When I first started practicing medicine I was somewhat “ignored” by the medical profession for applying the nutritional studies I found in the best of journals that I would-and still do-avidly read. Unfortunately, and true to the findings presented by the National Institute of Medicine[1] it takes about 17 years for new ideas to trickle down to the trenches.
Well, “new ideas” on health and nutrition, or very old ones finally getting proper attention, are ready for prime time. See for yourself:
Insulin, Inflammation, and the Link Between Body and Mind
“At the recent American Psychiatric Association meeting in Toronto, Ontario, Canada, there was a presidential symposium on how the mind affects the body and the body affects the mind—specifically, in terms of inflammation, depression, drugs, and disease.
The first presenter was Dr Roger S. McIntyre, professor of psychiatry and pharmacology, University of Toronto. His topic was “Cellular Energetics and Inflammation: Implications for Disease Modeling Opportunities for Common Connectopathies.”
Dr McIntyre began by noting that from 1999 to 2009, mortality in bipolar illness and depression increased rather than decreased. Cognitive impairment may be an important barrier to health outcomes in mood illnesses. He noted that diabetes increases the risk for mild cognitive impairment (MCI). A new meta-analysis by his group showed that A1c is associated inversely with scores on the digit symbol substitution test, a measure of cognitive function; obesity also correlates with this measure. The Diabetes and Aging Study showed that having both depression and diabetes markedly increased the risk for MCI, after correction for age, sex, and some clinical variables.
Insulin is a neurotrophic factor that has a major role in inhibiting apoptosis or cell death. Once it enters the brain, it is a critical neuropeptide. Ten percent to 20% of cases of Alzheimer disease are estimated to be the result of diabetes. Amyloid has proinflammatory and insulin-resistant effects—so once the process of dementia starts, the absence of insulin may hasten it.
Obesity also has been associated with reduced white-matter integrity, while insulin may be critical to normal brain circuitry. It’s interesting to think that these biological relationships might have been the basis for past observation of benefit with insulin coma therapy in psychiatry in the early to mid-20th century. Recent studies indicate that intranasal insulin improves measures of cognitive function in amnestic MCI.
Glucagon-like peptide I is a drug given for diabetes, which is an insulin secretagogue. In the brain, it improves cognition in rat models. It gets into the brain much more effectively than other exogenously administered neurotrophic factors, such as brain-derived neurotrophic factor. It may have some potential as a new mood treatment.
Dr McIntyre also noted that obesity-related inflammation may be an important mechanism of worsening mood illnesses. The mechanism for how inflammation may worsen mood illness has to do with the kynurenine system. Tryptophan converts into kynurenine instead of serotonin under pathologic conditions of inflammation, which then produces harmful effects (via metabolites that are proinflammatory cytokines, such as quinolinic acid) that are directly toxic to dopaminergic neurons. Obese bipolar patients have been shown to have more kynurenine peripherally than nonobese bipolar patients, who are similar to healthy controls.
Minocycline, an antibiotic used for acne, improves executive function in schizophrenia. A recent unpublished study by Dr McIntyre’s group found that minocycline also improved bipolar depression in 27 persons, for both depressive and cognitive symptoms.
Are NSAIDs Useful for Depression?
The second presenter was Dr Charles Raison, professor of psychiatry and human ecology, University of Wisconsin-Madison. His topic was “Anti-inflammatory Agents as Antidepressants: Truth or Dare?”
Dr Raison cautioned against overenthusiasm for the link between inflammation and mental illness, at least in terms of immediate treatments. His critique referred to a recent meta-analysis that concluded that nonsteroidal anti-inflammatory drugs (NSAIDs), especially celecoxib, may have antidepressant properties. Dr Raison noted that NSAIDs stimulate cadherin-11, a molecule that reduces anxiety in animal models but isn’t involved with inflammation processes at all. In addition, serotonin reuptake inhibitors increase some inflammatory cytokines, such as p11, which actually seem to be helpful in animal models of depression response. He noted that the impact of minocycline may have to do with profound effects on gut microbiota, which animal models show have major impact on behavior.
