The skin and stress connection

By Allison Evans, assistant managing editor, December 1, 2020

There is generally no question among dermatologists that psychological stress can affect the skin. This year, more than ever, the heightened stress of living through a year characterized by social isolation, illness, protests for racial justice, and divisive politics (to name a few) has made this relationship quite evident. Since the start of the pandemic, some dermatologists have reported an uptick in patients with flares of inflammatory conditions, adding to the wealth of clinical and scientific evidence indicating that a large number of skin diseases appear to be precipitated or exacerbated by stress.

This month, DermWorld examines the brain-skin connection and explores the impact of psychological stress on various skin conditions commonly treated by dermatologists, including psoriasis, rosacea, acne vulgaris, atopic dermatitis (AD), chronic urticaria, and alopecia areata (AA). Additionally, experts in dermatology and psychiatry/psychology offer simple ways to address patient stress without adding to your packed schedule or disrupting patient flow.

HPA axis

The hypothalamic pituitary adrenal (HPA) axis is the body’s central stress response system. At a glance, stress triggers physiological responses by activating the hypothalamus, which releases corticotropin-releasing hormone (CRH) and stimulates the pituitary gland, which releases adrenocorticotropic hormone (ACTH) into the blood stream and stimulates the adrenal glands and prompts the release of glucocorticoids and cortisol, explained Diane S. Berson, MD, associate professor of dermatology at Weill Cornell Medical College.

The brain-skin connection

Despite the growing body of evidence demonstrating the impact of stress on skin conditions, the specific pathogenic role of stress is still unknown. Studies exploring the brain–skin connection have revealed that the skin is both a prominent target organ and produces neuroendocrine, neurotransmitter, and neuropeptide signals, which profoundly affect skin biology. Upon perception of stress, the skin may respond by releasing inflammatory cytokines. In turn, this may lead to mast cell activation, which promotes immune dysregulation and neurogenic inflammation — inflammation caused by a neurological event like stress (doi:10.1111/bjd.16116).

Embryologically, the skin and brain both stem from the same origin tissue: the ectoderm. Research has revealed a complex brain-skin connection — an interplay of neurologic, endocrine, immune, and cutaneous systems — in which the skin may act as an independent local stress response system. It is believed that the skin may have a peripheral equivalent of the HPA axis, which may coordinate peripheral stress responses with the central HPA axis (doi:10.1155/2012/403908).

There are different types of inflammation caused by different cellular processes, Dr. Berson explained. “In the case of hives, it may be mast cells, which release histamine. For eczema, it may be T-cells. For acne, it may be inflammation around the sebaceous gland. The bottom line is that stress may increase inflammation and the release of cytokines, which then further increase inflammation.”

Stress responders and non-stress responders

As a dermatologist and clinical psychologist, Richard G. Fried, MD, PhD, is particularly sensitized to the role stress plays in clinical presentation. Dr. Fried is clinical director at Yardley Dermatology Associates. “Through clinical interactions, it is evident that the bi-directional relationship between stress and skin functioning is without question a key player — sometimes,” he said.

Among the psychophysiological disorders, there are stress responders and non-stress responders, said John Koo, MD, who is double board-certified in dermatology and psychiatry, professor of dermatology at the University of California San Francisco Department of Dermatology, and co-director of the psoriasis treatment center, phototherapy unit, and psychodermatology clinic. “You have to tease out which patients are stress responsive, and which ones are not.”

The proportion of stress responders versus non-stress responders varies by condition, ranging from 100% stress responders in hyperhidrosis, to 0% stress responders in skin carcinomas (see table). Even among stress responders, some people are extreme stress responders while others are only moderately stress responders, added Dr. Fried. The onset of clinical symptoms from the initial stress trigger can range by disease from seconds to multiple days. For example, in atopic dermatitis, 70% of the patient population responds to an emotional trigger that almost immediately results in increased pruritis. On the other hand, 62% of psoriasis patients take a few days to respond to stress and show clinical change, Dr. Koo said.

Source: Koo, John. Psychodermatology: A practice manual for clinicians. Curr Probl Dermatol. November/December. 1995.

How strong is the relationship between stress and skin disease?

Stress impairs the barrier function of skin, increases inflammation, and induces or worsens the course of various skin disorders. “As clinicians, we should always be aware that stress can and often does play a role in onset or exacerbation of disease,” Dr. Fried said. Because nearly everyone has some form of stress in their life, it can be difficult to determine the exact mechanisms that contribute to exacerbation or onset of certain skin diseases.

