Evidence-Based Reviews

Nothing to sneeze at: Upper respiratory infections and mood disorders

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URIs can destabilize mood disorders, and OTC cold/flu meds may increase risk of interactions.



Acute upper respiratory infections (URIs) often lead to mild illnesses, but they can be severely destabilizing for individuals with mood disorders. Additionally, the medications patients often take to target symptoms of the common cold or influenza can interact with psychiatric medications to produce dangerous adverse events or induce further mood symptoms. In this article, we describe the relationship between URIs and mood disorders, the psychiatric diagnostic challenges that arise when evaluating a patient with a URI, and treatment approaches that emphasize psycho­education and watchful waiting, when appropriate.

A bidirectional relationship

Acute upper respiratory infections are the most common human illnesses, affecting almost 25 million people annually in the United States.1 The common cold is caused by >200 different viruses; rhinovirus and coronavirus are the most common. Influenza, which also attacks the upper respiratory tract, is caused by strains of influenza A, B, or C virus.2 The common cold may present initially with mild symptoms of headache, sneezing, chills, and sore throat, and then progress to nasal discharge, congestion, cough, and malaise. When influenza strikes, patients may have a sudden onset of fever, headache, cough, sore throat, myalgia, congestion, weakness, anorexia, and gastrointestinal (GI) symptoms. Production of URI symptoms results from viral cytopathic activity along with immune activation of inflammatory pathways.2,3 The incidence of colds is inversely correlated with age; adults average 2 to 4 colds per year.4,5 Cold symptoms peak at 1 to 3 days and typically last 7 to 10 days, but can persist up to 3 weeks.6 With influenza, fever and other systemic symptoms last for 3 days but can persist up to 8 days, while cough and lethargy can persist for another 2 weeks.7

Upper respiratory infections have the potential to disrupt mood. Large studies of psychiatrically-healthy undergraduate students have found that compared with healthy controls, participants with URIs endorsed a negative affect within the first week of viral illness,8 and that the number and intensity of URI symptoms caused by cold viruses were correlated with the degree of their negative affect.9 A few case reports have documented instances of individuals with no previous personal or family psychiatric history developing full manic episodes in the setting of influenza.10-12 One case report described an influenza-induced manic episode in a patient with pre-existing psychiatric illness.13 There are no published case reports of common cold viruses inducing a full depressive or manic episode. If cold symptom severity correlates with negative affect among individuals with no psychiatric illness, and if influenza can induce manic episodes, then it is reasonable to expect that patients with pre-existing mood disorders could have an elevated risk for mood disturbances when they experience a URI (Box).


Case report: Unexplained recurrence of depression

Ms. E is a 35-year-old financial analyst with bipolar disorder type I and alcohol use disorder in sustained remission. She had been euthymic for the last 3 years, receiving weekly psychotherapy and taking lamotrigine, 350 mg/d, lithium ER, 900 mg/d (lithium level: 1.0 mmol/L), lurasidone, 60 mg/d, and clonazepam, 1 mg/d. At her most recent quarterly outpatient psychiatrist visit, she says her depression had returned. She reports 1 week of crying spells, initial and middle insomnia, anhedonia, feelings of worthlessness, fatigue, poor concentration, and poor appetite. She denies having suicidal ideation or manic or psychotic symptoms, and she continues to abstain from alcohol, illicit drugs, and tobacco. She has been fully adherent to her medication regimen and has not added any new medications or made any dietary changes since her last visit. She is puzzled as to what brought on this depression recurrence and says she feels defeated by the bipolar illness, a condition she had worked tirelessly to manage. When asked about changes in her health, she reports that about 1.5 weeks ago she developed a cough, nasal congestion, rhinorrhea, and fatigue. Because of her annual goal to run a marathon, she continues to train, albeit at a slower pace, and has not had much time to rest because of her demanding job.

The psychiatrist explains to Ms. E that an upper respiratory infection (URI) can sometimes induce depressive symptoms. Given the patient’s lengthy period of euthymia and the absence of new medicines, dietary changes, or drug/alcohol intake, the psychiatrist suspects that the cause of her mood episode recurrence is related to the URI. Hearing this is a relief for Ms. E. She and the psychiatrist decide to refrain from making any medication changes with the expectation that the URI would soon resolve because it had already persisted for 1.5 weeks. The psychiatrist tells Ms. E that if it does not and her symptoms worsen, she should call him to discuss treatment options. The psychiatrist also encourages Ms. E to take a temporary break from training and allow her body to rest.

Three weeks later, Ms. E returns and reports that both the URI symptoms and the depressive symptoms lifted a few days after her last visit.

Mood disorders may also be a risk factor for contracting URIs. Patients with mood disorders are more likely than healthy controls to be seropositive for markers of influenza A, influenza B, and coronavirus, and those with a history of suicide attempts are more likely to be seropositive for markers of influenza B.14 In a community sample of German adults age 18 to 65, those with mood disorders had a 35% higher likelihood of having had a cold within the last 12 months compared with those without a mood disorder.15 A survey of Korean employees found the odds of having had a cold in the last 4 months were up to 2.5 times greater for individuals with elevated scores on a depression symptom severity scale compared with those with lower scores.16 Because these studies were retrospective, recall bias may have impacted the results, as patients who are depressed are more likely to recall negative recent events.17

Proposed mechanisms

Researchers have proposed several mechanisms to explain the association of URIs with mood episodes. Mood disorders, such as bipolar disorder and major depressive disorder (MDD), are associated with chronic dysregulation of the innate immune system, which leads to elevated levels of cortisol and pro-inflammatory cytokines.18,19 Men with chronic low-grade inflammation are more vulnerable to all types of infection, including those that cause respiratory illnesses.20 High levels of stress,21 a negative affective style,22 and depression23 have all been associated with reduced antibody response and/or cellular-mediated immunity following vaccination, which suggests a possible mechanism for the vulnerability to infection found in individuals with mood disorders. On the other hand, after influenza vaccination, patients with depression produce a greater and more prolonged release of the cytokine interleukin 6, which perpetuates the state of chronic low-grade inflammation.24 Additionally, patients with mood disorders may engage in behaviors that reduce immune functioning, such as using illicit substances, drinking alcohol, smoking cigarettes, consuming an unhealthy diet, or living a sedentary lifestyle.

Conversely, there are several mechanisms by which a URI could induce a mood episode in a patient with a mood disorder. Animal studies have shown that a non-CNS viral infection can lead to depressive behavior by inducing peripheral interferon-beta release. This signaling protein binds to a receptor on the endothelial cells of the blood-brain barrier, inducing the release of additional cytokines that affect neuronal functioning.25 Among patients receiving interferon treatments for hepatitis C, a history of depression increased their likelihood of becoming depressed during their treatment course, which suggests people with mood disorders have a sensitivity to peripheral cytokines.26

Sleep interruptions from nighttime coughing or nasal congestion can increase the risk of a recurrence of hypomania or mania in patients with bipolar disorder,27 or a recurrence of depression in a patient with MDD.28 The stress that comes with missed work days or the inability to take care of other personal responsibilities due to a URI may increase the risk of becoming depressed in a patient with bipolar disorder or MDD. When present, GI symptoms such as vomiting and diarrhea can reduce the absorption of psychotropic medications and increase the risk of a mood recurrence. Finally, the treatments used for URIs may also contribute to mood instability. Case reports have described instances where patients with URIs developed mania or depression when exposed to medications such as intranasal corticosteroids,29 nasal decongestants,30,31 and anti-influenza treatments.32,33

Continue to: A diagnostic challenge

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