Journal Alergi Terhadap Depresi

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Curr Treat Options Allergy. Author manuscript; available in PMC 2018 March 01.
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Published in final edited form as:

Curr Treat Options Allergy. 2017 March ; 4(1): 71–97. doi:10.1007/s40521-017-0110-z.
Mental Health in Allergic Rhinitis: Depression and Suicidal

Behavior
Ameya U. Amritwar, MD1,2, Christopher A. Lowry, Ph.D3,4, Lisa A Brenner, Ph.D4,5,6,
Andrew J. Hoisington, Ph.D4,7, Robert Hamilton, Ph.D8, John W. Stiller, MD1,2, and Teodor
T. Postolache, MD1,4,9,*
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1Mood and Anxiety Program, University of Maryland School of Medicine, Baltimore, MD 21201,
USA 2Saint Elizabeths Hospital-DBH Psychiatry Residency Training Program, Washington DC,
USA 3Department of Integrative Physiology and Center for Neuroscience, University of Colorado
Boulder, Boulder, CO, USA 4Military and Veteran Microbiome Consortium for Research and
Education (MVM-CoRE) 5Rocky Mountain Mental Illness Research Education and Clinical Center
(MIRECC), Denver, CO, USA 6University of Colorado, Anschutz Medical Campus, Departments of
Psychiatry, Physical Medicine and Rehabilitation, and Neurology, Aurora, CO, USA 7Department
of Civil and Environmental Engineering, US Air Force Academy, 2354 Fairchild Dr. Suite 6H-161,
Colorado Springs, CO, 80840, USA 8Department of Medicine, Division of Allergy and Clinical
Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland 9VISN 5 Capitol
Health Care Network Mental Illness Research Education and Clinical Center (MIRECC),
Baltimore, MD, USA
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Opinion Statement
A high proportion of suicides visit their medical provider in the month prior to death, but
depression, suicidal thoughts, and substance use are seldom addressed. For the clinicians routinely
treating a substantial patient population with allergic diseases, there are additional concerns, as
allergy has been linked with both depression and suicidal behavior. While psychotropic
medications may affect diagnosis of allergies, medications used to treat allergies impact mood and
behavior. Thus, we present an overview of the overlap of allergic rhinitis with depression and
suicidal behavior in adults, based on clinical and epidemiological data, and our research and
clinical experience. In summary, we suggest: 1) inquiring among patients with allergies about
personal and family history of depression, substance use disorders, suicidal ideation and attempts
2) increased mindfulness regarding the potential effects of allergy medications on mood and
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behavior; and 3) for people identified with certain types of depression or increased suicide risk, a
systematic multilevel collaborative approach. While for practical reasons the majority of patients
with depression will continue to be treated by general or family practitioners, the allergy-treating
*
corresponding author. ([email protected], [email protected]).
Conflict of Interest
Dr. Christopher A. Lowry is a member of the Scientific Advisory Board of Immodulon Theraputics, outside of the submitted work. Dr.
Ameya U. Amritwar, Dr. Lisa A Brenner, Dr. Andrew J. Hoisington, Dr. Robert Hamilton, Dr. John W. Stiller, and Dr. Teodor T.
Postolache
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Amritwar et al. Page 2
provider should always consider integrated care for bipolar, psychotic or suicidal depression and
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incomplete remission, or relapsing and highly recurrent course. While awaiting results of much
needed basic and clinical research to guide clinical approach for patients with comorbid allergic
rhinitis and depression, the simple steps recommended here are expected to improved clinical
outcomes in depression, including, on a large scale, reduced premature deaths by suicide.
Keywords
Allergic rhinitis; Depression; Inflammation; Suicidal behavior; suicidality
Introduction
Allergic rhinitis (AR), colloquially referred to as hay fever, is among the most chief
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complaints among patients worldwide. According to the U.S. Department of Health and
Human Services survey, in 2012, 19.1 million individuals in the US [8%] above 18 years of
age, and 6.1 million under the age of 18 [10%] reported being diagnosed with hay fever [1,
2]; thereby, making it the most common chronic disease in children, and the fifth most
common disorder overall. Reported incidence rates in other countries vary between 10–30%
over all age groups [3, 4]. Treating those in the US with AR results in substantial healthcare
costs, with direct costs including prescriptions totaling about $3.4 billion. The cost of
associated loss of productivity is estimated at between $2–3 billion [5, 6]. Apart from being
a ‘nuisance disease’ leading to a significant decrease quality of life [7], AR can be comorbid
with other respiratory and non-respiratory disorders such as asthma [8], chronic otitis media
[9], rhinosinusitis [10], turbinate hypertrophy [11], secondary obstructive sleep apnea, and
sleep difficulties [12]. Evidence suggests that AR often occurs co-morbidly with mood
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disorders, such as depression [13], and suicidal behaviors [14]. AR is more prevalent in
patients with major depression and those having family history of depressive disorder [15–
17]. In adolescents, a pediatric diagnosis of AR is predictive of an adult diagnosis of major
depression [18] or bipolar disorder [19]. Additionally, in Finnish twins a potentially shared
genetic risk between allergic disorders and depressive symptoms has been described [20].
However, the association is likely not only genetic, as clinical studies involving symptomatic
subjects with AR secondary to ragweed pollen exposure have reported worsening mood and
energy levels during exposure [21]. Exposure to aeroallergens has also been associated with
death by suicide [22, 23]
The prevalence of AR has increased over the last several decades, and is expected to
continue to increase due to environmental influences [24, 25]. One hypothesis that has been
put forward to explain the dramatic increases in incidence of allergic disorders, including
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AR, over the last few decades is the hygiene hypothesis, or the “old friends” hypothesis.
Strachan proposed that the lower incidence of infection in early childhood could be an
explanation for the rapid rise in allergic diseases, including allergic asthma and AR,
documented during the 20th century [26, 27]. The “old friends” hypothesis was proposed to
emphasize that it is not a lack of exposure to childhood infections or outright pathogens per
se that is harmful, but instead, it is a lack of exposure to harmless environmental
microorganisms and symbiotic organisms, as well as a lack of exposure to specific chronic
infections that were common during the hunter gatherer period of human evolution, referred
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to as the “old infections”, that is harmful. It has since been proposed that this lack of
exposure to “old friends”, and thus lack of suppression of inappropriate inflammation,
increases vulnerability to both allergic disorders [28••] and anxiety and affective disorders
[29].
Here we provide a brief overview of our current understanding of AR, and review associated
literature that connects it with psychiatric disorders, namely anxiety and affective disorders
and suicidality. We also propose possible mechanisms linking them.
Allergic rhinitis [AR]: manifestations and diagnosis