In short, the effects of these agents may have nothing to do with an impact on central nervous system inflammation. We know that inflammation causes depression and that NSAIDs may improve depression in the setting of inflammation, but NSAIDs do not appear to improve depression in medically healthy persons who do not have abnormal inflammation.
Dr Raison then reviewed a key study that he had conducted on infliximab for treatment-resistant depression. Patients who did not have inflammatory diseases were randomly assigned to receive three infusions of infliximab vs saline (at baseline, 6 weeks, and 12 weeks). Over 50% of patients experienced major benefit, and the treatment seemed to have transformed their lives; but when Dr Raison and his colleagues broke the double-blinding, they found that infliximab was equivalent to placebo.
Of note, though, in a subgroup analysis of patients with more inflammation vs less, greater benefit of infliximab was seen in those with higher C-reactive protein levels. If the C-reactive protein level was > 5 mg/L, there was about 3-point improvement on Hamilton Rating Scale for Depression. Infliximab does not enter the central nervous system, so any benefit seen here is based on peripheral inflammation, which is an important hypothesis.
Dr Raison concluded that although there may be a role for some anti-inflammatory agents in some subtypes of depression with evidence of high inflammation, it would be premature to use NSAIDs broadly for depressive states. The benefits are minimal, and the risks are serious: He noted that about 100,000 persons are hospitalized yearly because of NSAID use. Celecoxib more than doubles the risk for myocardial infarction, and about 17,000 persons with rheumatoid arthritis die of gastrointestinal complications of NSAIDs yearly.
There are other, nonpharmacologic ways to reduce inflammation, Dr Raison noted: spirituality, Mediterranean diet, exercise, meditation, and prevention of early-life trauma or neglect.
Depression and Heart Disease
The third speaker was Dr Steven Roose, professor of psychiatry, New York State Psychiatric Institute, Columbia University Medical Center, New York, whose topic was treatment of depression in heart disease. He noted that depression causes vascular damage through increased sympathetic activity, increased platelet aggregation, increased hypothalamic-pituitary-adrenal axis activity and cortisol, and proinflammatory cytokines.
Depression increases the risk for coronary artery disease fourfold for syndromal depressive episodes and 1.5-fold to twofold for subsyndromal depressive symptoms. In addition, childhood depression leads to a 12-fold increased risk for smoking. Furthermore, depression (but not anxiety or anger) increased cardiac mortality after myocardial infarction (MI). Inflammation and increased platelet activity could be important mechanisms of this effect, he noted. Overall, there is about fourfold increased risk for mortality after MI in patients with depression, with the risk being highest in the first 6 months.
Dr Roose examined the classic SADHEART study which looked at sertraline (mean dosage, 68.8 mg/d) in 260 patients vs placebo. At 16 weeks, MI was reduced by an odds ratio of 0.70 (95% confidence interval, 0.23-2.16). The composite cardiovascular events score was somewhat reduced as well (odds ratio, 0.77; 95% confidence interval, 0.51-1.16).
The benefit of sertraline for depressive symptoms was greater among patients with preexisting depression before MI (73% with sertraline vs 43% with placebo) than among those whose depression began after MI (63% with sertraline vs 57% with placebo).
That study was followed up by another larger trial, ENRICHD, which was powered for mortality in over 2000 patients. Patients were randomly assigned to receive cognitive-behavioral therapy (CBT) for 6 months or no CBT, and serotonin reuptake inhibitors (SRIs) were allowed. Overall, there was no effect of CBT on mortality. But in the SRI group (n = 353), there was benefit, with about a 50% reduction in cardiovascular mortality (4.5% vs 9.8% with no SRI). However, because participants were not randomly assigned to receive SRI treatment vs no SRIs, this benefit cannot be known definitively to be causal.
If SRIs do provide some benefit for cardiovascular mortality, Dr Roose noted that we cannot assume that the mechanism involves anti-inflammatory effects. Instead, a mechanism could involve direct antiplatelet effects of SRIs; platelets contain most of the body’s serotonin. He noted that this effect also is related to the fact that SRIs can cause upper gastrointestinal bleeding in older patients.”
- Book “Crossing the Quality Chasm,” 2001 ↑
