Mood disorders and inflammation: Neurologic effects and treatment (Part 4 of 4)

TNF blockers like Enbrel and infliximab can lower depression independent of improvements with physical symptoms. 62% of patients with treatment resistant depression saw improvement on infliximab versus 33% with standard therapies. Infliximab also improved sleep, allowing patients to stay asleep longer. Infliximab successfully improved depression symptoms in patients with inflammatory disease as well as controls who had elevated CRP and TNF but not on controls with normal CRP and TNF. Patients who were not effectively treated with SSRIs were found to have higher IL-6 and TNF.

Chronic inflammation can cause structural and functional changes in the brain, interfering with its ability to make new connections and damaging existing function. Activation of microglial cells in the nervous system is associated with maladaptive behaviors and decreased brain function seen in bipolar disorder, major depressive disorder and other mood conditions. They also protect neurologic function in multiple sclerosis, Huntington’s and Alzheimer’s. Minocycline, an antibiotic, also has significant anti-inflammatory and neuroprotective effects.

In some encephalitis models, DMARDs can actually restore stem cells of the nervous system, reducing tissue and myelin damage. DMARDs, often used for autoimmune diseases, improve mood symptoms in rheumatoid arthritis patients. They can also mitigate hyperactivity from amphetamines. Clinical trials are currently investigating the full effects of these medications on psychiatric conditions.

Mood stabilizers often have anti-inflammatory effects. In bipolar disorder patients, lithium and valproate decreased IL-6. Medications that act on serotonin and dopamine receptors decrease production of inflammatory molecules like TNF, IL-6 and PGE2. Escitalopram, an SSRI antidepressant, can decrease cortisol production and IL-11.  ACTH production can be induced by fluoxetine.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

Mood disorders and inflammation: Inflammatory conditions and treatment (Part 3 of 4)

A number of inflammatory conditions coincide with mood disorders. Women with chronic health issues who pursue diagnosis are commonly labeled as having anxiety and the physical symptoms as a result of that. However, there is a significant body of evidence pointing to mood disorders as being organic symptoms of the inflammation rather than the psychological reaction to the changes that come with chronic illness. What we often frame as behavioral or psychiatric symptoms are perceived by some researchers as “sickness behavior” that promotes healing. Low energy, appetite and mood, along with sleeping more, redirect energy from less important functions to immune defense or wound repair.

Patients with autoimmune disease, diabetes, metabolic syndrome, asthma and allergies all experience mood disorders. Psoriasis dramatically increases the frequency of depressive symptoms. Cardiovascular disease patients are more likely to have major depressive disorder or bipolar disorder than the general population. Major depressive disorder increases risk of coronary artery and poorer prognosis with cardiovascular disease.

In one study with ISM and CM patients, 75% reported symptoms of depression. In a different study, 60% reported depressive symptoms and anxiety. Asthma and wheezing are independently associated with major depressive episodes in a massive study with almost 250,000 people from 57 countries.

Depression patients who have attempted suicide show increased TNF and IL-6, along with low IL-2, compared to depression patients who have not attempted suicide. Elevated CRP is also associated with depression. Alexithymia, in which the patient feels no emotions, affects 39-46% of patients with major depressive disorder. These patients also demonstrate very high CRP levels which can decrease cognitive functions.

Treatment of chronic illnesses can also improve associated mood disorders. Aspirin is currently being trialed as a treatment for bipolar disorder. Use of aspirin with an SSRI produced better response than just the SSRI.  Use of COX-2 inhibitors like celecoxib with antidepressants improves symptoms and decreases levels of IL-6 and IL-1b. NSAIDs, which also interfere with COX-2, reduce depression when compared to placebo.

Omega-3 polyunsaturated fatty acids have been found to be potent antidepressants. These molecules also decrease the production of prostaglandins and cytokines. Omega-3 polyunsaturated fatty acids interfere with the COX-2 enzyme that produces prostaglandins.  Curcumin also decreases cytokine production, as well as normalizing activity from the HPA axis and improving mood.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

Mood disorders and inflammation: High cortisol and low serotonin (Part 2 of 4)

There are multiple suspect pathways for causation of mood dysregulation in the setting of inflammation. One well described model hinges upon the ability of inflammatory mediators to impact the HPA axis, a system of hormone release that drives many physiologic functions in addition to the stress response.  Briefly, the central pathway of the HPA axis is that CRH causes production of ACTH, which causes production of cortisol, a stress hormone and a very potent anti-inflammatory under most circumstances.  Many molecules can affect the signaling of the HPA axis and contribute to inappropriate hormone regulation.