AR is an inflammatory, IgE-mediated disease characterized by inflammation of the mucosal
lining of the nose that occurs when a person inhales airborne allergens to which he or she is
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sensitized to, such as animal dander, dust mite fecal particles, and/or pollen. The resultant
immune reaction leads to characteristic AR-associated clinical symptoms of nasal
congestion, rhinorrhea (nasal drainage), sneezing, and/or nasal itching [30]. Two or more of
these symptoms, evident for at least one hour per day for more than 2 weeks, are diagnostic,
especially when a detailed history reveals a specific allergen trigger [31]. Alternative causes
of rhinitis include infectious, structural (secondary to mechanical airway aberrations like
deviated nasal septum) or vasomotor causes, but episodes of sneezing, and an itchy nose and
palate, with clear bilateral discharge and eye involvement (rhino-conjunctivitis) are
particularly suggestive of an allergic origin.
A detailed clinical history and physical examination is required to make the diagnosis, and
this includes differentiation between seasonal and non-seasonal AR [32]. Individuals with
history of AR may also reveal common comorbidities such as conjunctivitis, chronic otitis
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media, significant sleep impairment and sleep apnea, hyposmia, asthma, and laryngeal
involvement [33, 34]. All these factors can have a negative impact on one’s health and
overall performance, as well as on their quality of life and psychological wellbeing [35••]. In
vivo and laboratory-based IgE antibody testing for allergen sensitivity are used to confirm
the clinical suspicion of AR [36]. These tests are useful in pinpointing the offending
allergen(s) and making a definitive diagnosis. Skin prick testing (SPT) with aeroallergens
common to a particular geographic area is a widely accepted, safe, convenient and cost
effective [37] procedure, and one of the most widely used diagnostic screening tests [38, 39].
SPT is less useful in conditions involving generalized eczema, dermographism, in
individuals with recent uses of medications that have significant antihistaminic properties
like tricyclic antidepressants, or undergoing high dose corticosteroid treatment. In these
cases, allergen-specific IgE serological testing is an equally informative alternative for
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identifying allergic sensitization [36, 40]. Additionally, in patients with needle phobias or
acute psychiatric conditions limiting their cooperation with SPT, or those on medications
with antihistaminic properties (e.g., many psychotropic medications), measuring allergen-
specific IgE may be preferable. State-of-the-art IgE antibody serology autoanalzyers have
shown comparable diagnostic sensitivity and specificity to SPT [36]. A serum IgE test is
also indicated in the case of an equivocal SPT, or a negative SPT with strong clinical
suspicion, or in the case of a history of severe allergic reactions when allergen is
administered to the skin. A nasal provocation test (NPT), using a specific allergen that is
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administered to the nasal cavity, may be indicated when discrepancies remain between the
clinical evaluation, skin or serological IgE antibody tests. This technique is considered more
of a research procedure, as it is often used in research studies to evaluate the magnitude of
allergic sensitivity to an allergen [41].
Aeroallergens: sources and seasonality

Aeroallergens most relevant to AR are inhaled following their suspension in air, mostly as
the suspended particles (e.g., mold spores, pollen grains, dust mite fecal particles). Some are
seasonal in nature, such as pollen (the male gametophytes from wind-pollinated plants).
Plants pollinated by insects form pollen that is too large to remain suspended in air, and thus
are not relevant to eliciting AR symptoms. Depending on the allergen source (e.g., trees,
grass, weeds), the pollen counts in the air are generally highest during mid-spring to early
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summer when 75% of environmental pollen exposure occurs. The link between spring peaks
in highly allergenic trees (such as oak) and allergic rhinitis in spring is confirmed by
multiple lines of evidence, including over-the-counter allergy medication purchases [42]. In
temperate regions, grass pollen is principally released during the summer months. Although
it represents only about 10% of the annual pollen load, grass-derived pollen has significant
cross reactivity between different grasses, and food allergens [43]. The most important
source of pollen in late summer-early fall is the common ragweed (Ambrosia artemisiifolia),
possibly the most allergenic taxa in the northern Americas [44] accounting for 15% of the
yearly pollen load. Ragweed pollen production is controlled by the photoperiod and is
therefore latitude dependent [45]. Recent studies indicate an increasing duration of allergen
presence and increased pollen load of these plants potentially secondary to global warming
and increased CO2 levels [46]. Fungal spores are also important seasonal aeroallergens, with
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peak concentrations that occur in spring (Ascomycete spp.) and fall (Basidiomycetes e.g.,
mushrooms, puffballs and bracket fungus) [47, 48]
Apart from these seasonal allergens, AR also results from chronic or episodic exposure of
sensitized individuals to animal dander from pets, cockroach-related proteins, dust mites,
and non-seasonal indoor fungi. These allergens are ubiquitous and may be responsible for a
significant proportion of AR cases. One study found that a high percentage of North
American homes have moderate to high levels of dust mites [e.g. 78.5% in San Diego,
California], and detectable cockroach antigen [e.g. 21.5% in Boston, Massachusetts], which
were strongly associated with a positive SPT in children [49]. A recent review concluded
that dust mite is the most important indoor non-seasonal allergen [50]. Allergens causing AR
may also be food items like flour, through occupational exposure, such as bakers sensitized
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to enzymes or flour in bread mix [51].
Comorbidity of AR and certain psychiatric disorders

Clinicians have long observed co-existence of allergic diseases like AR and psychological
problems, such as “allergic toxemia”; a syndrome described in 1930s and characterized by
fatigue, slow psychomotor and thought process, poor memory, irritability and depression
[52]. The current body of literature suggests that this association is likely be secondary to
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cytokines and other macromolecules associated with inflammation in AR.
Depression: overview
In the Diagnostic and Statistical Manual 5 (DSM5) [53], all psychiatric disorders with
predominant sad, empty or, in younger individuals, irritable mood accompanied by
characteristic somatic and cognitive symptoms that cause significant disruption of an
individual’s capacity to function have been grouped under “Depressive Disorders” [54].
Another class of disorders with a predominant mood component is “Bipolar and Related
Disorders” [55]. Depressive disorders may have identifiable underlying medical-surgical,
gynecological, or substance-related precipitating factors and different time course-/severity-
related variables for diagnosing specific categories. Major depressive disorder (MDD), also
referred to as unipolar depression or clinical depression, represents the classic condition for
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this group. An individual is diagnosed with MDD if for two or more consecutive weeks
he/she reports or is reported by others to experience for most of the day, at least one of the
two defining symptoms of 1] sadness or 2] loss of interest or pleasure in previously
enjoyable activities (anhedonia), together with at least five of the following seven symptoms
for most of the days in a week: 1] significant unintentional loss of weight and/or appetite, 2]
insomnia or hypersomnia, 3] psychomotor agitation or retardation confirmed by objective
observation, 4] fatigue or loss of energy, 5] feelings of worthlessness or excessive guilt, 6]
diminished ability to concentrate or think and indecisiveness, or 7] recurrent thoughts of
death (not just fear of dying), recurrent suicidal ideation or plans/attempts. Depression may
be precipitated by psychosocial stressors such as loss of loved ones or financial difficulties.
It can also be precipitated and perpetuated or worsened by underlying medical conditions or
physiological stressors like peri-partum period or seasonal changes in vulnerable
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individuals. Diagnostic specifiers such as ‘seasonal’ or ‘peri-partum’ allow for accurately

capturing these factors. Symptoms may be episodic or recurrent. There may be associated
psychotic or anxiety symptoms with depression [54].
Major depressive disorder affects 6.7% of US adults or estimated 15.7 million US citizens in
2014 [56]. Depression, particularly when exhibiting atypical symptoms of increased sleep
and appetite, affects women more than men, [57]. Women also experience more somatic
symptoms like sleep and appetite difficulties, fatigue, and anxiety as compared to men,
possibly due to underlying biological predispositions such as hormonal differences [58].
Depression can result in significant personal and societal costs due to significant negative
impacts on performance, productivity and resultant, absenteeism, and disability. The annual
cost of depression in the US exceeds $26 billion for medical care, $5.4 billion due to
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suicide-related mortality, and $50 billion due to loss of productivity [59].
Bipolar disorder
Depressive episodes can occur as a manifestation of bipolar disorder, which requires at least
one episode of mania and/or hypomania (Bipolar II includes only hypomania) for diagnosis.
Mania is diagnosed when there is at least one week (or less, if the patient is admitted) of a
distinct period of abnormally and persistently elevated, expansive or irritable mood and
abnormally increased goal directed activity or energy, grandiosity, pressured speech,

