Meta-analyses have found links between elevated levels of inflammatory markers and many neuropsychiatric disorders, including depression, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD) and traumatic brain injury. Multiple studies also show that those with elevated inflammatory markers such as interleukin-1, interleukin-6, tumor necrosis factor (TNF) alpha, and c-reactive protein (CRP) also respond less well to typical treatments than those with normal levels of these markers in the blood.
These links suggest that it could be useful to measure levels of these inflammatory markers in the blood of people who are responding poorly to medications. If one or more of these markers are elevated, it might be a sign that treatment with an anti-inflammatory agent could be helpful. Preliminary studies have shown that some neuropsychiatric disorders may improve after treatment with anti-inflammatory drugs such as aspirin, celecoxib (Celebrex), and the antibiotic minocycline, among others.
A new study suggests that for people with bipolar depression, the anti-inflammatory drug celecoxib (Celebrex), typically used to treat arthritis, can boost the effectiveness of the antidepressant escitalopram (Lexapro).
In the 8-week study by researcher Angelos Halaris and colleagues, adults with bipolar depression were randomly assigned to one of two groups. The first group received the selective-serotonin reuptake inhibitor (SSRI) antidepressant escitalopram plus celecoxib to target inflammation. The second group received just the antidepressant escitalopram and a placebo.
By the end of the study, 78% of the group taking the anti-arthritis drug had seen major improvement in their depression, with 63% reporting that it had lifted completely. Meanwhile in the placebo group, only 45% reported major improvement, and 10% reported remission.
The group that received celecoxib with their escitalopram also began seeing improvement within one week of beginning treatment, instead of after four to six weeks, which is typical of antidepressant treatment.
Researchers think depression creates an immune response leading to chronic inflammation, which can upset the balance of neurotransmitters in the brain and make antidepressants less effective. Halaris suggests that reducing this inflammation with a drug like celecoxib can make antidepressants more effective.
The research was presented at the Fifth International Congress on Psychiatry and the Neurosciences and has not yet been published.
Inflammation has been linked to mood disorders. A 2016 meta-analysis in the journal Lancet Psychiatry described the role of inflammatory marker C-reactive protein (CRP) in bipolar episodes. Researchers led by Brisa S. Fernandes identified 27 studies that measured CRP levels in a total of 2,161 patients with bipolar disorder and 81,932 healthy participants. The researchers determined that compared to healthy controls, people with bipolar disorder have higher levels of CRP. CRP levels were moderately elevated between episodes and during depression, and substantially elevated during episodes of mania.
Editor’s Note: This meta-analysis shows that CRP is linked to bipolar disorder, and the inflammatory burden is highest during mania. It remains to be seen whether anti-inflammatory treatments work best in patients with high CRP levels compared to normal CRP levels.
CRP is also a risk factor for cardiovascular disease, and lithium and other treatments for bipolar disorder probably lower CRP levels.
The same group of researchers previously showed that statins, drugs typically used to lower cholesterol, could help alleviate depression. Since statins have anti-inflammatory effects, they can probably reduce depression risk in addition to lowering cardiovascular risk, as initial studies suggest.
Other drugs with anti-inflammatory effects that may improve depression include the anti-arthritis drug celecoxib and the antibiotic minocycline. The amino acid N-acetylcysteine and omega-3 fatty acids also have anti-inflammatory effects and have been found to improve depression in some studies.
Inflammation can interfere with the balance of neurotransmitters in the brain, making antidepressants less effective. Anti-inflammatory treatments (such as those used to treat rheumatoid arthritis) may help. In a 2016 meta-analysis published in the journal Molecular Psychiatry, researchers led by Nils Kappelmann analyzed the results of 20 clinical trials of chronic inflammatory conditions where depressive symptoms were also recorded. In a subset of 7 clinical trials that compared anti-inflammatory treatment to placebo, they found that anti-inflammatory treatment improved depressive symptoms significantly compared to placebo.
The anti-inflammatory drugs studied most often targeted the inflammatory marker tumor necrosis factor (TNF) alpha using an antibody. Some of the anti-inflammatory drugs that improved depressive symptoms were adalimumab, etanercept, infliximab, and tocilizumab.
The researchers also found that those participants with the most inflammation when they began treatment saw the largest improvement in their depression after taking anti-inflammatory treatments.
Kappelmann and colleagues suggest that inflammation may cause depression, and that anti-inflammatory drugs may be useful in the treatment of depression in people with high inflammation.
Evidence from multiple studies has indicated the importance of beginning preventative treatment, particularly with lithium, early in the course of bipolar disorder. A 2016 comprehensive literature review by researcher Katie Joyce and colleagues in the International Journal of Bipolar Disorders concluded that psychoeducation and medication are more effective in bipolar disorder when applied in earlier stages of the illness rather than later stages.