IL-1, IL-6, TNF and IFN-a are all inflammatory mediators released by mast cells and other cells. These mediators all activate the HPA axis, resulting in high production of CRH, ACTH and cortisol via a series of intertwined mechanisms. At the same time, inflammation also makes cortisol less effective.  There are several ways for this to occur. Inflammation can cause cells to make fewer receptors for cortisol, meaning that no matter how much cortisol is made, only a small fraction will be able to act on cells.  Persistently high cortisol levels decrease production of other anti-inflammatory molecules and molecules that mediate the anti-inflammatory action of cortisol.  High cortisol also tells the HPA axis that it doesn’t need to make more cortisol, so even though more may actually be necessary, your body doesn’t know that.

All of these factors coalesce to form a reality where cortisol may be elevated but with little anti-inflammatory effect because of the changes I mentioned above. High cortisol is associated with mood symptoms.

Decrease of serotonin activity is also seen in mood disorders. Tryptophan is a precursor to serotonin, a hormone and neurotransmitter that heavily regulates mood.  Cortisol increases the activity of a molecule called tryptophan 2,3-dioxygenase (TDO), which removes the amino acid tryptophan from the pool of molecules to break down. Inflammatory molecules like interferon increase activity of the enzyme IDO, which decreases serotonin production.  IDO breaks down tryptophan to molecules that cannot be made into serotonin, such as kynerenin and quinolonic acid.  These metabolites have been observed as elevated in models of depression and anxiety.

Another way that inflammatory mediators affect the action of serotonin is to hasten its degradation. Both TNF and IL-6 increase the breakdown of serotonin to 5-HIAA.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

Mood disorders and inflammation: Mediators (Part 1 of 4)

Mood disorders are the leading cause of disability in many countries around the world. Depression alone affects a staggering number of people, currently thought to be about 350 million people worldwide.  Its prevalence and diagnosis is increasing to such an extent that the WHO expects it to be the primary cause of global disease burden in less than 15 years.

Mood disorders are commonly found in patients diagnosed with inflammatory conditions.  Cardiovascular disease, diabetes, metabolic syndrome, asthma, allergies and many autoimmune diseases co-occur with these psychiatric conditions.  While providers are often tempted to attribute depression, anxiety and maladaptive behaviors to the stress of having chronic health issues, a significant body of evidence firmly supports the idea that mood disorders are themselves inflammatory conditions and therefore biologically ordained. Furthermore, having a mood disorder can affect prognosis in some diseases.

A number of inflammatory molecules participate in immune response, including histamine, prostaglandins, bradykinin, leukotrienes, CRP, interferon, cortisol and cytokines.  These substances are released in response to physical stresses such as infection, trauma or disease process.  Psychological stress also triggers inflammatory response with increases of molecules such as IL-6, IL-1b, TNF and CRP.

Several studies have definitively found that mood symptoms are associated with increased levels of inflammatory markers.  PGE2, CRP, TNF, IL-1b, IL-2 and IL-6 were all elevated in both peripheral blood and cerebrospinal fluid in patients with major depressive disorder.  A massive 25-80% of hepatitis C patients experience depressive symptoms when they begin treatment with interferon, a potent inflammatory molecule. Elevated interferon and IL-2 levels have been observed early in the depressive event.

In human patients, studies have simulated an inflammatory response by inoculation with toxins, proteins associated with infectious organisms, or interferon. In one study, an inflammatory response was provoked by inoculation with Salmonella endotoxin.  While they suffered no physical symptoms, anxiety, depressed mood and decreased memory function was observed along with elevated TNF, IL-6 and cortisol levels.  Another study found that inoculation with LPS (a substance found in bacterial cell membranes) triggered a dose dependent increase in IL-6, IL-10, TNF, cortisol and norepinephrine, which in turn triggered a dose dependent increase in anxiety, “poor mind” and decreased long term memory functions.