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decreased need for sleep, psychomotor excitation and distractibility, or excessive

involvement in hedonistic activity, which may have painful consequences. All of which must
lead to significant functional impairment. Hypomania is diagnosed with similar symptoms
but of lower intensity with no or minimal impairment and lasts for at least four consecutive
days. There may be extended periods of normal mood between bipolar mood episodes [55].
There is evidence that stress, both psychological and biological in origin, circadian
disruption and sleep impairment, particularly decreased sleep, which could be the
consequence of AR [60], and antidepressant medication are all important precipitating
factors for manic or hypomanic episodes [61]. The 12-month prevalence of bipolar disorder
in the US is 2.6% in the adult population [62]. Obtaining collateral information from family
members and health care providers may be very important in bipolar disorder, considering
that treatment differs from that of major depression, and that a sizable proportion of patients
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do not have an adequate insight into their history of hypomania or mania.
Suicide: overview
Suicide (or fatal suicidal self-directed violence) is death caused by self-directed injurious
behavior with intent to die as a result of the behavior. It may be preceded by suicide
attempt/s, defined as non-fatal, suicidal self-directed violence. Suicidal behavior includes
suicide (i.e. death by suicide) or suicide attempt generally takes place after the engaging
individual had been thinking about, considering or planning suicide, also termed as suicidal
ideation. [63]. Suicidal ideas often stem from feelings of worthlessness, hopelessness and
helplessness and cognitive biases such as fortune telling [predicting outcomes of a situation,
mostly the worst one] [64, 65], which often can be estimated with good clinical interview.
According to the Center for Disease Control (CDC), suicide was the tenth most common
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cause of death in all ages in the USA in 2013, with almost 13 suicides every minute. In the
USA more than 41,000 individuals die by suicide, and 494,000 receive medical care for self-
inflicted injuries annually, with an age-adjusted suicide rate of 13 per 100,00 individuals.
There has been a gradual increase in suicide-related deaths since 1999 [66]. Men died by
suicide 4 times more frequently than women, though women were much more likely to
attempt suicide. Nearly 24% of those who died by suicide were taking antidepressants at the
time of their death [67]. The World Health Organization (WHO) in 2004 describes suicide as
a “Huge but preventable public health problem [68]. Suicide is most frequently associated
with mood disorders such as MDD, or the depressive phase of bipolar disorder, but also
occurs among those with other psychiatric disorders like schizophrenia, personality
disorders and substance use disorders [69]. A history of anxiety disorders, either by
themselves or comorbid with other psychiatric disorders, may also increase an individual’s
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risk for death by suicide [70]. Nevertheless, in individual patients it is possible that treating
anxiety disorders, in particular with anxiolytics, may elevate suicide risk through
disinhibition, or lowering of fear of death or dying, a protective factor.
Past suicide attempts and current suicidal ideation are considered the most important clinical
predictors of future attempts/death by suicide, particularly in individuals previously
diagnosed with psychiatric illness [71]. For every suicide, there are about 25 suicide
attempts [72]. Risk of suicide post-suicide attempt is highest within the first 6 months,
though it remains significantly elevated for at least a few years [73]. A large national cohort-
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based study involving 2.46 million people from Denmark, with follow-up data from age 15
years onwards, showed that bipolar disorder presented maximum risk while comorbid
substance use and unipolar depression were associated with increased absolute risk, and past
history of self-harm nearly doubled the risk. The study also highlighted that risk of suicide
was greatest within the first few years of contact with mental health care [74] [75]
Clinical approach to suicidal behavior

A thorough clinical interview covering current or past wishes to be dead, “active” suicidal
thoughts with frequency, intent, plan with specificity and severity, past history of suicidal
behavior and resultant injury or damage is essential in suicide risk evaluation. Inquiry must
be made as to the availability of means to engage in suicidal behavior such as guns, other
weapons or stored medications. Validated scales such as the Columbia-Suicide Severity
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Rating Scale (CSSRS) help in clinical documentation of suicidality and potential for suicidal
behavior [76] [Available at http://www.cssrs.columbia.edu/]
The stress-diathesis model of suicidal behavior

The stress-diathesis model conceptualizes suicidal behavior as interplay between
vulnerability and triggering [77], and is currently one of the most accepted models of
suicidal behavior. The model posits that, in a predisposed individual, a psychological or bio-
physiological stressor leads to exacerbation of suicide risk, through mechanisms like
precipitating or worsening of psychiatric illness thus triggering suicide attempts. Further, the
interplay between supportive factors (family, friends, religion) and deterrents (e.g. minor
children), availability of means (e.g. firearms), and the presence or absence of adequate
social and healthcare services, moderates suicidal risk and behaviors increasing or limiting
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the probability of death by suicide. Another model gaining traction is interpersonal theory of
suicide, which attempts to explain desire towards suicidality as an outcome of perceived loss
of belongingness, burdensomeness with associated hopelessness, and repeated painful or
fear inducing experiences leading to acting on these desires [78]. It has been proposed that
substantial increases in exposure to aeroallergens, especially in allergen-sensitized
individuals such as those suffering from AR and asthma, may represent environmental
stressors that could lead to precipitation of suicidal behavior through biological and
psychological factors [79, 22, 80] Prevention of suicidal behavior by immediate safety
measures like inpatient admission, removing access to lethal means like guns, adequate and
prompt treatment of underlying psychiatric condition and psychosocial stabilization remains
the cornerstone of therapeutic approaches to managing risk for suicide.
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Immune mechanisms underlying AR

Individuals with a predisposition for allergic disorders like AR have predominant activation
of CD4+ T helper type 2 (Th2) cells in response to otherwise innocuous specific antigen
exposure, when presented by dendritic cells in the nasal epithelium. Th2 cells are important
in differentiation and recruitment of other immune cells such as eosinophils that participate
in anti-parasitic and allergic immunity and they secrete various cytokines including
interleukin (IL)-4, IL-5, IL-6, IL-10 and IL-13 that are involved in stimulating the humoral
and cellular immune responses. IL-4 from Th2 cells promotes B cell transformation to
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immunoglobulin-secreting plasma cells and class switching of immunoglobulin G (IgG) to

