inflammatory treatments for bipolar depression is needed. An open question is whether patients with particularly elevated levels of inflammatory markers in their blood would respond better to these anti-inflammatory treatments.
We have previously reported on the research by Martin Alda and colleagues that the chemical compound methylene blue had positive effects in patients with bipolar depression. The research was published in the British Journal of Psychiatry in 2016.
Now a new article by Ashley M. Feen and colleagues in the Journal of Neurotrauma reports that methylene blue has an antidepressant-like effect in mice with traumatic brain injury (TBI). Methylene blue reduced inflammation and microglia activation in the animals. Methylene blue reduced levels of the pro-inflammatory cytokine Il-1b and increased levels of the anti-inflammatory cytokine Il-10.
These findings are of particular interest as many patients with classical depression (and no brain injury) have abnormal levels of these inflammatory markers. It remains to be seen whether methylene blue is more helpful in those patients with elevated inflammatory markers and if levels of the markers can predict treatment response or not.
Methylene blue causes urine to turn blue, so low doses of the compound are used as a placebo. Alda and colleagues reported that the active dose 195mg reduced depression and anxiety significantly more than the placebo dose (15mg) in a 13-week crossover study. In that study, methylene blue was added to lamotrigine which had not had a complete enough effect.
In a 1986 study by G.J. Naylor and colleagues in the journal Biological Psychiatry, patients were treated with either 15mg/day or 300mg/day of methylene blue for one year and crossed over to the other dose in the second year. Participants had significantly less depression during the year of taking the active 300mg/day dose.
The FDA has issued a warning about the danger of a serotonin syndrome if methylene blue is combined with serotonin active agents (presumably because it inhibits MAO-A). Symptoms of the serotonin syndrome can include lethargy, confusion, delirium, agitation, aggression, decreased alertness, and coma. Neurological symptoms, such as jerky muscle contractions, loss of speech, muscle tension, and seizures; or autonomic symptoms, such as fever and elevated blood pressure, are also common. Patients should call their doctor if they are taking a serotonergic psychiatric medication and develop any of the above symptoms.
Inflammation has been linked to both unipolar and bipolar depression. New research shows that anti-inflammatory treatments may reduce bipolar depression, for which few treatments exist.
Researchers led by Jonathan Savitz divided people with bipolar depression into four groups. One group received two placebos, another received minocycline (a drug with neuroprotective and immune-modulating properties) plus a placebo, the third received aspirin plus a placebo, and the final group received both minocycline and aspirin. Of the 64 participants, those who took both minocycline and aspirin were most likely to respond to treatment and to enter remission. In people with body mass indexes (BMIs) above the median of 30, a sign of greater inflammation, 100% of those who received both anti-inflammatory drugs responded to treatment, compared to 36% of those who received aspirin alone, 33% of those who received minocycline alone, and 25% of those who received two placebos.
Dosages of the drugs were 100mg twice a day for minocycline and 81mg twice a day for aspirin. Savitz and colleagues believe that aspirin and minocycline must work particularly well together, and are modifying their study to more directly compare use of the two anti-inflammatory drugs together to the absence of anti-inflammatory treatments.
Lurasidone (Latuda) has been approved by the US Food and Drug Administration (FDA) for the treatment of bipolar depression. A new study indicates that lurasidone is also effective in those with unipolar depression complicated by a few manic features, i.e. mixed depression, which is often more severe and less responsive to traditional antidepressants than traditional unipolar depression.
At a 2015 scientific meeting, Andrew Nierenberg and colleagues presented the results of a six-week study comparing 20–60 mg of lurasidone to placebo in about 200 depressed patients who had some manic symptoms. Lurasidone significantly improved unipolar depressive symptoms in addition to the mixed manic symptoms.
At baseline, the patients’ manic symptoms included: flight of ideas/racing thoughts in 66.8% of the participants, pressured speech in 61.1%, decreased need for sleep in 40.8%, increased energy or activity in 28.0%, elevated or expansive mood in 18.0%, increased or excessive involvement in pleasurable activities in 15.6%, and inflated self-esteem or grandiosity in 6.6%.
Studies published in 2015 and 2016 have established that generic versions of the anti-convulsant lamotrigine are bioequivalent to the name-brand drug (Lamictal) and to each other. Lamotrigine is used to treat epilepsy and is also prescribed for the prevention of bipolar depression.
An article by T.Y. Ting and colleagues in the journal Epilepsia in 2015 established that generic lamotrigine works similarly enough to the name brand drug that patients with epilepsy could be switched from one drug to the other without worsening seizures. More recently, M.D. Privitera and colleagues reported in the journal Lancet Neurology that different generic versions of lamotrigine were bioequivalent. No significant changes in seizure frequency or other negative outcomes were reported.
These studies show that generic versions of lamotrigine have the same anticonvulsant effectiveness as the original drug. The same should also be true for lamotrigine’s effectiveness in preventing bipolar depression.
