Onset of Transient Sadness Following the Concomitant Use of a Triptan and Selective Serotonin Reuptake Inhibitor/Serotonin Norepinephrine Reuptake Inhibitors Therapy: A Case Report

Abstract

Background: Migraine and depression have a bi-directional, positive association. The likelihood of these conditions being comorbidities is high, thus, the possibility of concomitant use of an antidepressant and a triptan is also increased. Case Presentation: We present a case of a 39-year-old female with a history of migraine with aura and depression who had brief episodes of exacerbated depressive symptoms following oral administration of sumatriptan 100 mg daily as needed while taking various selective serotonin reuptake inhibitor (SSRI) and serotonin and norepinephrine reuptake inhibitor (SNRI) medications on different occasions. The patient experienced 30-minute episodes of sweating and subjective increase in temperature approximately 2–3 hours after administration of sumatriptan 100 mg. This was followed by a transient exacerbation of sadness described by the patient as unhappiness, hopelessness, and tearfulness, which lasted 1 to 2 hours. To date, there are no other published case reports that have described this particular presentation. Several studies have reported possible serotonin syndrome as a result of the combination. Current evidence and known pharmacological actions of SSRIs/SNRIs and triptans are not well-defined enough to explain how one can experience episodic worsening depression. Conclusion: This case illustrates that clinicians should consider other potential adverse effects of the combined use of triptans and SSRIs/SNRIs beyond serotonin syndrome.

Introduction

Migraine headaches and major depression have a bi-directional relationship. Patients who experience migraines are at a greater risk of developing depression and patients with depression are at a greater risk of developing migraines.^1,2 Antidepressants such as selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors (SSRIs/SNRIs) are first-line agents commonly prescribed for the treatment of major depressive disorder and anxiety. ³ Triptans are generally considered to be the most effective of the abortive migraine medications compared to analgesics such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs).^4,5 Additionally, there is some evidence for the efficacy of venlafaxine for migraine prophylaxis. ⁶ Due to the co-occurrence of migraine and depression, there is an increased possibility that SSRIs/SNRIs and triptans will be used together. ⁷ Clinical experience indicates the combined usage is generally safe and the majority of individuals do not experience adverse events. ⁸ The combined serotonergic mechanisms of SSRIs, SNRIs, and triptans may increase the risk of serotonin syndrome or toxicity, but it remains unclear if the combination is a definitive cause of serotonin syndrome.^8,9 Aside from serotonin syndrome, other adverse effects of the combination or significant drug-drug interactions have not been clearly defined. There is minimal literature describing the effects of triptans on depression. We describe a case of a 39-year-old female who experienced brief episodes of exacerbated depressive symptoms with concurrent use of sumatriptan 100 mg and a SSRI or SNRI. The patient is followed by a pharmacist from a pharmacist-led primary care clinic and receives regular care from a neurologist, psychiatrist, and family physician.

Case Summary

Patient Presentation

A 39-year-old female with a history of migraine headaches with aura, generalized anxiety, major depressive disorder, post-traumatic stress disorder (PTSD), insomnia, and seasonal allergies reported brief episodes of exacerbated depressive symptoms following administration of sumatriptan 100 mg daily as needed for migraine abortive therapy and while on an SSRI or SNRI.

The patient has experienced chronic migraines since her early twenties and has trialed various abortive and prophylactic therapies through the recommendation of several neurologists. (Table 1). The medications trialed had insufficient benefits or intolerable side effects. Her usage of sumatriptan was maintained at 2 days a week, as she was aware of the risk of medication-overuse headache. Other abortive medications included ketorolac or promethazine used on an as-needed basis to reduce sumatriptan usage or if sumatriptan did not provide sufficient relief. Non-pharmacological measures implemented by the patient included the use of cold and heat packs on the head in a dark, quiet room.

Table 1.

Patient’s Medication Trial List.

