Inflammation and Oxidative Stress in Bipolar Disorder
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders conference in Sao Paulo, Brazil in March reported new data relevant to inflammation and oxidative stress. Both inflammation and oxidative stress increase risk of cardiovascular disorders, and patients with inadequately treated mood disorders lose 10 or more years of life expectancy from cardiovascular disorders compared to the general population. Inflammation and oxidative stress may also contribute to the symptoms, evolution, and progression of the mood disorders themselves.
It is possible that these two processes could become new targets for therapeutic intervention in addition to more traditional psychopharmacological drugs that primarily target the neurotransmitters dopamine, norepinephrine, serotonin, and the neurotrophic factor BDNF.
Increases in inflammatory cytokines in the affective disorders
Various researchers have recently reported finding increases in inflammatory markers among patients with mood disorders.
Izabela Barbosa and colleagues reported increases in the cytokine CCL24 in patients with mania, as well as increases in plasma levels of soluble TNF-alpha receptors in bipolar patients, particularly TNF-R2. These elevated levels of Type 1 and Type 2 TNF-alpha receptors were correlated with duration of bipolar disorder, making these data consistent with other studies in which increases in oxidative stress and inflammatory cytokines occur as a function of either number of episodes or duration of illness.
Researcher Breno Diniz also found that TNF-R2 increases in unipolar depression and in late-life depression. In late-life depression there were also decreases in BDNF and increases in levels of the cytokine IL-1B, another sign of inflammation.
Mauricio Kunz and colleagues reported that patients with bipolar disorder exhibited increases in cytokines TNF-alpha, IL-6, and IL-10. IL-10 is an anti-inflammatory cytokine and its increase may be compensatory. Most interestingly, increases in IL-6 (an inflammatory cytokine) were proportional to the number of days depressed subsequently observed in one-year follow up, suggesting that some inflammatory markers may have prognostic significance.
From a therapeutic perspective, the findings suggest that clinical intervention directed at reducing inflammatory cytokine production and inhibiting its effects may be useful. There are not many data about this strategy in mood disorders, but there are data from other illnesses suggesting that this approach could work. Patients with rheumatoid arthritis (who have a high incidence of depression), when treated with genetically engineered inhibitors of TNF-alpha receptor activity, not only show improvement in their rheumatoid arthritis, but also in accompanied symptoms of depression.
Other anti-inflammatory approaches are possible. The anti-inflammatory/antibiotic minocycline has been used in the treatment of schizophrenia with some positive effects, not only on symptomatology, but cognitive function as well. Since minocycline has multiple positive ways of acting on systems that are abnormal in patients with bipolar disorder, it deserves to be more systematically studied in bipolar illness the way it is beginning to be studied in schizophrenia.
Among the many different mechanisms of action of minocycline that counter abnormalities found in bipolar illness are that it: decreases inflammatory cytokines; decreases cell suicide (apoptosis); inhibits high levels of PKC and GSK-3 alpha; and decreases nitric oxide synthetase, a substance that increases the levels of free radicals which damage neurons and glia. Surprisingly, minocycline has therapeutic effects on each one of these target areas as measured in a variety of in vivo animal systems and in vitro as well.
Oxidative stress increases in bipolar disorder
When energy is created within cells, toxic by-products can accumulate and potentially damage cells. This process is known as oxidative stress, and the toxins created include peroxides, nitrates, and free radicals.
Keila Ceresér and colleagues reported increases in serum levels of thiobarbituric acid reactive substances (TBARS) in patients with bipolar disorder. TBARS are indicators of damage to cells’ lipid membranes, and carbonyl is a measure of protein oxidative damage. These findings were replicated by Brisa Fernandes and colleagues, who found increases in TBARS during mania.
Editor’s note: These data on peripheral markers of oxidative stress and of inflammatory cytokines support the idea that cellular toxicity occurs in the affective disorders, a theory that has been described by Flavio Kapczinski. Patients with mood disorders face a double liability for cellular toxicity, experiencing increases in inflammation and oxidative stress at the same time as deficits in neuroprotective factors such as BDNF (brain derived neurotrophic factor) that occur with each episode of depression and mania in proportion to their severity. Thus, the increases in toxic factors that would be dangerous on their own may damage cells more because substances that protect neurons and glia are produced in smaller amounts during each affective episode.
The cell damage that results from these two processes occurring together could explain why cognitive dysfunction increases as a function of the number of affective episodes experienced.
Brain-derived Neurotrophic Factor
There were several findings about BDNF at the Conference of the International Society of Bipolar Disorders. BDNF is a substance that is necessary for long-term learning and memory, neural and glial cell health and survival, and for neurogenesis (the production of new neurons for the hippocampus that occurs throughout life).
Brisa Fernandes et al. reported that in a study of bipolar patients, BDNF decreased as a function of duration of illness, suggesting that with long-term illness and many recurrences, BDNF may eventually fail to normalize between episodes.
Marcia Kauer-Sant’Anna et al. reported that BDNF measured in blood decreases with aging, and does so more profoundly in women than in men.
Ronald Duman and colleagues reported that another neurotrophic factor, vascular endothelial growth factor (VEGF), like BDNF, decreases with episodes of affective illness and may be another important loss of neuroprotection that occurs in the mood disorders. Antidepressants increase the low levels of BDNF and VEGF found in depressed patients.
Fernandes and colleagues reported that in contrast to the low levels of BDNF and VEGF found during depression, another neurotrophin, NT3, increases in both mania and depression. In animal models of stress, while BDNF decreases in the hippocampus, NT3 increases in the brainstem areas where norepinephrine cell bodies are located (the locus coeruleus), and may be a mechanism for increasing long-lasting anxiety responses to places and cues that signal danger. Whether the NT3 increases represent a compensatory alteration in response to the decreases in BDNF and VEGF that occur with affective episodes, or whether the increases in NT3 are a part of the pathophysiology of the illness conveying mechanisms for increased anxiety, remains for further investigation.