Research continues on pioglitazone, a drug typically used to treat diabetes but with other positive effects on depression and stroke risk. Some researchers are working on determining whether the drug increases the risk of developing certain cancers, including bladder, prostate, and pancreatic cancers. A recent study by James D. Lewis and colleagues in the journal JAMA found no statistically significant increase in risk of bladder cancer among patients taking the drug, but the researchers said they also couldn’t rule out that the drug may increase this risk, as has been seen in previous studies. The study by Lewis did show an increase in pancreatic and prostate cancers in patients taking pioglitazone, but the researchers did not determine whether this was caused by the drug.
Another recent study by Walter N. Kernan and colleagues in the New England Journal of Medicine reported that pioglitazone reduced the incidence of stroke and heart attack in patients with a history of stroke or blocked blood vessels in the brain but without a diagnosis of diabetes. Patients who received pioglitazone also experienced side effects including weight gain, edema (an increase in fluids in the body’s tissues) and serious bone fractures.
Pioglitazone has had positive effects in bipolar depression and may one day be used as a treatment for bipolar disorder. For now, it may be worthy of consideration for the treatment of diabetes in patients who also have bipolar depression.
A recent study of 93 adults with bipolar disorder suggests that midday bright light therapy can be an effective adjunctive treatment for bipolar depression. The study by Dorothy Sit and colleagues was presented at the 2015 meeting of the Society for Biological Psychiatry. Participants had been diagnosed with bipolar I or II disorder, were in a current episode of depression, and were taking stable doses of mood stabilizing medication. They were randomized to receive either 7000-lux broad spectrum light for 45 to 60 minutes each day for six weeks or 50 lux dim red light. The comparison was dramatic: remission rates were 56.5% among those exposed to the 7000-lux light, and 14.3% among those who were exposed to the dim light. Those who received the bright light also reported better sleep quality and less suicidality.
Editor’s Note: These results are striking and raise the issue of whether midday bright light is more effective than early morning bright light, the usual recommendation for seasonal affective disorder (SAD) and other forms of depression. Until comparative studies are available, using midday light may be the way to go.
Studies of rodents with depression-like behaviors revealed that the combination of low (sub-therapeutic) doses of lithium and infusions of ketamine produced antidepressant-like effects. Researchers believed this might mean that in humans, lithium might have a unique effect potentiating the effects of ketamine.
In a small study by Mark J. Niciu presented at the 2015 meeting of the Society for Biological Psychiatry, patients with bipolar depression taking lithium or valproate mood stabilizers were given ketamine infusions or control infusions. In the 23 patients taking lithium and the 13 taking valproate, ketamine’s antidepressant effects were significantly better than placebo, but there was no difference between lithium and valproate with regard to these antidepressant effects. These preliminary data in a small number of subjects do not support the proposition that lithium augments the effects of ketamine in depression.
A study currently in progress indicates that the anti-inflammatory COX-2 inhibitor celecoxib (better known as the arthritis treatment Celebrex) may aid in the treatment of bipolar depression. In a panel session on inflammation at the 2015 meeting of the Society of Biological Psychiatry, researcher Angelos Halaris reported results from the first 26 participants.
Participants were taking mood stabilizers for bipolar disorder and became depressed. They received either 20mg/day of the selective serotonin reuptake inhibitor antidepressant escitalopram (Lexapro) plus either 200mg twice a day of celecoxib or placebo for a total of eight weeks. Those participants who received celecoxib showed greater and more rapid reductions in depression symptoms than those who received placebo.
The study will continue, and Halaris and colleagues will also observe whether measures of inflammation in patients’ blood are correlated with the patients’ responsiveness to the combined treatment with escitalopram and celecoxib.
Despite repeated studies, including meta-analyses, showing that antidepressants that work in unipolar depression do not work in bipolar depression as adjuncts to mood stabilizers, antidepressants remain widely used for the treatment of bipolar depression. A recent study of the antidepressant agomelatine has shown that it is not effective in bipolar depression. In patients taking lithium or valproate but still depressed, agomelatine was no better than placebo at reducing depression.
Agomelatine has an unusual mechanism of action (blockade of 5HT-2C receptors and activation of melatonin M1 and M2 receptors) that helps normalize sleep and circadian rhythms, but only in unipolar depression. Until this study by Lakshmi Yatham and colleagues in the British Journal of Psychiatry, it was thought that these properties would make the drug ideal for bipolar depression.
Three atypical antipsychotics are have been approved by the Federal Drug Administration for bipolar depression: quetiapine (Seroquel), lurasidone (Latuda), and the olanzepine-fluoxetine combination Symbyax. These, used alongside mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) are more effective treatments for bipolar depression. There are other adjunctive treatments that may be helpful, such as the antioxidant N-acetylcysteine, vitamin D3, and folate.