References:

Furtado M, Katzman MA. Examining the role of neuroinflammation in major depression. Psychiatry Research 2015: 229, 27-36.

Rosenblat JD, et al. Inflamed moods: a review of the interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 2014; 53, 23-34.

 

Neuropsychiatric features of mast cell disease: Part 2 of 2

Mast cell activation can induce neuropsychiatric symptoms. Degranulation has been linked previously to headache. It is possible that peptidergic and cholinergic neurons receive mast cell mediators and that this plays a role in headache pathology.  TNF is speculated to participate in depression.  Histamine may cause memory deficits, although there is conflicting information on this topic. Some patients have improvement in neuropsychiatric symptoms with antihistamines.

Mastocytosis patients who have GI and neuropsychiatric symptoms often have low serum serotonin.  Tryptophan is a precursor to serotonin. Plasma tryptophan is also often low in mastocytosis patients, while plasma IDO1 (indoleamine-2,3-dioxygenase 1) activity is higher. IDO1 breaks down tryptophan through an alternate pathway that does not form serotonin. In this pathway, IDO1 breaks down tryptophan, forming kynurenic acid and quinolinic acid.  The accumulation of these substances could explain the fatigue and cognitive impairment in mastocytosis patients.  Low tryptophan and low serotonin in this population were associated with perceived stress and depression.

Treatment of neuropsychiatric symptoms in mast cell patients can include a variety of medications.   SSRI medications can reduce fatigue and depression in some inflammation models.  Some mast cell patients take these medications, usually with low starting doses in case mast cell degranulation in these people has conversely led to higher serotonin levels.  Bupropion, SNRIs and tricyclic medications are also commonly used for depressive symptoms in many chronic illness populations.

Some tricyclic antidepressants have antihistamine properties, with doxepin being a common choice.  Another tricyclic, amitriptyline, can inhibit release of mast cell mediators. Mianserin and mirtazapine can be prescribed for insomnia but also have antihistamine properties. Aprepitant could potentially be used in treatment of depression and cognitive impairment in mastocytosis and MCAS patients. Prochloperazine also decreases mast cell mediator release. Amantadine has improved depression and fatigue symptoms in multiple sclerosis patients. Inhibition of TNF with infliximab has improved depression in patients with high levels of inflammation.

Kynurenic acid, formed in the alternate tryptophan breakdown pathway described above, can block acetylcholine receptors, causing neurologic symptoms.  A7 agonists like nicotine could potentially overcome this effect.  Quinolinic acid binds at the NMDA receptor, cause neurologic symptoms.  Ketamine, an NMDA antagonist, can produce significant improvements in depressive symptoms in treatment resistant depression. As quinolinic acid is typically present in higher levels than kynurenic acid in mastocytosis patients, ketamine might offer a treatment for these patients with depression and high perceived stress.

Masitinib, a tyrosine kinase inhibitor, was shown to decrease depression, anxiety and cognitive difficulties in a significant amount of mastocytosis patients. Mindful meditation may also help patients to lessen activation caused by psychological stress and therefore decreasing biological stress.

References:

Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9.

Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57.

Moura DS, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am 2014; 34(2): 407-422.

Moura DS, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011, 6: e.26375.

Moura DS, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012, 7: e.39468.

Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574.

Neuropsychiatric features of mast cell disease: Part 1 of 2

The fact that psychiatric symptoms occur as a function of mast cell disease on the nervous system is common knowledge to patients but less acknowledged by providers.  A significant population of mast cells is found in the brain in close association with both blood vessels and nerve cells.  Mast cells are present in large numbers in the hypothalamus, which regulates stress response, emotion and cognition; the amygdales, near the pituitary gland; and the thalamus.  Lesions and structural changes in the thalamus have previously been associated with altered perception of pain and emotional reactivity.

One study found that in a group of 88 patients with indolent systemic mastocytosis (ISM) and cutaneous mastocytosis (CM), 75% reported depressive symptoms.  In another study, a group of 288 mastocytosis patients had a prevalence of 60% depressive and anxiety-type symptoms.  The depressive symptoms seen most often in mastocytosis patients are affective and cognitive symptoms (depressed mood, low motivation, feelings of guilt and failure; and anxio-somatic symptoms (physical and mental effects of anxiety, insomnia).  Psychomotor difficulties (slowing of thought processes and/or neurologic control of movement) and lack of insight were rare in these patients.