Medical Condition	Drug Therapy
Migraine prophylactic therapy	OnobotulinumtoxinA Erenumab Valproic acid Gabapentin Nortriptyline Pregabalin Propranolol Topiramate	Verapamil SR Zonisamide Magnesium citrate Riboflavin Co-enzyme Q10 Butterbur SAMe
Migraine abortive therapy	Indomethacin Meloxicam Naproxen Sulindac Ketorolac Naratriptan	Zolmitriptan Morphine Dihydroergotamine nasal spray Caffeine/ergotamine Metoclopramide Diphenhydramine
Depression/Anxiety	Duloxetine (primary indication was migraine prophylaxis) Paroxetine	Venlafaxine Buspirone Pregabalin

The patient’s history of depression, anxiety, and PTSD started in the mid-2000s following an active-duty military deployment. Her anxiety was typically triggered by specific situations such as stress, sleep deprivation, and secondary to PTSD. The depressive symptoms were mild to moderate and patient denied thoughts of suicide or history of hospitalization due to depression or self-harm. She had no prior history or suspicion of personality disorder. She was regularly followed by a psychiatrist who provided counseling and cognitive behavioral therapy for depression and anxiety management. The patient’s depression became more prevalent in recent years due to personal events and the debilitating effects of her migraines (e.g., unable to work or see friends and exercising less).

The most recent medication history consisted of levonorgestrel/ethinyl estradiol, ketorolac, sumatriptan, promethazine, escitalopram, zolpidem, and loratadine (Table 2). Nutritional supplements included vitamin D drops and vitamin C. The patient had no medication allergies, but was prone to experiencing side effects from medications.

Table 2.

Patient’s Current Medication List.

Medical Condition	Drug Therapy
Migraine (abortive therapy)	Sumatriptan 100 mg po daily prn at onset of migraine Ketorolac 10  mg po daily prn Promethazine 25 mg po daily prn when sumatriptan and ketorolac are ineffective
Anxiety/Depression	Escitalopram 7.5 mg po daily (low dose due to intolerance at higher doses)
Hormonal contraception	Levonorgestrel 100 mcg/ethinyl estradiol 20 mcg po daily continuously for preventing menstruation
Insomnia	Zolpidem 5 mg po at bedtime prn
Allergic Rhinitis	Loratadine 5 mg/pseudoephedrine 120 mg daily prn for allergic rhinitis, used once or twice a week
Supplements	Vitamin C 125 mg po bid Vitamin D drops 2000 IU po daily for lab-tested deficiency

Abbreviations: prn, as needed; bid, twice a day; tid, three times a day; po, by mouth.

Adverse Drug Reaction History

The patient experienced 30-minute episodes of sweating and subjective increases in temperature approximately 2–3 hours after administration of sumatriptan 100 mg. This was followed by transient exacerbation of sadness, subjectively described as unhappiness, hopelessness, and tearfulness. Each low mood episode lasted 1 to 2 hours. The patient denied that the episodes were due to migraine pain as the abortive medications typically improved the pain 2 hours after ingestion and prior to experiencing depressive symptoms. The adverse drug reaction (ADR) occurred when the patient used sumatriptan in combination with duloxetine in November 2017 and escitalopram since October 2018. She continued to experience the ADR when sumatriptan was used while on escitalopram, her current antidepressant. The ADR may have occurred with paroxetine as well in February 2018 but the account of the experience was less clearly defined from the patient’s perspective.

The patient initiated sumatriptan 100 mg in January 2017 with no side effects reported. Due to multiple migraine episodes, she was started on duloxetine 30 mg daily for migraine prophylactic therapy in August 2017. Three months later in November 2017, the first occurrence of the ADR was reported by the patient. She described two episodes of sweating and subjective increased temperature, as well as low mood and agitation noticed by her family members after taking sumatriptan 100 mg. The patient was advised to discontinue duloxetine by her family physician due to the ADR and lack of benefit for migraines, but to continue sumatriptan as-needed.

In February 2018, the patient was started on paroxetine 10 mg once daily for mood swings prior to her menstrual cycle. In addition to suffering from daily chronic migraines, the severity of the migraine pain increased with menstruation. Initially, the patient experienced side effects of paroxetine such as non-migrainous headaches, anxiety, insomnia, and severe dyspepsia. The patient’s mood was reported to improve slightly overall, but the anxiety persisted and the migraines worsened. When sumatriptan was used, the patient experienced hot flashes which caused nighttime awakenings and led to self-discontinuation of paroxetine. Regarding the impact on her depressive symptoms, she was unable to recall specific details, but believed she did experience the ADR following sumatriptan administration.

