Improvement in Neuropsychiatric Symptoms With the Addition of Nortriptyline in the Context of Mast Cell Activation Syndrome

The body’s inflammatory response system has long been theorized to play a role in the pathology of mental disorders (1–3). Inflammation is part of the body’s immune response that maintains homeostasis and promotes repair during stress (1). Although the inflammatory response is meant to be protective, many studies have found higher levels of proinflammatory cytokines and acute phase reactants in patients with major depressive disorder (1–3). Studies have shown significant correlations between inflammation and depressive disorders; however, it has yet to be determined whether one causes the other or whether there are unknown confounding causative agents (1–3).

Mast cell activation syndrome (MCAS) is an immunological disorder with a high prevalence of comorbidity (4). MCAS falls into the broader category of mast cell activation disease (MCAD), which also includes mastocytosis, as well as secondary forms such as urticaria, allergic diseases, and chronic inflammatory diseases. World Health Organization diagnostic criteria require abnormal mast cell morphology or disseminated infiltrates in bone marrow biopsy and clinical history of symptoms correlated with mast cell activity (4). Criteria for MCAS were initially established in the 2010s, and they are continuously evolving as more information becomes available (4). It has been estimated that MCAS prevalence is 5%–10% in the general population, predominantly in Caucasian females (4, 5). In this subset, comorbid depressive disorder is estimated at 16%, and comorbid anxiety disorder is estimated at 12% (4).

MCAS is a condition caused by inappropriate activation of mast cells, leading to mast cell degranulation and release of inflammatory mediators, such as histamine, serotonin, tryptase, chymase, and cytokines (6). This results in a constellation of vague multisystem manifestations (endocrine, cardiovascular, digestive, lymphatic, and musculoskeletal systems) (4, 5, 7, 8). The most commonly reported neuropsychiatric symptoms are fatigue, cognitive dysfunction, paresthesia, neuropathic pain, brain fog, avolition, depression, anxiety, insomnia, and tremor (4, 5, 7, 8). These symptoms are extensive and nonspecific, leading to underdiagnosis of MCAS (5, 9). Many patients with MCAS also present with Ehlers-Danlos syndrome (EDS) or postural tachycardia syndrome (POTS), suggesting an underlying genetic mutation (4, 7). Whether these medical comorbidities have a shared confounding cause with MCAS remains unknown.

Studies show that alterations in neurotransmitters involved in mental disorders can have significant effects on modulating mast cell function (9). As such, different classes of psychiatric medications can have either positive or negative effects on MCAS. This case report provides clinical evidence to support ongoing research on the effects of medications used to treat neuropsychiatric symptoms in MCAS.

Case Presentation

A 29-year-old Caucasian female was diagnosed as having major depressive disorder, generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD), as well as borderline personality disorder. During college, she began to suffer from multiple physical issues—fatigue, generalized weakness, bowel and bladder incontinence, abdominal pain, flushing, palpitations, and lymphadenopathy. Two years later, at age 26, she was diagnosed as having EDS and POTS and given an MCAS diagnosis. As an adult, she was also diagnosed with numerous other medical conditions, including gastroparesis, migraines, and degenerative disc disease.

At the patient’s initial outpatient visit, she reported taking extended-release bupropion 300 mg once a day, nortriptyline 50 mg at bedtime, and clonazepam 0.5 mg twice a day as needed for major depressive disorder, GAD, and PTSD. She was maintained on levocetirizine 5 mg twice a day, famotidine 20 mg twice a day, montelukast 10 mg at bedtime, and cromoglicic acid 10 mg/5 mL daily as needed as prescribed by her allergist for MCAS. Stressors included her father’s death, starting online courses, and concurrent worsening of her MCAS. She experienced frequent episodes of fatigue, diarrhea, flushing, rash, and brain fog. At this initial visit, the Hamilton Depression Rating Scale (HDRS-17) score was 13, and she was tearful, appeared gaunt, and exhibited an anxious affect on a mental status examination. The decision was made to increase bupropion to 450 mg once per day to address mood symptoms.

One week after increasing bupropion, she called to report worsening rash, abdominal pain, lymphadenopathy, and higher anxiety. The decision was made to titrate bupropion down to 200 mg once a day.

Two weeks after this call, the patient came for a follow-up visit. Partial improvement in her physical symptoms had occurred. The HDRS-17 score at this visit was 17. On examination, she still appeared gaunt, and she had lymphadenopathy and a visible rash on her neck. Her thought content involved feelings of guilt and low self-worth. Additionally, she reported continued insomnia and anxiety despite a decreased dosage of bupropion. Nortriptyline was increased to 100 mg nightly to address this major depressive episode.