immunoglobulin E [81], peripherally or locally [82]. IL-5 is a major maturation and
differentiation factor for eosinophils [83]. The IgE molecules circulate in the bloodstream
and bind to high affinity Fc receptors (FcεRI) on mast cells in the nasal mucosa, which are
now “armed”. The other important receptors now identified to be involved in IgE activity
and dysregulation as observed in AR and other allergic disorders, are CD23 as well as
galactin-3, and several other CD23 co-receptors like CD21 and other integrins [84, 85]. AR
is triggered when re-exposure to the sensitizing allergen occurs and it cross-links preformed
IgE bound to nasal mucosal mast cells. The reaction is classified as either “early” or
“delayed” according to time sequence in relation to the allergen exposure. The early reaction
develops within 30 minutes and is mediated by mast cells activated by allergen exposure,
which secrete chemical inflammatory mediators like histamine, tryptase, kininogenase, and
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prostaglandins that are stored in preformed granules. The late reaction is mainly
characterized by eosinophil chemotaxis induced by synthesized leukotrienes and cytokines.
These inflammatory mediators cause increased vascular permeability, contraction of local
smooth muscles and increased mucus secretion and nerve irritation, which all lead to the
observed characteristic clinical features of AR. There is influx of inflammatory cells
including eosinophils and more Th2 cells. Activated mast cells and Th2 cells secrete
cytokines that augment eosinophil activation and degranulation, leading to further increases
in inflammatory cells and more differentiation of B cells to plasma cells and IgE production.
The mast cells also release cytokines normally associated with Th1 cells, such as tumor
necrosis factor (TNF) and IL-6, which promote more vascular permeability, tissue edema
and watery rhinorrhea. As the exposure to allergen continues, this cascade of inflammatory
responses persists, with a further increase in pro-inflammatory cytokines like IL-1α, IL-1β,
IL-6 and TNF [86, 87]. The aeroallergen-nasal epithelial cell interactions may have a role to
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play in allergic sensitization and airway inflammation, through increased permeability, and
the epithelial cells themselves release inflammatory mediators that can lead to preferential
Th2 responses. Chronic exposure to inflammatory mediators like TNF secondary to the AR
may cause tight junction barrier dysfunction in the nasal epithelium, and contribute to
further worsening of AR by making allergen readily available to underlying immune cells,
and ultimately leading to airway remodeling [88, 89]. Despite several years of research and
an increasing understanding of the allergic processes, the exact role and mechanism of IgE
antibodies and mast cells remain to be fully described [87]. To summarize, current
knowledge suggests that AR is associated with both Th2- (IL-4, IL-10, IL-13) and Th1-
(IL-1, IL-6, TNF) pro- and anti-inflammatory cytokine release [90] with potential effects on
psychological health.
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Other than cytokines, prostaglandins are also important in mediating an individual’s

response involving AR, with prostaglandin D2 (PGD2) produced by mast cells as possibly
the most important inflammatory mediator. One study based on a mouse model of AR
suggested that PGD2 contributes to AR symptomatology by stimulating vascular and other
inflammatory responses by interaction with D prostanoid receptors and a chemoattractant
receptor-like molecule expressed on Th2 cell receptors through possible CD3/CD28 co-
stimulation. They preferentially elicit production of the cytokines IL-4, IL-5 and IL-13,
without affecting anti-inflammatory IL-10 [91]. This may also contribute to psychological
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difficulties.
Nose-brain connection
Available research suggests that pro-inflammatory cytokines from the periphery are able to
reach the CNS and they have the capacity to interact with pathophysiological domains such
as neurotransmitter metabolism, neuroendocrine function, sleep disturbances and behaviors
that characterize psychiatric disorders like depression and anxiety [92]. Research has shown
that environmental macromolecules with inflammatory potential as well as peripherally
formed endogenous inflammatory molecules are able to reach the brain through various
routes, with the critical step being passing through the blood-brain barrier (BBB). Animal
models have demonstrated that peptides [93] and interleukins [94] can travel from the nose
to the brain along the trigeminal or olfactory pathways [95, 96], bypassing the BBB. Review
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of present evidence suggests potential neuro-immune mechanisms underlie the association

between peripheral inflammation and psychiatric symptoms [97]. In AR, neuroinflammation
may be mediated through passage of inflammatory molecular and cellular mediators from
the nasal cavities to the brain, though exact mechanism remains to be explained [98].
AR and depression
Causal pathways involving induction of inflammation by depression, or precipitation of
depression by inflammation, or a bidirectional relationship, can be expected, as both AR and
depression have been associated with activation of inflammatory pathways involving similar
mediators. AR presents with significant social and interpersonal difficulties and loss of
productivity, which itself may induce stress and lead to sadness [references in Part 1]. Apart
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from these psychological stressors, the causal association may be biologically driven, which
can be inferred from the observation that there are similar cytokine-mediated
neuroinflammatory processes in depression and AR, or AR markers like seasonality and
absolute peaks of aeroallergens, as well as the ability of these cytokine markers to induce a
depressive mood.
Medically healthy patients with major depression often have elevated levels of
neuroinflammatory markers that are also observed in AR. For example, they have been
reported to have increased levels of IL-6 [99] [100, 101], IL-1β, and TNF [102]. A meta-
analysis of 24 studies showed significantly higher concentrations of the proinflammatory
cytokines TNF and IL-6 in depressed subjects compared with control subjects [103].
Another systematic review of the literature showed positive associations between
inflammatory biomarkers IL-1, IL-6 and C-reactive protein (CRP) and depression [104].
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Some of these immune abnormalities may be responsive to effective treatment of depression

[105, 106].
Evidence for peripheral and neuroimmune inflammatory dysregulation being able to produce
depression comes from the association of immune inflammatory conditions with depressive
symptoms, as observed in studies of treatment of animals with lipopolysaccharide (LPS)
from bacterial cell walls. LPS induces expression of cytokines such as IL-1β in the brain
meninges, CVOs and brain parenchyma [107–109], responses that have been linked to
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“sickness behavior”, displaying depressive features like loss of appetite, inhibition of sexual
activity, increased sleepiness, concentration and memory difficulties along with fever and
hypothalamic-pituitary-adrenal (HPA) axis activation. Cytokines in circulation, even in
concentrations not sufficient to produce the sickness syndrome, have been associated with
depressed mood, anxiety and memory difficulty [97]. One recent study examined effect of
intraperitoneal injection of LPS in rats on sickness and depression like behavior. The study
showed early increase (2 hours) in cytokine levels in serum and CSF coinciding with
sickness behavior with specific alterations in mRNA transcription of IL-1β, IL-6 and TNF-α
in frontal cortex, hippocampus and striatum; and late onset of depression like behavior
paralleled by increasing iL-1β transcription and CSF levels. The study also reported
Cyclooxygenase (COX) enzyme downregulation in hippocampus. The study indicated
persistence of central inflammation even after peripheral inflammation and acute sickens
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behavior had ceased. [110] Circulating cytokines can also lead to increased glucocorticoid
output and receptor dysfunction under stressful situations[111], which has been shown to be
associated with MDD [112]. Some cytokines (i.e., IL-1β, IL-2, frequently elevated in AR
patients [113] can induce expression of the CNS enzyme indoleamine 2,3-dioxygenase
[114], which induces production of kynurenine from tryptophan. The kynurenine:
tryptophan ratio in turn is linked to depression and suicidal behavior through neurotoxic,
glutamatergic and possibly serotonergic dysregulation in the CNS [115••–117]. Peripheral
immune activation is capable of central up-regulation of proinflammatory cytokine
expression, microglia activation, and the production of neurotoxic substances like
kynurenine metabolites [118]. It is possible, therefore, that cytokines released during the
allergic reactions like AR may have similar neurobehavioral effects leading to precipitating
or perpetuating psychiatric and behavioral difficulties, particularly depression, [119].
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Evidence of AR being associated with exacerbation of depression comes from studies

showing temporal associations between aeroallergen exposure, a precipitating and
perpetuating factor for AR, and depressive mood. In a self-report study, self-reported lower
moods were associated with high pollen counts, with seasonality different than seasonal
affective disorder (i.e., fall-winter mood worsening) [120]. Subjective worsening of mood
with high pollen counts, which is similar to season of pollen exposure, has been reported
previously in college students [121]. More specific evidence comes from studies
demonstrating that pollen-specific IgE positivity is associated with worsening of depressive
scores in bipolar disorder patients during high pollen season [122]. AR in early life is
associated with depression later in life [18]. Moreover, bipolar disorder in later life [19] has
also been associated with AR, with a possible immune link involving a likely immune
causation.
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AR and suicidal behavior