Editor’s Note: As discussed in previous BNNs, this general pattern of episode-related increases in toxic factors (inflammation, cytokines, oxidative stress, and free-radicals) and decreases in neuroprotective factors (BDNF and VEGF) yields a plausible set of rationales for the increase in neural, glial, and somatic cell endangerment that occurs as a function of number of affective episodes.
These concepts could explain why so many neuropathological findings vary as a function of number of prior episodes and, in particular, why several measures of cognition in bipolar disorder, especially in frontal lobe-based executive functioning and long-term verbal learning and memory, are inversely correlated with number of prior episodes or duration of illness.
Data from Lars Vedel Kessing and collaborators illustrate the importance of long-term prophylaxis and episode prevention with medications and psychotherapy. While analyzing information from the huge number of patients in the Danish Case Registry, their research group found that a history of two prior unipolar or bipolar depressions was not associated with an increased risk of dementia in old age. However, a total of four depressions doubled the risk of a diagnosis of dementia in old age, and every depression thereafter further increased that risk.
This editor has recently reviewed the substantial evidence that many types of neurobiological dysfunction correlate with either duration of illness or number of previous episodes experienced. The results were reported in Neurotoxicity in 2010 and involve alterations in multiple areas of brain biochemistry, structure and function. While it cannot be definitively established that the number of episodes or duration of illness are causal in producing these defects (because it is possible that some of these defects may, themselves, be productive of greater severity of illness), nonetheless, it is clinically importance to assume the relationship is causal so that it helps encourage the most careful and judicious prevention of recurrent episodes possible.
This approach makes clinical sense because episode prevention in and of itself is of great benefit to patients, and any other potential benefit such as preventing disease progression and the worsening of neurobiological abnormalities would then only be a further bonus. However, with the considerable evidence that each episode is, in fact, associated with oxidative stress, increases in free radicals and toxic cytokines, as well as decrements in neuroprotective factors such as BDNF, scrupulous prevention of episodes appears to take on even greater importance beyond preventing considerable morbidity and disability associated with recurrence of a manic or depressive episode.
Preventing episodes of unipolar and bipolar affective episode could also change the long-term course of illness (i.e. preventing episode sensitization and kindling-like increases in vulnerability to recurrence), as well as preserving more optimal brain function.
Lithium has neuroprotective effects
There is a hopeful side to this story. Many treatments are neuroprotective and lower the risk of such adverse long-term outcomes. In particular, in the recurrent unipolar disorders, Yvette Sheline et al. reported that compared with patients treated with antidepressants less of the time, patients who were treated with antidepressants for more of the time did not experience hippocampal atrophy with aging. Similarly, lithium has been shown to increase hippocampal volume.
Preliminary findings from Kessing show that patients who have been on more chronic lithium and have renewed their lithium prescriptions at least once have a lower incidence of dementia in late life compared with patients who have not been exposed to regular lithium treatment. The bottom line from these and other studies is that not only can effective long-term prophylaxis prevent episodes of illness, but may also protect the brain and cognition.
Three studies have reported that bipolar patients treated with lithium have increases in grey matter volume in areas of the brain in which they were originally deficient and, interestingly, normal volunteers included in some of these studies did not show significant increases. Thus, it appears that lithium selectively acts on areas of brain that may be deficient in patients with bipolar disorder.
Now, in addition, new data from Brenda MacQueen of the University of Calgary shows that short-term treatment with lithium significantly increases hippocampal volume in patients with bipolar disorder. These investigators also had preliminary evidence that this was associated with improvement in recollective memory function as well.
Lithium also increases levels of a marker of neuronal integrity, n-acetyl aspartate (NAA), which can be measured directly in the brains of patients using magnetic resonance spectroscopy (MRS).
These new data on increases in hippocampal volume with lithium add to the growing rationale that lithium may have neurotrophic and neuroprotective effects in both animals and in humans. In particular, lithium not only increases neurotrophic factors such as BDNF and cell survival factors such as Bcl-2, but it inhibits factors that induce cell death, including BAX and P53. It also has a variety of other actions in cells that have appeared to increase cellular viability and function. Thus, the data that lithium actually increases hippocampal volume in patients with bipolar disorder provides further rationale for extended use of this compound in patients with the disorder.
This is particularly important for patients in the U.S., where new prescriptions for valproate have actually exceeded those of lithium. In a recent study in Europe, there were indications that both lithium and the lithium/valproate combination led to much better long-term outcomes than treatment with valproate alone (see BNN Issue 3 from 2009). In addition, studies of lithium have produced the best data for an anti-suicide effect in patients with bipolar disorder. This finding is crucial because some 25-50% of patients with the disorder make a serious suicide attempt during their course of illness, and some 10-15% of patients with this illness die via suicide.
The data about neuroprotective effects of lithium and other medications is important information for patients to be aware of while making choices about maintaining long-term treatment. Discontinuing effective treatment places the patient at high risk for relapse, and can potentially lead to further types of brain dysfunction. Patients get good information about the nature of the side-effects profiles of the various treatments most widely used for bipolar illness, but often fail to get the message that some of the treatments may also have direct neurochemical benefits and may help protect the brain. In addition to lithium, drugs used in the treatment of bipolar illness that also increase BDNF include valproate (Depakote), carbamazepine (Tegretol/Equetro), lamotrigine (Lamictal), the atypical antipsychotic quetiapine (Seroquel), and omega-3 fatty acids.
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