The patient’s depressive symptoms became more of a focal point in her health in recent years while continuing to experience chronic migraines, anxiety, and PTSD. Escitalopram was initiated in October 2018 with a starting dose of 5 mg daily. Overall, escitalopram provided a small benefit to the patient’s depressive symptoms, quality of life, and functioning. At the same time, the patient experienced the ADR of transient exacerbation of sadness lasting 1–2 hours after every single dose of sumatriptan while on escitalopram. She expressed her desire to continue escitalopram due to the overall mild improvement in her depression and the fewer side effects compared to the other antidepressants trialed.

During the investigation of the ADR experiences, other drug-drug interactions were ruled out as there were no other medication changes around the time of symptom presentation. Moreover, our patient does not meet either validated criteria of serotonin syndrome (i.e., Hunter and Sternbach criteria). In addition, using the Naranjo Adverse Drug Reaction Probability Scale to assess the likelihood of a medication-related cause, this situation resulted in a score of 7, which translated to a “probable” medication-related cause. ¹⁰

Subjectively, the patient had noticed the ADR more so with escitalopram, her current antidepressant as she gained more self-awareness of her mood changes over the years. When asked if she experienced the ADR with sumatriptan and duloxetine or sumatriptan and paroxetine, the patient identified with the experience, but was unable to fully recall or describe details.

Discussion

To our knowledge, no case reports related to this patient’s clinical presentation following the combination of a triptan and SSRI/SNRI therapy exist. Two case reports highlight worsening depression with either initiation or acute discontinuation of sumatriptan (i.e., drug-disease interaction). The first case outlined a patient with an extensive history of depression and migraines who experienced recurrence of severe depression requiring hospitalization secondary to initiation of sumatriptan. ¹¹ The patient had been in remission for two years, not requiring antidepressant therapy, but due to the ADR, she was restarted on fluoxetine to treat this relapse. The second case described a patient who experienced depressive symptoms following abrupt discontinuation of chronic daily sumatriptan use. ¹² Although these case reports are not directly applicable to our case, they demonstrate that the use of a triptan may impact depression.

SSRIs/SNRIs inhibit various cytochrome P450 isoenzymes (e.g., CYP2D6) which also metabolize triptans. Theoretically, triptan plasma levels may rise, but small pharmacokinetic studies have shown that dose adjustments of either of the medications are not necessary. ¹³ Sumatriptan is primarily metabolized via the monoamine oxidase pathway and generally has less potential for pharmacokinetic interactions, therefore, the possibility of SSRI or SNRI plasma levels being decreased due to sumatriptan metabolism is unlikely. ¹³

Several case reports suggest serotonin syndrome as a result of the combination of a SSRI or SNRI with a triptan. Consequently, the US Food and Drug Administration and other regulatory agencies have released a warning to patients and healthcare professionals to be aware that the use of a triptan in conjunction with an antidepressant, inclusive of an SSRI or SNRI, may result in serotonin syndrome. ¹⁴ However, it is important to note that there have been questions raised of whether serotonin syndrome is likely with the implicated drugs when considering the quality and quantity of evidence, and the pharmacology of these drugs. ¹⁵ Serotonin syndrome is associated with a classic triad of symptoms; neuromuscular excitation (clonus, hyperreflexia, myoclonus, and rigidity), autonomic excitation (hyperthermia, tachycardia, flushing, hypertension, or hypotension), and altered mental state (agitation, confusion, anxiety, coma, and drowsiness). ¹⁶ Symptoms can present in different combinations and degrees of severity, from a mild case of diarrhea and tremor to life-threatening complications such as seizures, coma, and rhabdomyolysis. The diagnosis is one of exclusion, based on medication history, physical examination, and differential diagnosis of other neurological disorders and toxicity syndromes (i.e., anticholinergic, sympathomimetic). ⁹ In almost all case reports and descriptions of serotonin syndrome, depressive symptoms are not mentioned in the clinical presentation of the respective cases. Accordingly, it is unlikely that the ADR experienced by our patient can be attributed to serotonin syndrome.