The associations of some skin conditions with stress are unquestioned, such as psoriasis, AD, and acne, because we see it so much in clinical practice and it’s been well documented over the decades, Dr. Koo said. Some conditions, like AA and vitiligo, are less well accepted. “Anecdotally, patients report the association of stress and exacerbation of their condition, but dermatologists are not entirely sure how strong the relationship is.”

“I want to give control. These skin conditions are enormously capricious. Patients never know if they will have a good day or a bad day. When we feel out of control, we release more inflammatory cytokines and more cortisol. How crucial is it that if patients have a stress-responsive skin disease, somebody gives them the tools to handle stress?” Dr. Fried said.

“If we don’t believe in a rapid and real interface between cognition and stress and the skin, there’s a simple question: What’s the blush?” Dr. Fried posed.

“About 10 years ago at Cornell, I was giving grand rounds and an elderly dermatologist stood up and told me that ‘this psychodermatology stuff is a bunch of nonsense.’ I respectfully disagreed. Immediately, a similarly elderly female dermatologist stood up and said, ‘If you’re going to give the guy a hard time, close your fly before you stand up.’ He turned beet red. She looked at him and said, ‘If you don’t believe in the mind-skin connection, why are you so red?’”

A single cognition can completely derange the vasculature in the face, the neck, and the chest. I don’t think there’s a more beautiful example of the brain-skin connection than that,” Dr. Fried remarked.

Psoriasis

While the role of stress on psoriasis is nearly universally accepted, the exact mechanism is still being worked out, Dr. Koo said. On the molecular level, there are some leading theories, including one involving the neuropeptide substance P. Substance P is a member of the tachykinin neuropeptide family that acts as a neurotransmitter and neuromodulator, but excess levels can lead to a variety of diseases. “There is a lot of evidence supporting the theory that neuropeptides can initiate inflammation, which is part of neurogenic inflammation,” Dr. Koo said.

Older treatments for psoriasis used capsaicin, which is known to deplete substance P, said Dr. Koo. Studies showed that topically applied capsaicin effectively treats pruritic psoriasis, which supports theories that substance P plays a role in psoriasis. Capsaicin may also help reduce inflammation, redness, and scaling associated with psoriasis, although more research is needed to assess its long-term benefits and safety.

Studies are also showing that stress-reducing activities are impacting the severity or course of the disease. In one study, cognitive behavior therapy, in combination with regular therapy, was shown to significantly improve the clinical severity of psoriasis during a six-week course of treatment and for at least six months afterward (doi:10.1046/j.1365-2133.2002.04622.x). Another small study found that psoriasis patients who listened to a stress-reduction tape as they were undergoing psoralen UVA (PUVA) photochemotherapy or UVB phototherapy had significantly faster improvement of their psoriasis compared with patients receiving standard PUVA or UVB therapy.

Studies have also shown that there is an elevation of cortisol in psoriatic plaques, and that increased levels of cortisol have been associated with the stress that exacerbates psoriasis, Dr. Berson explained.

Rosacea

A growing body of evidence suggests that stress can play a role in some patient flares of rosacea. In a National Rosacea Society survey on emotional stress and rosacea, two-thirds of respondents said they were able to reduce their flares by minimizing the causes of their stress and emotional reactions.

Rosacea is multifactorial, added Dr. Berson. “Factors include inflammation, an increase in antimicrobial peptides, and neurogenic, vascular, and endothelial influences. Stress also stimulates histamine, which can cause increased flushing.”

It is thought that emotional stress and endogenous hormones may stimulate the release of neurotransmitters, which contributes to vasodilatation, flushing, and increased skin sensitivity in rosacea patients.

Acne vulgaris

The effect of stress on acne may be more difficult to observe, noted Dr. Koo, because while acne can be made worse by stress, it can also get worse by many other things like hormonal surges, picking, and diet. Some studies suggest that stress is an important factor in the pathogenesis of up to 90% of acne cases.

“The adrenal cortex is responsible for secreting cortisol, but it also releases the precursors to the hormones that stimulate oil production in acne. When the adrenal gland is in overdrive from stress and is making adrenaline and cortisol, there is also an increase in secretion of androgens that stimulate the oil glands that lead to acne flares. Inflammation and increased sebaceous gland production are both pathogenic factors for acne,” Dr. Berson noted.

Atopic dermatitis

Epidermal permeability is an important factor in AD. Stress makes the skin more permeable and less able to function well as a barrier, said Dr. Koo, which is a separate mechanism from increasing immune reactivity. While AD is also characterized by inflammation, like psoriasis, patients with AD have an inherent barrier defect, he continued. Because their skin is more porous, more irritants can get through the barrier and cause inflammation or reactions.