Associations have been reported and replicated between AR/atopy and surrogate markers of
allergen exposure, such as season of highest aeroallergen (pollen) load or measured pollen
count, which are linked to triggering peaks in AR, biomarkers like inflammatory cytokines,
and suicidal ideation and behavior. Multiple studies on seasonality of suicide have confirmed
a highly replicated spring peak of suicide [123] across continents and hemispheres [124••].
This peak overlaps with peaks in AR and exposure to airborne aeroallergens, in particular
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atmospheric pollen. We hypothesized that, via immune mediators in the upper airways
reaching the brain and affecting modulation of suicidal behavior, allergen exposure and
seasonal rhinitis lead to a seasonal exacerbation of suicide risk. To further support our
hypothesis of a potential predictive association between exposure to atmospheric tree pollen
in vulnerable individuals and suicidal behavior, analysis of a 13-year database of all suicides
in Finland showed that those with hospital-treated atopy died by suicide predominantly
(78%) during spring and summer when pollen counts are highest, as compared to non-atopic
individuals who had a very similar distribution of completed suicides across half-yearly
intervals with different pollen exposure [125]. In a first test of our hypothesis, we reported,
ecologically, an increase in non-violent suicides in women associated with peak tree pollen
exposure in the US, after adjustment for surrogates of light exposure, a potential confounder
[22]. Later, we were unable to replicate our findings in a subsequent interval of time with a
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slightly modified methodology [126]. Yet, a year later, in the first population study that
connected death by suicide individually linked to allergen exposure, we confirmed a
relationship between measured pollen counts and suicides that remained significant after
correcting for other environmental factors like regional distribution, temperature, humidity
and cloud cover. We also identified sex difference, with women requiring an increase in
pollen count beyond a certain threshold [> 30 grains/M3] before increasing the suicide risk
significantly in contrast to men who experienced more uniform increases in relative risk
[23]. A more recent study analyzing data of nan-fatal self-directed violence (SDV) from
emergency department medical records over three years from Dallas, Texas found significant
positive temporal association between tree pollen peaks and SDV in women (p=0.04) and
grass pollen peaks and SDV in both men (p =0.03) and women (p < 0.0001), but no
association with ragweed pollen [127••].
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Later, suicidal ideation has also been linked with history of allergy after controlling for age,
sex, race, smoking, comorbid asthma and previous diagnosis of depression [128]. We have
also identified an association between allergy, including AR and suicide, independent of
seasonal exposure to allergens, even when accounting for the psychiatric history or socio-
economic status of individuals. The risk was slightly higher in women, and moderated by
history of mood disorders, contrary to our expectations, higher in individual without prior
diagnosis of mood disorders [14].
The question that persists is as follows: Is the association between suicidal behavior and
allergen exposure or allergy driven by psychological symptoms of illness, discomfort, or
medications for rhinitis, or is it a biological connection linked with mediators of
inflammation reaching the brain? Our evidence argues for the latter. First, we reported an
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increased gene expression for allergy-related cytokines in the prefrontal cortex of individuals
who died by suicide as compared with those who died by other causes [129]. Second, we
identified in rodents an increased expression of similar cytokine profiles in the prefrontal
cortex, and an amplification of anxiety-like behavior (though not depression-like behavior)
and impairment in social interactions as a result of sensitization and exposure to allergens
[130]. Third, in a pharmacoecological study we reported that intranasal corticosteroids,
known to reduce molecular mediators of inflammation in AR; were associated with
significantly lower rates of suicide, the effect not observed with second generation
antihistamines which are equally effective for symptoms, but do not affect molecular
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mediators of inflammation in AR. This suggests that the connection between upper airway
inflammation with suicidality is more than just psychological [131].
AR and sleep impairment as a potential mediator

Sleep disturbances are very common among those with AR, with 48% of seasonal AR and
68% of perennial AR patients reporting sleep disturbances [81]. Allergic rhinitis can impair
sleep through obstructive and molecular processes (e.g., production of cytokines), and sleep
impairment may be an important pathophysiological link between AR and mood, anxiety
disorders, and suicidal behavior [132]. Cytokines involved in allergic reactions such as IL-4
and IL-10 have been shown to inhibit spontaneous sleep in rodent models [133, 134].
Considering that sleep loss appears to be a consistent predictor of suicidal behavior [135,
136] and one that is more rapidly modifiable, interrupting sleep disruption in individuals
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with vulnerability for both AR and suicidal behavior is worth investigating. Supporting this
line of thinking, it had been reported that intranasal corticosteroids, previously associated in
our pharmacoecological study with lower rates of suicide, have a stronger effect on
improving sleep disruption than systemic antihistamines [137, 138]
Psychopharmacological management of depression

Clinical principles
In the following paragraphs, we are presenting a summary of our experience in treating
mood disorders, which is by no means exclusive. While the first line treatment of depression
is well documented by adequate placebo controlled trials, we do not have the same evidence
base when it comes to treating patients who fail or partially fail to respond to one
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intervention and especially several interventions. Also, the clinical practice of

psychopharmacologists who often treat patients who have failed previous antidepressants, is
often very divergent from evidence-based practice, and involves multiple combinations of
medications for augmentation strategies as well as reciprocally minimizing side effects.
These medication cocktails are often puzzling for non-psychopharmacologists, and yet,
often, in experienced hands, they represent rational polypharmacy rather than a cavalier
approach to practice.
This being said, the majority of patients with depression are not adequately treated. It is
estimated that approximately half of patients who would require treatment are not
diagnosed, and half of those diagnosed are not adequately treated. Most common issues with
treatment are the lack of sufficient education about side effects (and their often-transient
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nature), the lack of addressing side effects when they occur, the absence of tailoring the
treatment to patients’ response and side effect profile, the insufficient push for remission,
and the lack of reevaluation for adjustment of treatment. Treatment of depression is often too
short. It has been reported that majority of patients receive less than two month of treatment
[139] rather than the recommended minimum of 4 to 6 month [140] (going up to at least 2
years in the recurrent major depression). Patient’s preferences are sometimes disregarded,
and psychotherapy options as monotherapy for milder forms of depression, or in
combination with pharmacology in moderate or more severe depression are not considered.
The principle is to start with a first line agent (such as an SSRI), increase slowly to
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therapeutic response to use for an adequate amount of time before moving to step 2,
augmentation of treatment with another agent (e.g., bupropion, buspirone, a second-
generation neuroleptic, or replacing the SSRI with an SNRI in monotherapy). Duration of
treatment and any changes in treatment, as well as the rapidity of changes, is governed by
side effects and treatment response. Agents with potentially more severe side effects, and
with higher lethality in overdose, such as tricyclic antidepressants and monoamine oxidase
inhibitors, represent further steps. The goal of treatment is to induce remission, defined as
improvement in symptoms such that the individuals no longer meets the criteria for clinical
diagnosis and has minimal symptoms at the most, and then to maintain it by preventing
recurrence. Another useful term is treatment response, which is defined as 50 %
improvement in depression scores. After response but before remission, a worsening of
depression symptoms back to a full-blown episode is called relapse, while after remission is
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called recurrence. In all research and clinical trials settings, and also in clinical settings that
desire thriving for best outcomes, the use of standardized self-report or clinically
administered scales in clinical determination of remission and response [141] is paramount.
In particular, a number of self-report tools have shown adequate psychometric properties and
convenience of use [142]. Among them, perhaps the most used is Patient Health
Questionnaire-9 (PHQ-9), a self-report survey containing nine questions, is useful in
identifying and monitoring depression treatment in primary care. [143]. It is important to
emphasize that, in reading literature of depression, that majority of studies have been
powered for improvement in depression scores vs. placebo, not for remission, and yet,
remission remains the most important research outcome.
Mild to moderate depressive symptoms respond well to psychotherapeutic interventions like

