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The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 10

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

17. Does mast cell disease impact mood, anxiety, and depression?
• Yes. This has been described in literature for over 30 years. In 1986, a paper described a series of patients with systemic mastocytosis who had severe psychiatric symptoms as a result of their disease. It was called “mixed organic brain syndrome”.
• Depression, anger, bipolar disorder, attention deficit disorders, anxiety, irritating, and panic disorders have all been associated with mast cell disease.
• One study found that in a group of patients with cutaneous mastocytosis and systemic mastocytosis, 75% of the patients had symptoms of depression. In another study, 60% had symptoms of depression or anxiety.
• Many patients have been diagnosed with a psychiatric condition before learning that they have mast cell disease. For many mast cell patients, managing their diseases lessens the severity of their psychiatric symptoms. Antihistamines have been reported many times to improve these symptoms.
• Mast cells are often sitting right next to nerve cells throughout the body. Mast cells are found in large numbers in the brain. Chemicals released by mast cells can cause psychiatric symptoms.
• Some of the chemicals released by mast cells are specifically intended to talk to nerve cells. Histamine is one such chemical. When histamine is not released in the right amounts at the right times, it can affect how other chemicals are released. Some of these chemicals are also for cells to talk to nerves, like serotonin and dopamine. Mast cells can also release serotonin.

18. Are medications for depression, anxiety or other psychiatric conditions used in mast cell patients?
• Yes. As with every medication, only you and your care team can decide if a medication is safe for you. No medication is universally safe or always dangerous.
• Benzodiazepines are usually well tolerated in mast cell patients. Benzodiazepines actually interact with mast cells and can make them release fewer chemicals. (Be aware that the IV forms of these medications sometimes have alcohol in them).
• SSRIs are sometimes taken by mast cell patients. Mast cell patients should be cautious because they can increase serotonin levels and mast cells can also release serotonin.
• Tricyclic antidepressants are more commonly used in mast cell patients. Tricyclic antidepressants actually work as antihistamines, too.
• Other drugs that can manage psychiatric symptoms, like mirtazapine, olanzapine, and quetiapine, also have antihistamine properties.
For more detailed reading, please visit these posts:

 

Neuropsychiatric features of mast cell disease: Part 1 of 2

Neuropsychiatric features of mast cell disease: Part 2 of 2

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.

PTSD and Medical Trauma

On the Tuesday before Thanksgiving in 2009, I had an emergency appointment with my neurotologist.  “You have borderline profound hearing loss in your left ear and moderate to severe hearing loss in your right ear,” she said, showing me the audiogram.  I knew it was bad.  I could barely hear anymore. 

“We can try transtympanic steroid injections, do you want to try that?”  I couldn’t understand speech and all my music sounded weird.  I wanted to try it.  I would have tried anything. 
An hour later, I was in a procedure room curled up on my side.  They put a cone in my left ear and numbed my ear drum, which hurt a shocking amount.  Then they punctured my ear drum and injected steroids into it.  I watched it on the tv, the needle withdrawing threw the hole, the fluid spilling out behind it.  It felt like having water up my nose, but in my ear.  Once the steroids were injected, I was temporarily deafened, even loud sounds heard only by the vibrations in my chest.  I lay still for thirty minutes, then rolled over and did the other ear.
I got five injections in each ear drum over a three week period.  I never regained any hearing in my left ear.  My right ear retained some hearing, though what was left fluctuated heavily for years.  I had several hearing tests over the next few years.  Every time, it was nerve wracking and terrifying, even though it was painless and easy.  I eventually realized I was reacting to my ears being touched.  I could no longer handle having things put into my ears without having a visceral reaction. 
I underwent a lot of invasive examinations, tests and procedures while trying to identify what was wrong with me.  I often had things inserted into my body for medical purposes.  After diagnosis, I had more procedures and surgery.   I got bad news a lot.
A couple of years ago, I was having a lot of anxiety, to the point that it interfered with daily activities.  One of my doctors commented that I probably had PTSD.   “The whole process of finding a rare disease is traumatic,” he said.  I have to agree.  Once I realized what was happening, it made perfect sense.  I deal with it and it’s mostly not a problem anymore.  Sometimes though, it comes back.  When I was in the hospital in May, a resident argued with me about using epinephrine and I started hysterically crying.  I knew someone from the immunology team would address this issue shortly but the lack of control brings me right back to the stress of trying to convince doctors I am sick.  I function and am not generally anxious but you can only ever get so far from it.  When you are chronically ill, you are only as removed from these feeling as your next medical event. 
Johns Hopkins did a study a few years ago and found that PTSD lasting at least two years is common in people who have been in the ICU.   1 in 3 patients requiring ventilation has PTSD.  When you have surgery or an accident, you are often treated with powerful drugs by people you don’t know without thorough explanations.  The medications often have psychiatric effects, and patients in comas often report dreaming of fires and having paranoid delusions upon awaking.  The whole experience is terrifying.  For people like me, we have these experiences often, sometimes several times a year. 
If you have flashbacks of medical procedures, hate going to the doctor or panic at the idea of going to the ER, you are not alone.  I think because these events are part of our daily lives, we forget how long reaching the effects can be.  Seeking and receiving treatment for chronic illness, even under the best circumstances, has the possibility of being traumatizing.  It is additionally complicated for people who are chronically ill because we cannot avoid the experience that traumatized us as we need ongoing care.  The reality is that we can traumatize ourselves over and over. 
People experiencing PTSD often have flashbacks, nightmares (of the event or not) and physical responses to reminders of the event (sweating, nausea, rapid heartbeat, emotional distress.)  They often avoid places or things that remind them of the traumatic event.  They may not be able to remember the trauma fully or at all and feel detached from and disinterested in things and relationships they used to enjoy.  They often feel a “sense of limited future” in spite of evidence to the contrary, meaning they think they will die young, never get married, or otherwise have a short and unfulfilling life.  They often have difficulty sleeping, have outbursts of rage, feel jumpy and are hypervigilant. 
Cognitive-behavior therapy can be a helpful tool for patients with PTSD.  Medications can help, but therapy to address the underlying trauma is crucial.  If you think you have PTSD, please seek help from a mental health provider.  This stuff is hard enough without being scared all the time.