Several studies suggest that treatment for bipolar disorder should be started specifically after the first manic episode.
A 2014 study by researcher Lars Kessing and colleagues in the British Journal of Psychiatry examined 4,700 patients treated with lithium in Denmark. Kessing and colleagues found that those who started treatment after one manic episode were less likely to find lithium ineffective than those who started later.
Another study by researcher Michael Berk and colleagues presented at the International Society for Bipolar Disorders found that after a first manic episode, a year of treatment with lithium was much more effective on all measures of outcome, including mania and depression ratings, brain imaging, and neuropsychological functioning, than a year when patients were randomized to quetiapine (Seroquel).
Researcher Lakshmi Yatham and colleagues presented research at the International Society for Bipolar Disorders showing that patients recovered from the neuropsychological deficits associated with a first episode of mania if they were well treated and had no further episodes, while those who had new episodes did not return to their baseline capabilities. This suggests that early treatment that prevents future episodes helps maintain a healthy brain.
Kessing and colleagues previously reported in the British Journal of Psychiatry in 2013 that patients randomized to two years of treatment in an outpatient clinic specializing in mood disorders following a first hospitalization for mania had 40% fewer recurrences of bipolar episodes over the next six years than those who received treatment as usual. These data indicate that early treatment, which may include psychotherapy, medications, mood charting (i.e. keeping a daily record of symptoms) and illness education, can improve the long-term course of illness. Lithium is often a key component of such treatment.
Editor’s Note: This type of intensive, ongoing treatment is not the norm after a first manic hospitalization in the United States, but it should be. Given the new data on the impact of starting lithium after a first episode of mania, and lithium’s superiority over quetiapine in the year following a first episode, lithium treatment should be standard following a diagnosis of bipolar disorder.
In the past, sometimes doctors have recommended waiting until a patient has had multiple episodes of mania before beginning preventative treatment with lithium. This now appears to be a mistake.
Lithium protects against depressive as well as manic recurrences, and there is also evidence that it increases hippocampal and cortical volume, helping prevent cognitive deterioration in those with mild cognitive impairment. Lithium is also the most effective mood stabilizer for preventing suicide, and it increases the length of telomeres (caps on the end of DNA strands), thus preventing a wide range of medical and psychiatric illnesses. Lithium may need to be combined with other drugs to achieve a complete remission, but using it after a first mania is a good place to start.
In some studies, vitamin D supplementation (1,500 IU/day) has been found to improve unipolar depression. Recently, researchers led by Wendy K. Marsh found that compared to placebo, 12 weeks of vitamin D3 supplementation (5,000 IU/day) did not produce greater improvement in depressive symptoms. The study, presented at the 2016 meeting of the Society of Biological Psychiatry, included 33 adult participants whose vitamin D levels remained deficient throughout the study.
Editor’s Note: Caution is urged in interpreting this small study, especially because the participants did not achieve healthy levels of vitamin D.
Low levels of vitamin D are common in children and adults with bipolar disorder. Future research may explore whether raising vitamin D levels to healthy levels has a beneficial effect on mood. There are many other benefits to vitamin D supplementation. It can improve cognition, regulate calcium and phosphorus absorption, and maintain healthy bones and teeth. It may also protect against diseases such as cancer, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, and Crohn’s disease. Improved cardiovascular health is also a possible benefit of vitamin D supplementation.
Some studies have suggested that omega-3 fatty acids may be helpful in the treatment of schizophrenia, but data to support this idea have been inconsistent. A recent meta-analysis of research on omega-3s and schizophrenia suggests that this nutritional supplement might be more useful in early-stage schizophrenia than in later illness.
At the 2016 meeting of the Society of Biological Psychiatry, researchers led by Alexander T. Chen presented the findings of their meta-analysis. First they analyzed six studies that shared a common scale for measuring schizophrenia symptoms. In these studies, omega-3 fatty acids did not outperform placebo when used as an add-on treatment to antipsychotics for people with schizophrenia.
In four remaining studies of omega-3 fatty acids and schizophrenia, the omega-3s were associated with improvement only in patients in the early stages of schizophrenia. Compared to placebo, the supplements decreased non-psychotic symptoms, decreased the dosage of antipsychotic medication patients required, and improved early treatment response (but not late treatment response) in patients in their first episode of schizophrenia.
In the same study, omega-3 fatty acids also reduced conversion to full-blown schizophrenia and psychotic symptom severity in patients at high risk for schizophrenia who were having preliminary symptoms of the illness.
