Migraines and Mood Disorders: A Case of Hospitalization for Depression and Mania After Eptinezumab-jjmr Infusion
Publication: American Journal of Psychiatry Residents' Journal
Migraines and depression are fairly common neurological and psychological ailments affecting millions of people throughout the world. Depression is a mood disorder that afflicts about 5% of the world’s population (1), and migraine headaches affect about 10% (2). Various studies have established an association between migraines and depression among individuals who experience these conditions at some point in their life. As such, clinicians can expect significant overlap in the number of individuals treated for both migraine headaches and depression (3).
A 2-year prospective cohort study (4) reported a bidirectional association between first-onset migraine or depression episodes and subsequent development of migraines or depression. Another study (5) found that about one-third of individuals with bipolar disorder within the general population experience migraines and that comorbidity of migraines and psychiatric illness has a direct effect on the chronicity of migraine headaches. Additionally, the investigators advised clinicians to screen patients with migraines for coexisting mood disorders because such comorbidity has been linked to increased hospital visits, medication misuse, complications in medical management of migraines, and a decrease in quality of life (5). In addition, it has been speculated that the pathophysiologies of depression and migraines share several similarities, and a nonstructured review (6) found structural and chemical similarities between both disease states, with structural changes in the medial prefrontal cortex among individuals with migraines and depression.
The prefrontal cortex is known to be abundant in 5-HT1A, 5-HT2A, and 5-HT3A receptors (7), which are the pharmaceutical targets to treat patients who experience migraines and depression. Moreover, investigators have reported that low levels of serotonin and polymorphisms in the serotonin transporter–linked polymorphic region in the serotonin transporter gene SLC6A4 (encoding solute carrier family 6 member 4) may be factors in the development of migraine headaches (6). Because migraines and depression affect so many people worldwide, the scientific and pharmaceutical research into these disease states is ever evolving. Therefore, novel medications and receptor targets enter the pharmaceutical market with promising results. However, these medications are not without significant adverse effects or drug-drug interactions. One specific medication in question is a calcitonin gene–related peptide (CGRP) antagonist called eptinezumab-jjmr, a new class of medication used for the management of migraine headaches (8). The present case report is the first to our knowledge to highlight the importance of understanding potential risks in prescribing eptinezumab-jjmr in populations with underlying mood disorders.
Case
A 53-year-old female patient with a psychiatric history of bipolar I disorder, which at the time was managed with 450 mg lithium per day and 4.5 mg cariprazine per day for 12 months, presented to our unit. Aside from three psychiatric hospital admissions 3–6 years before this presentation, she had been stable on these medications with no depressive or manic episodes. Her pertinent medical history included daily intractable migraines and Guillain-Barré syndrome.
The patient had been trialed on various medications to address her migraines, with minimal effect. These medications included propranolol, carbamazepine, topiramate, erenumab-aooe, and rimegepant. She was started on 100 mg of an eptinezumab-jjmr infusion by her neurologist. This treatment relieved her daily migraines. However, 2 days after the infusion, she sought outpatient care with worsening depression and suicidal ideation. Her daily lithium dose was increased to 600 mg daily, and cariprazine was increased to 6 mg per day. Despite this aggressive medication management, her depression worsened, and her suicidal ideations evolved into plan with intent. On day 4 after her infusion, the patient was psychiatrically hospitalized. Upon admission, a lithium level was drawn and found to be close to normal limits at 0.59 mEq/L. All laboratory tests on admission, including a urine drug screen, indicated no abnormal results, and no evidence of any delirium or medical symptomatology was observed. After 7 days of hospitalization, the patient was safely discharged on a daily dose of 6 mg cariprazine and 750 mg lithium.
The prescribing neurologist was contacted regarding the adverse effects the patient had experienced. The neurologist reported not being aware of these potential adverse effects of eptinezumab-jjmr and believed that this hospitalization event may have been a single episode. Therefore, because the initial eptinezumab-jjmr infusion helped relieve the patient’s migraine symptoms, it was believed that she should continue these infusions.
Approximately 3 months after the first eptinezumab-jjmr infusion, the patient received another 100-mg infusion. Five days after the second infusion, she was followed up in the outpatient clinic. After the infusion, the patient was in significant distress due to significant manic symptoms, including sleeping for 1 hour a night and impulsive spending (for instance, $5,000 online shopping in one night); more concerning, she had begun to experience auditory and visual hallucinations, which she had never experienced before. Her visual hallucinations consisted of ballet dancers similar to those in a music box. Her lithium level was checked and found to be 0.73 mEq/L. Because of the distress from these new symptoms, her suicidal ideations reemerged. Again, she was hospitalized; this time, the length of her hospital stay was 12 days. She was discharged on 1,000 mg lithium and 6 mg cariprazine daily.