interpersonal therapy, CBT, mindfulness-based therapy and behavioral therapy, and these
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interventions also prove effective in preventing relapse. Common clinical considerations for
pharmacological therapy, are based on the relative efficacy and safety. In the choice of a first
or “next” line agent, the clinician should factor in the nature of prior response to medication,
tolerability, anticipated side effects, co-occurring psychiatric or general medical conditions
with potential drug interactions, half-life of medication deciding frequency of administration
and possibly compliance, patient preference, and cost of treatment. Management of
depression in special populations like children, adolescents, pregnant women, the medically
ill, those with a history of substance abuse and the elderly, involves additional
considerations. In severe and resistant cases, or in depressed patients with psychotic
symptoms, neurostimulation like electroconvulsive therapy [ECT] may play a substantial
role in successful treatment. Recently, newer forms of treatment such as transcranial
magnetic stimulation have gained indication in certain forms of treatment resistant
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depression. All in all, considering the importance of remission as a goal, even in fragile
patients, the principle is to “START LOW, GO SLOW, BUT GET THERE”. Among those
with bipolar disorders, those with depression with psychotic features, those with imminent
danger of suicidal behavior or a history of suicidal behavior, are also best managed through
referral to mental health specialists. We have included a list with resources for treatment of
depression in particular in primary care. Evidence based approaches are summarized in
those tables. (see Table 1
What to expect when treating depression in real life: Effectiveness data

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National Institute of Mental Health conducted the Sequenced Treatment Alternative to

Relieve Depression [STAR*D], a federally funded, large-scale, long-term effectiveness
study, directly comparing treatment strategies, which has improved understanding of
sequenced psychopharmacological treatment of depression. It emphasizes on measuring
treatment at regular intervals using validated scales for dose adjustment, titration and
optimization of medication under trial before switching or augmenting. The trial involved
four different treatment levels, and patients were encouraged to enter the next level of
treatment if they failed to achieve remission or response (50% reduction in symptoms) after
a specified number of weeks. In level one, patients received the selective serotonin reuptake
inhibitor (SSRI) citalopram for up to 14 weeks, with adjustment of the dose being managed
by their own physicians. If patients achieved remission or response during that time period,
they could enter a 12-month naturalistic follow-up, during which time the researchers did
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not have any influence over the treatment plan. Non-remitters were encouraged to enter level
two. In level two, there were seven different treatment options, and cognitive behavioral
therapy (CBT) was included as the psychotherapy option. There were three combination
options (either an antidepressant or CBT added to citalopram), and four switch options (to
either a different antidepressant or CBT). Those who remitted or responded were offered 12-
month naturalistic follow-up; non-remitters after two medication trials were encouraged to
enter level 3; other non-remitters entered level 2A, which involved a second antidepressant
trial. In level three, patients were offered the addition of lithium or triiodothyronine (a
thyroid hormone) to their antidepressant, or a switch to another antidepressant (mirtazapine
or nortriptyline) for 12 weeks. Level four consisted of the monoamine oxidase inhibitor
tranylcypromine or a combination of venlafaxine and mirtazapine Per STAR*D outcome:
[ available for review at: http://www.nimh.nih.gov/funding/clinical-research/practical/stard/
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allmedicationlevels.shtml]
Level 1] SSRI medication [Citalopram], were effective in about 1/3rd participants.
Level 2] if First treatment with one SSRI fails, about one in four people who choose to
switch to another medication will get better, regardless of whether the second medication is
another SSRI or a medication of a different class [SNRI/Bupropion]. Psychological
interventions [CBT, CBT+ Citalopram] were equally effective. And if patients choose to add
a new medication to the existing SSRI, about one in three people will get better. It makes
modest difference if second medication is an antidepressant from a different class (e.g.
bupropion) or if it is a medication that is meant to enhance the SSRI (e.g. buspirone).
Whether patients are more likely to get better by switching medications or by adding another
medication could not be investigated.
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Level 3] those who do not get better after two medication treatment steps. By switching to a
different antidepressant medication [TCA, Mirtazapine], about one in seven people will get
better. By adding a new medication to the existing one, about one in five people will get
better. Adding T3 may have some advantages over adding lithium for patients who have
tried two other treatments without success.
Level 4] patients with the most treatment-resistant depression, level 4 results suggest that
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tranylcypromine [MAO inhibitor] is limited in its tolerability and that up to 10 percent may
benefit from the combination of venlafaxine/mirtazapine [SNRI +Atypical].
There is no proven pharmacology that acutely reduces suicide risk. Recently much hope has
been generated from the rapid antidepressant response to ketamine and the reduction of
suicidal ideation beyond its antidepressant effects [144]. At the time this review is finalized,
ketamine is not yet ready to be used clinically, as more studies regarding efficacy and safety
are needed.
Bipolar Depression Treatment

Treatment principles based on clinical practice
The cornerstone of pharmacological management of bipolar disorder is the use of mood
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stabilizers such as valproate, lithium, or more commonly recently, lamotrigine,

oxcarbazepine, and second-generation neuroleptics (olanzapine, aripiprazole, quetiapine,
etc.). Analogous to unipolar depression treatment, a stepped approach is adopted. It is
important to obtain a detailed history whenever depression is suspected in patients,
especially to attempt to differentiate unipolar depression from depressive phase of bipolar
disorder, as the management differs significantly.
This is not always easy even in experienced hands, mainly because of reduced insight into
mania, concerns for stigma, and side effects of mood stabilizer treatments. In a depressed
phase, mood stabilizers with known antidepressant properties (lithium, lamotrigine) are
preferred, frequently with addition of antidepressants and second-generation neuroleptics,
sometimes at lower dosages than when used for manic episodes (quetiapine, aripiprazole,
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olanzapine, etc.) A non-judicious use of antidepressants may induce mood cycling and
precipitate further manic episodes followed by episodes of depression [145]. While, in
general, long-term use of antidepressants for patients with bipolar depression type 1 is
contraindicated, the long-term use of antidepressants for patients with type II or bipolar
disorder (exclusively hypomanic rather than manic episodes) is a matter of debate.
Psychotherapeutic approaches that have been found to be useful for bipolar disorder (in
contrast to major depression, – always in combination with psychopharmacology), are CBT
and family focused therapies may help in improving compliance, reducing precipitating
stressors and decreasing relapse [146].
At this point- mood stabilizing treatment in bipolar disorder should be life long, and requires
a very intense effort to address non-compliance, in particularly when patient is euthymic. We
are not detailing steps for the treatment for bipolar depression, as most often physicians
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treating allergy are advised to request a mental health consultation for specific patients.
Occasionally, a patient who was considered unipolar treated in a primary or medical settings
will manifest hypomanic or manic symptoms as a result of treatment with antidepressants.
Similarly, a patient with allergy taking systemic decongestants (e.g. pseudoephedrine) or
systemic corticosteroids may have emerging hypomanic or manic symptoms. In contrast to
previous versions- DSM5 is now recognizing the medication induced condition as true
bipolar disorder, and thus a referral to a mental health professional for possible mood
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stabilizing treatment is recommended.
For useful guidelines by various agencies, please refer to Table 1
Management of AR: special considerations in patients with mood disorders

and increased risk for suicide
An important element in the treatment of AR limiting exposure to responsible allergens.
This can be achieved by physically removing the allergen from the indoor environment [e.g.,
by frequent use of HEPA filter-assisted cleaning of households and workplaces] or avoiding
environments where exposure is likely [i.e., avoiding outings during pollen season]. These
interventions can add to academic and occupational limitations and result in reducing social
interactions. This may contribute to lowering quality of life and worsening of mood
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difficulties. Moreover, as isolation is a prosuicidal factor, and access to social networks a

protective factor, it might further increase suicide risk. It remains unclear at this point to
what degree virtual communication (e.g. Skype) would correct social isolation in the context
of active avoidance of seasonal allergen exposure., Furthermore allergen avoidance
interventions have limited efficacy [Bernstein, 2016].
There may be a need to modify the diagnostic approach in patients with mood disorders,
such as preferring IgE antibody serology over SPT. This is based on the considerations of
modifying effects of psychotropic medications as well as compliance and comfort of
patients.
Pharmacoecological data suggest that intranasal corticosteroids might be associated with