Editor’s Note: Researcher Paul E. Keck has also found that omega-3 fatty acids may be more effective early in bipolar disorder rather than later. He reported that younger patients with bipolar depression and rapid cycling showed more improvement when taking the omega-3 fatty acid EPA than when taking placebo. In contrast, patients with bipolar depression who were over the age of 45 did worse on EPA than on placebo.
Part of the ambiguity about whether omega-3 fatty acids can help treat or prevent mental illness may be explained by the supplements working better in younger people or earlier in the course of an illness.
In 1996, the US began to require that enriched cereal grain products be fortified with folate, a vitamin that is particularly important to fetal brain development. A new study of children born before and after this policy change suggests that the increased folate in commercial foods after 1996 led to increases in cortical thickness in the children born after the change.
At the 2016 meeting of the Society of Biological Psychiatry, Joshua L. Roffman and colleagues described their research into the effects of folate fortification. The researchers identified 3,309 children born between 1993 and 2001 who had had a magnetic resonance imaging (MRI) brain scan. Analysis of the scans showed that children born after folate fortification began had thicker cortices than those born before the change. The frontal and temporal regions of the brain were particularly affected.
A thin cortex is a risk factor for schizophrenia and other cognitive problems.
Editor’s Note: Folate supplementation has also been shown to enhance the effects of selective serotonin reuptake inhibitor (SSRI) antidepressants in adults with lingering symptoms of depression.
Up to a third of the population may have a deficit of MTHFR, an enzyme important for folate metabolism, and for these people, l-methylfolate is recommended rather than folate itself.
A recently completed clinical trial suggests that NeuroAD, a treatment system that combines transcranial magnetic stimulation and cognitive training targeted at brain regions affected by Alzheimer’s disease, may be effective at treating mild to moderate cases of the illness.
Neuronix Ltd, the company that produces the device used to deliver transcranial magnetic stimulation in the trial, plans to seek Food and Drug Administration approval for NeuroAD. It would be the first device approved for the treatment of Alzheimer’s in the US. The device is already in use in Europe and Asia.
In the clinical trial, 131 patients received six weeks of the NeuroAD treatment or a sham treatment used as a comparison. Those participants who received the real intervention performed better on an assessment of Alzheimer’s and experienced minimal side effects.
In transcranial magnetic stimulation, a non-invasive procedure, magnets placed near the skull stimulate electrical impulses in the brain. This activates neurons, releasing excitatory transmitters and brain-derived neurotrophic factor (BDNF), which is important for new synapse formation and long-term learning and memory.
Editor’s Note: This editor (Robert Post) has long advocated the use of repeated transcranial magnetic stimulation (rTMS) with simultaneous cognitive behavioral or other positive therapy to activate and enhance specific neural circuits and relieve depression. The trial of NeuroAD adds evidence of the positive effects of this approach in domains other than depression. Cognitive training enhanced by rTMS may be helpful with a variety of cognitive difficulties.
Several researchers have found that lithium has some value in fighting dementia. The researcher Lars Kessing has published several studies showing that people taking clinical doses of lithium for bipolar disorder have a lower incidence of dementia in old age.
In 2011, another researcher, Oreste Vicentes Forlenza, reported that a year of low-dose lithium (typically around 300mg/day) slowed deterioration in people with mild cognitive impairment compared to placebo.
In an article published in the journal Current Alzheimer Research in 2013, researchers led by Marielza Andrade Nunes reported that very small doses of lithium (more than a thousand times lower than doses used to treat mood disorders) also improved mild cognitive impairment in people with Alzheimer’s disease.
In Nunes’ study, participants with Alzheimer’s disease were randomly assigned to receive either 300 micrograms of lithium daily or a placebo. Beginning at three months of treatment, those receiving the microdoses of lithium showed stable performance on a common Alzheimer’s evaluation tool that measures how well patients remember, recall information, and follow directions; while those taking placebo got worse.
This continued over the 15 months of the study, with the difference between the two groups intensifying over time—those taking placebo got worse, while those getting the microdoses of lithium remained stable.
There were no complaints of side effects from the microdoses of lithium, and participants showed no sign of impairment to their kidney or thyroid function (a risk with the higher doses of lithium used to treat bipolar disorder).
In 2015, Nunes and colleagues reported in the journal PLOS ONE that in a mouse model of Alzheimer’s disease, mice treated with chronic low doses of lithium in their water had less memory disruption, fewer plaques in the brain, and fewer reductions in cortex and hippocampus size compared to mice given plain water.
These studies suggest that low or micro doses of lithium may be a promising treatment for Alzheimer’s disease. Much more research is needed to determine appropriate lithium dosing for the treatment of dementia or cognition problems.