At the following two monthly appointments, the patient reported positive changes in mood, anxiety, energy, and concentration, which were reflected in her schoolwork. HDRS-17 scores were 7 and then 3 at these two visits. On subsequent visits, she appeared to be more alert and well groomed and exhibited an overall cheerful affect. Lymphadenopathy and rash were notably absent. She stated that the physical symptoms of MCAS had resolved. Improvements were also noted by her allergist, who made no changes to her medications during this time frame. A trial to taper bupropion was attempted. However, she felt more down and less motivated, and the dosage was maintained at 200 mg. Overall, she noted that her MCAS symptoms had abated and observed improvements in daily functioning.

The patient remained in remission for 6 months under our care. With no recurrence in her MCAS and consistent low depression scores, her functioning improved to the point where she was admitted to graduate school and obtained a research position. Her care was transferred to a psychiatrist in the geographic area of her program.

Discussion

This case report highlights the connection between the inflammatory system and mood disorders, along with the challenges of managing major depressive disorder in the context of medical conditions in which psychiatric medications can also have an effect. Serotonin is believed to facilitate mast cell degranulation and migration while simultaneously being secreted by degranulating mast cells (9). As such, serotonin-modulating agents, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), can have a far-reaching impact (9). Some studies have shown that SSRIs can inhibit mast cell activation, proliferation, granule formation, and serotonin reuptake (9). Other studies have shown that SSRIs may not be tolerated well, because serotonin reuptake inhibition may induce mast cell degranulation and lead to further release of histamine and inflammatory cytokines (5, 9). Therefore, it is difficult to predict a patient’s response to SSRIs (5). Research on TCAs has shown a consistent beneficial effect on MCAS (5, 9, 10). These beneficial effects occur primarily through inhibition of serotonin secretion and prevention of mast cell degranulation by lowering levels of intracellular calcium (5, 9, 10). Benzodiazepines have been successfully used to treat overactive mast cells through activation of inhibitory benzodiazepine receptors (4). Selective dopamine and norepinephrine reuptake inhibitors have been shown to worsen MCAS through the suspected mechanism of stimulating histamine release from mast cells (5, 10).

Because the extent of symptoms of patients with MCAS is so varied and broad, MCAS is often underrecognized, and symptoms are often attributed to somatization disorders (4). This patient did not meet criteria for factitious disorder, conversion disorder, or illness anxiety disorder due to the diagnosis of an underlying medical condition as the cause of her physical symptoms (11). Somatic symptom disorder was considered in the differential diagnosis, but it was ruled out because the content of her anxiety involved all aspects of her life and was not limited to one persistent physical symptom.

It is also important to recognize that the presentation of worsening depression and anxiety may appear as somatic complaints misattributed to MCAS. That is, treating her major depressive disorder and GAD may have alleviated the somatization, rather than targeting MCAS. Other signs pointing to potential somatization include the diagnosis of several psychiatric comorbidities, nonspecific medical conditions, and timing of worsening symptoms following life stressors.

Because the patient had experienced medication trials with SSRIs prior to presentation, we were unable to directly assess these effects. The patient experienced worsening of her physical MCAS symptoms on a higher dose of bupropion, but it is unknown whether she experienced any decompensation during initiation. The decision to increase nortriptyline was to target concerns regarding insomnia and worsening of major depressive disorder and GAD symptoms. Furthermore, her MCAS symptoms appeared to improve with the higher dose. Literature reviews have documented benefits of benzodiazepine use in MCAS, and thus, clonazepam administration was maintained during treatment (4, 5). Although the timing of medication changes and clinical improvement could be attributed to coincidence, the patient’s progression is consistent with recent findings on bupropion and TCAs.

Conclusions

Certain medical conditions can have a significant causal or exacerbating contribution to the development and progression of depressive and anxiety disorders. Knowing how psychiatric medications can affect these medical conditions is essential. Our case report illustrates how crucial this can be for patients with MCAS, because most such patients experience neuropsychiatric symptoms. As researchers continue to explore MCAS and the interplay between neuropsychiatric conditions and the immune system, newer treatment approaches may be discovered. To develop focused treatment strategies for patients with autoimmune disorders, research is needed to explore the mechanisms by which individual classes of psychiatric medications can influence the immune system.

Key Points/Clinical Pearls