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lower risk for suicide, as opposed by a slightly increased risk with second generation
antihistamine [131] However, ecological studies contain a too high potential for bias to draw
clinical conclusions from these data. There is need to advance large scale, preferentially
longitudinal pharmacoepidemiological studies to confirm these results, and ultimately,
clinical trials to compare the use of intranasal corticosteroids vs. second generation
antihistamine in clinical samples with depression, and perhaps, suicidal ideation. Systemic
corticosteroids are associated with depression, mania, and psychosis. [147], and an inquiry
about these conditions, and monitoring treatment is important when initiating systemic
corticosteroids. Dosages of antidepressants, mood stabilizers and neuroleptics may have to
be increased or augmenting agents added when systemic corticosteroids are administered to
a psychiatric patient. Antihistamines may act additively or synergistically with certain
psychotropic medications in beneficial (treatment of insomnia, potentiation of anxiolytic
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effects) or detrimental (worsening of sedation- elevating risk of accidents). Insomnia,

present in many patients during exacerbation of allergy and in patients with mood disorder,
exacerbating both depression and potentially triggering cycling and manic episodes is a
treatment target, more-rapidly modifiable than reduction of depressive symptoms. It should
always be an early element of attention and treatment in comorbid patients. Systemic
decongestants with α-Adrenergic agonist mechanism of action can precipitate hypomania or
mania, and exacerbate insomnia and anxiety in vulnerable individuals. Also, SNRIs, TCAs
and stimulants (medications used for ADD) may have additive effects with decongestants in
elevating their arrythmogenic potential. There have been reports that montelukast can
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precipitate depression, anxiety and behavioral changes, and thus titration of the medication,
in patients with history of those conditions, needs to be more closely monitored. Suicidality
has also been reported, but reports have not been further substantiated. [148]. Yet the
practice of inquiring about depressive symptoms and suicidal ideation when initiating or
restarting treatment will in the very long run benefit an occasional patient at increased risk.
It is recommended to include a psychiatrist in the team management cases with history of

bipolar disorder, psychotic depression, history of suicide attempts or suicidal ideation, and
depression that appears resilient to treatment, of often reoccurs.
Managing suicide risk in primary care

It is impossible to fully predict or prevent suicide. However, many suicides can be prevented,
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and although the yield of identifying patients at risk is low, the expected impact on mortality
is high. Suicide of a patient has a lifelong effect on his friends, family especially offspring,
and his treating medical professionals. It is important to remember that patients who died by
suicide visit a primary physician twice as often than a mental health professional prior to
suicide [149]. Approximately 45% of patients who die by suicide visit their primary
physician during the month preceding death. Although the great majority of antidepressants
are prescribed in primary care, half of simulated patients with depression are not being asked
about suicide ideation and history[150]. In an actual treatment of depression, it appears that
majority of patients are treated for too short duration of treatment, that only a quarter are
asked about suicidal ideation [139], and when asked, a positive response most commonly
leads to no further workup or treatment.
We recommend that in allergy treating settings patients be asked about suicide ideation at
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the initial evaluation and follow-up. A stepwise approach, starting with hopelessness and
desire to be dead, moving towards active thoughts of suicide intent, plan, and finally history
of prior attempts and family history is particularly recommended. Sometimes, patients may
be more likely to endorse ideation on a questionnaire. However, responses on these
questionnaires must be checked during the visit, rather than at a later time. Resources such
as CSSRS and training in its administration and decision point are freely available to
clinicians CSSRS: Information and Training available at: http://www.cssrs.columbia.edu/
training_cssrs.html. However, physicians are advised to not rule out risk of suicide based on
negative responses on any questionnaire. A clinical interview is also necessary. Sometimes,
getting collateral information is also important, as patients are not always forthcoming about
history or ideation. Primary physicians should obtain consent to contact mental health
professionals (psychiatrist, psychotherapist or councilor) upon intake and during routine
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visits, and should contact them in case of emergency even if patient does not offer consent in
acute situations. Involving family members/significant others is beneficial when acute
suicide risk is suspected, and considerations for patient’s life outweigh considerations for
confidentiality.
Thus, ask primary care, such as the settings where allergy is treated the most, to promise a
potential role in reduction of the resilient worldwide suicide epidemics. Physicians should be
mindful of risk factors, as warning signs. Risk factors for suicide, as being a Caucasian
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male, divorced or single, having previous suicide attempts and family history of suicide, are
generally considered to be relatively stable and less modifiable. However, warning signs, or
precipitating factors- such as increased isolation, increased substance use, psychomotor
agitation are state-dependent, and could be investigated and addressed in their own right.
One of these factors, substance use is rarely investigated in primary care. For example, less
than ¼ of individuals in primary care are asked about alcohol use [139] and only 11 % of
people with alcohol use disorders receive recommendations for treatment [151]. Considering
the importance of identifying and addressing alcohol use disorders, as individuals often
more easily reveal substance use on questionnaires rather than face to face, we argue in favor
of using the Alcohol Use Disorders Identification Test (AUDIT) in its longer 10 question
form or, under more challenging time pressure circumstances, the brief 3-question version
(AUDIT-C). The AUDIT is free, used worldwide, and has relatively good psychometric
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properties in identifying use, abuse and dependence with at least 50% sensitivity for ruling
in and 80% specificity for ruling out. [152]
It is recommended that a mental health professional is consulted in patients with suicidal

ideation, or history of attempt, and that with patients with acute intent, plan, or suspicion of
unrevealed intent or plan (e.g. report of writing “good bye” letters, distributing belongings)
in patients with increasing isolation, increased substance use, worsening depression should
lead to continuous observation until examined by a mental health professional (e.g. escorting
to an emergency room). In those cases, whenever the location of the treating facility is not in
the proximity of an emergency room, calling 911 may be the correct intervention. For all
patients, the National Suicide Prevention Lifeline is available 24 hours a day regardless of
location by call or text. It is important to also educate family or significant others that they
can call suicide hotline at any time. As an important piece of information, suicide hotline
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can be accessed anonymously, and can provide further resources for the patient or family.
Suicide Hotline information for acutely suicidal patients:
National Suicide Prevention Lifeline: 1-800-273-TALK (8255)