Depression is often assessed using the Hamilton Depression Rating Scale.  This tool may not be ideal for use in mast cell patients because the somatic symptoms correlated with depression are often the same as physical symptoms of mast cell disease.  When excluding symptoms that could be from mastocytosis rather than depression, patients still had a high prevalence of sadness and loss of motivation.

One mastocytosis cohort reported 38.6% had cognitive impairment of some kind. Inability to focus and pay attention is the cognitive symptom most commonly reported by mastocytosis patients.  This was not linked to depression, age, education or staging of mastocytosis.  Importantly, it was also independent of amount of antihistamine use.  Memory impairment was also not related to age or education.  Cognitive difficulties were found to be much more prevalent in mastocytosis patients than in other chronic disease populations.

Fatigue is a common neuropsychiatric symptom for mast cell patients and has been seen in populations with both mastocytosis and mast cell activation syndrome.  Patients who have moderate to severe fatigue often experience pain and cognitive deficits.  The level of fatigue can be disabling as it makes it difficult to focus or perform even simple tasks.

35% of mastocytosis patients in one study reported 35% had either acute or chronic headaches.  37.5% had migraines, while 17.2% had tension type headaches.  Headache patients often reported episodic flushing or itching at the time of the headache. In the migraine group, 66% experienced aura symptoms.  Overall, 39% of patients in this group with or without migraines experienced aura symptoms, usually visual.

Exaggeration of the stress response could explain neuropsychiatric symptoms in mast cell patients. In one population, 42% of patients perceived their stress level to be high. Persistent stress response could lead to negative emotions.  These symptoms could be reinforced by mast cell hyperactivity in the brain, which can affect stress response, emotionality and cognition.

References:

Georgin-Lavialle S, et al. Mastocytosis in adulthood and neuropsychiatric disorders. Translational Resarch 2016; x:1-9.

Georgin-Lavialle S, et al. Leukocyte telomere length in mastocytosis: correlations with depression and perceived stress. Brain Behav Immun 2014; 35: 51-57.

Moura DS, et al. Neuropsychological features of adult mastocytosis. Immunol Allergy Clin North Am 2014; 34(2): 407-422.

Moura DS, et al. Depression in patients with mastocytosis: prevalence, features and effects of masitinib therapy. PLoS One 2011, 6: e.26375.

Moura DS, et al. Evidence for cognitive impairment in mastocytosis: prevalence, features and correlations to depression. PLoS One 2012, 7: e.39468.

Smith JH, et al. Neurologic symptoms and diagnosis in adults with mast cell disease. Clin Neurol Neurosurg 2011, 113: 570-574.

Winter, the dark.

I am not a summer girl. I never have been. Years before the heat made me sick, I would look forward to fall and the smell of fallen leaves and the way they crunched underfoot.

Summer was never for me. It was just too bright.

September and October are my favorite time of the year. I am a Boston girl and I love everything about New England autumn. I love the way the light looks icier, bluer coming through the trees. I love the feel of chilly air on my cheeks as I walk through the city. I love opening the window at night and falling asleep to the scent of frost. I love Halloween. I love watching scary movies every night while I write in my journal. I love the way bare tree branches silhouette against the swollen harvest moon.

I love all these things; but I still feel the coming dark.

I get very introspective in the fall. For the rest of the year, I look forward, move forward, but in the fall, it seems I can only think back. Festive October gives way to cold November nights, to bleak Decembers, where the horizon swallows the sun before 4:30 and everything tastes like regret. I write a lot about life, about my past. I wonder about the moments that my life hinged upon, about who I would be if I had turned differently.

I like my life. It’s just that the darkness makes the past seem so large. It unlocks in me this door to melancholy and it unfurls around me, splendid and devastating.

Depression is an organic process of mast cell disease. It is part of the disease, not a side effect of living with a chronic illness. I know that these racing thoughts and weariness with the world are from masto. I know that I’m not really hopeless on the bad days, but it doesn’t matter. By the time December is half over, I don’t even think I can tell the difference.

Tomorrow is the shortest day of the year. Then the light will return.

There is beauty in the darkness. It’s just so cold here.