Denda et al demonstrated that defects in skin barrier function could be reversed by adding anti-anxiety medications to treatment (doi:10.1152/ajpregu.2000.278.2.R367). In another study, Garg et al found that increased psychological stress during medical student examination periods is associated with a reversible deterioration in transcutaneous water permeability (doi:10.1001/archderm.137.1.53).

Urticaria

According to Neuroimmunology of the Skin, the underlying etiology of urticaria is not identifiable in about 70% of cases, although psychogenic factors are important among approximately 50% of urticaria patients.

“When people are anxious, the autonomic nervous system releases cortisol and adrenaline, which leads to inflammation and the release of histamine. If a patient scratches, they will release more inflammatory mediators and histamine,” Dr. Berson explained, which initiates the vicious itch-scratch cycle.

The effect of stress on urticaria is most likely mediated by CRH, which can increase mast cell degranulation. CRH is also elevated during stress and in psychiatric disorders such as depression.

Alopecia areata

In September, the New York Times published a story about how physicians are seeing an increase in hair loss cases since the pandemic began. In addition to patients recovering from COVID-19 experiencing hair loss from the physiological stress of fighting it off, others who have never contracted the virus are losing hair because of emotional stress from living through a pandemic: job loss, financial strain, deaths of family members, or any number of other stressful events people are currently experiencing.

Although dermatologists are treating more patients with alopecia areata during the pandemic, it is less agreed upon whether AA flares are associated with stress. While the way in which stress triggers these conditions is not fully known, experts think it may be related to increased levels of cortisol, or to effects on blood supply, said Sara Hogan, MD, a dermatologist at the David Geffen School of Medicine at the University of California, Los Angeles, who has been seeing up to seven patients a day with telogen effluvium, a form of temporary hair loss experienced after stress or trauma.

AA is not a visibly inflammatory condition like psoriasis and atopic dermatitis. However, when you biopsy a hair follicle, there is inflammation at the root of the hair. “In the same way that inflammation can go awry in other conditions,” said Dr. Koo, “it may potentially do the same thing in alopecia areata.”

What’s on the horizon?

There are data dating back to the late 1990s indicating that severity and duration of eczema and psoriasis are significantly reduced when selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are used.

“We know that SSRIs and SNRIs can decrease inflammation and help skin conditions to be more responsive to traditional dermatologic therapy. Additionally, this type of medication also guards against neurotransmitter depletion, which would lead to becoming depressed or more distressed,” Dr. Fried explained. “When inflammatory cytokines cross the blood-brain barrier, they act at the level of the synapse and increase uptake of neurotransmitters, essentially sucking the synapse dry and decreasing the availability of norepinephrine, serotonin, and dopamine.”

“For example, the antidepressant doxepin is generally recognized as a more powerful antipruritic and antihistaminic agent than most of the traditional antihistamines that dermatologists use for this purpose. The antidepressant amitriptyline is also the treatment of choice for postherpetic neuralgia because its analgesic effects can be helpful even for patients who are not depressed,” Dr. Koo wrote in Psychodermatology: a practical manual for clinicians.

Some dermatologists are not comfortable prescribing SSRIs or SNRIs because they haven’t been specifically trained to use them, Dr. Fried remarked. He recommends dermatologists choose one and test it out in low doses. “Perhaps, incorporating a depression or anxiety medicine with traditional dermatologic treatment may effectively augment our treatment.”

Another newer development is the use of oral beta-blockers to treat facial flushing and erythema associated with rosacea. A recent JAAD study found that the use of beta-blockers, including propranolol, showed a large reduction of erythema with a rapid onset of symptom control doi:10.1016/j.jaad.2020.04.129).

Treating the patient

“What is the biggest enemy we have in our society in recent years?” asked Dr. Fried. Inflammation. Whether it’s psoriasis, eczema, rosacea, acne, sinusitis, fibromyalgia — the list is endless. “We know that stress management of all kinds decreases inflammation, so we have a responsibility to our bodies to find techniques to decrease that inflammation.”

If patients will continue to flare because of an underlying stress or anxiety, then it would be unfair not to offer them something that could help, Dr. Berson said.

“Skin disease often insidiously robs people of the range of interaction — their degree of engagement in people, places, and things,” Dr. Fried said. “There’s never been a time where there’s a more ubiquitous stress and never been a time where our patients need us to proverbially hold their hand.”

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