Text: “GO” to 741741
Lithium is the only psychotropic used to treat mood disorders (bipolar disorder, and
augmentation of major depression, in particular highly recurrent depression) that has also
demonstrated a reduction in risk of suicidal behavior, and as such may be considered in
high-risk patients. Nevertheless, its potential suicide protective benefit should be weighed
against its narrow therapeutic margin and relatively high potential for lethal overdose. As
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such, we do not suggest that primary clinicians initiate treatment with Lithium for this
purpose. Clozapine is FDA approved for lowering suicide risk, but only for patients with
schizophrenia, Ketamine, a medication that holds promise for acute lowering of suicide
ideation (as well as rapid antidepressant response), should wait further research until
clinically indicated.
No pharmacological treatments for suicide risk

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No pharmacological treatments for suicide risk: although multiple counseling/

psychotherapeutic interventions have been proposed for reduction of suicide risk, and for
having positive effects for suicide ideation, in a medical setting, ER, as well as a general
hospital setting, we believe that a brief intervention focus on safety planning makes most
immediate sense and is easily implemented by non-mental health providers in an
individualized mode [153]. It is long term focused and includes considerations for warning
signs, individual coping strategies, social situations, people and professionals who can be
helpful, and increasing safety of the environment (such as not keeping guns or alcohol at
home, only having minimal number of pills available).
A role for an integrated collaborative care

Literature on collaborative approaches in primary care supports an increased depression
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remission rate and suicidal ideation (at least in older adults) [154]. Metanalyses further
documents benefits in terms of effectiveness [155], and, in the longer run, cost-effectiveness
[156]. Although the setting was not focused on patients for allergy, it supports the idea that a
collaborative care implementation in an allergy setting is likely to improve depression
outcomes and potentially lower suicide risk, with no additional costs in the long run.
Screening for depression, alcohol use disorders and suicide risk alone, even with education
efforts are not likely to make a major impact in the absence of adequately referring and
treating those conditions, ideally through integration of care.
Conclusions
Allergic rhinitis is associated with higher rates of depression and suicidal behavior than
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those found in the general population. Reciprocal directions of causality between allergy and
mood anxiety disorders are possible, and likely, with potential for cascading in a vicious
circle. Associations between aeroallergen outdoor exposure and suicide peaks have been
reported and replicated, with animal, postmortem and pharmacoecological studies
suggesting at least a component of biological mediation of these links. Allergists and general
practitioners should therefore actively inquire about depression, anxiety symptoms, suicidal
ideation and history of suicidal behavior in patients with AR and other manifestations of
allergic disease. Certain conditions (bipolar disorder, psychotic depression, treatment
resistant depression or anxiety disorder) are criteria for referring the patient to a mental
health professional. Alcohol use disorders must be identified and addressed. There is a major
need of experimental and longitudinal investigations, as well as clinical trials to further our
understanding of best practices in patients with comorbid allergy and depression and to find
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new therapeutic and preventative interventions. Ultimately, increases in collaborations

between allergists and mental health professionals are expected to lead to synergistic results,
with potential reduction in mortality and morbidity, and improvement in functioning and
quality of life.
Acknowledgments
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Supported by the Military and Veteran Microbiome Consortium for Research and Education (MVM-CoRE),
Denver, CO, USA; Rocky Mountain Mental Illness Research Education and Clinical Center (MIRECC), Denver,
CO, USA; Tuning Inc., Silver Spring, MD, USA; and the DC Department of Mental Health, St. Elizabeths Hospital
Residency Training Program, Washington DC, USA
The authors thank to Ms. Aline Dagdag and Dr. Naila Karim for their comments on an earlier draft of the
manuscript, and to Ms. Winny Mwaura for her excellent administrative support.
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Learning Objectives
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Present overlaps between allergy, allergen exposure, depression, and suicidal

behavior in adults
Familiarize allergists with the principles of diagnosis and treatment of depression

in adults and importance to monitor suicide risk
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Figure 1. Allergy, depression and suicidal behavior

CVO, circumventricular organs; HPA axis, hypothalamic-pituitary-adrenal axis; IDO,
indoleamine 2,3-dioxygenase; KYN, kynurenine; TRP, tryptophan.
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Table 1
Management of Depression: Useful Links
Agency Link
APA http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf
Amritwar et al.
Depression
mAgency for Healthcare Research and Quality

https://www.guideline.gov/summaries/summary/39324/depression)
[Depression: Adults]
https://www.guideline.gov/summaries/summary/47315/adult-depression-in-primary-care
Revised SEPT 2013
Agency for Healthcare Research and Quality

[Depression: Children and Young adults] https://www.guideline.gov/summaries/summary/49118/depression-in-children-and-young-people-identification-and-management-in-primary-community-and-secondary-care
Revised MAR 2015
Agency for Healthcare Research and Quality https://www.guideline.gov/summaries/summary/48565/bipolar-disorder-the-assessment-and-management-of-bipolar-disorder-in-adults-children-and-young-people-in-primary-and-secondary-care

[Bipolar Mood Disorder: Adult/Children]
Revised SEP 2014
National Institute of Health and Care Excellence [NICE]-NHS https://www.nice.org.uk/guidance/cg90/documents/cg90-depression-in-adults-update-evidence-update2
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Mental Health in Allergic Rhinitis: Depression and Suicidal

Allergic rhinitis [AR]: manifestations and diagnosis

Aeroallergens: sources and seasonality

to enzymes or flour in bread mix [51].

Comorbidity of AR and certain psychiatric disorders

cytokines and other macromolecules associated with inflammation in AR.

individuals. Diagnostic specifiers such as ‘seasonal’ or ‘peri-partum’ allow for accurately

suicide-related mortality, and $50 billion due to loss of productivity [59].

abnormally increased goal directed activity or energy, grandiosity, pressured speech,

decreased need for sleep, psychomotor excitation and distractibility, or excessive

do not have an adequate insight into their history of hypomania or mania.

Clinical approach to suicidal behavior

The stress-diathesis model of suicidal behavior

Immune mechanisms underlying AR

immunoglobulin-secreting plasma cells and class switching of immunoglobulin G (IgG) to

Other than cytokines, prostaglandins are also important in mediating an individual’s

of present evidence suggests potential neuro-immune mechanisms underlie the association

Some of these immune abnormalities may be responsive to effective treatment of depression

Evidence of AR being associated with exacerbation of depression comes from studies

AR and suicidal behavior

AR and sleep impairment as a potential mediator

Psychopharmacological management of depression

intervention and especially several interventions. Also, the clinical practice of

Mild to moderate depressive symptoms respond well to psychotherapeutic interventions like

What to expect when treating depression in real life: Effectiveness data

National Institute of Mental Health conducted the Sequenced Treatment Alternative to

Level 1] SSRI medication [Citalopram], were effective in about 1/3rd participants.

Bipolar Depression Treatment

stabilizers such as valproate, lithium, or more commonly recently, lamotrigine,

stabilizing treatment is recommended.

For useful guidelines by various agencies, please refer to Table 1

Management of AR: special considerations in patients with mood disorders

difficulties. Moreover, as isolation is a prosuicidal factor, and access to social networks a

Pharmacoecological data suggest that intranasal corticosteroids might be associated with

effects) or detrimental (worsening of sedation- elevating risk of accidents). Insomnia,

It is recommended to include a psychiatrist in the team management cases with history of

Managing suicide risk in primary care

It is recommended that a mental health professional is consulted in patients with suicidal

National Suicide Prevention Lifeline: 1-800-273-TALK (8255)

No pharmacological treatments for suicide risk

No pharmacological treatments for suicide risk: although multiple counseling/

A role for an integrated collaborative care

new therapeutic and preventative interventions. Ultimately, increases in collaborations

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