The patient was evaluated 3 days postdischarge from the inpatient unit. She reported improvement in her psychiatric symptoms; however, she was still experiencing hallucinations. The prescribing neurologist was again involved in the case, and with the patient’s consent, use of eptinezumab-jjmr infusions was terminated.
Discussion
We present the case of a middle-aged woman diagnosed as having bipolar I disorder who had been stable on lithium and cariprazine for 12 months. After receiving an initial infusion of eptinezumab-jjmr for intractable migraines, the patient psychiatrically decompensated with significant depressive symptoms and was hospitalized. A similar event occurred 3 months later, after she had received a second infusion. This time, she developed manic symptoms and hallucinations. Although a definitive cause for her decompensation could not be established, given that the patient adhered to medication regimens and had a lithium blood level within therapeutic range (9), it was believed that a potential cause could be the patient’s CGRP antagonist infusion. To our knowledge, this is the first reported case of such adverse effects occurring with eptinezumab-jjmr and may represent rare adverse effects of the medication or a constellation of the patient’s various medications and medical comorbid conditions interacting to cause this reaction.
CGRP antagonists are commonly used as a second- or third-line treatment for migraines, usually for individuals whose symptoms respond poorly to other antimigraine medications. This class of antimigraine medications is relatively new in the market (e.g., eptinezumab-jjmr was approved in 2020). Furthermore, they are significantly more expensive and therefore less accessible. As such, adverse effects and uncommon adverse reactions are not fully known given the cost, relatively recent introduction, and routes of administration of these drugs.
The CGRP antagonist class of medications is believed to block the release of CGRP at the trigeminal nerve. Animal and human studies have revealed that CGRP is released during migraines and that exogenous administration may provoke migraine symptoms (10). CGRP exists in two isoforms, alpha and beta, both of which can dilate cerebral arteries and cause degranulation of mast cells, predominantly in the trigeminal vascular network, which could explain increased induction of nociception by this drug class (10). Similarly, in psychiatry, the use of neuromodulation of the trigeminal nerve can help manage depression; however, such use is not a standard treatment modality (11).
Furthermore, CGRP and psychiatric illness significantly overlap. In a study exploring the relationship between the two systems after stress exposure (12), mice exhibited depression-like behavior and decreased CGRP mRNA levels in the hippocampus without CGRP pretreatment. Mice that were administered CGRP in the brain 15 days before stress exposure had normalized behavioral dysfunctions and increased levels of nerve growth factor (12). Although no direct model is available for humans, CGRP may have a specific role in the mediation of depression symptoms. Consequently, the blockade of such receptors by CGRP inhibitors may significantly worsen depression but continue to mitigate migraine headaches.
Additionally, triptans work as serotonin agonists on 5-HT1B and 5-HT1D receptors, causing vasoconstriction (13). It is theorized that the modulation of serotonin and its signaling cascade is one of the primary ways that depression can be managed. As mentioned above, a defective serotonergic system has been conjectured to lead to both depression and migraines (14). Low serotonin levels are implicated in cortical-spreading depression variance, which influences migraine risk (14). Given that migraines and depression often co-occur, significant commonality may exist between their origin and treatment. Yet some recent evidence shows that CGRP inhibitors can improve depressive symptoms regardless of migraine improvement (15). However, it must also be considered that some patients may have idiosyncratic responses to these medications.
Conclusions
This case highlights the importance of understanding the common overlap in neurotransmitters and the pathways that are involved in psychiatric disorders as well as migraine headaches. With new therapies entering the market, we must consider the possibility that some medications for managing migraines may destabilize patients with mood disorders. The introduction of novel therapies highlights the importance of an integrative approach to treating patients to address both medical and psychiatric symptoms.
Key Points/Clinical Pearls
•
Calcitonin gene–related peptide (CGRP) inhibitors are a relatively new treatment modality for migraines and are now more commonly used.
•
Patients who have migraines are more likely to also have a concomitant mental illness.
•
CGRP inhibitors can have a significant and destabilizing effect on the mental health of persons previously considered mentally stable.
•
Psychiatrists should collaborate with a patient’s neurologist, especially if the patient has some form of severe mental illness.
Footnotes
Written consent was obtained from the patient for the publication of this article.
The authors have confirmed that details of the case have been disguised to protect patient privacy.
References
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American Journal of Psychiatry Residents' Journal
Pages: 6 - 8
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Published online: 6 December 2024
Published in print: December 6, 2024
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