Pharmacodynamically, the currently known mechanisms of action of triptans and SSRIs/SNRIs do not support serotonin syndrome as the cause of depressive symptoms.^14,15,17 Triptans act as agonists of peripheral 5-hydroxytryptamine (5HT) _1B/1D/1F receptors with weak affinity for the 5HT_1A receptor and no activity towards the 5HT₂ receptor subtype. Serotonin syndrome is supposedly due to the activation of the 5HT_1A and 5HT_2A receptors.^12,18 SSRIs and SNRIs increase extracellular levels of serotonin via blocking the action of the serotonin transporter and therefore increase serotonergic neurotransmission. ¹⁹

A study by Millson et al ²⁰ suggests that patients treated with sumatriptan have significantly higher consultation rates for depression (23.2% vs 16.8%), defined as consulting a physician at least once for depression between the study period of 1993-1997 inclusive, compared with non-triptan users (absolute difference 6.4%, CI 4.6-8.4%, P < .001). The study also demonstrated that triptans with enhanced lipophilicity (naratriptan and zolmitriptan) are associated with a higher prevalence of depression than sumatriptan. However, this finding was not statistically significant once factoring in prior diagnosis of depression. The possible implication of antidepressant use was not reported.

The involvement of 5HT_1B/1D receptors in depression, specifically 5HT_1B autoreceptors, has been in question the last several decades. Literature suggests the increase of 5HT_1B autoreceptor expression levels in the brain tissue can increase serotonin transporter activity (i.e., decrease serotonin in extracellular space).^21,22 Highly lipophilic triptans (e.g., rizatriptan, eletriptan, and zolmitriptan) can theoretically pass the blood-brain barrier and reduce central serotonin levels by agonizing central 5HT_1B/1D receptors thus increasing serotonin transporter (SERT) activity or counteract the actions of the SSRI/SNRI. ¹² The lipophilicity of triptans positivity correlate with the incidence of CNS-related side effects according to data from a meta-analysis of 53 clinical trials.^23,24 The incidence of CNS-related side effects (e.g., abnormal dreams, agitation, confusion, dizziness, fatigue, and somnolence) was found to be greater in rizatriptan, eletriptan, and zolmitriptan while lower in almotriptan and naratriptan. Thus, we speculate that sumatriptan is moderately lipophilic compared to other triptans. Triptans’ effect on central 5HT_1B/1D receptors and their ability to cross the blood-brain barrier may be a possible mechanism behind the depressive symptoms experienced by this patient.

Depressive symptoms are not a typical presentation of migraines, rather, and depression is often a comorbidity in those who experience migraines. In patients with headaches referred for specialist consultation, 27% had moderate to severe depression, which was strongly associated with being on disability or welfare, unemployment, and age under 50 years. ⁴ Co-occurrence of depression and migraine may be due to the possibilities of having shared risk factors and common neurobiological mechanisms.^25,26 In the case of the above patient, the episodes of low mood are likely to be medication-related and not caused by her comorbidities independently given the Naranjo Adverse Drug Reaction Probability rating. Other medications or conditions such as pseudoephedrine and vitamin D deficiency are unlikely to play a role in this case due to the patient’s infrequent usage of pseudoephedrine and long-term supplementation with oral vitamin D. Acute adverse effects such as malaise, fatigue, and sensation of warm are possible reactions listed in the sumatriptan prescribing information. ²⁷ It is possible that general fatigue and hot flashes can be explained by the side effect profile of sumatriptan, but it does not address the impact on depressive symptoms in this patient. It is a possibility that triptans and SSRIs/SNRIs both have disease-drug interactions with depression and migraine, respectively, although the neurobiological link is still not well-defined. Patients who experience a similar presentation may benefit from switching to a non-serotonergic antidepressant, trialing non-triptan migraine abortive therapies (e.g., NSAIDs and acetaminophen), or trialing newer calcitonin gene-related peptide (CGRP) receptor antagonists for prophylaxis (e.g., erenumab, galcanezumab, and fremanezumab).

Conclusion

To our knowledge, this is the first case of episodic depressive symptoms caused by a combination of SSRI/SNRI and a triptan documented in the medical literature. Current evidence and known pharmacological actions of SSRIs/SNRIs and triptans are not well-defined enough to explain how one can experience episodic exacerbated depressive symptoms. This case illustrates that clinicians should consider other potential adverse effects of the combined use of triptans and SSRIs/SNRIs beyond serotonin syndrome.

ORCID iDs

Yuki Meng https://orcid.org/0000-0002-0486-2447

Jamie Yuen https://orcid.org/0000-0002-5020-4285